Sjögren syndrome and pseudolymphoma.
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Autoantibodies↗
Biomedical subjects
N Talal
Publications and source records attributed to N Talal.
Characteristics of a human monoclonal anti-Sm autoantibody expressing an interspecies idiotype.
A human-human hybridoma secreting an anti-Sm mAb designated 4B4 was established by fusion of GM4672 (a lymphoblastoid B cell line) with PWM-activated mononuclear cells from a patient with active SLE. Competitive Ag inhibition assays showed that 4B4 was specific for Sm and did not bind with native or denatured DNA or RNA. Western blot analysis with 4B4 showed that this mAb binds to the B/B' ribonucleoprotein of the Sm/ribonucleo-protein complex. By competitive inhibition assay, 4B4 was demonstrated to partially share idiotypic expression with a mouse anti-Sm mAb designated Y2. This was demonstrated by the ability of each mAb (Y2 or 4B4) to inhibit a homologous anti-idiotypic antibody (either anti-Y2 or anti-4B4) better than the nonhomologous anti-idiotypic antibody. These results confirm previous findings that idiotypes related to Sm-binding are highly conserved in nature. Furthermore, this report is the first idiotypic analysis of a human anti-Sm mAb.
Animals↗
B cells expressing CD5 are increased in Sjögren's syndrome.
In this investigation of B cells expressing the CD5 (Leu-1) cell surface marker, we found increased numbers of these cells in 13 of 19 patients with primary Sjögren's syndrome (SS) (68%), as well as in the rheumatoid arthritis patients. The percentage of B cells that demonstrated increased expression of CD5 was 46% in SS patients, 47% in rheumatoid arthritis patients, 24% in systemic lupus erythematosus patients, and 26% in normal subjects. Over a 2-year period, CD5 expression on B cells was a stable finding in several patients, except for 2 who required either steroid therapy or combined chemotherapy and irradiation for malignant lymphoma. Both of these patients had clinical remissions and their levels of CD5+ B cells returned to normal. The first patient had a clinical picture of SS/systemic lupus erythematosus overlap, associated with polyclonal B cell activation and decreased production of interleukin-2 in response to stimulation with phytohemagglutinin. These cellular immune abnormalities returned to normal after the institution of corticosteroids. Our observations suggest a relationship between the CD5+ B cell abnormality and disease activity. The results are discussed in relation to immunoregulatory properties of CD5+ B cells in autoimmune mice and the characteristic predisposition to malignant lymphoma among SS patients.
Adrenal Cortex Hormones↗
Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum.
Synovial fluids from 6 of 12 patients with rheumatoid arthritis (RA) and from 3 of 11 patients with reactive arthritis contained measurable levels of tumor necrosis factor alpha (TNF alpha). Seven of 12 sera from RA patients contained TNF alpha, while only 1 of those from reactive arthritis patients was positive. Gamma-interferon was detected in the synovial fluids and sera of only the RA patients. Tumor necrosis factor beta was not detected in any sera or synovial fluids. RA patients with detectable TNF alpha had higher erythrocyte sedimentation rates and synovial fluid leukocyte counts.
Adult↗
Synergistic interaction between anti-CD3 and IL-2 demonstrated by proliferative response, interferon production, and non-MHC-restricted killing.
Anti-CD3 monoclonal antibody acts on normal peripheral blood mononuclear cells to induce T cell proliferation, interferon-gamma production, and non-MHC-restricted cytotoxicity against both NK (CD16+)-sensitive and -resistant target cells. Moreover, anti-CD3 and interleukin 2 (IL-2) act synergistically to give greater proliferative, interferon-gamma (IFN-gamma), and natural cytotoxicity responses than those expected by the simple addition of the individual responses to each stimulus acting alone. This synergistic response is macrophage independent, greatest at low concentrations of anti-CD3, inhibited by anti-IL2 receptor, and depends upon the induction of IL-2 receptors by CD3 activation which are then available to respond to exogenously added IL-2. Natural cytotoxicity induced by anti-CD3 and IL-2 correlates with IFN-gamma production, is inhibited by anti-IFN-gamma, and is still present after depletion of CD16-positive cells by specific monoclonal antibody and complement. The use of anti-CD3 in concert with IL-2 may be worthy of examination in a clinical setting, presumably because CD3/IL-2-generated LAK effector cells could be followed by in vivo administration of potentially lower and less toxic quantities of IL-2 than have been used in the past.
