==================================BSR43================================== 43. Lymphocytic organ infiltration in autoimmune disease. Molecular genetic studies in autoimmune disease. Clonal T-cell defects in autoimmune diseases. 1 UI - 87058081 AU - Sedgwick JD ; Mason DW TI - The mechanism of inhibition of experimental allergic encephalomyelitis in the rat by monoclonal antibody against CD4. AB - Lewis rats with actively induced or passively transferred experimental allergic encephalomyelitis (EAE) were treated with a monoclonal antibody (MAb) which binds to the CD4 antigen of rat helper/inducer T cells. Actively immunized animals treated at the first onset of clinical signs experienced only a mild form of the disease and rapidly recovered while the majority of those treated prophylactically never showed clinical signs of EAE. Passively transferred EAE was also completely inhibited with anti-CD4 MAb. In treated animals which exhibited only mild clinical signs of EAE, spinal cord and cerebellar leukocyte infiltrates were quite similar to those in untreated rats but where anti-CD4 MAb treatment completely prevented clinical EAE, histological signs were minimal or absent. Like Lewis rats which have recovered naturally from EAE, those treated with anti-CD4 MAb were both resistant to a secondary challenge with myelin basic protein and harboured potential encephalitogenic cells which were capable of transferring disease to recipient rats. Disease in these recipients was, however, of much greater severity than that experienced by animals receiving cells from naturally recovered (untreated) donors. These data demonstrate that administration of anti-CD4 MAb to rats can prevent EAE by a mechanism which does not ablate the encephalitogenic CD4+ cells or prevent the development of resistance to EAE but which may inhibit the disease by preventing the function of already activated effector cells. MH - Animal ; Antibodies, Monoclonal/*THERAPEUTIC USE ; Antigens, Immune Response/BIOSYNTHESIS ; Antigens, Surface/*IMMUNOLOGY ; Encephalomyelitis, Allergic/IMMUNOLOGY/*THERAPY ; Female ; Immunity, Natural ; Macrophages/IMMUNOLOGY ; Male ; Rats ; Rats, Inbred LEW ; Support, Non-U.S. Gov't ; T Lymphocytes/IMMUNOLOGY SO - J Neuroimmunol 1986 Dec;13(2):217-32 2 UI - 87034940 AU - Lemire JM ; Weigle WO TI - Passive transfer of experimental allergic encephalomyelitis by myelin basic protein-specific L3T4+ T cell clones possessing several functions. AB - Mouse myelin basic protein (mBP)-specific T cell clones were generated from lines established from SJL/J mice immunized with mBP in complete Freund's adjuvant. These clones proliferated specifically to mBP and were propagated weekly with the same antigen for up to 8 mo. It is of particular interest that four of these phenotypic T helper clones were able to induce several T cell functions, including that of antibody production. These mBP-reactive T cell clones induced inflammatory infiltrations of the white matter of the central nervous system when transferred i.v. to irradiated (350 R) syngeneic naive recipients in concentrations as low as 0.5 X 10(6) cells/mouse. Lesions characteristic of experimental allergic encephalomyelitis (EAE) were observed as early as 5 days after transfer in the absence of clinical paralysis. Encephalitogenic clones, when added in vitro to a population of mBP-primed B cells in the presence of antigen, induced the production of anti-mBP antibodies determined by ELISA. In addition, the same clones, when transferred i.v., were found to mediate in vivo helper activity by inducing serum anti-mBP antibodies in the recipients. This response was delayed until 20 days after transfer and was abrogated by irradiation of the clones before injection. Finally, these mBP-specific specific clones were capable of mediating a specific delayed-type hypersensitivity (DTH) response. Although all four clones generated displayed the Thy-1.2+, L3T4+, Lyt-2- phenotype and proliferated specifically to mBP, only three were able to induce EAE, transfer DTH, and mediate helper activity. MH - Animal ; Antibody Formation ; Antigens, Surface/ANALYSIS ; Autoantibodies/ BIOSYNTHESIS ; Encephalitogenic Basic Proteins/*IMMUNOLOGY ; Encephalomyelitis, Allergic/*IMMUNOLOGY ; Female ; Helper Cells/ IMMUNOLOGY ; Hypersensitivity, Delayed/IMMUNOLOGY ; Immunization, Passive ; Lymphocyte Cooperation ; Mice ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/CLASSIFICATION/*IMMUNOLOGY SO - J Immunol 1986 Nov 15;137(10):3169-74 3 UI - 87123240 AU - Eilat D TI - Protein and gene structure of autoantibodies in the study of autoimmune disease. AB - The development of the hybridoma technology and the recent advances in molecular biology have opened new directions in the study of autoimmune mechanisms. Monoclonal autoantibodies can now be isolated and their structural elements may be studied in detail. In addition, the immunoglobulin genes which code for the production of antiself antibodies may now be cloned and analyzed for their structure and regulation in normal and autoimmune individuals. Initial results in this new field of molecular immunology are reviewed in this article, and their implications for the understanding of autoimmune phenomena are discussed. MH - Amino Acid Sequence ; *Autoantibodies/GENETICS ; Autoimmune Diseases/ *FAMILIAL & GENETIC ; DNA/IMMUNOLOGY ; Gene Expression Regulation ; Genes, Structural ; Human ; Immunoglobulins/GENETICS ; Structure-Activity Relationship ; Support, Non-U.S. Gov't SO - Acta Haematol (Basel) 1986;76(2-3):101-6 4 UI - 87120759 AU - Shen HH ; Winchester RJ TI - Susceptibility genetics of systemic lupus erythematosus. AB - The etiology of systemic lupus erythematosus (SLE) is determined in part by genetic factors which influence susceptibility to the disease. These factors presumably have a major role in determining the clinical and laboratory manifestations of SLE. Certain newer observations which may pertain to an understanding of the genetic basis of SLE will be critically reviewed in this chapter. These observations are based on advances in the analysis of human SLE and the increased knowledge provided by various murine models of human autoimmune processes. However, the specific genes involved and the mechanisms by which they exert their effect are at present still unknown. Special attention will be given newer insights into the role of genes of the major histocompatibility complex (MHC) and their relationship to the genes encoding the T cell antigen receptor. The role of classic immunoglobulin genes as well as more complex mechanisms involving preferential maternal or paternal genetic effects are also discussed. The contribution of genes encoding complement and complement receptors toward the expression of the disease state are discussed in brief. RF - REVIEW ARTICLE: 88 REFS. MH - Animal ; Antigenic Determinants/IMMUNOLOGY ; Antigens, Immune Response/ ANALYSIS/GENETICS ; Autoantibodies/GENETICS/IMMUNOLOGY ; Disease Susceptibility ; Genetic Code ; Human ; HLA-DR Antigens/IMMUNOLOGY ; Immunoglobulins/GENETICS ; Lupus Erythematosus, Systemic/ETIOLOGY/ *FAMILIAL & GENETIC ; Major Histocompatibility Complex ; Mice ; Molecular Weight ; Protein Conformation ; Receptors, Antigen, T-Cell/ANALYSIS/ GENETICS/IMMUNOLOGY ; Receptors, Complement/GENETICS ; Review SO - Springer Semin Immunopathol 1986;9(2-3):143-59 5 UI - 87105641 AU - Makino S ; Harada M ; Kishimoto Y ; Hayashi Y TI - Absence of insulitis and overt diabetes in athymic nude mice with NOD genetic background. AB - NOD mice spontaneously develop diabetic syndrome similar to that of insulin-dependent diabetes mellitus in man. Insulitis, i.e., lymphocytic infiltration into the pancreatic islets is the etiologic pathological lesion in the development of diabetes mellitus in NOD mice. In the present study, we examined the role of the T cell in the development of insulitis and overt diabetes in NOD mice using NOD athymic and euthymic congenic mice. None of the NOD athymic mice developed insulitis at 9 weeks of age or overt diabetes up to 30 weeks of age. In contrast, NOD euthymic littermates showed almost the same incidences of insulitis and overt diabetes as those of NOD mice. These observations suggest that T cells are essential for the development of insulitis and overt diabetes in NOD mice. MH - Animal ; Diabetes Mellitus, Experimental/*ETIOLOGY/IMMUNOLOGY/PATHOLOGY ; Diabetes Mellitus, Insulin-Dependent/*ETIOLOGY/IMMUNOLOGY/PATHOLOGY ; Female ; Immunity, Cellular ; Islands of Langerhans/PATHOLOGY ; Male ; Mice ; Mice, Nude/*GENETICS ; T Lymphocytes/IMMUNOLOGY SO - Jikken Dobutsu 1986 Oct;35(4):495-8 6 UI - 87103758 AU - Lindahl G ; Lefvert AK ; Hedfors E TI - Periductal lymphocytic infiltrates in salivary glands in myasthenia gravis patients lacking Sj:ogren's syndrome. AB - In eight of eleven patients with clinical and serological evidence of myasthenia gravis (MG), immunohistological analysis of biopsies from labial salivary glands (LSG) showed focal periductal lymphocytic infiltrates, mainly composed of anti-Leu 3a+ T helper lymphocytes, a finding usually regarded as indicative for Sj:ogren's syndrome (SS). None of the patients could however, according to functional criteria, be considered as having SS. This study thus indicates that lymphocytic infiltrates in LSG can be seen in MG, which has been thought of as an organspecific autoimmune disease with symptoms and signs confined to striated muscles. MH - Adolescence ; Adult ; Aged ; Autoimmune Diseases/*IMMUNOLOGY ; Cell Movement ; Child ; Female ; Helper Cells/*IMMUNOLOGY/PHYSIOLOGY ; Human ; Immunoenzyme Technics ; Lip/IMMUNOLOGY ; Lymphocytes/CLASSIFICATION ; Male ; Middle Age ; Myasthenia Gravis/*IMMUNOLOGY ; Salivary Glands/ *IMMUNOLOGY ; Salivary Glands, Minor/*IMMUNOLOGY ; Sjogren's Syndrome/ *IMMUNOLOGY ; Support, Non-U.S. Gov't SO - Clin Exp Immunol 1986 Oct;66(1):95-102 7 UI - 87095584 AU - Kirchner T ; Schalke B ; Melms A ; von K:ugelgen T ; M:uller-Hermelink HK TI - Immunohistological patterns of non-neoplastic changes in the thymus in Myasthenia gravis. AB - Non-neoplastic thymuses from 20 patients with myasthenia gravis (MG) have been studied by routine stains on paraffin sections and by immunohistological methods on frozen sections using a panel of monoclonal antibodies against thymic epithelial cells, macrophages/reticulum cells, lymphoid cells and myoid cells. Three types of thymic histology in MG were distinguished: (1) thymitis with lymphoid follicular hyperplasia (11 cases), (2) thymitis with diffuse B-cell infiltration (5 cases) and (3) thymic atrophy (4 cases). Thymitis was more common in younger females and thymic atrophy in older patients. Both types of thymitis were associated with conspicuous structural disturbance of the thymic perivascular space (PVS) and medulla, characterized by a distinct enlargement of the PVS and disruption of the epithelium and reticulin fibre network at the medullary boundary, leading to fusion of the two compartments. The PVS and medulla contained a striking B-cell infiltration. Large well-developed germinal centers (GCs), showing the same cellular organization as in the peripheral lymphatic system, occurred in thymitis with lymphoid follicular hyperplasia, whereas thymitis with diffuse B-cell infiltration merely exhibited a few tiny lymphoid follicles, which could be demonstrated only by immunostaining of dendritic reticulum cells. In thymic atrophy a diffuse B-cell infiltration of the PVS and the medulla was also observed, but only minor alterations of the epithelial framework were seen. There was an increased number of interdigitating reticulum cells with variable expression of the T-6 antigen in all the thymuses examined, indicating an immune stimulation of the intrathymic T-cells. Myoid cells, the supposed target of the intrathymic immune reaction in MG, were found to be less frequent in thymic atrophy than in thymitis. This variable number of myoid cells may explain the different grades of immune stimulation and different types of histology seen in the thymus in MG. MH - Adolescence ; Adult ; Aged ; Atrophy ; B Lymphocytes/PATHOLOGY ; Child ; Child, Preschool ; Female ; Human ; Immunoenzyme Technics ; Immunologic Technics ; Lymphatic Diseases/PATHOLOGY ; Male ; Middle Age ; Myasthenia Gravis/*PATHOLOGY ; Thymus Gland/*PATHOLOGY SO - Virchows Arch [B] 1986;52(3):237-57 8 UI - 87078972 AU - Del Prete GF ; Vercelli D ; Tiri A ; Maggi E ; Mariotti S ; Pinchera A ; Ricci M ; Romagnani S TI - In vivo activated cytotoxic T cells in the thyroid infiltrate of patients with Hashimoto's thyroiditis. AB - High proportions of T8+ cells with inverted T4/T8 ratio were found in freshly isolated thyroid lymphocytes from patients with Hashimoto's thyroiditis. In addition, about one third of thyroid infiltrating cells expressed the TAC antigen, whereas in patient peripheral blood (PB) or normal lymphocytes from PB or lymphoid organs the percentage of TAC-positive cells was consistently lower than 10%. Following negative selection with OKT4 or OKT8 monoclonal antibodies and complement, TAC+ T cells were enriched in the T8+ cell population. Thyroid infiltrating T cells from two patients underwent two different cloning procedures. In the first, single T cells were initially activated with phytohaemagglutinin (PHA) and interleukin 2 (IL-2), in the other with recombinant IL-2 (rIL-2) alone. The majority of T cell clones obtained by initial PHA-stimulation (55-65%) had the T8+ phenotype, but the frequency of T8+ clones obtained by stimulating T cells with rIL-2 alone was even higher (78 & 71%, respectively). The majority of T8+ clones