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)

Systemic lupus erythematosus is characterized by B cell production of pathogenic autoantibodies dependent upon cooperation from CD4+ Th cells. The interaction between CD40 on B cells and CD40 ligand (CD40L) on Th cells is necessary for normal thymus-dependent Ab production. An anti-murine CD40L mAb blocks binding of CD40L to CD40 and prevents primary and secondary immune responses to thymus-dependent Ags. In this study, New Zealand Black x New Zealand White lupus-prone mice treated with this anti-CD40L Ab from ages 4 to 10 mo had reduced anti-DNA autoantibody production and renal disease and significantly prolonged survival compared with control mice. Pathologic examination verified the absence of significant renal damage or immune deposition in responding mice. Mice that responded to treatment did not develop an Ab response to the administered Ab. Long-term survivors mounted a substantial Ab response to keyhole limpet hemocyanin after completion of anti-CD40L Ab treatment, suggesting that some of the immunosuppressive effects of the Ab may be reversible. These results suggest a human form of this Ab may have therapeutic utility in human systemic lupus erythematosus.
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PMID:Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice. Response correlates with the absence of an anti-antibody response. 881 28

The role of costimulation was examined in an in vivo model of alloantigen-driven Th1 or Th2 cytokine responses, the parent-into-F1 model of acute or chronic graft-vs-host disease (GVHD), respectively. The soluble fusion protein, murine CTLA4Ig, which blocks engagement of CD28 by its natural ligand B7-1 and B7-2, was administered either early, at the time of GVHD induction, or delayed, after the establishment of Th1 or Th2 effector responses (day 7). Early administration of CTLA4Ig prevented the development of both acute and chronic GVHD by preventing the activation of donor T cells, i.e., by blocking characteristic Th1 or Th2 cytokine production and blocking memory marker up-regulation on donor T cells. Delayed CTLA4Ig administration was unable to alter acute GVHD but did reverse chronic GVHD as evidenced by normalization of serum autoantibody levels, normal host B cell numbers and MHC class II expression, reduced donor T cell expression of CD40 ligand, and reduced numbers of donor CD4+ memory T cells. The percentage of donor memory cells was not altered by delayed CTLA4Ig. We conclude that in this model, alloantigen-driven Th1 or Th2 responses are equally susceptible to costimulatory blockade at the onset of disease; however, once effector mechanisms become established, only Th2-driven responses have a requirement for further costimulation for the continued expansion of CD4+ T cells. These data suggest that humoral, lupus-like autoimmunity requires continuous T cell help for B cells, and agents that interrupt this process may be beneficial.
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PMID:Differential effect of CTLA4Ig on murine graft-versus-host disease (GVHD) development: CTLA4Ig prevents both acute and chronic GVHD development but reverses only chronic GVHD. 889 65

To explore the mechanisms by which alpha beta T cells and gamma delta T cells regulate systemic autoimmunity, lupus-prone mice were rendered deficient in CD40 ligand and/or alpha beta T cells by intercrossing CD40L -/- and TCR-alpha -/- knockouts, generating CD40L-intact or -deficient (CD40L+ or CD40L-), alpha beta T cell-intact or -deficient (alpha beta+ or alpha beta-) MRL-lpr/lpr animals. As expected, CD40L+ alpha beta+ mice developed high titer autoantibodies along with severe renal and cutaneous disease. CD40L+ alpha beta- animals developed lower levels of autoantibodies, accompanied by less severe or delayed renal and cutaneous disease. CD40L- alpha beta+ mice developed even lower titers of autoantibodies and less severe renal disease yet developed cutaneous lesions indistinguishable from those of CD40L+ alpha beta+ disease. Most surprisingly, CD40L- alpha beta- animals developed higher levels of some autoantibodies than did CD40L- alpha beta+ mice and developed renal disease similar in severity to CD40L+ alpha beta- counterparts; however, they failed to develop skin disease. Thus, disruption of CD40L and alpha beta T cells provides a novel dissection of the physiology and pathology of murine lupus; while these data confirm previous findings demonstrating a role for CD40L-dependent, alpha beta T cell-dependent mechanisms in autoantibody production and renal disease in murine lupus, they also: 1) establish that alpha beta T cells may drive autoimmune skin disease by a CD40L-independent mechanism; 2) identify a role for CD40L in non-alpha beta T cell-dependent autoantibody production and autoimmune skin disease; and 3) suggest a role for alpha beta T cells in the down-regulation of autoimmunity driven by other T cells. Thus, both alpha beta and non-alpha beta T cells, such as gamma delta T cells, regulate systemic autoimmunity by CD40L-dependent and -independent mechanisms.
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PMID:alpha beta T cell regulation and CD40 ligand dependence in murine systemic autoimmunity. 903 98

