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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The polyclonal B cell activation is the earliest and most common immunologic abnormality in lupus-prone mice. However, its cellular mechanism(s) has not been well defined. To determine the contribution of CD4+ T cells in this immunologic abnormality, we have depleted CD4+ T cells in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice by treating them with anti-CD4 mAb from birth and determined the development of IgM and IgG polyclonal antibody formation. Our results indicate that first, different mechanisms control the development of IgM polyclonal B cell activation in these two autoimmune mice; in (NZB x NZW)F1 mice, IgM polyclonal B cell activation is likely to be a result of an intrinsic B cell defect, whereas CD4+ T cells seem to be responsible for this immunologic abnormality in MRL/MpJ-lpr/lpr mice. Second, the increased production of IgG antibodies, including the IgG3 subclass, was totally regulated by CD4+ T cells in both autoimmune mice. Because IgG3 antibodies can be highly nephritogenic, independent of their immunologic specificities, which is the result of the antibodies' cryoglobulin activity, the active role of CD4+ T cells in the production of IgG3 antibodies in lupus-prone autoimmune mice further strengthens the implication of CD4+ T cells in murine systemic lupus erythematosus.
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PMID:Polyclonal B cell activation arises from different mechanisms in lupus-prone (NZB x NZW)F1 and MRL/MpJ-lpr/lpr mice. 790 78

MRL-lpr mice develop aggressive autoimmune kidney disease associated with increased or de novo renal expression of major histocompatibility complex (MHC) class II molecules and a massive systemic expansion of CD4-CD- double negative (DN) T cells. Whereas non-MHC linked genes can have a profound effect on the development of nephritis, lymphadenopathy, and anti-DNA antibody production in MRL-lpr mice, the role of MHC molecules has not been unequivocally established. To study the role of MHC class II in this murine model of systemic lupus erythematosis, class II-deficient MRL-lpr mice (MRL-lpr -/-) were created. MRL-lpr -/- mice developed lymphadenopathy but not autoimmune renal disease or autoantibodies. This study demonstrates that class II expression is critical for the development of autoaggressive CD4+ T cells involved in autoimmune nephritis and clearly dissociates DN T cell expansion from autoimmune disease initiation.
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PMID:Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice. 790 20

A role for helper T cells in the induction of pathogenic lupus autoantibodies is increasingly supported by data from studies of murine lupus and patients with systemic lupus erythematosus (SLE). However, the poor in vitro function of SLE T cells has hampered the identification and characterization of autoantigen-specific T cells. We used recombinant fusion proteins to study the T cell proliferative response of 31 lupus patients and 27 healthy subjects to a well-characterized SLE autoantigen, the ribosomal P2 protein. Although PBMC from SLE patients showed marked impairment in the proliferative response to the common recall antigen tetanus toxoid when compared with normal subjects, a significantly greater proportion of SLE patients (32%) than normal individuals (0%) showed a T cell response to a recombinant P2 fusion protein. When the SLE patients were subgrouped according to the presence of serum anti-P autoantibody, 7 of 10 anti-P antibody-positive patients, but 0 of 20 anti-P antibody-negative SLE patients, demonstrated > 2,000 cpm [3H]thymidine incorporation and a P2 stimulation index > 5. The specificity of the T cell proliferative response for the P2 protein was confirmed by studies using a second recombinant human P2 fusion protein and by the specific activation of P2-primed T cells by recombinant P2 in secondary cultures. Moreover, the T cell proliferative response to the P2 autoantigen was mediated by CD4-positive T cells and was inhibited by anti-MHC class II antibodies. These data demonstrate the presence of autoantigen-specific T helper cells in patients with SLE and suggest that these T cells drive the production of autoantibodies by B lymphocytes.
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PMID:Autoantigen-specific T cell proliferation induced by the ribosomal P2 protein in patients with systemic lupus erythematosus. 791 11