Antibodies, Monoclonal↗
T-cell antigen receptor studies in mice expressing the lpr genetic defect.
Mice having the lpr genetic defect bear an expanding lymphoid T-cell population with unusual cell surface characteristics. Using SDS-PAGE analysis, the T cells from lpr mice were shown to have two forms of the T-cell antigen receptor. A conventional (nonreduced) 90-kDa receptor and a lighter 70- to 85-kDa form were both detected. The 70- to 85-kDa antigen receptor was also shown to be present on lpr thymocytes. Only the normal 90-kDa receptor was found in MRL-++ mice. Treatment of the receptor with N-glycanase shows that the 70- to 85-kD form may be a product of abnormal glycosylation. The low-molecular-weight antigen receptor on lpr T cells is unusual and might contribute in some way to the disordered immunoregulation and autoimmunity that occur spontaneously in these mice.
Animals↗
Rheumatoid arthritis: an editorial perspective based on cytokine imbalance.
Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) are distinct systemic rheumatic and autoimmune diseases with overlapping clinical features and laboratory findings. Although the majority of patients fit the textbook descriptions of these disorders, there are occasional patients whose illness defies precise diagnostic classification. Examples are mixed connective tissue disease, rheumatoid arthritis and systemic vasculitis, and the overlap SS/SLE syndrome with anti-Ro autoantibodies [1]. Cytokine abnormalities are prominent in all rheumatic diseases. This editorial focuses on cytokine abnormalities in RA and particularly in the rheumatoid synovium, but because of these disease interrelationships has implications for SS and SLE as well. The pathology in RA can be dominated by the systemic features, particularly when rheumatoid lung, severe vasculitis or Felty's syndrome are present. Rheumatoid factor was the first autoantibody to be extensively studied from functional, pathological and immunogenetic aspects. For most patients, however, joint inflammation with its predilection to progress to joint destruction comes to dominate the clinical picture. For the clinical immunologist, the ability to study synovial fluid and cells offers an investigative opportunity not generally found in other rheumatic diseases, i.e. to take measurements where the action is, directly at the site of autoimmune attack. Careful histopathologic studies performed decades ago are the basis for our understanding of immunopathogenic events in the rheumatoid synovium. These studies highlight the intense chronic inflammatory activity with activated macrophages, lymphocytic and plasma cell infiltration, germinal center formation, and tissue destruction. Local production of rheumatoid factor and immune complexes, as well as complement consumption, were demonstrated 20 years ago in an investigative era dominated by humoral immunity.(ABSTRACT TRUNCATED AT 250 WORDS)
Arthritis, Rheumatoid↗
Defective induction of T-cell help and natural killing following anti-CD3 stimulation of autoimmune lymphocytes.
Anti-CD3 monoclonal antibody (MoAb) stimulates T cells in normal peripheral blood to proliferate and develop cytotoxic activity against NK-sensitive tumor cell lines. We now find that anti-CD3 MoAb also generates cytotoxic activity against a cell line (MEL-21) resistant to classical NK cell killing. After activation in vitro with anti-CD3 MoAb for 18 h, normal peripheral blood mononuclear cells (PBMNC) develop more HLA-DR-positive helper than suppressor T cells, manifest a functional helper effect as measured by increased IgG synthesis (P less than 0.01), as well as kill MEL-21 target cells. PBMNC from rheumatoid arthritis (RA) patients respond normally but mononuclear cells from rheumatoid arthritis synovial fluid (RASF) respond poorly. PBMNC from systemic lupus erythematosus (SLE) patients also respond poorly to anti-CD3 stimulation. Thus, the ability of anti-CD3 to stimulate IgG production and generate enhanced natural cytolytic activity are defective in both RASF and SLE lymphocytes.
Adult↗
Two patients illustrating lymphoma transition and response to therapy in Sjögren's syndrome.