elicited by PHA (35/37 & 36/38) and all the T8+ clones (36/36 & 22/22) obtained from thyroid infiltrates with initial stimulation by rIL-2 displayed cytolytic activity. Most of cytolytic T8+ clones obtained from thyroid infiltrates with both cloning procedures, displayed NK activity against human K562 and MOLT-4 target cells, but not against a NK-resistant target, such as Raji cells. These data suggest that in Hashimoto's disease a considerable proportion of thyroid infiltrating T cells are in vivo activated T8+ cytolytic T cells with NK activity, which may be of importance in determining or maintaining the tissue damage of the target gland. MH - Adult ; Antigens, Surface/ANALYSIS ; Female ; Human ; Interleukin 2/ IMMUNOLOGY ; Killer Cells, Natural/IMMUNOLOGY ; Lymphocyte Transformation ; Middle Age ; Phenotype ; Receptors, Antigen, T-Cell/ANALYSIS ; Support, Non-U.S. Gov't ; T Lymphocytes, Cytotoxic/*IMMUNOLOGY ; Thyroid Gland/ IMMUNOLOGY ; Thyroiditis, Autoimmune/*IMMUNOLOGY SO - Clin Exp Immunol 1986 Jul;65(1):140-7 9 UI - 87078951 AU - Ofosu-Appiah WA ; McKenna RM ; Warrington RJ ; Wilkins JA TI - Characterization of synovial T lymphocytes in rheumatoid arthritis. I. Production of IL-2 dependent T cell clones from synovial fluid and peripheral blood. AB - Lymphocytes obtained from the peripheral blood (PBL) or synovial fluids (SFL) of patients with rheumatoid arthritis (RA) or other inflammatory joint diseases were compared with the PBL from normal individuals, by cloning under limiting dilution conditions in the presence of interleukin 2 (IL-2). The precursor frequency estimates of IL-2 responsive cells from these sources did not differ appreciably. However there were marked differences in the surface marker phenotypes of the clones derived from the PBL as compared to SFL. There was a predominance of OKT4-8+ cells in SFL from RA and non RA donors with inflammatory joint disease while PBL from all sources showed a marked prevalence of OKT4+8- cells. Comparison of precursor frequencies in the presence of PBL and SFL indicated that there were variations in the capacities of the SFL and PBL IL-2 dependent cells to grow on these fillers. SFL derived cells grew equally well on PBL or SFL filler, while PBL clones grew efficiently only on PBL fillers. Collectively these results indicate that there are marked differences in the surface phenotypes and growth requirements of IL-2 responsive SFL as compared to PBL. MH - Antigens, Surface/*ANALYSIS ; Arthritis, Rheumatoid/*IMMUNOLOGY ; Clone Cells ; Human ; Interleukin 2/*IMMUNOLOGY ; Support, Non-U.S. Gov't ; Synovial Fluid/*IMMUNOLOGY ; T Lymphocytes/CLASSIFICATION/*IMMUNOLOGY SO - Clin Exp Immunol 1986 Jun;64(3):555-62 10 UI - 87074507 AU - Todd I ; Londei M ; Pujol-Borrell R ; Mirakian R ; Feldmann M ; Bottazzo GF TI - HLA-D/DR expression on epithelial cells: the finger on the trigger? AB - The findings we have described here show a clear association between epithelial HLA-D/DR expression and autoimmunity. Furthermore, the ability of class II+ thyrocytes to present both exogenous antigens and autoantigens indicates an active role for these HLA-D/DR molecules in autoimmune pathogenesis. IFN-gamma is capable of inducing HLA-D/DR expression by thyroid epithelium, but a number of observations suggest the involvement of other inducers as well. Overall, we conclude that epithelial class II expression very probably plays a key role in the propagation and also in possibly the initiation of autoimmune attack. This is in accord with the proposal of a more general relationship between inappropriate or excessive class II expression and pathogenesis. MH - Antigen-Presenting Cells/IMMUNOLOGY ; Autoimmune Diseases/*IMMUNOLOGY ; Epithelium/IMMUNOLOGY ; Gene Expression Regulation/DRUG EFFECTS ; HLA-D Antigens/BIOSYNTHESIS/*IMMUNOLOGY ; HLA-DR Antigens/BIOSYNTHESIS/ *IMMUNOLOGY ; Interferon Type II/PHARMACOLOGY ; Support, Non-U.S. Gov't ; Thyroid Diseases/*IMMUNOLOGY ; Thyroid Gland/*IMMUNOLOGY SO - Ann NY Acad Sci 1986;475:241-50 11 UI - 87065066 AU - Zamvil SS ; Mitchell DJ ; Moore AC ; Kitamura K ; Steinman L ; Rothbard JB TI - T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. AB - Chronic relapsing paralysis and demyelination within the central nervous system (CNS), features associated with the human disease multiple sclerosis (MS), develop in mice after injection of murine T-cell clones specific for the autoantigen myelin basic protein (MBP). We examined the fine specificity of three independently derived encephalitogenic T-cell clones using synthetic polypeptides derived from portions of the N-terminal sequence of MBP. These clones appear functionally identical; they all respond to an epitope in the N-terminal nine amino acid residues in association with the same class II (I-A) molecules of the major histocompatibility complex (MHC). Both the N-terminal acetyl moiety and the first residue (Ala) are necessary for recognition. Only N-terminal MBP peptides recognized by these clones were found to cause encephalomyelitis (EAE) in vivo. These results show that the N-terminal MBP-specific T lymphocytes that mediate autoimmune encephalomyelitis are a small population with a limited repertoire; they all recognise the same combination of MHC and target. MH - Animal ; Antigenic Determinants/*ANALYSIS ; Autoantigens/*IMMUNOLOGY ; Clone Cells ; Encephalitogenic Basic Proteins/*IMMUNOLOGY ; Encephalomyelitis, Allergic/*IMMUNOLOGY ; Mice ; Mice, Inbred Strains ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/ *IMMUNOLOGY SO - Nature 1986 Nov 20-26;324(6094):258-60 12 UI - 87062054 AU - D'Agati VD ; Appel GB ; Estes D ; Knowles DM 2d ; Pirani CL TI - Monoclonal antibody identification of infiltrating mononuclear leukocytes in lupus nephritis. AB - Populations of mononuclear inflammatory cells infiltrating the renal interstitium in LN were studied by means of an avidin-biotin immunoperoxidase technique applied to cryostat sections of 26 renal biopsies (3 WHO class IIb; 4 class III; 8 class IV; 4 class V; 4 class III and V; and 3 class IV and V). The majority of interstitial leukocytes were T cells (mean 65.7 +/- 14.1). The number of cells reactive with OKT8 (47.3 +/- 11.0) exceeded the number of OKT4 positive cells (32.5 +/- 11.3) in 22 of 26 biopsies. Cells reactive with antimonocyte antibodies OKM1 and OKM5 (6.7 +/- 5.9 and 7.9 +/- 5.9, respectively) and B lymphocytes (OKB2 3.9 +/- 3.5) were a minor component of the interstitial infiltrates. Monocytes were the predominant cell type among stained cells in glomerular tufts and crescents. Tissue T4/T8 ratios varied widely (range 0.31 to 1.81), and were less than 1 in 22 of 26 patients. There was no correlation between tissue T4/T8 ratios and simultaneous peripheral blood T4/T8 ratios. Using stepwise multivariate linear regression, tissue T4/T8 ratio was found to correlate highly with renal histologic activity (P less than 0.001) but was not independently predictive of any other histopathologic or clinical variable studied. Mean tissue T4/T8 ratio in LN was significantly lower than that of other glomerular and interstitial diseases studied (P less than 0.001), a finding which may reflect differences in the pathogenesis of renal injury. These findings suggest that local cellular immune mechanisms may be important in the modulation of disease activity in LN. MH - Adolescence ; Adult ; Antibodies, Monoclonal/*ANALYSIS ; Antigens, Surface/IMMUNOLOGY ; Child ; Comparative Study ; Female ; Human ; Immunoenzyme Technics ; Kidney/IMMUNOLOGY ; Leukocyte Count ; Lupus Nephritis/*IMMUNOLOGY ; Male ; Middle Age ; Monocytes/*IMMUNOLOGY ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/IMMUNOLOGY SO - Kidney Int 1986 Oct;30(4):573-81 13 UI - 87058985 AU - Linington C ; Mann A ; Izumo S ; Uyemura K ; Suzuki M ; Meyermann R ; Wekerle H TI - Induction of experimental allergic neuritis in the BN rat: P2 protein-specific T cells overcome resistance to actively induced disease. AB - T lymphocyte lines specific for the peripheral nerve myelin protein P2 were selected from the lymph nodes of Brown Norway (BN) rats immunized with bovine P2 protein in complete Freund's adjuvant. These T cells expressed the W3/25+, OX8-phenotype and responded specifically to bovine P2 protein, but not to PPD or bovine basic protein, in T cell proliferation assays. When injected i.v. into syngeneic recipients, BN P2-specific T cell lines induced both clinical and histologic signs of experimental allergic neuritis (EAN), overcoming the resistance of this rat strain to actively induced EAN. Although the histopathology of the disease was indistinguishable from that seen in T cell-mediated EAN in the Lewis rat, disease onset was considerably later, 7 to 8 days after cell transfer, as opposed to 4 days in Lewis. This lag phase between inoculation and disease onset could not be further reduced even by raising the cell dose to 50 X 10(6) cells/host. The fine specificity of the T cell response to P2 differs between Lewis- and BN-derived T cell lines. At least one neuritogenic epitope for each strain was present in the cyanogen bromide-derived peptide CB2 (residues 21-113), as shown by the ability of CB2-specific T cell lines derived from each strain to transfer EAN to the appropriate host strain. However, neuritogenic BN T lines fail to mount a response to the sequence 53-78 (SP4), which encompasses an epitope that is neuritogenic for Lewis rats. These results demonstrate that the resistance of BN rats to actively induced EAN is not due to the lack of appropriate P2-specific autoreactive T cell clones in the normal T repertoire. Furthermore, the results suggest that two distinct epitopes of P2 are responsible for EAN in Lewis and BN rats. MH - Animal ; Antigenic Determinants/IMMUNOLOGY ; Cell Line ; Comparative Study ; Encephalitogenic Basic Proteins/ADMINISTRATION & DOSAGE/ *IMMUNOLOGY ; Immunity, Natural ; Immunization ; *Immunization, Passive ; Neuritis, Experimental Allergic/ETIOLOGY/*IMMUNOLOGY/PATHOLOGY ; Rats ; Rats, Inbred BN/*IMMUNOLOGY ; Rats, Inbred LEW/*IMMUNOLOGY ; Rats, Inbred Strains/*IMMUNOLOGY ; Spinal Nerves/PATHOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/*IMMUNOLOGY/TRANSPLANTATION SO - J Immunol 1986 Dec 15;137(12):3826-31 14 UI - 87053724 AU - Lahtela JT TI - Effect of long-term anticonvulsant therapy on glucose metabolism in humans. AB - This study was undertaken to evaluate the effect of anticonvulsants on glucose metabolism in humans. Tissue sensitivity to insulin (euglycemic clamp technique) and liver microsomal enzyme activity (oral antipyrine test) were measured in six subjects with epilepsy plus type 1 diabetes mellitus. They had received anticonvulsant drugs for greater than 8 years. Three groups--type 1 diabetics, persons with epilepsy, and healthy subjects--matched for sex, and weight, served as controls. Glucose disposal rate (M) was faster in subjects on anticonvulsant therapy as compared with the corresponding control group (p less than 0.01) and in nondiabetics as compared with diabetics (p less than 0.001). Antipyrine metabolism was rapid among patients on anticonvulsants and high normal in diabetics. Liver microsomal enzyme activity and glucose metabolism were related among diabetic (r = 0.593) and nondiabetic (r = 0.649) groups, respectively. Anticonvulsants with liver microsomal enzyme-inducing properties appear to enhance insulin sensitivity. These findings may serve to understand the long-term effect of anticonvulsants on glucose metabolism in humans. MH - Adult ; Aged ; Anticonvulsants/*METABOLISM/THERAPEUTIC USE ; Antipyrine/ BLOOD ; Blood Glucose/*METABOLISM ; Diabetes Mellitus, Insulin-Dependent/ *METABOLISM ; Enzyme Induction ; Epilepsy/*METABOLISM ; Female ; Human ; Insulin/METABOLISM/PHARMACOLOGY ; Male ; Microsomes, Liver/ENZYMOLOGY ; Middle Age ; Mixed Function Oxidases/BIOSYNTHESIS ; Support, Non-U.S. Gov't ; Time Factors SO - Epilepsia 1986 Nov-Dec;27(6):711-6 15 UI - 87028791 AU - M:ost J ; Wick G TI - Class II antigens in Hashimoto thyroiditis. II. Expression of HLA-DR on infiltrating mononuclear cells in peripolesis. AB - Surgical specimens from patients with Hashimoto thyroiditis (HT) or colloid goiter (CG) were analyzed using an immunofluorescence double staining technique to characterize the infiltrating mononuclear cells (MNC) and to determine the possible expression of HLA-DR antigens by these cells. In HT the majority of infiltrating MNC were T cells. In the interstitium T cells with helper/inducer phenotype (Leu 3a+) were more abundant than those with suppressor/cytotoxic phenotype (OKT8+) and approximately 10-25% of all T cells expressed HLA-DR. Among the cells in peripolesis [i.e., protruding between thyroid epithelial cells (TEC)] OKT8+ cells were observed more frequently than Leu 3a+ cells, expression of DR antigens being 7 and 12%, respectively. The occurrence of Leu 3a+ cells in peripolesis is in marked contrast to the findings in colloid goiter where the intraepithelial population of MNC is almost exclusively composed of OKT8+ cells. The various ways in which the peripoletic Leu 3a+ cells could contribute to the special pathogenesis of HT are discussed. MH - Antibodies, Monoclonal/DIAGNOSTIC USE ; Antigens, Surface/ANALYSIS ; Epithelium/IMMUNOLOGY ; Fluorescent Antibody Technic ; Goiter/IMMUNOLOGY ; Human ; HLA-D Antigens/*IMMUNOLOGY ; HLA-DR Antigens/*IMMUNOLOGY ; Immunity, Cellular ; Immunoenzyme Technics ; Killer Cells, Natural/ IMMUNOLOGY ; Macrophages/IMMUNOLOGY ; Plasma Cells/IMMUNOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/*IMMUNOLOGY ; Thyroid Gland/*IMMUNOLOGY/ PATHOLOGY ; Thyroiditis, Autoimmune/*IMMUNOLOGY/PATHOLOGY SO - Clin Immunol Immunopathol 1986 Nov;41(2):175-83 16 UI - 87028790 AU - M:ost J ; Knapp W ; Wick G TI - Class II antigens in Hashimoto thyroiditis. I. Synthesis and expression of HLA-DR and HLA-DQ by thyroid epithelial cells. AB - Aberrant expression of HLA-DR antigens on epithelial cells is seen in various organ-specific autoimmune disorders including Hashimoto thyroiditis (HT). Expression of HLA-DQ has so far not been demonstrated on these cells. We report here that thyroid epithelial cells (TEC) in HT, in addition to the known aberrant expression of HLA-DR, coexpress HLA-DQ antigens. Furthermore we provide evidence that class II antigens are synthesized by TEC themselves by demonstration of intracellular HLA-DR gamma-chain. These findings support the theory that TEC may be able to present (auto)antigens in vivo thus perhaps contributing to the perpetuation of thyroid destruction. As expression of class II antigens on TEC was never observed in non- or weakly infiltrated areas, we propose that infiltration by T cells is necessary to induce this aberrant expression of class II antigens. MH - Epithelium/IMMUNOLOGY ; Fluorescent Antibody Technic ; Goiter/IMMUNOLOGY ; Human ; HLA-D Antigens/*IMMUNOLOGY ; HLA-DQ Antigens/*IMMUNOLOGY ; HLA-DR Antigens/*IMMUNOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/ IMMUNOLOGY ; Thyroid Gland/CYTOLOGY/*IMMUNOLOGY ; Thyroiditis, Autoimmune/ *IMMUNOLOGY SO - Clin Immunol Immunopathol 1986 Nov;41(2):165-74 17 UI - 87018684 AU - Berden JH ; Faaber P ; Assmann KJ ; Rijke TP TI - Effects of cyclosporin A on autoimmune disease in MRL/1 and BXSB mice. AB - MRL/1 and BXSB mice were treated daily with cyclosporin A (CyA) in an oral dose of 25 mg/kg body weight. With this dose, blood levels within the therapeutic range were obtained. In normal mice CyA in this dose significantly prolonged the survival of an H-2 incompatible skin graft, and suppressed delayed-type hypersensitivity (DTH). It had no influence on the magnitude of a primary antibody response. Autoimmune mice were treated from 6 to 22 weeks of age. CyA treatment did not alter significantly the anti-DNA and anti-IgG autoantibody levels in either strain compared with control mice, who received olive oil. There was a slight but significant increase in serum IgG levels in CyA-treated MRL/1 mice. Clinical signs of glomerulonephritis (decreased kidney function and albuminuria), and glomerular proliferation were not altered by CyA treatment in either strain. The amount of mesangial IgG deposits was reduced in CyA-treated MRL/1 mice, and remained unchanged in BXSB mice. The extent of the interstitial and perivascular infiltrates and the frequency and severity of necrotizing arteritis in the kidneys of MRL/1 mice were reduced by CyA treatment. The most prominent effect of CyA was an evident reduction in lymphoproliferation in MRL/1 mice. Mortality was not reduced by CyA treatment in MRL/1 and BXSB mice. MH - Animal ; Autoantibodies/BIOSYNTHESIS ; Autoimmune Diseases/*DRUG THERAPY/ IMMUNOLOGY ; Cyclosporins/PHARMACOLOGY/*THERAPEUTIC USE ; Disease Models, Animal/DRUG THERAPY/IMMUNOLOGY ; Glomerulonephritis/ETIOLOGY ; IgG/ BIOSYNTHESIS ; Lupus Erythematosus, Systemic/*DRUG THERAPY/IMMUNOLOGY ; Lymphoproliferative Disorders/FAMILIAL & GENETIC/IMMUNOLOGY ; Mice ; Mice, Inbred Strains/*IMMUNOLOGY ; Mice, Mutant Strains/*IMMUNOLOGY ; T Lymphocytes/DRUG EFFECTS/IMMUNOLOGY SO - Scand J Immunol 1986 Oct;24(4):405-11 18 UI - 87009858 AU - Richert JR ; Rose JW ; Reuben-Burnside C ; Kearns MC ; Jacobson S ; Mingioli ES ; Hartzman RJ ; McFarland HF ; McFarlin DE TI - Polypeptide specificities of measles virus-reactive T cell lines and clones derived from a patient with multiple sclerosis. AB - Eleven cloned and uncloned measles virus-specific T cell lines were generated from peripheral blood lymphocytes obtained from a patient with multiple sclerosis and were assayed for measles polypeptide specificity. Three clones reacted specifically with the fusion (F) protein and one recognized the hemagglutinin (HA). Two reacted with whole virus but not with any of the purified proteins. Five cell lines proliferated in response to multiple measles polypeptides. The addition of anti-HA or anti-F monoclonal antibodies to two of the multispecific cell lines each resulted in partial suppression of the proliferative response to whole virus by the cell lines. Two of the three F-reactive clones recognized antigen in association with a subgroup of HLA-DR4; the third responded to F only in the presence of autologous antigen-presenting cells. Of the two clones that reacted only with whole virus, one was restricted to DP3 and one to autologous cells. The HA-specific clone was DP3 restricted. Several cell lines recognized multiple measles polypeptides in association with a single HLA antigen. Recognition of individual measles polypeptides does not segregate with specific genetic restriction elements. MH - Antigenic Determinants ; Antigens, Viral/*IMMUNOLOGY ; Capsid/IMMUNOLOGY ; Clone Cells/IMMUNOLOGY ; Hemagglutinins, Viral/IMMUNOLOGY ; Human ; Lymphocyte Transformation ; Measles Virus/*IMMUNOLOGY ; Multiple Sclerosis/*IMMUNOLOGY ; Phosphoproteins/IMMUNOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/*IMMUNOLOGY ; Viral Core Proteins/IMMUNOLOGY ; Viral Fusion Proteins/IMMUNOLOGY ; Viral Proteins/*IMMUNOLOGY SO - J Immunol 1986 Oct 1;137(7):2190-4 19 UI - 87009855 AU - Coppin HL ; McDevitt HO TI - Absence of polymorphism between HLA-B27 genomic exon sequences isolated from normal donors and ankylosing spondylitis patients. AB - Ninety percent of individuals with ankylosing spondylitis (AS) express HLA-B27. To determine if HLA-B27 coding sequences from normal vs AS individuals show differences that might relate to the etiology of the disease, the gene coding for this allele was cloned from three different partial genomic libraries. These libraries were made with DNA from three different cell lines expressing HLA-B27: MRWC (HLA-B27, 14), obtained from an AS patient; KCA (HLA-B27, w44), obtained from a known normal individual; and MVL (HLA-B27, 27), a homozygous consanguineous cell line of unknown origin. To increase the number of clones coding for the HLA-B locus, partial libraries were made using a complete Eco RI digestion of genomic DNA in the lambda vector 607. The libraries were screened with two probes; one probe hybridizes to all HLA-A, B, C class I genes, and the other to a small subpopulation of class I genes, including the B locus. DNA from clones hybridizing with both probes was transfected into murine L cells. Cell surface expression of HLA-B27 on murine L cells was detected with a polymorphic monoclonal antibody (ME1) specific for HLA-B27, 7, 22. DNA from those clones positive for HLA-B27 by transfection was subcloned into the Xba I site of M13mp18 and the DNA sequence for exons 2 through 4 (encoding domains alpha 1, alpha 2, and alpha 3) was determined by the dideoxy technique by using synthetic oligonucleotide primers or the M13 primer. The resulting sequences show no difference between HLA-B27 alpha 1, alpha 2, alpha 3 domains from a known AS patient and a known normal individual. MH - Base Sequence ; Cloning, Molecular ; Exons ; Gene Expression Regulation ; Gene Frequency ; Human ; HLA Antigens/*GENETICS ; Polymorphism (Genetics) ; Spondylitis, Ankylosing/*FAMILIAL & GENETIC ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Transfection SO - J Immunol 1986 Oct 1;137(7):2168-72 20 UI - 87009196 AU - Andrews BS ; Schenk A ; Barr R ; Friou G ; Mirick G ; Ross P TI - Immunopathology of cutaneous human lupus erythematosus defined by murine monoclonal antibodies. AB - Skin biopsy specimens obtained from involved skin from sixteen patients with systemic and discoid lupus erythematosus were studied. Murine monoclonal antibodies with a biotin-avidin-horseradish peroxidase staining system were used. The findings consisted of a marked reduction in the number of epidermal Langerhans cells defined by surface antigens, reduced HLA-DR (Ia-like) antigens on the surface of dermal capillary endothelium, and mononuclear cell infiltrates characterized by a predominance of helper T lymphocytes and an increase in the number of mononuclear phagocytic cells. B lymphocytes were rarely identified. The number of T lymphocytes within the dermis correlated inversely with both the number of HLA-DR-positive epidermal Langerhans cells (p less than 0.01) and the HLA-DR staining of dermal capillary endothelium (p less than 0.01). These findings suggest that a T lymphocyte-mediated immune response associated with a reduction in Langerhans cells and capillary endothelium HLA-DR antigens is involved in the inflammatory process of lupus erythematosus skin. MH - Adult ; Antibodies, Monoclonal/*DIAGNOSTIC USE ; Epidermis/PATHOLOGY ; Female ; Human ; Langerhans Cells/PATHOLOGY ; Lupus Erythematosus, Discoid/DRUG THERAPY/IMMUNOLOGY/*PATHOLOGY ; Lupus Erythematosus, Systemic/DRUG THERAPY/IMMUNOLOGY/*PATHOLOGY ; Macrophages/PATHOLOGY ; Male ; Middle Age ; Skin/PATHOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/PATHOLOGY SO - J Am Acad Dermatol 1986 Sep;15(3):474-81 21 UI - 86305843 AU - Sgroi D ; Cohen RN ; Lingenheld EG ; Strong MK ; Binder T ; Goldschneider I ; Greiner D ; Grunnet M ; Clark RB TI - T cell lines derived from the spinal cords of mice with experimental allergic encephalomyelitis are self reactive. AB - Experimental allergic encephalomyelitis (EAE) is an animal model of T cell-mediated, central nervous system neuropathology that may be a relevant animal model for multiple sclerosis. EAE is usually induced by sensitization of animals with a xenogeneic myelin basic protein (MBP). Recently, MBP-reactive T cell lines and clones derived from lymphoid tissue of animals with EAE have proved very useful in elucidating certain aspects of the pathogenesis in EAE. However, questions relating to how T cells actually mediate the pathologic changes seen in EAE remain unresolved. We now report for the first time the derivation of long-term, interleukin 2-dependent T cell lines and sublines from a site of pathology in murine EAE--the spinal cord. All of the spinal cord-derived T cell lines and sublines were found to be "autoreactive: in that they responded to self (murine) MBP as well as to the xenogeneic immunogen, porcine MBP. The ability to derive T cell lines and sublines from the spinal cords of mice with EAE should now aid in the elucidation of pathogenetic mechanisms in EAE by allowing for a characterization of those T cells found at the site of pathology. MH - Animal ; Antigens, Surface/ANALYSIS ; Autoimmune Diseases/*IMMUNOLOGY ; Cell Line ; Encephalitogenic Basic Proteins/*IMMUNOLOGY ; Encephalomyelitis, Allergic/*IMMUNOLOGY ; Immunity, Cellular ; Lymphocyte Transformation ; Mice ; Spinal Cord/*IMMUNOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/CLASSIFICATION/*IMMUNOLOGY SO - J Immunol 1986 Sep 15;137(6):1850-4 22 UI - 86302675 AU - M:uller I ; Maier B ; Brinkmann V ; Kaufmann SH TI - Autoreactive T cell clones from mice infected with Mycobacterium bovis, strain Bacillus Calmette-Gu:erin (BCG). I. Phenotype, specificity and in vitro function. AB - Mice were infected with the intracellular microorganism, Mycobacterium bovis BCG, and draining lymph node cells were collected. A T cell line was established which was cultured in the presence of syngeneic accessory cells (AC) and killed BCG. Stimulation of this line depended on syngeneic accessory cells and did not require BCG as a source of antigen, indicating that it was autoreactive. T cell clones derived from this line had the L3T4 helper/inducer phenotype and reacted with self-Ia on syngeneic macrophages or B cell blasts. Cloned T cells were also stimulated by syngeneic accessory cells pretreated with the lysosomotropic agent chloroquine and by H-2 compatible, background gene disparate, accessory cells, suggesting that they were specific for self-Ia. After in vitro stimulation, the T cell clones secreted interleukin 2 (IL 2) and interferon-gamma (IFN-gamma), helped B cells in antibody production and activated macrophages for secretion of reactive oxygen metabolites. MH - Animal ; Antigen-Presenting Cells/IMMUNOLOGY ; Antigens, Surface/ANALYSIS ; Autoimmune Diseases/*IMMUNOLOGY ; B Lymphocytes/IMMUNOLOGY ; Chloroquine/PHARMACOLOGY ; Clone Cells/IMMUNOLOGY ; H-2 Antigens/ IMMUNOLOGY ; Helper Cells/IMMUNOLOGY ; Hypersensitivity, Delayed/ IMMUNOLOGY ; Immunization, Passive ; Interleukin 2/BIOSYNTHESIS ; Lymphocyte Cooperation ; Lymphocyte Transformation ; Macrophage Activation ; Macrophages/IMMUNOLOGY ; Mice ; Mice, Inbred Strains ; Mycobacterium Bovis/*IMMUNOLOGY ; Mycobacterium Infections/*IMMUNOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/*IMMUNOLOGY SO - Immunobiology 1986 Jul;171(4-5):366-80 23 UI - 86313702 AU - Singer PA ; McEvilly RJ ; Noonan DJ ; Dixon FJ ; Theofilopoulos AN TI - Clonal diversity and T-cell receptor beta-chain variable gene expression in enlarged lymph nodes of MRL-lpr/lpr lupus mice. AB - The autosomal recessive lpr gene accelerates a systemic lupus erythematosus-like disease in genetically predisposed mice and induces autoantibodies in mice of normal genetic background. The molecular mode(s) of action of the lpr gene and its chromosomal location remain unknown, but it is primarily expressed as a massive T-cell proliferation manifested only in the presence of a thymus. To define the clonal diversity and maturational stage of the abnormally proliferating T cells found in enlarged lymph nodes of MRL-lpr/lpr mice, and their possible role in autoreactive