To evaluate the role of V beta 8+ T cells in the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice, we treated them with the F23.1 anti-V beta 8 monoclonal antibody (mAb) from birth to 4 months of age. Here we report that almost complete depletion of V beta 8+ T cells by the F23.1 mAb treatment neither inhibited nor delayed the development of hypergammaglobulinemia, autoantibody production and autoimmune glomerulonephritis in MRL-lpr/lpr mice. In addition, the F23.1 mAb treatment did not prevent the development of lymphadenopathy and the generation of a CD4-CD8- double-negative T cell subset, characteristically accumulating in lpr lymph nodes. Our results strongly argue against the idea that the V beta 8+ T cells play a critical role in the development of lupus-like autoimmune syndrome in MRL-lpr/lpr mice.
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PMID:Lack of association of V beta 8+ T cells with lupus-like syndrome in MRL-lpr/lpr mice. 802 33

To investigate the role of IL-6 in systemic lupus erythematosus (SLE), we selectively inhibited IL-6 in lupus-prone NZB/NZW F1(B/W) mice by chronic administration of a rat mAb to mouse IL-6. Anti-IL-6 alone elicited an anti-rat response that blocked its biologic effects. To circumvent this problem, we rendered B/W mice tolerant to the rat mAb by administration of anti-CD4 concurrent with the first dose of anti-IL-6. Thereafter, the mice received weekly injections of anti-IL-6 alone. There were two control groups: one group received the tolerizing regimen of anti-CD4 along with a control rat IgG1 mAb (GL113) instead of anti-IL-6; the other control group received PBS. Mice that received anti-CD4 were tolerant to the rat mAb for 6 mo. Throughout this period, treatment with anti-IL-6 prevented production of anti-dsDNA, significantly reduced proteinuria, and prolonged life. Mice that received anti-IL-6 without anti-CD4 developed an immune response to the rat mAb and then developed anti-dsDNA antibodies, proteinuria, and mortality comparable with control mice. These findings establish that IL-6 promotes autoimmunity in B/W mice. They further indicate that, although mAb to IL-6 can suppress murine lupus, the development of host immunity to the mAb abrogates its beneficial effects. Finally, this is the first study to demonstrate that a brief course of anti-CD4 can induce tolerance to another therapeutic mAb, in this case an anti-cytokine mAb.
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PMID:Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. 804 Mar 14

Extensive studies in lupus-prone mice strongly suggest that mAbs to CD4 may be effective in SLE. By virtue of their selectivity for distinct cells within the immune system, anti-CD4 mAbs may be both more potent and less toxic than current therapies for SLE. In addition, their potential to block the host immune response to therapy may provide a critical advantage for anti-CD4 compared to other forms of mAb therapy. The problem of generalized immune suppression remains a significant obstacle to the use of anti-CD4 in humans, but it may be minimized by the use of mAb fragments or mAb isotypes that can reversibly inhibit immune function without depleting CD4+ T cells.
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PMID:Treatment of murine lupus with anti-CD4 monoclonal antibodies. 809

Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) alpha, beta, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of alpha-Ii and beta-Ii chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, alpha-Ii and beta-Ii; (e) the displacement of Ii chains by peptides to form alpha-beta-peptide complexes in the endosome; and (f) the migration of alpha-beta-peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the alpha-beta-peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Lupus 1993 Feb
PMID:Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation. 809 45

The autosomal recessive mutant gene, lpr, has been shown to accelerate the progression of lupus-like autoimmune disease, which is associated with a massive expansion of a unique CD4-CD8- double-negative T cell subset, in MRL/MpJ mice. Here we report a substrain of MRL/MpJ-lpr/lpr (MRL-lpr) mice which live almost twice as long with delayed development of glomerulonephritis, compared with conventional MRL-lpr mice. This substrain, termed MRL-lpr.II (II for long-lived), develops generalized lymphadenopathy characteristically seen in MRL-lpr mice. However, the expansion of a double negative lpr T cell subset is markedly limited with a mean value of 15% in their lymph nodes compared to about 70% in conventional MRL-lpr mice. Overall production of autoantibodies, such as anti-DNA and rheumatoid factors, does not significantly differ between the two MRL-lpr mice. However, serum levels of cryoglobulins, whose major component is IgG3, are markedly diminished in MRL-lpr.II mice with a parallel decrease in IgG3. Since MRL-lpr.II mice still carry the lpr mutation, as documented by the presence of defects in the Fas antigen, a possible new mutation in this substrain may play a significant role in the pathogenesis of lupus-like autoimmune syndrome.
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PMID:An MRL/MpJ-lpr/lpr substrain with a limited expansion of lpr double-negative T cells and a reduced autoimmune syndrome. 831 55