Two patients with Sjögren's syndrome (SS) who subsequently developed malignant B-cell lymphomas are reported in detail. The first patient had both benign- and malignant-appearing lymphoid infiltrates on the same submandibular gland specimen and was successfully treated with combined chemotherapy and irradiation. The second patient developed cutaneous lymphoid infiltrates difficult to diagnose by light microscopy but containing a monoclonal IgM-Kappa population revealed by immunoperoxidase staining and immunoglobulin gene rearrangement studies. Her lesions resolved rapidly and completely on cyclophosphamide, recurred rapidly when this drug was discontinued, and resolved again on a second course of cyclophosphamide which is currently maintained at 50 mg daily. Both patients are doing well without recurrence two and three years after initial treatment. This clinical experience is presented to emphasize: (1) the clinical use of molecular biologic techniques to define the earliest appearance of malignant transformation in Sjögren's syndrome, and (2) the successful outcome that can be achieved with prompt institution of appropriate treatment. The phenomenon of lymphoma development in SS is discussed with regard to immunoregulatory abnormalities predisposing to malignancy in the setting of autoimmune disease.
Cyclophosphamide↗
Ro(SS-A) positive Sjogren's/lupus erythematosus (SC/LE) overlap patients are associated with the HLA-DR3 and/or DRw6 phenotypes.
Ro(SS-A) positive female Sjögren's syndrome (SS) lupus erythematosus (LE) overlap patients are a clinically and serologically homogeneous group generally demonstrating prominent subacute cutaneous lupus erythematosus (SCLE) lesions, cutaneous vasculitis, peripheral and central nervous system disease, pulmonary disease, and a low frequency of glomerulonephritis. They commonly demonstrate rheumatoid factor, hypergammaglobulinemia, antinuclear and Ro(SS-A) La(SS-B) antibody activity. This study indicates that these patients are also immunogenetically similar, sharing a statistically significant increased frequency of HLA-B8, DR3, DRW6, DQ2, and DRw52. Sixty-three percent of these SS/LE patients possess the extended haplotype (P-value 6.0 X 10(-3); RR 9.5) HLA-B8, DR3, DQ2, DRw52. One hundred percent of this SS/LE cohort was DR3 or DRw6 (P-value less than or equal to 5.0 X 10(-3); relative risk 19.1). Fifty percent of these patients were HLA DR3/DRw6 heterozygotes (P-value 1.5 X 10(-6); relative risk 31.2). Thus, HLA-DR3 and DRw6 Ro(SS-A) positive SS/LE patients may possess a similar, if not unique, DR region DNA nucleotide sequence involved in disease susceptibility or immune regulation.
Autoantigens↗
Abnormalities of T cell activation in the rheumatoid synovium detected with monoclonal antibodies to CD3.
The chronic inflammation of rheumatoid arthritis (RA) is associated with hypofunction of synovial fluid (SF) T cells. We studied the mechanisms leading to this abnormality using a mitogenic monoclonal antibody specific for the T cell receptor-associated CD3 complex. We found that SF cells are defective in their response to anti-CD3 antibodies as measured by proliferation, generation of natural cytotoxicity, and induction of the Tac (p55) component of the IL2 receptor. Nevertheless, these cells do bear functional IL2 receptors and are more responsive to IL2 than are resting peripheral blood T cells. In searching for a mechanism to explain the reduced IL2 production, we found that polyamines (whose oxidation products can down-regulate proliferation and IL2 production) are elevated in RA cells from both blood and SF. We postulate that the chronic activation of RA T cells triggers this feedback loop which constitutes a defensive mechanism aimed at reducing the T cell driven autoimmune and inflammatory process.
Adult↗
The relationship between anti-Ro (SS-A) antibody-positive Sjögren's syndrome and anti-Ro (SS-A) antibody-positive lupus erythematosus.
Ten Ro(SS-A) antibody-positive patients with Sjögren's syndrome and lupus erythematosus are described. These patients have a disease process characterized by the frequent appearance of annular polycyclic lupus lesions of subacute cutaneous lupus erythematosus (SCLE), as well as neurologic and pulmonary disease. The Ro(SS-A) antibody-positive patients may have Sjögren's syndrome for many years and then suddenly develop lupus erythematosus, and vice versa. These studies demonstrate that the patient with Ro(SS-A) antibody may exhibit a dynamic clinical disease expression over time and that there is a closer pathologic relationship between Sjögren's syndrome and SCLE in these patients with Ro(SS-A)-antibody than has previously been appreciated. Furthermore, Ro(SS-A)-positive patients with Sjögren's syndrome and lupus erythematosus appear to have a much more guarded prognosis than those Ro(SS-A)-positive lupus patients described under the classifications of antinuclear antibody-negative lupus erythematosus and SCLE.
Adult↗
Expression of an interspecies idiotype in sera of SLE patients and their first-degree relatives.
