Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is generally accepted that human Th cells express the surface glycoproteins CD4 and alpha/beta-chain heterodimer of the TCR whereas cytotoxic/suppressor cells are usually CD8+ and alpha/beta TCR+. Another minor set of T cells found in the periphery are CD4-/CD8- (double negative) and express the gamma/delta TCR; these cells can manifest MHC-restricted or nonrestricted cytotoxicity but no helper function. Herein we describe the existence of an unusual Th population in the peripheral blood of humans that are CD4-/CD8- and alpha/beta TCR+. These double-negative Th were markedly expanded in patients with the autoimmune disease SLE and along with CD4+ Th, they induced production of the pathogenic variety of anti-DNA autoantibodies that are IgG in class and cationic in charge. The cationic anti-DNA antibodies induced by the Th were markedly restricted in spectrotype indicating that an oligoclonal population of B cells were committed to produce the pathogenic autoantibodies in active lupus. IL-2-dependent T cell lines were also derived from the patients with active lupus nephritis but the majority of those T cell lines lacked pathogenic autoantibody-inducing capability. Only 4 out of 42 T cell lines from a lupus patient could induce the production of cationic IgG class anti-DNA autoantibodies. The phenotypes of the pathogenic autoantibody-inducing Th lines were similar to the Th subsets: CD4+, alpha/beta TCR+ or CD4-/CD8-, alpha/beta TCR+. These studies suggest that production of pathogenic autoantibodies in human lupus is mediated by mechanisms that are distinct from the generalized, nonspecific polyclonal B cell hyperactivity that leads to excessive production of natural autoantibodies.
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PMID:T cell receptor alpha/beta expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. 252 44

Our understanding of the immune mechanisms that lead to systemic lupus erythematosus has been greatly advanced by the availability of murine models which display both serological and clinical features of the human disease. Studies have demonstrated that CD4+ T cells are required for the full expression of disease in these mice. (NZB X NZW)F1 mice exhibit a lupus-like disease (elevated levels of IgG antinuclear antibodies and a fatal glomerulonephritis) that is not characteristic of either parent. At least three gene loci have been identified in NZW mice that could potentially contribute to a T cell-dependent autoimmune disease, including the T cell receptor alpha- and beta-chain gene complexes and the major histocompatibility complex (MHC). The NZW T cell receptor beta-chain complex appeared to be particularly unusual in that the C beta 1, D beta 2, and J beta 2 gene segments have been deleted. However, an analysis of (NZB X NZW)F1 X NZB back-cross mice revealed no association of disease expression with the presence of this allele. There was also no correlation of disease incidence with the presence of the NZW T cell receptor alpha-chain allele. In contrast, nearly 90% of the backcross mice with the NZW MHC expressed severe autoimmune disease compared with 12% of the mice that did not carry this haplotype. Additional studies strongly suggested that the gene(s) within the NZW MHC is the only dominant NZW genetic contribution to F1 disease. We also determined if self-reactive T cells are able to escape thymic tolerance in autoimmune New Zealand and MRLlpr/lpr mice. In nonautoimmune mice expressing I-E, T cells utilizing V beta 17a and V beta 11 encoded domains have been shown to be clonally eliminated in the thymus. Similarly, V beta 8.1+ and V beta 6+ T cells are tolerized in nonautoimmune mice expressing Mls-1a. These T cell subsets were quantified in the lymph nodes and spleens of (NZB X NZW)F1, (NZB X SWR)F1, and MRL-lpr/lpr mice before and after the development of lupus-like disease. The results indicate that peripheral T cells in these mice, including the massive CD4-, CD8- T cell population in lpr mice, have been modified by normal mechanisms of tolerance such that potential self-reactive V beta specificities have been eliminated in the thymus.
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PMID:Self-reactive T cells in murine lupus: analysis of genetic contributions and development of self-tolerance. 257 38

A subset of normal peripheral B lymphocytes expresses a T surface antigen recognized by monoclonal CD5. They form rosettes with mouse erythrocytes (MRBC). Other studies suggest that these B cells may have regulatory and helper properties. An expanded subset of lymphocytes forming MRBC was demonstrated in the peripheral blood of 31 Systemic Lupus Erythematosus (SLE) patients (14.4 +/- 2.8%) compared with normal controls (4.3 +/- 1.4%) and patients with tuberculosis (6.4 +/- 1.7%). Increased MRBC values correlated with disease severity. Investigation of cell surface antigen expression was attempted with enriched sedimented fractions using several monoclonal antibodies and immunofluorescent staining. Complete inhibition of MRBC formation was obtained with monoclonal antibodies against CD5, CD3 and CD8 while partial inhibition was observed with anti-Ia and no activity with CD4 and CD10 antibodies. Indirect evidence supports the concept that antilymphocyte antibodies cause T and B cell depletion and dysfunction. Sera from 12 patients with SLE and 28 with leprosy (LL) were analyzed for antibodies to lymphocytes in the microcytotoxicity assay: 87% of SLE and 57% of LL were positive. Lymphocytotoxic activity towards each cell type of a panel with 98 different HLA antigens was essentially the same and most sera were not specific for either T or B cells. Lymphocytotoxic sera from SLE and LL contained antibodies which inhibited MRBC formation.
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PMID:[Lymphocyte imbalance in autoimmunity]. 264 Apr 77

