Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Biopsy specimens from mixed connective tissue disease (MCTD) and discoid lupus erythematodes (DLE) skin lesions were stained with monoclonal antibodies to differentiation and activation antigens. In addition, the blast cells were studied by combining autoradiography with immunoperoxidase staining. In both disease conditions most of the inflammatory cells in situ were positive for T11 antigen, the CD4/CD8 ratio being low. Only a few of the cells were pan-B positive B cells. The expression of various activation antigens did not differ significantly between MCTD and DLE biopsy specimens; the number of T9, Tac, and 4F2 antigen carrying cells was relatively low, whereas Ia-positive cells were more numerous. 3H-Thymidine incorporating T blasts comprised less than 1% of all inflammatory cells. T4 and T8 marker-carrying blast cells were present in about equal proportions. These findings suggest that Ia antigen-expressing T cells are important from the pathogenetic point of view in both MCTD and DLE. Because the local proliferation of T cells was extremely low according to the lack of interleukin-2 receptor and OKT9 markers and 3H-thymidine incorporation, it seems probable that most of the T cells are recruited from the circulation to the site of the inflammation.
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PMID:Evaluation of lymphocyte activation in skin lesions of patients with mixed connective tissue disease and discoid lupus erythematodes. 325

Monoclonal antibodies (MoAb) to L3T4 have been used successfully to suppress autoimmunity in murine models for several human autoimmune diseases. To clarify the immunologic and clinical consequences of treatment with anti-L3T4, we examined the effects of chronic administration of anti-L3T4 on the composition of lymphoid organs, the function of lymphocytes, and the histopathology of autoimmune disease in lupus-prone NZB/NZW F1 (B/W) mice. Weekly treatment with anti-L3T4 (2 mg/mouse) from age 5 to 8 months depleted L3T4+ cells from the spleen and lymph nodes, and prevented the development of splenomegaly and lymphadenopathy. The MoAb bound to target cells in the thymus and modulated their expression of the L3T4 antigen but, in contrast to its effect in extrathymic sites, anti-L3T4 did not deplete the target population from the thymus. In fact, after 3 months of therapy, mice that had been treated with anti-L3T4 had much larger thymuses than control mice that had been treated with saline, suggesting that treatment with anti-L3T4 prevented the thymic atrophy that occurs spontaneously in murine lupus. Despite depleting L3T4+ cells from the spleen, treatment with anti-L3T4 did not diminish the response of splenic lymphocytes to T and B cell mitogens, and it augmented splenic natural killer (NK) cell activity. Finally, treatment with anti-L3T4 decreased the diverse histopathologic manifestations of murine lupus. It dramatically reduced glomerular immunoglobulin and complement deposition and diminished lymphocytic infiltration and vasculitis in the kidneys. Treatment also reduced extrarenal immunopathology, including focal hepatitis and salivary gland infiltration. These observations have implications regarding the use of CD4 MoAb in people with autoimmune diseases.
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PMID:Treatment of murine lupus with monoclonal antibody to L3T4. I. Effects on the distribution and function of lymphocyte subsets and on the histopathology of autoimmune disease. 326 85

Double-negative CD4-CD8-T cells (DNT) have been shown to be the major population of T cells responsible for the massive lymphadenopathy associated with the early onset of the lupus-like syndrome in mice bearing the lpr gene. Previously, we demonstrated that these cells do not proliferate in the peripheral lymphoid organs that they invade; furthermore, we showed that a wide range of CD4 Ag expression was observed on lymph node CD4+ T cells. In this study, we used an in vivo transfer system to analyze the progeny of CD4+ T cells from B6-lpr/lpr mice. Purified CD4+ T cells injected into B6 nude mice are able to generate DNT cells; furthermore, phenotypic and functional characterizations of the DNT cells generated in vivo show that they share the same properties as DNT cells from B6-lpr/lpr mice. We also show that, after in vitro bromodeoxyuridine incorporation, only CD4+ cells cycle. From these studies, we conclude that the lymphoproliferation occurs at the CD4+ stage and that down-regulation of this Ag probably is followed by arrest of the cell cycle.
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PMID:In vivo CD4+ lymph node T cells from lpr mice generate CD4-CD8-B220+TCR-beta low cells. 752 11

