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)

It is generally accepted that the interaction between CD40 and its ligand (CD154) plays a decisive role in contact-dependent help for T and B cells. In CD154-deficient MRL/Mp-Fas(lpr) (MRL/lpr) mice, however, high titres of IgG2a-type autoantibodies against small nuclear ribonucleoproteins (snRNPs) are observed. We successfully isolated two CD154-deficient MRL/lpr Th1 lines, which could provide B cell help for anti-snRNP antibody production. The proliferative responses of the Th1 cell lines were MHC class II (I-Ek)-restricted. Although syngeneic B cell proliferation was induced by Th1 lines in both a contact-dependent and -independent manner, the soluble form of TNF-alpha (sTNF-alpha) was not involved in contact-independent B cell proliferation. On the other hand, both anti-TNF-alpha and TNF-receptor 2 (TNF-R2, p75) monoclonal antibody (MoAb) blocked contact-dependent B cell proliferation, suggesting that the transmembrane form of TNF-alpha (mTNF-alpha)-TNF-R2 co-stimulation participates in B cell activation. Similarly, anti-TNF-alpha and TNF-R2 MoAb inhibited anti-snRNP antibody production in vitro, but anti-CD154 or TNF-R1 MoAb did not. These results indicate that the interaction of mTNF-alpha on activated Th1 cells with TNF-R2 on B cells may be involved in the autoimmunity seen in MRL mice, and that the blockade of CD40-CD154 co-stimulation may not always be able to suppress some Th1-related manifestations of lupus.
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PMID:The transmembrane form of TNF-alpha drives autoantibody production in the absence of CD154: studies using MRL/Mp-Fas(lpr) mice. 1239 Mar 9

Monocytes/macrophages activated by Th1 stimulation such as interferon-gamma (IFN-gamma) and CD40 ligand (CD40L) infiltrate the kidney and play a critical role in the progression of lupus nephritis (LN). We examined the monocyte response to Th1 stimulation and their effector function toward activating renal resident cells in patients with LN. Following stimulation with IFN-gamma granulocyte macrophage-colony stimulating factor (GM-CSF)/recombinant CD40L the production of tumor necrosis factor-alpha and IL-12 p70 by PBMC was significantly higher in LN patients. In coculture experiments employing activated monocytes and human mesangial cells, there was a trend toward higher monocyte chemoattractant protein-1 production by lupus monocytes compared to normal controls. Basal expression of CD40, ICAM-1, and STAT-1 was significantly higher in monocytes from LN patients, suggesting ongoing activation. Monocyte response to IFN-gamma, as accessed by intercellular adhesion molecule-1 upregulation and phosphorylation of STAT-1, was comparable between the two groups. Thus, in contrast to earlier reports, Th1-dependent monocyte activation is not impaired. In this disease activated monocytes appear to be fully capable of inducing renal injury.
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PMID:Monocyte response to Th1 stimulation and effector function toward human mesangial cells are not impaired in patients with lupus nephritis. 1258 53

Long-lived humoral immune responses are a hallmark of thymus-dependent immunity. The cellular basis for enduring antibody-mediated immunity is long-lived memory B cells and plasma cells (PCs). Both of these cell populations acquire longevity as a result of antigen-specific, CD40-dependent, cognate interactions with helper T cells within germinal centers (GCs). At the molecular level, defined functional domains of CD40 control the post-GC fate of B cells. PC precursors that emerge from these GC reactions are highly proliferative and terminally differentiate to end-stage cells within the bone marrow (BM). The striking phenotypic similarities between the PC precursors and the putative malignant cell in multiple myeloma (MM) suggests that MM may result from the transformation of PC precursors. Within the domain of autoimmune disease, recent studies have shown that dysregulated migration of PCs to the BM may impact immune homeostasis and the development of lupus. Understanding the processes of normal PC differentiation will provide strategic insights into identifying therapeutic targets for the treatment of differentiated B-cell disorders.
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PMID:The rise and fall of long-lived humoral immunity: terminal differentiation of plasma cells in health and disease. 1284 8