A major advance in understanding the basic mechanism driving the pathogenic autoimmune response in SLE has been the identification of nucleosome as a primary immunogen. The production of pathogenic antinuclear antibodies in SLE is mediated by a MHC class II restricted, cognate interaction between select populations of autoimmune T helper cells and autoimmune B cells that recognize epitopes in the different molecular components of the nucleosome particle: a form of intermolecular-intrastructural help. In the SNF1 model, we have localized the critical peptide autoepitopes for lupus nephritis-inducing Th cells in the core histones of nucleosomes, at amino acid positions 10-33 of H-2B and 16-39 and 71-94 of H4. Remarkabely, the nephritogenic epitopes are located in the regions of histones that are also targeted by lupus B cells, as well as the sites where the histones contact DNA in the nucleosome, indicating that they are specially protected during antigen processing. Identification of the peptide epitopes is a basic step toward defining how the pathogenic Th cells emerge in lupus. In addition, we found that the pathogenic Th cells and B cells of lupus have a regulatory defect in the expression of CD40 ligand (CD40L or gp39), which results in abnormal costimulatory signals that sustain the production of pathogenic autoantibodies. Specific immunotherapy that blocks the pathogenic T and B cell interaction in lupus can be designed based on the knowledge of these disease mechanisms.
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PMID:T cells of lupus and molecular targets for immunotherapy. 904 81

Studies reported during the past year have added new knowledge to our understanding of the pathogenesis of systemic lupus erythematosus. A study of sibpairs with lupus revealed a strong linkage of a region located at chromosome 1q41-42 that crossed ethnic barriers. B-cell receptor-initiated signaling events, such as tyrosine protein phosphorylation and intracellular calcium concentrations, were found to be increased in patients with lupus in a disease- and clinical activity-independent manner. T cells from patients with lupus express increased amounts of the CD40 ligand, which is functional because it helps B cells to produce anti-DNA antibodies and express more CD80 (B7-1) on their surface. Only occasionally do lupus patients display structural defects of either Fas antigen or ligand molecules, and although spontaneous apoptosis is increased in lupus cells (as well as in other systemic autoimmune disorders), the activation-induced T-cell death is defective.
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PMID:Lymphocytes, cytokines, inflammation, and immune trafficking. 930 92

Male BXSB mice, unlike female BXSB, develop a severe early onset lupus-like disease that has been linked to an intrinsic B cell defect. In investigating this B cell defect the present study showed that male, but not female, BXSB contained a higher percentage of large, activated splenic B cells that were more responsive to anti-CD40 mAb-induced proliferation. The hyperactivity of the large B cells from the male mice was also observed in the absence of anti-CD40 mAb or any other stimuli. In examining the mechanism of the B cell hyperactivity, it was found that 20% of unstimulated large B cells from male mice, unlike large B cells from female mice, expressed CD40 ligand (CD40L), a molecule normally expressed on activated CD4+ cells. The percentage of large B cells from the male BXSB that expressed CD40L was increased to 43% by stimulation with LPS. A functional role for CD40L expression on B cells was confirmed by showing that CD40-Ig blocked the spontaneous proliferation of the large B cells from male mice. In addition, the stimulatory capacity of the large B cells from the male mice was demonstrated by their ability to induce DNA synthesis in small B cells in a CD40L-dependent manner. These results demonstrated that large B cells from male BXSB expressed functionally active CD40L. It is likely that the B cell CD40L expression and increased susceptibility to CD40 signaling due to an intrinsic B cell hyperactivity promotes autoimmune disease in BXSB mice.
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PMID:CD40 ligand expressed on B cells in the BXSB mouse model of systemic lupus erythematosus. 937 59

Prior studies have demonstrated that treatment of young, prenephritic lupus-prone mice with Ab directed against CD40 ligand (CD40L) prolongs survival and decreases the incidence of severe nephritis. In this report, we show that for (SWR x NZB)F1 (SNF1) animals with established lupus nephritis, long-term treatment with anti-CD40L beginning at either 5.5 or 7 mo of age prolonged survival and decreased the incidence of severe nephritis. "Older" mice were chosen for these studies to more closely resemble the clinical presentation of patients with established renal disease. We show that age at the start of treatment, which typically correlates with severity of disease, is an important factor when determining an efficacious therapeutic protocol since animals that began treatment at 7 mo of age required a more aggressive treatment protocol than animals at 5.5 mo of age. Remarkably, several anti-CD40L-treated animals beginning treatment at age 5.5 mo demonstrated a decline in proteinuria, as opposed to increasing proteinuria levels seen in hamster IgG (HIg)-treated controls, and histologic examination of kidneys from anti-CD40L-treated mice revealed dramatically diminished inflammation, sclerosis/fibrosis, and vasculitis, in marked contrast to the massive inflammation and kidney destruction observed in control animals that received hamster IgG. Spleens from anti-CD40L-treated mice also exhibited markedly reduced inflammation and fibrosis compared with controls. Together, these results show that treatment of older, nephritic SNF1 animals with long-term anti-CD40L immunotherapy significantly prolongs survival, reduces the severity of nephritis, and diminishes associated inflammation, vasculitis, and fibrosis.
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PMID:Anti-CD40 ligand antibody treatment of SNF1 mice with established nephritis: preservation of kidney function. 949 53