Autoimmunity is paradoxically a physiologic phenomenon. One finds in normal sera natural autoantibodies that are encoded by germ line genes. Autoimmunity is at the origin of common and severe diseases such as diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus and perhaps psoriasis and Crohn's disease. The disease may be due according to cases to exacerbation of physiologic autoimmunity or to appearance of autoreactive clones producing autoantibodies encoded by mutated genes. The respective role of triggering environmental factors and genetic predisposition (HLA and non HLA genes) is not determined. New immunotherapeutic methods, particularly cyclosporine, monoclonal antibodies (against T cells, CD4 and T cell receptor molecules and Ia antigens) and autoantigen-specific vaccination open new major therapeutic perspectives that presage major improvement in the prognosis of these diseases.
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PMID:[Evolution of the concept of autoimmunity and its therapeutic implications]. 267 84

In 24 patients with systemic lupus erythematosus the proliferating response of lymphocytes of the peripheral blood stream to mitogens PHA, ConA and PWM was examined. The spontaneous incorporation of 3H-thymidine was increased in two patients. The mean response to PHA and PWM was reduced, while the response to ConA was within the normal range. In the active stage of the disease the lymphocyte response was in general lower in the stage of low activity. There was no correlation between the number of CD4 and CD8 lymphocytes nor the CD4/CD8 index and the lymphocyte response to mitogens. In systemic lupus erythematosus the response to PWM was lower than in rheumatoid arthritis, while in rheumatoid arthritis the response to PHA and ConA was lower than in systemic lupus erythematosus.
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PMID:[Response of peripheral blood lymphocytes to antigenically nonspecific mitogens in systemic erythematosus]. 276 36

The T lymphocytes of patients with active systemic lupus erythematosus (SLE) exhibit impaired capping of the surface molecules CD3, CD4, and CD8 and a defective cAMP-dependent pathway. Since the mobility of these molecules is regulated in part by cAMP, we sought to determine whether there is a specific defect(s) along the T cell cAMP pathway that contributes to the persistent capping disorder observed during inactive SLE. The data suggest that a defect may exist at the level of cAMP-dependent protein kinase activation or at a point distally. We propose that a disorder of cAMP-dependent protein kinase activity might account for the defect of capping observed in both the CD3, CD4 (helper/inducer) and CD3, CD8 (suppressor) subsets observed in SLE.
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PMID:Impaired mobility of human T lymphocyte surface molecules during inactive systemic lupus erythematosus. Relationship to a defective cAMP pathway. 283 Aug 91

This study was undertaken to examine the levels and function of peripheral blood immunoregulatory T cell subpopulations in systemic lupus erythematosus (SLE). T cell subpopulations can be distinguished by the T cell differentiation antigens CD4 (recognized by the monoclonal antibodies OKT4 or Leu3) and CD8 (recognized by the monoclonal antibodies OKT8 or Leu2). All SLE patients tested had normal percentages of CD8 cells in their peripheral blood. The SLE patients, however, fell into two groups based on their CD4 cell numbers. Fifty-five percent of the SLE patients had normal levels of CD4 cells (Group A) and therefore normal CD4/CD8 cell ratios, whereas 45% of the SLE patient population had markedly depressed CD4 cell levels (Group B) and significantly low CD4/CD8 cell ratios. T cells from normal donors and SLE patients were further examined for their ability to stimulate allogeneic normal B/M phi cells to secrete IgM in the presence of pokeweed mitogen (PWM). Utilizing this assay system two forms of immunosuppression were observed: (1) that mediated by high concentrations of purified CD4 cells and (2) that mediated by CD8 cells. High concentrations of purified CD4 cells, added to a constant number of allogeneic normal B/M phi cells, suppressed PWM-stimulated IgM synthesis. Group B SLE patients, with significantly low CD4 cell numbers, had defective CD4 cell-mediated suppression which was concentration dependent. This result was confirmed in a study using identical twins discordant for SLE. In this case CD4 cells from the SLE twin did not induce immunosuppression at a high concentration of CD4 cells whereas similar concentrations of CD4 cells from the normal twin resulted in suppression. SLE patients (Group A) with normal levels of CD4 cells had normally immunosuppressive CD4 cells. Suppression mediated by CD8 cells was demonstrated by the fact that removal of CD8 cells resulted in enhanced IgM synthesis induced by the remaining CD4 cells. Although all the SLE patients in this study had normal peripheral blood levels of CD8 cells, SLE Group A patients had defective CD8 cell suppression whereas CD8 function appeared to be normal in Group B patients. These results suggest that in SLE patients with depressed CD4 cell numbers (Group B) there is a corresponding defect in CD4 cell function. We demonstrate that in SLE Group B patients, defective suppression is due to a subset of T cells that bear the CD4 antigen. The SLE patient population (Group A) with normal CD4/CD8 ratios and normally functioning CD4 cells, however, appear to have normal CD4 cell-mediated suppression but defective CD8 suppressor cell function.
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PMID:Two distinct subsets of patients with systemic lupus erythematosus. 297 Mar 55