B-cell activation, we analyzed their T-cell receptor beta-chain variable region (V beta) gene sequences. Twenty-five VDJ-containing beta-chain cDNA sequences were examined, each of which was found to derive from a distinct rearrangement in the correct reading frame, yielding translatable beta-chain mRNAs. An additional 10 clones were derived from truncated nonfunctional mRNAs. D beta 1 and D beta 2 elements were used equally in the sequenced clones, and 10 of the possible 12 mouse J beta elements were represented. Remarkably, 60% of the functional beta-chain mRNAs expressed V beta 8.2 or V beta 8.3 genes, whereas the equally homologous V beta 8.1 gene was not represented at all. Other V beta genes were found at lower frequencies in the library, including one previously unidentified V beta gene. The results indicate that the clonal makeup of the abnormally proliferating lymph node T cells in MRL-lpr/lpr mice is heterogeneous, but V beta gene expression is significantly skewed in favor of V beta 8.2/8.3 genes. The preferential representation of V beta 8 genes might be caused by lpr gene-induced modification of T-cell thymic processing and relate to the lpr gene-associated autoimmunity. MH - Animal ; Base Sequence ; DNA/ANALYSIS ; Lupus Erythematosus, Systemic/ ETIOLOGY/*FAMILIAL & GENETIC/IMMUNOLOGY ; Lymph Nodes/*ANALYSIS/PATHOLOGY ; Mice ; Receptors, Antigen, T-Cell/*GENETICS ; Recombination, Genetic ; Support, U.S. Gov't, P.H.S. SO - Proc Natl Acad Sci USA 1986 Sep;83(18):7018-22 24 UI - 86294786 AU - Moutsopoulos HM ; Hooks JJ ; Chan CC ; Dalavanga YA ; Skopouli FN ; Detrick B TI - HLA-DR expression by labial minor salivary gland tissues in Sj:ogren's syndrome. AB - Minor salivary gland biopsy specimens from patients with Sj:ogren's syndrome (primary and secondary) and from normal controls were examined with the four step biotin-avidin-immunoperoxidase assay. The composition of the infiltrating cells was similar in patients with both primary and secondary Sj:ogren's syndrome, consisting primarily of T lymphocytes with predominance of T helper/inducer cells. B lymphocytes (Leu-14) were approximately 20-35% of the infiltrating lymphocytes, while only a few OKM1 (monocytes/macrophages) cells and Leu-7+ (natural killer; NK) cells were observed. The majority of infiltrating lymphocytes expressed HLA-DR antigens. In the biopsy specimens of the controls there were no infiltrates; the scattered lymphocytes, however, were also predominantly T lymphocytes. Finally, the glandular epithelial cells (ducts and acini) were inappropriately expressing HLA-DR antigens, in contrast with controls where minimal HLA-DR expression was found. MH - Adult ; Aged ; Antigens, Immune Response/*ANALYSIS ; Female ; Human ; Immunoenzyme Technics ; Lymphocytes/IMMUNOLOGY ; Male ; Middle Age ; Salivary Glands/*IMMUNOLOGY ; Salivary Glands, Minor/*IMMUNOLOGY/ PATHOLOGY ; Sjogren's Syndrome/*IMMUNOLOGY/PATHOLOGY SO - Ann Rheum Dis 1986 Aug;45(8):677-83 25 UI - 86276773 AU - Owerbach D ; Rich C ; Taneja K TI - Characterization of three HLA-DR beta genes isolated from an HLA-DR 3/4 insulin-dependent diabetic patient. AB - Three HLA-DR beta genes were isolated from a Swedish HLA-DR3/4 insulin-dependent diabetes mellitus (IDDM) patient and characterized by restriction endonuclease mapping and nucleotide sequence analysis. Two out of the three DNA sequences differed from those of published DR beta-chain sequences. A DR beta-gene probe prepared from exon 4 and flanking sequences was used in a Southern blot analysis of blood donors' DNA and DNA from HLA-DR3/4 IDDM patients and HLA-DR-matched healthy control subjects. This probe differentiated HLA-DR3/4 IDDM patients and HLA-DR-matched controls in the Scandinavian population but not in the North American Caucasoid population. MH - Amino Acid Sequence ; Antigens, Immune Response/*GENETICS ; Base Sequence ; Chromosome Mapping ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY ; DNA Restriction Enzymes/DIAGNOSTIC USE ; Genes, Structural ; Human ; Polymorphism (Genetics) ; Support, Non-U.S. Gov't SO - Immunogenetics 1986;24(1):41-6 26 UI - 86267438 AU - Hauser SL ; Bhan AK ; Gilles F ; Kemp M ; Kerr C ; Weiner HL TI - Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. AB - Immunohistochemical staining of 16 brains post mortem from patients with progressive multiple sclerosis and of two biopsy specimens from patients with acute demyelinating disease was performed using a panel of monoclonal antibodies reactive with T cells and T-cell subsets, B cells, and Ia (HLA-DR) antigens. Lymphocytic perivascular cuffs were most prominent at the edge of active plaques and were occasionally seen in areas with no evidence of demyelination or macrophage infiltration. Perivascular cuffs consisted predominantly of T cells and Ia+ cells, with many T8+ cells and variable numbers of T4+ cells. T8/T4 ratios in cuffs varied between 1:1 and 50:1. In normal-appearing white matter, cuffs were sparse and were predominantly T8+. The distribution of T cells in the parenchyma resembled that seen in perivascular cuffs, namely, predominantly T8+ cells and variable numbers of T4+ cells. Many Ia+ cells were present in active lesions, and the majority of these cells appeared, by histological criteria, to be macrophages. Tissue macrophages were also stained lightly by the anti-T4 antibody. No brain had more T4+ than T8+ cells, determined using both T4 and Leu3a monoclonal antibodies. B1+ cells were rare. These results suggest that the cellular infiltrate in multiple sclerosis consists predominantly of T cells and macrophages and that there is an overrepresentation of T8+ cells compared with T4+ cells. MH - *Antibodies, Monoclonal ; *Antigens, Immune Response ; Brain/*IMMUNOLOGY/ PATHOLOGY ; Immunoenzyme Technics ; Lymphocytes/*IMMUNOLOGY/PATHOLOGY ; Multiple Sclerosis/*IMMUNOLOGY/PATHOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - Ann Neurol 1986 Jun;19(6):578-87 27 UI - 86253068 AU - Nepom BS ; Palmer J ; Kim SJ ; Hansen JA ; Holbeck SL ; Nepom GT TI - Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ insulin-dependent diabetes mellitus and DR4+ seropositive juvenile rheumatoid arthritis. AB - HLA-DR4, Dw4-associated haplotypes associated with IDDM and JRA were compared using genomic DNA restriction fragment analysis to distinguish among DQ beta and alpha alleles linked to DR4. DQ beta polymorphisms that subdivide the HLA-DQw3 specificity into DQ3.1 and 3.2 alleles were identified. More than 90% of DR4+ IDDM patients express one of these alleles, DQ3.2; restriction enzyme mapping indicates that the presence of this allele also accounts for the genomic fragment patterns previously reported in IDDM. Furthermore, haplo-identical siblings of DQ3.2 IDDM patients also carry the DQ3.2 allele, regardless of clinical presentation. In contrast, DR4+ JRA patients show no allelic preference at DQ beta, implicating different HLA genetic contributions in these two DR4-associated diseases. MH - Alleles ; Antigens, Immune Response/*GENETICS ; Arthritis, Juvenile Rheumatoid/FAMILIAL & GENETIC/*IMMUNOLOGY ; Base Sequence ; Comparative Study ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/ *IMMUNOLOGY ; DNA Restriction Enzymes ; Genetic Marker ; Genotype ; Human ; Phenotype ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - J Exp Med 1986 Jul 1;164(1):345-50 28 UI - 86252216 AU - Greenstein JI ; McFarland HF ; Richert JR TI - Characterization of antigen-specific T cells in multiple sclerosis twins with elevated proliferative responses to measles virus. AB - The proliferative response to measles virus in normal individuals is low compared with the response to mumps virus. This is probably due to a low precursor frequency of OKT4+, IL 2-secreting helper cells. The presence of a measles high-responder state has previously been identified in some twin individuals with multiple sclerosis. Further characterization of the measles response in these high-responder individuals has demonstrated that the enhanced measles responses are due to a greater response by OKT4+ cells, which secrete higher levels of IL 2; this contrasting with the low levels of IL 2 secretion and OKT4+ cell proliferation seen in the unaffected twins. No evidence for suppression by either accessory or T cells, which would account for the quantitative differences between the high responders with multiple sclerosis and their unaffected low-responder twin siblings, was detected. The results indicate that a clonally expanded population of measles-specific responder cells is responsible for the high-responder state in these twins with multiple sclerosis. The mechanism producing this state may have relevance to possible immunoregulatory abnormalities producing autoimmunity in multiple sclerosis. MH - Antigen-Presenting Cells/IMMUNOLOGY ; Antigenic Determinants ; Dose-Response Relationship, Immunologic ; Human ; HLA Antigens/ANALYSIS ; Interleukin 2/BIOSYNTHESIS ; *Lymphocyte Transformation ; Measles Virus/ *IMMUNOLOGY ; Multiple Sclerosis/FAMILIAL & GENETIC/*IMMUNOLOGY ; Phenotype ; T Lymphocytes/CLASSIFICATION/*IMMUNOLOGY/METABOLISM ; *Twins SO - J Immunol 1986 Jul 15;137(2):546-50 29 UI - 86252208 AU - Fox RI ; Chilton T ; Rhodes G ; Vaughan JH TI - Lack of reactivity of rheumatoid arthritis synovial membrane DNA with cloned Epstein Barr virus DNA probes. AB - Rheumatoid arthritis (RA) synovial membranes contain a 62,000 dalton (62 Kd) molecule that shares an antigenic epitope with the EBNA-1 antigen of Epstein Barr virus (EBV). This cross-reactive epitope(s) is defined by a monoclonal anti-EBNA-1 antibody (MoAb P135) and by a rabbit antibody directed against a (glycine-alanine)-containing synthetic peptide from the internal repeat region-3 (IR-3) of EBNA-1. To determine whether this 62 Kd protein may result from EBV infection of RA synovial membranes, we used cloned DNA probes from the Bam M, Bam V, and Eco D regions of EBV. These probes did not show detectable reactivity with RA synovial membrane DNA in Southern blotting or slot blotting experiments. Reconstruction experiments performed with purified EBV DNA demonstrated the ability to detect 0.03 pg of viral DNA per 20 micrograms of normal genomic DNA, or approximately 1 EBV copy per 100 cells. In contrast, we found a low but significant level of reactivity of RA synovial membrane DNA with the EBV-encoded Bam K probe that encodes the EBNA-1 antigen. However, this probe also was reactive with normal genomic DNA to a similar extent. These results suggest that the 62 Kd antigen in RA synovial lining cells is probably encoded by cellular genes similar to the IR-3 region of EBV and does not result from EBV infection of the RA synovial membrane. MH - Aged ; Antibodies, Monoclonal/DIAGNOSTIC USE ; Antibodies, Viral/ DIAGNOSTIC USE ; Antigens, Viral/IMMUNOLOGY ; Arthritis, Rheumatoid/ *IMMUNOLOGY ; Cloning, Molecular ; Cross Reactions ; DNA ; DNA, Viral/ *IMMUNOLOGY ; Epstein-Barr Virus/*IMMUNOLOGY ; Female ; Human ; Male ; Middle Age ; Nucleic Acid Hybridization ; Support, U.S. Gov't, P.H.S. ; Synovial Membrane/*IMMUNOLOGY SO - J Immunol 1986 Jul 15;137(2):498-501 30 UI - 86305793 AU - Sakai K ; Namikawa T ; Kunishita T ; Yamanouchi K ; Tabira T TI - Studies of experimental allergic encephalomyelitis by using encephalitogenic T cell lines and clones in euthymic and athymic mice. AB - The role of T-T cell interactions in the clinical course of acute experimental allergic encephalomyelitis (EAE) in mice was investigated. Myelin basic protein (MBP)-reactive and encephalitogenic T cell clones were established from long-term lines derived from susceptible strain SJL/J mice and resistant strain DDD/1 mice. The lines and clones from DDD/1 mice were obtained by immunization of congenitally athymic mice of DDD/1 origin, which had been reconstituted with syngeneic Lyt-2+-depleted splenic T cells. The clones derived from both strains bore surface phenotypes of Lyt-1+, 2- and L3T4+, and proliferated well in response to rat, rabbit, bovine, and guinea pig MBP in the presence of antigen-presenting cells with I-As. Passive EAE could be induced in syngeneic normal recipients by these clones as well as by the lines from which the clones were derived. The clinical features of the clone-induced EAE were essentially the same as those of the line-induced EAE. Furthermore, DDD/1 athymic recipients developed signs of acute EAE by the adoptive transfer of I-A-compatible syngeneic and allogeneic T cell clones, in which there was no significant difference in time of onset, maximum severity, or prognosis. These results indicate that the entire clinical course of acute EAE can be elicited by a single population of MBP-reactive T cells in the absence of the thymus and other populations of primed or unprimed T cells. MH - Animal ; Cell Line ; Clone Cells/IMMUNOLOGY/TRANSPLANTATION ; Comparative Study ; Encephalomyelitis, Allergic/*IMMUNOLOGY/PATHOLOGY ; Immunization, Passive ; Mice ; Mice, Inbred Strains ; Mice, Nude/*IMMUNOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/*IMMUNOLOGY/TRANSPLANTATION SO - J Immunol 1986 Sep 1;137(5):1527-31 31 UI - 86298524 AU - Antoniou AV ; Parker D ; Turk JL ; Tan BT ; Scheper RJ TI - Immunocytochemical identification and quantitation of mononuclear cells in the meninges during the development of chronic relapsing experimental allergic encephalomyelitis (CREAE) in the guinea pig. AB - To investigate the role of mononuclear cells in the meninges at all stages of chronic relapsing experimental allergic encephalomyelitis, juvenile guinea pigs were inoculated with isogeneic spinal cord in Freund's complete adjuvant (FCA) in parallel