Systemic lupus erythematosus (SLE) is characterized by autoantibody production of unknown origin. Since T-B cell interaction is a key event to produce antibodies, we investigated this interaction through study of CD69, CD40 ligand (CD40L) and CD23 expression (three very early activation antigens). Peripheral blood mononuclear cells (PBMC) from inactive lupus patients were studied following culture with either medium alone, anti-CD3 monoclonal antibody (mAb), recombinant interleukin-4 (rIL-4) or phorbol myristate acetate (PMA)+/-ionomycin. Analysis of CD23 expression on lupus B cells in basal conditions and after anti-CD3 challenge of PBMC, a reflection of cognate interaction between T and B cells, was clearly defective. Conversely, CD23 expression on lupus B cells following non-cognate T cell signals (rIL-4) was preserved. CD69 and CD40L expression was also impaired in lupus T cells following anti-CD3 challenge. Nonetheless, activation by means of PMA and/or ionomycin was preserved both in T cells (CD69 and CD40L expression) and in B cells (CD23 expression). These results indicate that B cells from inactive lupus patients display a normal early response to direct B-cell stimuli. Conversely, T-dependent B-cell stimuli are clearly defective in SLE patients in remission. These results indicate that T-B cognate interaction related to defective T cell activation located between surface membrane and protein kinase C (PKC)/ionomycin function is an intrinsic characteristic of these patients.
Lupus 1998
PMID:Defective early T and T-dependent B cell activation in systemic lupus erythematosus. 969 35

Abnormalities in the regulation of both cell-mediated and humoral immunity have been implicated in the pathophysiology of systemic lupus erythematosus (SLE). Cognate contact-dependent T-B cell interactions involving CD154 (CD40 ligand) on activated T cells and CD40 on B lymphocytes have a critical role in antibody production. Abnormal CD154 expression on lymphocytes may play a role in the production of potentially pathogenic autoantibodies and defects in self-tolerance mechanisms may be important. Failure of intrathymic or peripheral deletion of autoreactive T cells may also result in an autoimmune phenotype. Elevated levels of CD3(+)CD4(-)/8(-) (double negative) T cells (DNT) in the peripheral blood are a surrogate marker for defects of this type. The expression of CD154 on T and B cells was evaluated and levels of double negative T cells in the peripheral blood were assessed by two and three colour flow cytometric analyses. We studied peripheral blood lymphocytes in 48 patients with SLE. Twenty-five normal subjects and 12 patients with rheumatoid arthritis (RA) were studied as disease controls. T cells in 22/48 (45%) lupus patients expressed CD154 between 20-80% (median=52%). In normal controls and RA patients 8-18% T cells were CD154(+). Twelve patients (30%) had elevated expression of CD154 (20-50%) on B cells. In the control RA patients, less than 15% T cells were CD154(+). Twelve of 48 SLE patients had elevated numbers of DNT cells (18-27%). The control subjects had DNT cell numbers <10. These observations suggest that defects in either the intrathymic or peripheral deletion of potentially pathogenic T lymphocytes may play a role in the pathogenesis of SLE. The high expression of CD154 on both T and B cells may also be important in mediating the production of potentially harmful autoantibodies.
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PMID:Peripheral blood lymphocytes in SLE--hyperexpression of CD154 on T and B lymphocytes and increased number of double negative T cells. 980 31

A select population of autoimmune T-helper (T(H)) cells drive the production of pathogenic anti-DNA autoantibodies in SLE. These T(H) cells recognize nucleosomal peptides that are processed and presented by the anti-DNA B cells that they help. The critical peptide epitopes for the T(H) cells reside in the core histones of the nucleosome particle. Remarkably, the nucleosomal peptide epitopes do not obey the rule of MHC-restriction; they can be promiscuously presented and recognized in the context of diverse MHC alleles. Such promiscuous antigens, called pantigens, are also recognized by autoimmune T cells, in a degenerate fashion, and this promiscuous recognition is conferred by the lupus TCR alpha chains. High-affinity interactions between the lupus TCRs and MHC-nucleosomal peptide complex due to reciprocally charged residues probably overcome the requirement for MHC restriction. These studies open up the possibility of developing 'universally' tolerogenic epitopes for therapy of lupus in humans despite their diversity of HLA alleles. The results also have profound implications regarding the selection of autoimmune T cells in the lupus-prone thymus and their expansion in the periphery. Furthermore, the T(H) cells, as well as B cells of lupus, have a regulatory defect causing markedly increased and prolonged expression of CD40 ligand (CD40L), which mediates abnormal co-stimulatory signals to autoimmune B cells, sustaining the production of pathogenic autoantibodies. These observations suggest a new paradigm for B cell hyperactivity in lupus and provide alternative targets for immunotherapy. Indeed, giving only three injections of anti-CD40L antibody in a one-week period to mice with manifest lupus selectively blocks the pathogenic autoimmune response and delays the development of lupus nephritis by one year (equivalent to three decades in humans). Thus, possession of promiscuous, high-affinity receptors and prolonged expression of CD40L by lupus T cells probably lowers activation threshold, leading to an autoimmune response against nucleosomes derived from apoptotic cells that are normally ignored by the immune system.
Lupus 1998
PMID:Production of pathogenic antibodies: cognate interactions between autoimmune T and B cells. 988 95


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