We have used MAb to L3T4 to examine the function of L3T4+ T cells in normal and autoimmune mice. Treatment of mice with MAb to L3T4 profoundly depleted L3T4+ cells from the blood, spleen, and lymph nodes, but not the thymus. In BALB/c and C57BL/6 mice, selective depletion of L3T4+ cells blocked both primary and secondary humoral immune responses and inhibited, but did not prevent, cellular immune responses. In lupus-prone B/W and BXSB mice, depletion of L3T4+ cells significantly retarded autoimmune disease. Because the L3T4 antigen in mice is homologous to the CD4 antigen in humans, these findings have implications regarding the function of CD4+ T cells and the prospects for using MAb to CD4 as therapeutic agents.
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PMID:Analysis of the function of L3T4+ T cells by in vivo treatment with monoclonal antibody to L3T4. 309 10

Murine lupus in NZB/NZW F1 (B/W) mice can be prevented by weekly treatment with monoclonal antibodies (MAb) to L3T4 (on "helper/inducer" T cells) if treatment is begun prior to the onset of clinical illness. To determine whether anti-L3T4 could reverse as well as prevent murine lupus, we monitored a cohort of 30 B/W females until age 7 mo, when severe autoimmune disease was established, and then we examined the effects of weekly treatment with MAb to L3T4. The rate of target cell clearance by MAb was considerably slower in old B/W mice than it was in young B/W mice or in normal (BALB/c and C57BL/6) mice. Nonetheless, treatment with anti-L3T4 depleted 90% of circulating L3T4+ cells over 3 mo. In treated mice, the concentration of anti-DNA antibodies fell by 80%, renal insufficiency was reversed, and 1 yr survival was 75% compared to 17% in controls. These findings indicate that L3T4+ cells play an important role in perpetuating murine lupus in B/W mice even after severe disease is present. Because the L3T4 antigen in mice is homologous to the Leu-3/T4 (CD4) antigen in humans, these findings suggest that treatment with CD4 MAb may be effective in people with systemic lupus erythematosus.
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PMID:Reversal of advanced murine lupus in NZB/NZW F1 mice by treatment with monoclonal antibody to L3T4. 310 78

Several studies have produced evidence for anti-lymphocytic antibodies (ALA) in AIDS. We attempted to demonstrate ALA by immunofluorescent flow cytometry. Normal human peripheral blood lymphocytes (PBL) and the T-cell line, CEM, were incubated with sera from patients with AIDS, patients with chronic HIV infection and HIV-seronegative blood donors. ALA were not detected in the AIDS sera with fluorescein isothiocyanate (FITC)-labelled rabbit anti-mu, anti-alpha or the F(ab)2 fragment of anti-human gamma. A small number of CEM cells (2%) fluoresced with either AIDS or normal serum. A larger proportion of PBL were immunofluorescent after serum treatment but there was no difference between normal and AIDS serum. We were able to detect ALA in the serum of patients with systemic lupus erythematosus with both CEM and PBL. In contrast, incubation of either CEM or PBL with some AIDS sera, and to a lesser degree normal sera, enhanced the binding of intact FITC-rabbit anti-gamma. Anti-gamma was not bound by CEM cells unexposed to human serum. The binding was blocked by rabbit immunoglobulin, demonstrable with CEM fixed in 1% formalin, and unrelated to the density of CD4 on CEM cells.
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PMID:Failure to demonstrate anti-lymphocytic antibody in serum of patients with AIDS. 312 58


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