with animals inoculated with FCA alone as age-matched controls. Cytospins were prepared of the meningeal inflammatory cells obtained by washing the brains of these animals. These cytospins were stained by indirect immunoperoxidase, using a panel of monoclonal antibodies (Mabs) recognizing "activated: macrophages (M phi s), Ia antigen, total T cells and a putatively T-cell-suppressor subset, and an antiserum against immunoglobulins. The inflammatory response was quantitated and the proportions of the different cell types were determined. It was found that the total number of infiltrating cells correlated with the neurological symptoms of the disease. "Activated: M phi s increased significantly during the disease, in line with clinical signs. The expression of the Ia antigen, found on both lymphocytes and M phi s, also appeared to correlate with the disease. There was no increase in putative T-suppressor-cells during remission but there was a significant rise in the proportion of both cells staining with anti-immunoglobulins and plasma cells during relapse. MH - Animal ; Antibodies, Monoclonal/DIAGNOSTIC USE ; B Lymphocytes/IMMUNOLOGY ; Encephalomyelitis, Allergic/IMMUNOLOGY/*PATHOLOGY ; Guinea Pigs ; Immunoglobulins, Surface/ANALYSIS ; Leukocyte Count ; Macrophage Activation ; Macrophages/IMMUNOLOGY ; Meninges/IMMUNOLOGY/*PATHOLOGY ; Phagocytes/IMMUNOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/ IMMUNOLOGY SO - Cell Immunol 1986 Feb;97(2):386-96 32 UI - 86294260 AU - Boumpas DT ; Mark GE ; Tsokos GC TI - Oncogenes and autoimmunity. AB - Vertebrate cells harbor genes (proto-oncogenes) which carry the potential to become dominant transforming genes or oncogenes. Evolutionary conservation is the hallmark of these genes which implies that they have a major role in the growth and differentiation of the cells. In vitro activation of various cell types (immune cells, fibroblasts, etc.) leads to increased expression of various oncogenes in a certain temporal sequential order. Lymphoid cells from mice with autoimmune disorders have been shown to exhibit increased oncogene expression. Mononuclear cells from patients with angioimmunoblastic lymphadenopathy and certain autoimmune disorders (systemic lupus erythematosus and rheumatoid arthritis) express increased quantities of certain oncogenes. In this review, we discuss the role of oncogenes in the activation of immune cells and the pathogenesis of human autoimmunity. RF - REVIEW ARTICLE: 62 REFS. MH - Animal ; Autoimmune Diseases/*FAMILIAL & GENETIC ; Gene Expression Regulation ; Human ; Lymphocyte Transformation ; Lymphocytes/*PHYSIOLOGY ; Lymphokines/PHYSIOLOGY ; *Oncogenes ; Proto-Oncogene Proteins, Cellular/ *GENETICS ; Proto-Oncogenes ; Review ; RNA, Messenger/GENETICS ; RNA, Neoplasm/GENETICS ; Transcription, Genetic SO - Anticancer Res 1986 May-Jun;6(3 Pt B):491-7 33 UI - 86277148 AU - Zamansky GB TI - Recovery from UV-induced potentially lethal damage in systemic lupus erythematosus skin fibroblasts. AB - The repair of ultraviolet light-induced potentially lethal damage was investigated in density-inhibited skin fibroblast cell strains derived from patients with systemic lupus erythematosus. The effect of exposure to polychromatic ultraviolet light composed of environmentally relevant wavelengths or to the more commonly studied, short wavelength (254 nm) ultraviolet light was studied. Systemic lupus erythematosus cells, which are hypersensitive to ultraviolet light under growth promoting conditions, were able to repair potentially lethal damage as well as normal cells. MH - Cell Line ; Cell Survival/RADIATION EFFECTS ; Cells, Cultured ; DNA Repair/*RADIATION EFFECTS ; Fibroblasts/RADIATION EFFECTS ; Human ; Lupus Erythematosus, Systemic/*PATHOLOGY ; Skin/*RADIATION EFFECTS ; Sunlight/ ADVERSE EFFECTS ; Support, U.S. Gov't, P.H.S. ; Ultraviolet Rays/*ADVERSE EFFECTS SO - Int J Radiat Biol 1986 Aug;50(2):305-12 34 UI - 86259077 AU - Braun RP ; Lee JS TI - Variations in duplex DNA conformation detected by the binding of monoclonal autoimmune antibodies. AB - Four monoclonal antibodies (Jel 229, 239, 241, 242) which bound to duplex DNA were prepared from two autoimmune female NZB/NZW mice. Their binding to various nucleic acids was investigated by a competitive solid phase radioimmune assay which allows the estimation of relative binding constants. None of the antibodies showed any consistent variation of binding constant with base composition and thus they must recognize features of the DNA backbone. Jel 241 binds across the major groove but the interaction with poly(pyrimidine) X poly(purine) DNAs was barely detectable. This antibody appears to recognize the "alternating-B: conformation which is promoted by methylation of pyrimidines in alternating sequences. The other three antibodies bind in the minor groove. In particular, for Jel 229 the preferred antigen was poly(dG) X poly(dC) with only weak binding to poly(dA) X poly(dT). This suggests a requirement for a wide minor groove. Thus autoimmune antibodies provide examples of "analogue: recognition and can be used to detect structural variations in the grooves of duplex DNA. MH - Animal ; Antibodies, Monoclonal/*IMMUNOLOGY ; Antibody Affinity ; Antibody Specificity ; Autoimmune Diseases/*IMMUNOLOGY ; Base Sequence ; DNA/*IMMUNOLOGY ; DNA-Binding Proteins/METABOLISM ; Mice ; Mice, Inbred NZB ; Molecular Weight ; Nucleic Acid Conformation ; Oligodeoxyribonucleotides/CHEM SYNTHESIS/IMMUNOLOGY ; Structure-Activity Relationship ; Support, Non-U.S. Gov't SO - Nucleic Acids Res 1986 Jun 25;14(12):5049-65 35 UI - 86254106 AU - Johnston CA ; Russell AS ; Kovithavongs T ; Dasgupta M TI - Measures of immunologic and inflammatory responses in vitro in rheumatoid patients treated with methotrexate. AB - We examined the effects of low dose parenteral methotrexate (MTX) on immunologic and inflammatory responses of potential importance in the pathogenesis of rheumatoid arthritis. Only 2 significant changes were noted: the number of esterase positive cells in the peripheral blood decreased, and the uptake of tritiated thymidine by incubated peripheral blood mononuclear cells fell markedly. These changes were present 48 h after an injection of MTX, before decreased disease activity became clinically apparent. We therefore conclude that they were direct effects of the drug itself. MH - Antibody Formation/DRUG EFFECTS ; Arthritis, Rheumatoid/DRUG THERAPY/ *IMMUNOLOGY/PATHOLOGY ; DNA Replication/DRUG EFFECTS ; Esterases/ANALYSIS ; Human ; Immunity, Cellular/DRUG EFFECTS ; Inflammation ; Methotrexate/ PHARMACOLOGY/*THERAPEUTIC USE ; Monocytes/DRUG EFFECTS/ENZYMOLOGY/ IMMUNOLOGY ; Support, Non-U.S. Gov't SO - J Rheumatol 1986 Apr;13(2):294-6 36 UI - 86252251 AU - Mountz JD ; Huppi KE ; Seldin MF ; Mushinski JF ; Steinberg AD TI - T cell receptor gene expression in autoimmune mice. AB - Autoimmunity in mice with the lpr/lpr and gld/gld genotypes is accompanied by profound lymphadenopathy characterized by the presence of a massive expansion of an unusual T cell subset. The abnormal lymph node T cells were found to express TcR beta and TcR alpha transcripts of expected sizes. There was a 10-fold increase in the 1.3-kb TcR beta transcript and a twofold increase in TcR alpha gene expression, even though Thy-1 expression was in general similar to controls. A study of T cell receptor expression during ontogeny failed to reveal any striking differences between lpr/lpr and congenic mice. There was a strong correlation between TcR beta expression and c-myb expression; however, there was no necessary association of TcR beta and c-myb expression when various T cell lines were examined. Background genes were found to influence the expression of T cell receptor genes in lpr/lpr mice. AKR-lpr/lpr lymph node cells, but not cells from other lpr/lpr mice or AKR +/+ mice, had the predominance of the 1.0-kb TcR beta transcript, which represents the nonfunctional D-J TcR beta rearrangements. Lymph nodes from MRL-lpr/lpr mice, but not C57BL/6-lpr/lpr or AKR-lpr/lpr mice, were found to express small amounts of the TcR gamma transcript. In addition, MRL-lpr/lpr but not C57BL/6-lpr/lpr mice had an age-related decrease in thymic TcR beta expression along with a decrease in thymic c-myb expression. The current study extends the characterization of T cell gene expression abnormalities in peripheral T cells of gld/gld and lpr/lpr and describes certain similarities of these cells to immature thymocytes at a molecular level. Furthermore, it illustrates the complex interactions between "background genes: and genes responsible for lymphoproliferation, which in concert lead to specific molecular and cellular abnormalities. MH - Animal ; Autoimmune Diseases/*FAMILIAL & GENETIC/IMMUNOLOGY ; Female ; Fetal Development ; Gene Expression Regulation ; *Genes, Recessive ; Lymph Nodes/METABOLISM ; Mice ; Mice, Inbred AKR ; Mice, Inbred BALB C ; Mice, Inbred CBA ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mice, Inbred NZB ; Nucleic Acid Hybridization ; Oncogenes ; Receptors, Antigen, T-Cell/*GENETICS/METABOLISM ; T Lymphocytes/ METABOLISM ; Thymus Gland/EMBRYOLOGY/GROWTH & DEVELOPMENT SO - J Immunol 1986 Aug 1;137(3):1029-36 37 UI - 86245764 AU - Kradin RL ; Divertie MB ; Colvin RB ; Ramirez J ; Ryu J ; Carpenter HA ; Bhan AK TI - Usual interstitial pneumonitis is a T-cell alveolitis. AB - Usual interstitial pneumonitis (UIP) is an idiopathic inflammatory disorder that produces scarring of the lung parenchyma. We studied open-lung biopsies of 13 patients with UIP using immunohistological staining and monoclonal antibodies. T lymphocytes (Leu 4+) accounted for 59% of cells in the alveolar septal infiltrates in UIP and OKT8+ cells accounted for the majority of T lymphocytes in most cases. OKM1+ granulocytes comprised a smaller percentage (14%) of the alveolar infiltrates. Granulocytes were most frequent within cystic airspaces and inflamed small airways. Class II HLA (Ia) antigens were expressed on lymphocytes, macrophages, endothelial cells, and alveolar type II cells in lungs with UIP. This study demonstrates that altered immunoregulatory subsets are present in the lungs of patients with UIP and suggests the possibility that activated T cells may play a role in the pathogenesis of this disorder. MH - Adult ; Aged ; Antibodies, Monoclonal/IMMUNOLOGY ; Antigens, Surface/ ANALYSIS ; Autoimmune Diseases/*IMMUNOLOGY/PATHOLOGY ; Female ; Granulocytes/IMMUNOLOGY ; Human ; Immunoenzyme Technics ; Male ; Middle Age ; Pulmonary Alveoli/PATHOLOGY ; Pulmonary Fibrosis/*IMMUNOLOGY/ PATHOLOGY ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/CLASSIFICATION/ *IMMUNOLOGY SO - Clin Immunol Immunopathol 1986 Aug;40(2):224-35 38 UI - 86206007 AU - DeFreitas EC ; Sandberg-Wollheim M ; Schonely K ; Boufal M ; Koprowski H TI - Regulation of interleukin 2 receptors on T cells from multiple sclerosis patients. AB - Receptors for interleukin 2 (IL-2) are absent on resting T lymphocytes and are induced by antigenic and mitogenic stimulation. After a limited time (8-12 days), these receptors on normal T cells are down-regulated despite the presence of receptor-saturating concentrations of IL-2. We report here that both antigen- and mitogen-induced T-cell lines and clones obtained from peripheral blood and cerebrospinal fluid of multiple sclerosis patients show prolonged expression of IL-2 receptors. This expression is coincident with a prolonged responsiveness to the proliferative effects of IL-2. In addition, Leu 3+, IL-2 receptor-positive T-cell clone from the cerebrospinal fluid of a multiple sclerosis patient has been established and maintained for more than 1 year without IL-2. This clone has some morphologic and histochemical properties of T cells transformed or infected by human T-lymphotropic virus type I. MH - Antibodies, Monoclonal/DIAGNOSTIC USE ; Antigens, Surface/ANALYSIS ; Cerebrospinal Fluid/CYTOLOGY ; Human ; Interleukin 2/*PHARMACOLOGY ; Lymphocyte Transformation ; Multiple Sclerosis/CEREBROSPINAL FLUID/ *IMMUNOLOGY ; Receptors, Immunologic/*PHYSIOLOGY ; Recombinant Proteins/ *PHARMACOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/*IMMUNOLOGY SO - Proc Natl Acad Sci USA 1986 Apr;83(8):2637-41 y 39 UI - 86197723 AU - Matsumoto Y ; Hara N ; Tanaka R ; Fujiwara M TI - Immunohistochemical analysis of the rat central nervous system during experimental allergic encephalomyelitis, with special reference to Ia-positive cells with dendritic morphology. AB - The rat central nervous system (CNS) during experimental allergic encephalomyelitis (EAE) was analyzed immunohistochemically from the preclinical to recovery stage by using monoclonal antibodies specific for rat T lymphocyte subsets and Ia antigen. Through combination of the avidin-biotin technique and carefully selected fixative, cells with dendritic morphology (DC) and infiltrating mononuclear cells were clearly and intensely demonstrated in the CNS parenchyma during EAE. In normal and complete Freund's adjuvant (CFA)-injected controls, there were no inflammatory foci. Ia (OX3)-positive parenchymal cells were not detected, whereas W3/25 stained DC that were located mainly in the white matter and W3/13 stained axons. At the preclinical stage, 11 days after CNS/CFA sensitization, a few clusters of Ia+ DC were detected in some sections of the spinal cord. The number of Ia+ DC increased as clinical signs developed (P less than 0.001). In rats with a clinical score of 1 or 2, Ia+ DC were mainly located in the perivascular region and closely associated with infiltrating T lymphocytes. However, at moribund state (score 3), Ia+ DC were evenly distributed in gray and white matter on almost all sections of the spinal cord. In recovered rats, the numbers of inflammatory foci and Ia+ DC were less than those in clinical EAE rats (P less than 0.001). Rats without clinical signs throughout the course also contained a few clusters of Ia+ DC. Double immunofluorescent staining with OX3 and anti-glial fibrillary acidic protein (GFAP) antiserum demonstrated that Ia+ DC were negative for GFAP. Their morphology and distribution were similar to those of nucleoside diphosphatase-positive cells, suggesting that Ia+ DC are microglia. In contrast to DC, no astrocytes or endothelial cells express detectable levels of Ia antigen in control and clinical EAE rats. These findings suggest that brain cells other than Ia+ DC may not be involved in the local immune interaction. Ia+ DC may play a significant role in antigen presentation in the CNS with EAE. MH - Animal ; Antibodies, Monoclonal/DIAGNOSTIC USE ; Antigen-Presenting Cells/ *IMMUNOLOGY ; Antigens, Immune Response/*IMMUNOLOGY ; Antigens, Surface/ ANALYSIS ; Brain/IMMUNOLOGY ; Central Nervous System/*IMMUNOLOGY/ PATHOLOGY ; Encephalomyelitis, Allergic/*IMMUNOLOGY/PATHOLOGY ; Inflammation/IMMUNOLOGY/PATHOLOGY ; Male ; Rats ; Rats, Inbred LEW ; Spinal Cord/IMMUNOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/ CLASSIFICATION/IMMUNOLOGY ; Time Factors SO - J Immunol 1986 May 15;136(10):3668-76 40 UI - 86197721 AU - F:assler R ; Schauenstein K ; Kr:omer G ; Schwarz S ; Wick G TI - Elevation of corticosteroid-binding globulin in obese strain (OS) chickens: possible implications for the disturbed immunoregulation and the development of spontaneous autoimmune thyroiditis. AB - Basal plasma levels of corticosterone and corticosteroid-binding globulin (CBG) have been investigated in Obese strain (OS) chickens afflicted with spontaneous autoimmune thyroiditis (SAT). Corticosterone was determined radioimmunologically, and CBG by using a highly sensitive radioligand saturation assay. OS chickens displayed total corticosterone levels not different from healthy normal White Leghorn (NWL) chickens. CBG, however, was found to be twice as high in OS chickens as compared with their healthy counterparts, irrespective of sex or age. This quantitative difference in the CBG level is not compensated for by either altered affinity or specificity of the molecule. Furthermore, no differences were found in the response of OS and NWL lymphocytes to the suppressive effect of glucocorticoids in vitro. We therefore assume that OS animals are deficient in free, hormonally active corticosterone. An additional indication for such a diminished glucocorticoid tonus was that in vivo treatment of OS chickens with glucocorticoid hormones, thus increasing the free and active hormone fraction, normalizes the T cell hyperreactivity and significantly reduces thyroid infiltration. Possible pathophysiological implications of a diminished glucocorticoid tonus for spontaneous autoimmunity, as well as possible explanations for the beneficial effects of glucocorticoid treatment on the development of SAT, are discussed. MH - Animal ; Chickens/*BLOOD ; Corticosterone/BLOOD ; Hydrocortisone/ THERAPEUTIC USE ; Lymphocyte Transformation/DRUG EFFECTS ; Obesity/BLOOD/ COMPLICATIONS/*IMMUNOLOGY ; Spleen/CYTOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/IMMUNOLOGY ; Thyroid Gland/IMMUNOLOGY ; Thyroiditis, Autoimmune/*BLOOD/COMPLICATIONS/DRUG THERAPY/IMMUNOLOGY ; Transcortin/ *BLOOD SO - J Immunol 1986 May 15;136(10):3657-61 41 UI - 86169619 AU - Gregerson DS ; Obritsch WF ; Fling SP ; Cameron JD TI - S-antigen-specific rat T cell lines recognize peptide fragments of S-antigen and mediate experimental autoimmune uveoretinitis and pinealitis. AB - Two S-antigen-specific rat T cell lines expressing the T helper cell surface phenotype (W 3/25+, OX 8-) have been isolated from the spleen and lymph node cells of retinal S-antigen-immunized Lewis rats, one of which displayed neither clinical nor histopathologic signs of experimental autoimmune uveoretinitis. The other rat had recovered from severe experimental autoimmune uveoretinitis for 2 mo before isolation of the cell line. Both lines are specific for S-antigen presented by histocompatible antigen-presenting cells, and also respond in vitro to several of the peptides produced by cyanogen bromide cleavage of bovine retinal S-antigen. The lesions induced by the i.v. transfer of from 1 to 10 X 10(6) viable line cells involve the retina and pineal gland, as is found when Lewis rats are immunized with immunopathogenic doses of S-antigen. Histologic examination of the eyes and pineal glands revealed pathologic lesions typical of experimental autoimmune uveoretinitis, and consisted of marked infiltration of the retina and surrounding tissues and the pineal gland by lymphocytes and inflammatory cells. T cells capable of mediating autoimmune disease are clearly present and readily isolated from both asymptomatic and convalescent animals. No significant differences in specificity for the cyanogen bromide peptides of S-antigen or cell surface phenotype were found in the T cell lines isolated from these two rats, nor was any difference found in the specificity or titer of serum antibodies taken from the original rats for the cyanogen bromide peptides of S-antigen. MH - Animal ; Antibody Specificity ; Antigenic Determinants/ANALYSIS/ IMMUNOLOGY ; Antigens/ANALYSIS/*IMMUNOLOGY ; Antigens, Surface/ANALYSIS ; Autoimmune Diseases/*IMMUNOLOGY/PATHOLOGY ; Cattle ; Cell Line ; Cyanogen Bromide ; Female ; Histocompatibility Antigens/GENETICS/IMMUNOLOGY ; Immunization, Passive ; Peptide Fragments/*IMMUNOLOGY ; Phenotype ; Pineal Body/*IMMUNOLOGY/PATHOLOGY ; Rats ; Rats, Inbred BN ; Rats, Inbred F344 ; Rats, Inbred LEW ; Retinitis/*IMMUNOLOGY/PATHOLOGY ; Species Specificity ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/*IMMUNOLOGY/TRANSPLANTATION ; Uveitis/*IMMUNOLOGY/PATHOLOGY SO - J Immunol 1986 Apr 15;136(8):2875-82 42 UI - 86059961 AU - del Prete GF ; Maggi E ; Mariotti S ; Tiri A ; Vercelli D ; Parronchi P ; Macchia D ; Pinchera A ; Ricci M ; Romagnani S TI - Cytolytic T lymphocytes with natural killer activity in thyroid infiltrate of patients with Hashimoto's thyroiditis: analysis at clonal level. AB - T Lymphocytes from thyroid infiltrates and peripheral blood (PB) of 3 patients with Hashimoto's thyroiditis (HT) were cloned using a microculture system previously shown to allow the clonal expansion of virtually all PB T lymphocytes from normal individuals. The phenotypic and functional features of a total number of 153 clones from thyroid infiltrates and 206 clones from PB were examined and compared with those of 272 clones derived from normal PB and spleens. The majority of clones derived from thyroid infiltrates of patients with HT had the cytotoxic/suppressor (T8+) phenotype, whereas the majority of clones from PB expressed the helper/inducer (T4+) phenotype. In addition, a consistent proportion (25%) of clones derived from PB of one patient had a phenotype (T3+T4-T8-) that was only occasionally found on clones obtained from PB or spleens of normal subjects. Most clones derived from both PB and thyroid infiltrates of the patients with HT had cytolytic activity, assessed by a lectin-dependent cytolytic assay against the murine P815 tumor cell line. The high frequency of cytotoxic T cells in thyroid infiltrates was related to the increased proportion of T8+ cells, whereas enhanced percentages of cytotoxic cell precursors with T4+ and T3+T4-T8- phenotypes primarily accounted for the high frequency of cytolytic T cells in the PB of the same patients. Many cytolytic T cell clones derived from thyroid infiltrates also had natural killer activity against human K562 and MOLT-4 target cells. These data provide the first functional analysis of T lymphocytes infiltrating the thyroid gland in patients with HT and suggest that the high proportions of cytolytic T cell precursors found in both thyroid infiltrates and PB of these patients may be of importance in determining the tissue damage in thyroid autoimmune disease. MH - Antibodies, Monoclonal/DIAGNOSTIC USE ; Antigens, Surface/ANALYSIS ; Cells, Cultured ; Clone Cells ; Human ; Killer Cells, Natural/CYTOLOGY/ *IMMUNOLOGY ; Phenotype ; Support, Non-U.S. Gov't ; T Lymphocytes, Cytotoxic/CYTOLOGY/*IMMUNOLOGY ; Thyroid Gland/*IMMUNOLOGY/PATHOLOGY ; Thyroiditis, Autoimmune/*IMMUNOLOGY/PATHOLOGY SO - J Clin Endocrinol Metab 1986 Jan;62(1):52-7 43 UI - 86218702 AU - Perez Leiros C ; Sterin-Borda L ; Cossio P ; Bustuoabad O ; Borda E TI - Potential role of mononuclear cells infiltration on the autoimmune myocardial dysfunction. AB - In autoimmune myocarditis significant alterations in contractility when the heart is studied in vitro could be demonstrated. The isolated atria from mice hyperimmunized with heart exhibited tachycardia, decrease in contractility and dysrhythmia. Spleen lymphocytes from mice with autoimmune myocarditis, can react in vitro with spontaneously beating normal atria inducing dysrhythmias and negative inotropic effect. The alterations in contractility of normal atria induced by immune cells, resemble those observed in atria from animals with autoimmune myocarditis. The use of pharmacologic inhibitors strongly suggests that the cardiac dysfunction is generated by the release of endogenous SRS-A as a result of the hyperimmunization with heart. The possibility that autoimmune lymphocyte can influence the contractile behavior of the heart is interesting and could provide some evidence for the role of lymphocytic infiltration in the mechanism operating in primary and specific myocarditis. MH - Animal ; Autoimmune Diseases/*PATHOLOGY ; Cell Movement ; Disease Models, Animal ; Heart Atrium/PHYSIOPATHOLOGY ; Lymphocytes/*PHYSIOLOGY ; Mice ; Myocardial Contraction/DRUG EFFECTS ; Myocarditis/*PATHOLOGY/ PHYSIOPATHOLOGY ; Myocardium/IMMUNOLOGY ; Spleen/IMMUNOLOGY ; Support, Non-U.S. Gov't ; Time Factors SO - Clin Exp Immunol 1986 Mar;63(3):648-55 44 UI - 86198531 AU - Klinman DM ; Mushinski JF ; Honda M ; Ishigatsubo Y ; Mountz JD ; Raveche ES ; Steinberg AD TI - Oncogene expression in autoimmune and normal peripheral blood mononuclear cells. AB - PBMC from patients with autoimmune diseases and from normal controls were studied for the expression of several cellular oncogenes. Gene expression was assessed by Northern blot analysis of poly(A)+ RNA obtained from leukapheresis samples. Patients with SLE expressed significantly more c-myc protooncogene RNA than did normal controls. Increased expression of the N-ras protooncogene was found in that subset of patients whose autoimmune disease was very active. Cells from individuals with SLE, but not from those with other autoimmune illnesses, showed significantly decreased levels of the c-myb and c-fos protooncogenes. To examine the implications of these findings, B and T cells were purified from apheresis samples donated by normal volunteers. When mitogen was used to activate the B cells in vitro, their pattern of protooncogene expression changed to resemble that found in freshly isolated cells from lupus patients. These results suggest that the differences detected in the expression of protooncogenes by patients with SLE may be due to the abnormal activation of their B cells in vivo. The pattern of protooncogene expression found in patients with other autoimmune illnesses is consistent with the activation of additional cell types in those diseases. MH - Autoimmune Diseases/FAMILIAL & GENETIC ; Cell Cycle ; Gene Expression Regulation ; Human ; Lupus Erythematosus, Systemic/*FAMILIAL & GENETIC/ PATHOLOGY ; Lymphocyte Transformation ; Lymphocytes/*PHYSIOLOGY ; *Proto-Oncogenes ; Translocation (Genetics) SO - J Exp Med 1986 May 1;163(5):1292-307 45 UI - 86182721 AU - Lassmann H ; Vass K ; Brunner C ; Wisniewski HM TI - Peripheral nervous system lesions in experimental allergic encephalomyelitis. Ultrastructural distribution of T cells and Ia-antigen. AB - The distribution of T cells and Ia-antigen in peripheral nervous system (PNS) lesions of experimental allergic encephalomyelitis was studied by light- and electron-microscopic immunocytochemical techniques. Sprague Dawley rats, sensitized with guinea pig spinal cord tissue, developed a biphasic disease with acute inflammatory and chronic inflammatory demyelinating lesions in the PNS. In both the acute non-demyelinating and the chronic demyelinating disease inflammatory infiltrates were composed of T cells and Ia-positive monocytes/macrophages. Dependent upon the stage of the disease a variable percentage of T-lymphocytes carried the Ox 8 antigen (suppressor/cytotoxic cells). In demyelinating lesions no evidence for an interaction of T cells with myelin or Schwann cells was observed, thus arguing against a direct T-cell cytotoxicity in demyelination. The whole sequence of myelin destruction and digestion was performed by W3/13-, Ia+ mononuclear cells with ultrastructural features of monocytes/macrophages. In contrast to the acute inflammatory stage of the disease, high titers of anti-myelin antibodies were present in sera of affected animals sampled during the chronic inflammatory demyelinating stage. The sera from the latter animals also showed pronounced in vivo demyelinating activity when transferred into the cerebrospinal fluid (CSF) of normal recipient rats. It is thus suggested that demyelination in this model is induced by a co-operation of cell-mediated and humoral immune mechanisms. We did not find evidence for Ia-antigen expression on local elements of the PNS (Schwann