We have investigated the phenotypic and functional characteristics of murine pre-B cells obtained in semisolid and liquid culture with stem cell factor (SCF) and interleukin 7 (IL-7). Both serum-supplemented and serum-deprived culture conditions were used. The source of bone marrow cells was either normal mice (CD1 and C3H) or the lupus strain of mice MRL/lpr and its congenic strain MRL/+. SCF (100 ng/ml) and IL-7 (250 ng/ml) supported murine B cell proliferation in vitro from all the murine strains analyzed both in serum-supplemented and serum-deprived conditions. Maximal colony growth was observed in both cases when the factors were used in combination. The growth factors alone induced some colony growth in serum-supplemented cultures but were either ineffective or had modest activity in serum-deprived cultures. Cells harvested from the colonies or generated in liquid cultures and stimulated with SCF + IL-7 in the absence of serum had almost exclusively a pre-B cell phenotype (BP-1+, B220+, slg-, CD4-, CD8-, Mac-1-, RB-6-). Both the maximal colony growth in semisolid culture and the maximal number of cells in liquid culture were observed at day 12-14. At this time, the pre-B cells failed to differentiate further and started to die. Pre-B cells generated in vitro were, however, capable of differentiating in vivo. SCID mice injected with 2 x 10(6) pre-B cells had readily detectable serum levels of IgM (54 +/- 26 micrograms/ml) and IgG (60 +/- 95 micrograms/ml) at 4 weeks and 6 weeks posttransplantation, respectively. Mature B and T cells of the donor major histocompatibility complex type were detected in the SCID mice at sacrifice 14 weeks posttransplantation. These data indicate that purified (> 80% BP-1+) populations of functional pre-B cells can be grown from murine bone marrow of normal mice as well as of lupus mice in serum-deprived cultures stimulated with SCF and IL-7. These cultures, therefore, provide a highly enriched source of pre-B cells but also contain T cell precursors that differentiate upon adoptive transfer into SCID mice.
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PMID:Functional characterization of lymphoid cells generated in serum-deprived culture stimulated with stem cell factor and interleukin 7 from normal and autoimmune mice. 754 56

Pathological skin reactions were induced with both UVA and UVB in 12 patients with lupus erythematosus (LE) and with UVA in 7 with polymorphous light eruption (PMLE) but in none of the controls. Biopsy specimens taken from UV-induced lesions showed that in dermal infiltrates of LE cases CD4-positive cells predominated, whereas in the majority of PMLE cases CD8-positive cells predominated. Keratinocytes expressed intercellular adhesion molecule-1 (ICAM-1) in 7 of the 12 UVA- and in eight of the ten UVB-induced LE lesions, and in three of the UVA-induced lesions of PMLE patients. Three different staining patterns were found. In subacute cutaneous LE (SCLE) cases staining throughout the epidermis resembled that seen in genuine SCLE lesions. In discoid LE (DLE) lesions, the staining was most prominent in and near the basal cell layer. In the one systemic LE case and in the PMLE cases, ICAM-1 expression was seen only in association with epidermal spongiosis and T-cell infiltration. Keratinocytes did not express ICAM-1 in the controls or in the non-irradiated skin of the LE patients. In five on the UVA-induced lesions, in eight of the UVB-induced LE lesions and in one of the PMLE cases, keratinocytes expressed CD36. In four of the six LE lesions with fewer CD1a-positive cells, dendritic CD36-positive cells were seen in the epidermis. In conclusion, the pattern of activated keratinocytes and immunocompetent cells in the dermis was similar to that seen in genuine LE and PMLE lesions, but dissimilar to each other and to the controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of intercellular adhesion molecule-1 (ICAM-1) and OKM5 in UVA- and UVB-induced lesions in patients with lupus erythematosus and polymorphous light eruption. 769 27

We have determined the effect of anti-CD4 or anti-CD8 monoclonal antibody (mAb) treatment from birth on the generation of the lpr CD4- CD8- double-negative (DN) T cell subset and on the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice. Both anti-CD4 and anti-CD8 mAb treatments resulted in a marked inhibition of lymph-adenopathy, whereas the development of the lpr DN T cells and of the lupus-like autoimmune syndrome strikingly differed in these two groups of mice. The treatment with anti-CD8 mAb almost completely blocked the appearance of the lpr DN T cells without any significant effect on the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice. In contrast, mice treated with anti-CD4 mAb failed to develop a lupus-like syndrome, while they still developed the lpr DN T cell subset, the predominant population in their lymph nodes, although absolute numbers were markedly diminished. Our results support the idea that CD8+ T cells are a major source of the lpr DN T cells, and that the lpr DN T cells play a minor, if any, role in the pathogenesis of lupus-like autoimmune syndrome in MRL-lpr/lpr mice.
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PMID:Effect of long-term anti-CD4 or anti-CD8 treatment on the development of lpr CD4- CD8- double negative T cells and of the autoimmune syndrome in MRL-lpr/lpr mice. 773 35

A variety of rheumatic disorders has been reported during the course of human immunodeficiency virus (HIV) infection; however, its association with systemic lupus erythematosus (SLE) is extremely rare. The effect of HIV infection on CD4 lymphocytes may ameliorate SLE activity and spur remission. We observed 2 patients with SLE who later developed HIV infection. Both patients' lupus went into remission, and their course was complicated by aseptic necrosis of the bone. These findings suggest that HIV infection may have an important effect on the natural course of SLE and may also have a pathogenic role in avascular necrosis.
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PMID:Coexistence of human immunodeficiency virus infection and systemic lupus erythematosus. 910 27


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