Sera from 29 SLE patients and 81 first-degree healthy family members were tested for quantitative expression of a cross-reactive idiotype present on a murine monoclonal anti-Sm autoantibody (Y2). Forty-one percent of SLE patients and 27% of all relatives showed increased serum levels of the Y2 idiotype compared to 6% in a normal, unrelated control group. In addition, female relatives of SLE patients showed slightly increased levels of anti-Sm antibodies compared to male relatives (15% vs 3%). In one of the 28 families and three unrelated SLE patients studied, there was a significant correlation between the Y2 idiotype expression and expression of another idiotype present on anti-DNA antibodies (1341d). Affinity column absorption studies showed that these two idiotypes were present on different antibody molecules. This study demonstrates: (1) a genetic predisposition for an anti-Sm antibody idiotype expression in humans; and (2) that two different idiotypes may be under parallel or coordinate regulation.
Antibodies, Antinuclear↗
Sex hormones, CD5+ (Lyl+) B-cells, and autoimmune diseases.
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Animals↗
Cyclosporine as an immunosuppressive agent for autoimmune disease: theoretical concepts and therapeutic strategies.
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Arthritis, Rheumatoid↗
Autoantibodies of various specificities encoded by genes from the VH J558 family bind to foreign antigens and share idiotopes of antibodies specific for self and foreign antigens.
We examined the binding to foreign antigens and the expression of crossreactive idiotypes by a panel of 20 murine monoclonal autoantibodies encoded by V genes from the VH J558 family. 9 of 20 antibodies bound to foreign antigens such as bacterial polysaccharides, poly(Glu50, Tyr50), poly(Glu54,Lys37,Phe9), arsonate, and lysozyme, known to interact with antibodies encoded by genes from the VH J558 family. A high proportion of our panel of autoantibodies expressed crossreactive idiotypes originally borne by monoclonal rheumatoid factors, anti-Sm, and anti-DNA antibodies, all encoded by V genes from the VH J558 family. Some of these VH J558+ autoantibodies shared crossreactive idiotypes with VH J558+ antibodies directed against foreign antigens such as influenza virus hemagglutinin, poly(Glu60,Ala30,Tyr10), arsonate, and dextran. The implications of these findings are discussed with respect to the process of activation of self-reactive clones.
Animals↗
Genetic regulation of testosterone-induced immune suppression.
Genes in the major histocompatibility complex (H-2) of the mouse control several immune functions as well as various facets of testosterone (Te) physiology. In order to study the genetic control of Te-induced immune suppression, complete Freund's adjuvant (CFA; containing Mycobacteria tuberculosis) was administered parenterally to several mouse strains differing at the H-2 complex which were either sham- or Te-treated. The specific lymphocyte proliferative response to purified protein derivative (PPD) was measured in draining lymph node cells. The response to PPD in strains bearing H-2b (B6 and B10) but not H-2d (B10.D2 and DBA/2) or H-2k (B10.BR and AKR) haplotypes was markedly lower in Te-implanted compared to sham-implanted controls. This result suggests that the ability of Te to dampen the immune response to PPD is regulated by H-2-linked gene(s).
Animals↗
A shared B-T cell phenotype in autoimmune mice bearing the lpr gene.
MRL-lpr mice and MRL-+/+ mice are identical except for the presence of an autosomal recessive lymphoproliferation gene (designated lpr) in the former. Mice bearing the lpr gene develop autoimmune and lymphoproliferative abnormalities. An antigenic marker designated 14D10, characteristically expressed on the surface of Lyt-2+ T cells and B cells of normal mice, is expressed in unusually high levels on Thy-1+ cells of lpr mice which are Lyt-2-. In younger lpr animals, 14D10+ cells are a minor subpopulation of Ia+ cells which, when expanded in diseased animals, continue to express Ia. 14D10+ cells from lpr mice are elevated in fetal spleen and adult bone marrow (BM) but are absent on pre-B cells in the BM. Medullary thymocytes of lpr mice are enriched in 14D10+ cells compared to congenic (+/+) controls. Although 14D10 appears to be present on the activated, proliferating T-cell population, coculture of lpr cells with IL-2 leads to minimal proliferation. 14D10+ Lyt-2- T cells can be isolated from normal spleens, indicating the lpr gene may be responsible for the disregulated proliferation of a minor cell subset. The functional significance of this molecular complex is still undetermined.
Animals↗