cells, axons, or endothelial cells). MH - Animal ; Antibodies/ANALYSIS ; Antigens, Immune Response/ANALYSIS ; Demyelinating Diseases/BLOOD/PATHOLOGY/PHYSIOPATHOLOGY ; Encephalomyelitis, Allergic/IMMUNOLOGY/*PATHOLOGY/PHYSIOPATHOLOGY ; Myelin Sheath/IMMUNOLOGY ; Peripheral Nerves/IMMUNOLOGY/*PATHOLOGY/ ULTRASTRUCTURE ; Rats ; Rats, Inbred Strains ; Support, Non-U.S. Gov't ; T Lymphocytes/PATHOLOGY/*ULTRASTRUCTURE ; Tissue Distribution SO - Acta Neuropathol (Berl) 1986;69(3-4):193-204 46 UI - 86163298 AU - Stollar BD TI - Antibodies to DNA. AB - Antibodies that recognize specific conformational variations of DNA structure provide sensitive reagents for testing the extent to which such conformational heterogeneity occurs in nature. A most dramatic recent example has been the development and application of antibodies to left-handed Z-DNA. They provided the first identification of Z-DNA in fixed nuclei and chromosomes, and of DNA sequences that form Z-DNA under the influence of supercoiling. Antibodies have also been induced by chemically modified DNA and by synthetic polydeoxyribonucleotides that differ from the average B-DNA structure. These antibodies recognize only the features that differ from native DNA. In most experiments, native DNA itself is not immunogenic. Antibodies that do react with native DNA occur in sera of patients with autoimmune disease, but even monoclonal anti-DNA autoantibodies usually react with other polynucleotides as well. Anti-DNA antibodies, especially those of monoclonal origin, provide a model for the study of protein-nucleic acid recognition. RF - REVIEW ARTICLE: 189 REFS. MH - Animal ; Antibodies, Monoclonal/IMMUNOLOGY ; Antibody Specificity ; Autoantibodies/IMMUNOLOGY ; Base Sequence ; Chromosomes/ULTRASTRUCTURE ; DNA/*IMMUNOLOGY ; DNA, Superhelical/IMMUNOLOGY ; Human ; Lupus Erythematosus, Systemic/*IMMUNOLOGY ; Nucleic Acid Conformation ; Nucleosides/IMMUNOLOGY ; Nucleotides/IMMUNOLOGY ; Polydeoxyribonucleotides/IMMUNOLOGY ; Purines/IMMUNOLOGY ; Pyrimidines/ IMMUNOLOGY ; Review ; Structure-Activity Relationship ; Support, U.S. Gov't, Non-P.H.S. ; Support, U.S. Gov't, P.H.S. SO - CRC Crit Rev Biochem 1986;20(1):1-36 47 UI - 86159144 AU - de Wilde PC ; Baak JP ; Slootweg PJ ; Hen:e RJ ; Kater L TI - Morphometry in the diagnosis of Sj:ogren's syndrome. AB - Sublabial salivary gland biopsies of 20 patients with Sj:ogren's syndrome and 58 controls were analyzed morphometrically to determine which histologic changes in the tissue are specific enough to justify a diagnosis of Sj:ogren's syndrome and which changes are due to physiologic aging. The acinar atrophy, fibrosis, ductal hyperplasia and ductal dilatation mentioned in the literature as features of Sj:ogren's syndrome are also observed in the tissue of aging individuals, and the lymphocytic focus score cited as the most important diagnostic parameter gives rise to about 9% of false-positive diagnoses. When using single quantitative histologic parameters, the volume percentages (Vol%) of lymphocytic foci, diffuse lymphoplasmacytic infiltrate (DLPI), acini and the inner diameter of intralobular ducts (ILD) were able to discern between the patients and the controls at a significant level, regardless of age, although considerable overlap was still present. This overlap could be reduced by consideration of at least two histologic parameters. The inhomogeneity within the tissue constituents was also used in discriminating between the patients and the control subjects. The best bivariate discriminating combination of histologic parameters was Vol% of lymphocytic foci and DLPI. Compared with qualitative subjective evaluation, this morphometric decision rule in the present material gave a 5 X reduction in the number of false-positive diagnoses of Sj:ogren's syndrome, with only 1 of the 58 control subjects erroneously classified as having the syndrome. We conclude that quantitative investigation of sublabial salivary gland tissue will improve the diagnostic criteria needed for the definition of Sj:ogren's syndrome. MH - Adult ; Age Factors ; Aged ; Biometry ; Diagnostic Errors ; Evaluation Studies ; *Histological Technics ; Human ; Lymphocytes/PATHOLOGY ; Middle Age ; Salivary Glands/PATHOLOGY ; Sjogren's Syndrome/*DIAGNOSIS ; Support, Non-U.S. Gov't SO - Anal Quant Cytol Histol 1986 Mar;8(1):49-55 48 UI - 86155126 AU - Boitard C ; Debray-Sachs M ; Bach JF TI - Autoimmune disorders in diabetes. AB - The development of IDDM correlates with the presence of biologic markers pointing to the involvement of the immune system in the disease process. In addition to clinical observations of association of IDDM with other autoimmune disease and morphologic evidence of a mononuclear cell infiltration of the islets of Langerhans at the onset of the disease, anti-islet cell antibodies are detected in the serum of IDDM patients. Moreover, a strong genetic association with HL-A DR3 and DR4 identifies a genetic background compatible with autoimmune phenomena. Whether autoimmune phenomena are primary or secondary to an initial damage of the islets by infectious agents or other environmental factors is unknown. Whether or not the autoimmune response participates in the selective destruction of insulin-secreting cells has been a major issue in the past five years. The presence of T lymphocytes and anti-islet cell antibodies, which selectively inhibit or lyse insulin-secreting cells in vitro, strongly suggests that it may be the case. A definitive demonstration is difficult to provide in human IDDM. The development of animal models for IDDM has allowed useful insight into the pathogenetic mechanisms responsible for IDDM. In both the BB rat and the low-dose streptozotocin mouse model, the role of the immune system in the destruction of the islets of Langerhans is supported by the prevention of the disease by treatments interfering with the immune system. The BB rat develops a spontaneous autoimmune disease on a genetic background defined by the association with a major histocompatibility complex allele without any evidence for a role in initial damage of islets of a triggering infectious or chemical process. The low-dose streptozotocin model is an autoimmune IDDM secondary to the selective damage of islet cells by a toxin. The present scheme of an islet cell target and specific autoreactive T and B lymphocyte clones raises two major issues: what is the target antigen on islet cells and what is the role at the molecular level of class II major histocompatibility complex genes in susceptibility for IDDM? The first issue is presently being addressed in several laboratories using the hybridoma technology. The second issue is addressed at the biochemical level by studying restriction site polymorphism of major histocompatibility genes in susceptible individuals and IDDM patients, and at the functional level by studying the action of monoclonal antibodies to class II antigen on the development of IDDM in animal models. These steps are likely to be a prerequisite to antigen-specific immunotherapy in IDDM. RF - REVIEW ARTICLE: 133 REFS. MH - Animal ; Antibody-Dependent Cell Cytotoxicity ; Antigen-Antibody Complex/ IMMUNOLOGY ; Antigens, Surface/IMMUNOLOGY ; Autoantibodies/*IMMUNOLOGY ; Autoimmune Diseases/FAMILIAL & GENETIC/*IMMUNOLOGY/THERAPY ; Cytotoxicity, Immunologic ; Diabetes Mellitus, Experimental/IMMUNOLOGY ; Diabetes Mellitus, Insulin-Dependent/FAMILIAL & GENETIC/*IMMUNOLOGY/ THERAPY ; Disease Models, Animal ; Genetic Marker ; Human ; HLA Antigens/ GENETICS/IMMUNOLOGY ; Islands of Langerhans/IMMUNOLOGY ; Mice ; Rats ; Rats, Inbred BB ; Review ; T Lymphocytes/IMMUNOLOGY SO - Adv Nephrol 1986;15:281-305 49 UI - 86146876 AU - Sun D ; Wekerle H TI - Ia-restricted encephalitogenic T lymphocytes mediating EAE lyse autoantigen-presenting astrocytes. AB - T lymphocytes specific for myelin basic protein (MBP) are responsible for the cellular events leading to autoimmune disease within the central (CNS) and peripheral (PNS) nervous systems. Both in actively induced and T-cell transfer versions of experimental autoimmune encephalomyelitis (EAE) and neuritis (EAN), the autoaggressive T cells are activated outside the nervous system and reach their target tissue via the blood circulation. The target specificity of the autoaggressive T cells is impressive; T-cell lines specific for MBP predominantly home to and affect the white matter of the CNS whereas T cells specific for PNS myelin protein P2 exclusively infiltrate peripheral nerves. Having penetrated the tight blood tissue barriers, the lymphocytes seem to interact with local cells expressing the relevant autoantigen in an immunogenic form. Although the exact mechanism of target finding and destruction is unknown, studies from our laboratory have shown that astrocytes, a main component of the normal CNS glia, can actively present antigen to specific T cells. This observation suggests that astrocytes are involved in natural immune reactivity within the CNS, and that they may be involved in pathological aberrations, such as in the development of autoimmune lesions. Having studied astrocyte/T-cell interactions in more detail, we discovered that encephalitogenic T-cell lines recognizing MBP on astrocytes will subsequently proceed to kill the presenting cells. Here we report that astrocyte killing follows the rules governing 'classical' T-cell-mediated cytolysis; it is antigen-specific, restricted by antigens of the major histocompatibility complex (MHC) and apparently contact-dependent. Our data suggest that the nature of the recognized antigenic epitope determines whether or not antigen recognition is followed by killing; moreover, killing of antigen-presenting astrocytes seems to be correlated with the capacity to transfer encephalomyelitis to normal syngeneic rats. MH - Animal ; Antigen-Presenting Cells/IMMUNOLOGY ; Antigenic Determinants ; Antigens, Immune Response/*IMMUNOLOGY ; Astrocytes/*IMMUNOLOGY ; Autoantigens/IMMUNOLOGY ; Cytotoxicity, Immunologic ; Encephalitogenic Basic Proteins/*IMMUNOLOGY ; Encephalomyelitis, Allergic/*IMMUNOLOGY ; Macrophages/IMMUNOLOGY ; Rats ; Support, Non-U.S. Gov't ; T Lymphocytes/ *IMMUNOLOGY SO - Nature 1986 Mar 6-12;320(6057):70-2 50 UI - 86145354 AU - Sakai K ; Tabira T ; Endoh M ; Steinman L TI - Ia expression in chronic relapsing experimental allergic encephalomyelitis induced by long-term cultured T cell lines in mice. AB - Chronic relapsing experimental allergic encephalomyelitis was induced in SJL mice by adoptive transfer of long-term cultured T cell lines. The T cells which were activated with myelin basic protein (MBP) derived from various species, all induced chronic relapsing experimental allergic encephalomyelitis with a similar high incidence. During the relapsing stage, lymphocytes obtained from the spleen responded well to MBP and were capable of transferring experimental allergic encephalomyelitis, whereas thymus lymphocytes did not respond to MBP. There was no difference in the proliferative response of splenocytes to MBP when splenocytes were isolated either from mice with clinical relapse or from mice that did not relapse. Pathological examination revealed a transient appearance of inflammatory cells during the acute stage. Similar cell infiltrates were also observed at the relapsing stage. The I-region associated (Ia) antigens appeared on vessels and astrocytes in the acute inflammatory lesions which coincided with the appearance of inflammatory cell infiltrates. Ia antigen expression diminished with the disappearance of inflammatory cells. During the relapsing stage, the Ia antigens were also expressed on the vessels and astrocytes in the fresh lesions. Our data indicate that MBP-reactive T cells persist at least in the spleen, for a long time. They may be reactivated by certain mechanisms probably in the central nervous system associated with the Ia-antigen expression, which facilitates the effector phase again. The initial event that triggers the Ia-expression is not known as yet. MH - Acute Disease ; Animal ; Antigens, Immune Response/*ANALYSIS ; Cell Division ; Cell Line ; Central Nervous System/IMMUNOLOGY/PATHOLOGY ; Chronic Disease ; Encephalitogenic Basic Proteins/IMMUNOLOGY ; Encephalomyelitis, Allergic/*IMMUNOLOGY/PATHOLOGY ; Female ; Histocytochemistry ; Immunoenzyme Technics ; Mice ; Recurrence ; Spleen/ CYTOLOGY ; Support, Non-U.S. Gov't ; T Lymphocytes/IMMUNOLOGY/ TRANSPLANTATION ; Thymus Gland/CYTOLOGY SO - Lab Invest 1986 Mar;54(3):345-52 51 UI - 86142511 AU - Noonan DJ ; Kofler R ; Singer PA ; Cardenas G ; Dixon FJ ; Theofilopoulos AN TI - Delineation of a defect in T cell receptor beta genes of NZW mice predisposed to autoimmunity. AB - In an attempt to determine whether genes involved in T cell antigen recognition are structurally abnormal and thereby promote murine systemic lupus, we analyzed the structural integrity of the D, J, and C region elements of the T cell receptor alpha and beta chain genes in all major lupus strains and several normal strains. Within the limits of restriction fragment length polymorphism analysis, all strains had an identical genomic organization, except the NZW mice, in which a deletion of the C beta 1-D beta 2-J beta 2 elements was found. Sequence analysis of NZW genomic elements containing this deletion placed its probable origin within the first exon of C beta 1, and extending to a complementary region within the first exon of C beta 2. The significance of this abnormality in the pathogenesis of systemic autoimmune disease remains to be determined. MH - Animal ; Autoimmune Diseases/*FAMILIAL & GENETIC ; Base Sequence ; Chromosome Deletion ; Chromosome Mapping ; DNA Restriction Enzymes/ DIAGNOSTIC USE ; Genes, Structural ; Linkage (Genetics) ; Mice ; Mice, Inbred Strains/GENETICS/*IMMUNOLOGY ; Polymorphism (Genetics) ; Receptors, Antigen, T-Cell/*GENETICS ; Support, U.S. Gov't, P.H.S. SO - J Exp Med 1986 Mar 1;163(3):644-53 52 UI - 86140716 AU - Goronzy J ; Weyand CM ; Fathman CG TI - Shared T cell recognition sites on human histocompatibility leukocyte antigen class II molecules of patients with seropositive rheumatoid arthritis. AB - Seropositive rheumatoid arthritis (RA) in adult and juvenile patients is associated with the serologic marker HLA-DR4. This association is incomplete; about one-third of the patients lack the disease-associated HLA-DR4 haplotype. The main biological function of class II molecules is to restrict the recognition of antigen by T lymphocytes. We therefore tested the hypothesis that patients with seropositive RA share T cell recognition sites for an unknown antigen and that such T cell "epitopes: are not identified by conventional serologic typing. We generated alloreactive human T cell clones by stimulating peripheral blood lymphocytes of normal donors against a lymphoblastoid cell line from a juvenile patient with seropositive RA. A panel of clones that recognized only HLA-Dw14 cells on a panel of homozygous typing cells was used to analyze class II molecules of adult patients with seropositive RA. By inhibition studies using monoclonal antibodies, the epitopes recognized by the different clones could be further characterized and assigned either to DR- or to DQ-encoded cell surface products. By using four different clones, it was possible to identify Dw14-associated T cell epitopes on all seropositive rheumatoid patients tested who typed HLA-DR4-positive and also on all eight DR4-negative patients tested. Approximately one-half of nonrheumatoid DR4-positive donors carried one or more determinants recognized by these clones; the expression of these allodeterminants in DR4-negative nonrheumatoid patients was rare (less than 10%). Thus, alloreactive human T cell clones are powerful tools to define T cell recognition sites on class II molecules that are not identified by conventional typing. Using T cell clones with specificities for determinants expressed on Dw14 homozygous typing lines, we were able to demonstrate shared epitopes on cells of all patients tested with seropositive RA irrespective of their HLA-D or HLA-DR type. These data suggest that major histocompatibility complex class II antigens of RA patients might be much more homogeneous than demonstrated by the incomplete HLA-DR4 association. MH - Antigenic Determinants ; Antigens, Immune Response/*ANALYSIS/GENETICS ; Arthritis, Rheumatoid/*IMMUNOLOGY ; Clone Cells/IMMUNOLOGY ; Genotype ; Histocompatibility Testing ; Human ; Linkage (Genetics) ; *Major Histocompatibility Complex ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/*IMMUNOLOGY SO - J Clin Invest 1986 Mar;77(3):1042-9 53 UI - 86138715 AU - Suzuki H ; Nakanishi K ; Steinberg A ; Green I TI - Induction of c-myc expression early in the course of B-cell activation: studies in normal humans and patients with systemic lupus erythematosus. AB - The proliferative response of B lymphocytes to stimulation with anti-IgM antibodies and B-cell growth factors was studied in 27 patients with systemic lupus erythematosus (SLE) and 17 normal donors. In addition, the expression of messenger RNA of the proto-oncogene c-myc was also studied in B cells from SLE patients and normal donors. The proliferative response of lupus B cells to anti-IgM and B-cell growth factors as compared to normal B cells demonstrated a wide range of responses, 10 were lower than normal and 8 were either normal or supernormal. As compared to normals, expression of B-cell c-myc RNA from SLE patients was either normal or depressed. In general in patients with SLE there was a positive correlation between levels of c-myc expression and the degree of proliferation in B-cells after stimulation with anti-IgM and B-cell growth factors. MH - Adolescence ; Adult ; Aged ; Anti-Antibodies/PHARMACOLOGY ; B Lymphocytes/ *IMMUNOLOGY ; Female ; Gene Expression Regulation ; Growth Substances/ GENETICS ; Human ; IgM/IMMUNOLOGY ; Lupus Erythematosus, Systemic/ *FAMILIAL & GENETIC ; *Lymphocyte Transformation ; Lymphokines/GENETICS ; Male ; Middle Age ; Oncogenes SO - Int Arch Allergy Appl Immunol 1986;79(4):380-7 54 UI - 86112520 AU - Iguchi T ; Ziff M TI - Electron microscopic study of rheumatoid synovial vasculature. Intimate relationship between tall endothelium and lymphoid aggregation. AB - The relationship between (a) "tallness: and (b) cross-sectional area of the endothelial cells (EC) of postcapillary venules (PCV) and capillaries and the cellular composition of adjacent perivascular mononuclear cell infiltrates in rheumatoid (RA) synovial membrane has been examined by electron microscopy. "Tallness: of the EC was measured as the ratio of the height of the EC to its base (H/B). H/B showed a strong positive correlation with the number and percent of perivascular lymphocytes, i.e., the denser the lymphoid aggregation, the taller the EC. In contrast, H/B showed negative correlations with percent perivascular plasma cells, macrophages, and fibroblast(cyte)s. No such correlations were observed with pericapillary infiltrates. A computer-based morphometric technique yielded similar relationships between the cross-sectional area of the EC and the composition of the perivascular infiltrates. These results indicate that the EC of PCV in lymphocyte-rich areas of synovium tend to be tall and to occupy an increased fraction of the cross-sectional area of the vessel. In contrast, in areas rich in macrophages and plasma cells, EC tend to be flat and to occupy a smaller fraction of the cross-sectional area. PCV in uninfiltrated interstitial areas and in normal synovium had flat EC, and capillaries had flat EC regardless of the character of the surrounding infiltrate. Finally, PCV in lymphocyte-rich areas closely resembled those of tonsil in appearance. Our findings indicate that the PCV of the RA synovial membrane from which lymphocytes emigrate to form perivascular lymphoid aggregates resemble those of lymphoid tissue. They suggest that chronic inflammatory tissue and normal lymphoid tissue share mechanisms of lymphocyte emigration. MH - Arthritis, Rheumatoid/*PATHOLOGY ; Capillaries/PATHOLOGY ; Endothelium/ PATHOLOGY ; Human ; Lymphocytes/PATHOLOGY ; Macrophages/PATHOLOGY ; Microscopy, Electron ; Plasma Cells/PATHOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Synovial Membrane/*BLOOD SUPPLY ; Venules/ PATHOLOGY SO - J Clin Invest 1986 Feb;77(2):355-61 55 UI - 86108346 AU - Pruijn GJ ; Kusters HG ; Gmelig Meyling FH ; van der Vliet PC TI - Inhibition of adenovirus DNA replication in vitro by autoimmune sera. AB - Sera from patients suffering from autoimmune diseases were analyzed for the presence of antibodies that inhibit adenovirus DNA replication in vitro. DNA replication was studied in a reconstituted system containing purified viral proteins (DNA binding protein, DNA polymerase and the precursor to the terminal protein) and a crude nuclear extract from HeLa cells. About half the autoimmune sera analyzed inhibited DNA replication by more than 50% while only 2 out of 31 control sera showed strong inhibition. The inhibition was caused by the IgG fractions of the sera and was most frequently observed with sera from scleroderma patients. Several lines of evidence indicate that the inhibition is not due to anti-DNA antibodies. The mechanism of inhibition of two strongly inhibitory sera was further investigated. The IgG fractions from these sera blocked DNA chain elongation more than 80% but had no effect on the initiation step or the synthesis of the first 26 nucleotides. Using a dot blot assay and different incubation conditions, evidence was obtained that the inhibition is due to immunorecognition of a nuclear factor from HeLa cells. Two nuclear proteins are known to be required for adenovirus DNA replication, nuclear factors I and II. DNA replication in the presence of purified nuclear factor I instead of a crude nuclear extract was only slightly inhibited by the antisera. In agreement with this, immunorecognition of nuclear factor I could not be detected using a dot blot assay. Since nuclear factor II is not required in our assay system, these results suggest the existence of another nuclear component involved in adenovirus DNA replication which is neutralized by these antibodies. MH - Adenoviridae/GENETICS/IMMUNOLOGY/*PHYSIOLOGY ; Autoimmune Diseases/ *IMMUNOLOGY ; Chromatography, Affinity ; Chromatography, DEAE-Cellulose ; DNA/IMMUNOLOGY ; *DNA Replication ; Human ; IgG/IMMUNOLOGY ; Immune Sera/ PHARMACOLOGY ; Precipitation ; Support, Non-U.S. Gov't ; *Virus Replication SO - Eur J Biochem 1986 Jan 15;154(2):363-70 56 UI - 86087158 AU - Fox RI ; Chen P ; Carson DA ; Fong S TI - Expression of a cross-reactive idiotype on rheumatoid factor in patients with Sjogren's syndrome. AB - Primary Sjogren's syndrome (SS) is a systemic autoimmune disorder characterized by lymphocytic infiltration of salivary and lacrimal glands. These patients have evidence of marked B cell hyperactivity, including the production of autoantibodies such as rheumatoid factor (RF) and an increased frequency of non-Hodgkin's lymphoma. We now demonstrate that RF from 12/15 SS patients contains a cross-reactive idiotype (CRI) on their kappa light chain defined by a monoclonal antibody (MoAb 17-109) and immunoblotting. This CRI was associated with immunoglobulin (Ig) A-RF, and to a lesser extent with IgM-RF molecules on the basis of direct binding studies. With the use of immunoperoxidase techniques to stain frozen tissue sections, B cells containing cytoplasmic Ig reactive with MoAb 17-109 were detected in the salivary gland biopsies from 11/12 SS patients at high frequencies, and in the blood from the same patients at much lower frequencies. One patient with pre-existant SS developed non-Hodgkin's lymphoma with tumor cells and RF paraprotein reactive with MoAb 17-109. Evaluation of serial biopsies over a 4-yr period showed a progressive increase in the proportion of B cells bearing the CRI. In contrast, synovial membrane biopsies from RA patients lacking sicca symptoms did not contain B cells expressing the CRI. Because previous studies have demonstrated that MoAb 17-109 detects a CRI on RF paraproteins from patients with lymphoma, B cells bearing this CRI may have increased frequency of neoplastic transformation. SS patients provide an opportunity to study the expression of this CRI and to understand the transition of B cell clones from autoimmune proliferation to neoplastic transformation. MH - Adolescence ; Adult ; Antibodies, Monoclonal/IMMUNOLOGY ; Cross Reactions ; Female ; Human ; Immunoglobulin Allotypes/ANALYSIS ; Immunoglobulin Idiotypes/*ANALYSIS/IMMUNOLOGY ; Immunoglobulins, Kappa Chain/IMMUNOLOGY ; Lymphocytes/CLASSIFICATION/IMMUNOLOGY/METABOLISM ; Middle Age ; Rheumatoid Factor/*ANALYSIS/BIOSYNTHESIS/IMMUNOLOGY ; Salivary Glands/ CYTOLOGY ; Sjogren's Syndrome/*IMMUNOLOGY ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. SO - J Immunol 1986 Jan;136(2):477-83 57 UI - 86060938 AU - Sobel RA ; van der Veen RC ; Lees MB TI - The immunopathology of chronic experimental allergic encephalomyelitis induced in rabbits with bovine proteolipid protein. AB - The role of myelin proteolipid apoprotein (PLP) in the central nervous system (CNS) immune response of rabbits has been investigated by analyzing the immunopathology of chronic experimental allergic encephalomyelitis (EAE) induced by sensitization with PLP. Clinical disease occurred in seven out of nine rabbits sensitized with bovine PLP and monitored for up to 6 mo. Positive delayed hypersensitivity skin test reactions to PLP occurred in all but one of the PLP-sensitized animals. All PLP-sensitized animals had meningeal and CNS parenchymal inflammation that correlated with disease severity. Serial blood samples were stained with a panel of antibodies to rabbit T and B cells, as well as Ia, and large and small mononuclear cell populations were analyzed by flow cytometry. Peripheral leukocyte population staining did not correlate with clinical signs or sensitization to PLP. Cryostat CNS tissue sections were stained with the same set of antibodies by using an immunoperoxidase technique, and positive cells and vessels were counted. T cells and macrophages were numerous and in equal numbers in perivascular parenchymal inflammatory infiltrates, whereas B cells were less numerous (p less than 0.001). T cells also diffusely infiltrated the parenchyma. Most perivascular inflammatory cells and many scattered parenchymal cells were Ia+; Ia vascular expression was increased over controls (p less than 0.001), and also correlated with disease severity. The immunopathology of this chronic EAE model is the same as that of whole CNS tissue- and myelin basic protein-induced EAE in other species, and is similar to that of multiple sclerosis. Cellular immune responses to PLP may therefore contribute to systemic and in situ responses in CNS tissue demyelinating diseases. MH - Animal ; Antigens, Immune Response/ANALYSIS ; Cattle ; Chronic Disease ; Encephalomyelitis, Allergic/ETIOLOGY/*IMMUNOLOGY/PATHOLOGY ; Freund's Adjuvant/ADMINISTRATION & DOSAGE ; Myelin Proteins/*ADMINISTRATION & DOSAGE ; Phenotype ; Rabbits ; Skin Tests ; Support, U.S. Gov't, P.H.S. ; T Lymphocytes/CLASSIFICATION/IMMUNOLOGY/PATHOLOGY SO - J Immunol 1986 Jan;136(1):157-63