We have studied the ability of the lupus prone MRL lpr/lpr (MRL/lpr) and (NZBxNZW)F1 (NZB/W) female mice to raise granulocyte mediated inflammatory responses. These autoimmune strains, known to exhibit severe anergy as concerns T cell dependent immune function, are not well analysed with respect to neutrophil-mediated inflammatory responses. An in vivo model of granulocyte mediated inflammation has been developed in our laboratory. A single intradermal injection of olive oil into mouse footpad induces massive infiltration of polymorphonuclear cells (PMNC) within 24 h. This extravasation of PMNC gives rise to a localized footpad swelling, which can be easily and reproducibly measured and relates to severity of the inflammatory process. T cell independence of this inflammatory model was ascertained by in vivo T cell depletion using monoclonal antibodies to CD4 and CD8 molecules. Olive oil triggered inflammation was inducible in both young and aged lupus mice. The intensity of footpad swelling upon olive oil injection was similar in lupus mice and in healthy control strains. In contrast, aged MRL/lpr and NZB/W mice showed severely depressed T cell dependent inflammatory responses as assessed by delayed type hypersensitivity reaction to sheep red blood cells. We conclude that the PMNC mediated inflammatory potential is not affected in severely diseased lupus mice. The increased numbers of circulating PMNC together with intact PMNC function may explain why severely immune deficient lupus mice seldom show clinical signs of bacterial infection.
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PMID:Neutrophil mediated inflammatory response in murine lupus. 832 62

To further understand the contribution of I-A to the development of disease in murine lupus, we compared the incidence and/or titers of natural thymocytotoxic autoantibodies (NTAs), autoantibodies to red blood cells, gp70 immune complexes (gp70), antibodies to Sm, and rheumatoid factor in NZB (H-2d), NZB.H-2b and NZB.H-2bm12 mice. There were striking and significant differences among the three NZB strains in several of these parameters. NZB (H-2d) and NZB.H-2bm12 mice had a 100% incidence of NTA. In contrast, NZB.H-2b mice were found to have NTA in only 36% of animals at 8-10 months of age. Furthermore, the NTA titers of NZB.H-2bm12 mice were relatively low. There were also distinct differences between these strains with respect to the presence of antibodies to anti-erythrocytes (positive Coombs' test). NZB (H-2d) and NZB.H-2bm12 both had high titers of anti-erythrocyte autoantibodies (AEAs), whereas there was a delayed onset and lower titers in NZB.H-2b mice. Additionally, there was a dramatic increase in gp70 IC levels in NZB.H-2bm12 mice. In previous studies, NZB.H-2bm12 as well as NZB.H-2bm12 x NZB.H-2b F1 mice were found to produce high autoantibody titers to single-stranded (ss) and double-stranded (ds) DNA. Using unfractionated or fractionated splenic T cells (CD4+ CD8-, CD4- CD8+, or CD4-CD8-) from NZB.H-2b or NZB.H-2bm12 mice, we compared their relative abilities to cooperate with T-depleted splenocytes from NZB.H-2bm12 x NZB.H-2b F1 mice to produce antibodies to ss- and ds-DNA. Only T cells, including both CD4+ CD8- and CD4- CD8- populations, from NZB.H-2bm12 mice, were able to induce such autoantibody production among F1 splenocytes. Finally, marked alterations in splenic T cell subsets were found in NZB.H-2bm12 mice compared to NZB.H-2b mice, and to a lesser extent, in B6.C-H-2bm12 mice compared to C57BL/6 (H-2b) mice. These data further highlight the influence of I-A on autoimmunity and in particular the influence of the bm12 mutation on altering the natural history of disease expression in NZB mice.
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PMID:The contribution of I-Abm12 to phenotypic and functional alterations among T-cell subsets in NZB mice. 838 89


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