The autoimmune response is executed via cognate interactions between effector immune cells and antigen presenting cells. Cognate interactions provide the immune effectors with specific signals generated through the antigen receptor as well as with second, non-specific signals, generated from the interaction of pairs of cell-surface molecules (costimulatory molecules) present on their plasma membrane. Disruption of this second, non-specific costimulatory signal results in the interruption of the productive (auto)immune response, leading to anergy, a state of immune unresponsiveness. The CD28:B7 families of molecules and the CD40:CD40L pair of molecules are considered as critical costimulatory elements. Disruption of the CD28:B7 interaction using a genetically engineered soluble form of the inhibitory molecule CTLA4 in vitro, as well as in experimental models of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), led to the inhibition of the autoimmune response. Similarly, promising data stem from the use of an anti-CD40L monoclonal antibody (mAb) in murine SLE. While such treatments prevent the development of autoimmunity in animal models, this preventive approach is inapplicable to human diseases. However, the rational bench-to-bedside approach led investigators to clinical trials of CTLA4-Ig and of two different humanized anti-human CD40L mAbs in patients with RA and SLE, respectively. Initial experience with the use of CTLA4-Ig in patients with RA is encouraging, since in one short-term trial the construct was well-tolerated and produced clinically meaningful improvement of the disease in a significant proportion of those treated. Surprisingly, the anti-CD40L mAb treatment approach in human lupus was not fruitful, since short-term administration of the anti-CD40L mAb ruplizumab in lupus nephritis was correlated with life-threatening prothrombotic activity despite initial encouraging data in the serology and renal function of the patients. Also, IDEC-131 anti-CD40L mAb treatment did not prove to be clinically effective in human SLE, despite being well tolerated. Precise tailoring of the administration schemes for these novel therapeutic modalities is awaited.Finally, conceptually different approaches to block costimulation by inhibiting the induced expression of costimulatory molecules or the transmission of their specific intracytoplasmic signal have already produced encouraging preliminary results.
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PMID:Costimulation blockade in the treatment of rheumatic diseases. 1504 25

CD40 ligand (CD40L, also known as CD154 or gp39) is a member of the tumor necrosis superfamily of transmembrane proteins. The interaction of CD40L on activated T cells with its receptor, CD40 on B cells, is necessary for normal immune function, including B cell differentiation, germinal center formation, and antibody isotype switching. Abnormal expression of CD40L in patients with systemic lupus erythematosus (SLE) may contribute to autoantibody production and disease pathogenesis. Although murine models of monoclonal antibodies directed against CD40L initially showed promise, human trials either have failed to demonstrate efficacy or have been associated with adverse events. This review will summarize in vitro and murine model data and human clinical trials involving anti-CD40L monoclonal antibody.
Lupus 2004
PMID:The role of CD40 ligand in systemic lupus erythematosus. 1523 Feb 96

The CD40-CD40L system has pleiotropic effects in a variety of cells and biological processes including immune response, thrombosis and atherogenesis. Within the immune system, these molecules represent a critical link between its humoral and cellular arms. As a result of these attributes and based on preclinical data in animals, anti-CD40L antibodies were tested in a variety of immunologic diseases including idiopathic thrombocytopenic purpura, psoriasis, Crohn's disease, systemic lupus erythematosus and transplantation. Phase I/II studies in humans with lupus nephritis demonstrated reduction of anti-double-stranded DNA (anti-dsDNA) antibodies but not of protective antibodies. Reduction of anti-DNA was associated with increased serum complement levels and reduced glomerular inflammation. As a result of thrombotic effects, observed even in patients negative for anti-cardiolipin antibodies, there is a temporary halt on further human studies. The reasons for the prothrombotic effects are not clear at present but may represent effects on platelets and/or the endothelium. In view of the significant immunomodulatory effects of anti-CD40L treatment in patients with lupus nephritis, the increasing realization of the importance of premature atherosclerosis in lupus and an increasing amount of data supporting a role for the CD40-CD40L interactions in this process, inhibition of this pathway deserves further exploration in lupus.
Lupus 2004
PMID:Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. 1523 Feb 98

Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligand (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L-/- mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.
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PMID:Costimulation requirements of induced murine systemic autoimmune disease. 1549 42

