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)

Activation-induced deaminase (AID) is a prerequisite for immunoglobulin (Ig) class-switch recombination and somatic hypermutation, which is critical for antibody affinity maturation. IgM and IgG autoantibodies are characteristic of the systemic autoimmune disorders such as lupus. However, the relative contributions of hypermutated high-affinity IgG antibodies and germline-encoded IgM antibodies to systemic autoimmunity are not defined fully. The role of AID in autoimmunity is unclear. The current study used AID-deficient mice to investigate the role of AID in the development and pathogenesis of murine lupus. C57BL/6 mice deficient in both Fas and AID were generated. Compared to their AID-competent littermates, AID(-/-) lymphoproliferative (lpr) mice produced significantly elevated levels of IgM autoreactive antibodies with enhanced germinal centre (GC) response, developed more advanced splenomegaly and exhibited more severe glomerulonephritis. Thus, AID may play an important role in the negative regulation of systemic autoimmune manifestations in murine lupus. The results also indicate that hypermutated high-affinity IgG antibodies are not necessary for the development of autoimmune syndrome in lpr mice on a C57BL/6 background.
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PMID:Deficiency in activation-induced cytidine deaminase promotes systemic autoimmunity in lpr mice on a C57BL/6 background. 1992 98

Systemic lupus erythematosus (SLE) is an autoimmune disease posing threats to multiple organs in the human body. As a typical manifestation of SLE, lupus nephritis is characterized by a series of pathological changes in glomerulus as well as accumulation of pathogenic autoreactive IgG with complement in the kidney that dramatically disrupts renal functions. Activation-induced deaminase (AID), which governs both somatic hypermutation (SHM) and class-switch recombination (CSR), has been shown to be essential for the regulation of SLE. However, the relative contributions of SHM and CSR to SLE pathology have not been determined. Based on the available AIDG23S mice, we successfully established an AIDG23S MRL/lpr mouse model, in which SHM is specifically abolished, although CSR is largely unaffected. We found that the abrogation of SHM effectively alleviated SLE-associated histopathological alterations, such as expansion of the mesangial matrix and thickening of the basement membrane of Bowman's capsule as well as infiltration of inflammatory cells. Compared with SLE mice, AIDG23S MRL/lpr mice exhibited decreased proteinuria, blood urea nitrogen, and creatinine, indicating that the loss of SHM contributed to the recovery of renal functions. As a consequence, the life span of those SHM-deficient MRL/lpr mice was extended. Together, we provide direct evidence pinpointing a vital role of SHM in the control of SLE development.
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PMID:Abrogation of Lupus Nephritis in Somatic Hypermutation-Deficient MRL/lpr Mice. 3091 43