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

Effective humoral responses to protein antigens require the precise execution of carefully timed differentiation programs in both T and B cell compartments. Disturbances in this process underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Interferon regulatory factor 4 (IRF4) is induced upon the activation of T and B cells and serves critical functions. In CD4(+) T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch recombination and plasma cell differentiation. IRF4 function in T helper cells can be modulated by its interaction with regulatory protein DEF6, a molecule that shares a high degree of homology with only one other protein, SWAP-70. Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4(+) T cell IL-21 production and increased IL-21 B cell responsiveness. We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner. Collectively, these data provide novel insights into the mechanisms that normally couple and coordinately regulate T and B cell responses to ensure tight control of productive T-B cell interactions.
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PMID:Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity. 2237 Jul 18

Interferon Regulatory Factors (IRFs) play fundamental roles in dendritic cell (DC) differentiation and function. In particular, IRFs are critical transducers of TLR signaling and dysregulation in this family of factors is associated with the development of autoimmune disorders such as Systemic Lupus Erythematosus (SLE). While several IRFs are expressed in DCs their relative contribution to the aberrant phenotypic and functional characteristics that DCs acquire in autoimmune disease has not been fully delineated. Mice deficient in both DEF6 and SWAP-70 (= Double-knock-out or DKO mice), two members of a unique family of molecules that restrain IRF4 function, spontaneously develop a lupus-like disease. Although autoimmunity in DKO mice is accompanied by dysregulated IRF4 activity in both T and B cells, SWAP-70 is also known to regulate multiple aspects of DC biology leading us to directly evaluate DC development and function in these mice. By monitoring Blimp1 expression and IL-10 competency in DKO mice we demonstrate that DCs in these mice exhibit dysregulated IL-10 production, which is accompanied by aberrant Blimp1 expression in the spleen but not in the peripheral lymph nodes. We furthermore show that DCs from these mice are hyper-responsive to multiple TLR ligands and that IRF4 plays a differential role in in these responses by being required for the TLR4-mediated but not the TLR9-mediated upregulation of IL-10 expression. Thus, DC dysfunction in lupus-prone mice relies on both IRF4-dependent and IRF4-independent pathways.
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PMID:IRF4-Dependent and IRF4-Independent Pathways Contribute to DC Dysfunction in Lupus. 2654 14

Recent studies have revealed the existence of a T-bet dependent subset of B cells, which expresses unique phenotypic and functional characteristics including high levels of CD11c and CD11b. In the murine system this B cell subset has been termed Age/autoimmune-associated B cells (ABCs) since it expands with age in non-autoimmune mice and it prematurely accumulates in autoimmune-prone strains. The molecular mechanisms that promote the expansion and function of ABCs are largely unknown. This review will focus on the SWEF proteins, a small family of Rho GEFs comprised of SWAP-70 and its homolog DEF6, a newly identified risk variant for human SLE. We will first provide an overview of the SWEF proteins and then discuss the complex array of biological processes that they control and the autoimmune phenotypes that spontaneously develop in their absence, highlighting the emerging involvement of these proteins in regulating ABCs. A better understanding of the pathways controlled by the SWEF proteins could help provide new insights into the mechanisms responsible for the expansion of ABCs in autoimmunity and potentially guide the design of novel therapeutic approaches.
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PMID:Regulation of systemic autoimmunity and CD11c+ Tbet+ B cells by SWEF proteins. 2878 Sep 65

Age-associated B cells (ABCs) are a subset of B cells dependent on the transcription factor T-bet that accumulate prematurely in autoimmune settings. The pathways that regulate ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that control both cytoskeletal dynamics and the activity of the transcription factor IRF4. Notably, DEF6 is a newly identified human risk variant for systemic lupus erythematosus. Here we found that the lupus syndrome that developed in SWEF-deficient mice was accompanied by the accumulation of ABCs that produced autoantibodies after stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment for motifs bound by transcription factors of the IRF and AP-1 families and the transcription factor T-bet. Enhanced ABC formation in SWEF-deficient mice was controlled by the cytokine IL-21 and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated activity of IRF5 in response to stimulation with IL-21. These studies thus elucidate a previously unknown signaling pathway that controls ABCs in autoimmunity.
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PMID:Regulation of age-associated B cells by IRF5 in systemic autoimmunity. 2956 29