Inflammation and tissue damage in systemic lupus erythematosus (SLE) are mediated by class-switched autoantibodies reactive with nucleic acids, nucleic acid-binding proteins, phospholipids and other self-antigens. While some healthy individuals produce IgM antibodies with specificities similar to those of lupus patients, immunoglobulin class switching to mature downstream isotypes appears to be required for the generation of pathogenic autoantibodies. To characterize the cellular and molecular basis of pathogenic autoantibody production in SLE, we studied the capacity of peripheral blood B cells of naive phenotype from patients with SLE, rheumatoid arthritis (RA) or healthy control subjects to spontaneously switch to IgG and IgA. In addition, we determined the DNA sequences of the upstream evolutionary conserved sequence (ECS)-Igamma promoter regulatory regions that control germline IH-CH transcription and class switch DNA recombination (CSR) to IgG1, IgG2 and IgG4. IgM+IgD+ B cells from patients with SLE, but not those from RA or healthy control subjects, underwent spontaneous CSR, as assessed by expression of germline Igamma1-Cgamma1, Igamma2-Cgamma2, Igamma3-Cgamma3, Igamma4-Cgamma4 and Ialpha1-Calpha1 transcripts, mature (switched) VHDJH-Cgamma1, VHDJH-Cgamma2, VHDJH-Cgamma3 and VHDJH-Calpha1 transcripts and secreted IgG and IgA. Although polymorphic DNA sequences were identified in the ECS-Igamma1, ECS-Igamma2 and ECS-Igamma4 promoter regions, the transcription factor-binding sites that mediate germline Igamma-Cgamma transcription were conserved in patients and controls. However, distinct patterns of nuclear protein binding to an ECS-Igamma promoter sequence that contains both positive and negative regulatory elements were observed in SLE patients and controls. These results support a role for exogenous signals, such as through CD40 ligation, rather than altered genomic sequence, in the increased production of class switched autoantibodies in SLE.
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PMID:Ongoing immunoglobulin class switch DNA recombination in lupus B cells: analysis of switch regulatory regions. 1562 69

Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin-IgG complexes activate autoreactive B cells by co-engaging B-cell receptor (BCR) and TLR-9, thus suggesting a role for innate signaling in systemic autoimmunity. Spleen cells from lupus prone Palmerston North (PN) mice produce several fold less IL-12p40 than controls in response to CpG-oligodeoxynucleotides (ODNs). Here we show that B cells are primarily responsible for this abnormality. The removal of B cells from PN cultures markedly increased IL-12p40. Moreover, the addition of purified B cells back to PN splenocyte cultures resulted in a B-cell number dependent/ IL-10-mediated suppression of IL-12p40. The B cells were the major source of IL-10. In response to CpG, B cells from several lupus strains produced twice as a much IL-10 as controls, but failed to produce IL-10 when stimulated through BCR or CD40. PN and control mice expressed IL-10R similarly, and the difference in IL-10 secretion remained when anti-IL-10R blocking antibodies were used. IFN-gamma and IL-4 regulated CpG-induced IL-10 secretion in opposite directions. The abnormal IL-10 response in lupus mice was derived from B cells with the marginal zone phenotype, and could be downregulated with inhibitory ODNs. We hypothesize that TLR-9 activated lupus B cells can modulate T-cell mediated inflammatory responses through IL-10 production. Therefore, B cells may contribute to the lupus pathogenesis in many different ways: as antigen-presenting cells for self antigens, as effector cells for autoantibody production, and as IL-10 secreting regulatory cells.
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PMID:TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production. 1574 55

Sle3 is an NZM2410-derived lupus susceptibility locus on murine chromosome 7. Congenic recombination has resulted in a novel mouse strain, B6.Sle3, associated with serum antinuclear autoantibodies (ANAs), T cell hyperactivity, and elevated CD4/CD8 ratios. An OVA-specific TCR transgene was used as a tool to demonstrate that Sle3 facilitated heightened T cell expansion in vitro, and in vivo, following antigen challenge. Indeed, continued T cell expansion was noted even in response to a tolerogenic signal. However, these phenotypes did not appear to be T cell intrinsic but were dictated by hyperstimulatory B6.Sle3 APCs. Importantly, B6.Sle3-derived DCs and macrophages appeared to be significantly more mature/activated, less apoptotic, and more proinflammatory and were better at costimulating T cells in vitro, compared with the B6 counterparts. Finally, the adoptive transfer of B6.Sle3-derived DCs into healthy B6 recipients elicited increased CD4/CD8 ratios and serum ANAs, 2 cardinal Sle3-associated phenotypes. We posit that their heightened expression of various costimulatory molecules, including CD80, CD106, I-A, and CD40, and their elevated production of various cytokines, including IL-12 and IL-1beta, may explain why Sle3-bearing DCs may be superior at breaching self tolerance. These studies provide mechanistic evidence indicating that intrinsic abnormalities in DCs and possibly other myeloid cells may dictate several of the phenotypes associated with systemic lupus, including ANA formation and T cell hyperactivity.
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PMID:T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells. 1595 39


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