Genetic regulation of serum cytokines in systemic lupus erythematosus

Abstract

Genetic association studies in systemic lupus erythematosus (SLE) have been extremely successful in recent years, identifying a number of loci associated with disease susceptibility. Much work remains to integrate these loci into the functional pathogenic pathways which characterize the disease. Our working hypothesis is that many of the genetic variations linked to SLE and autoimmunity mediate risk of disease by altering cytokine profiles or responses to cytokine signaling. Genetic polymorphisms affecting cytokine signaling could alter thresholds for immune responses, resulting in pro-inflammatory presentation of self antigens and the subsequent misdirection of adaptive immunity against self which is observed in autoimmune disease. SLE is clinically heterogeneous and genetically complex, and we expect that individual genes and cytokine patterns will be more or less important to different disease manifestations and subgroups of patients. Defining these genotypecytokine-phenotype relationships will increase our understanding of both initial disease pathogenesis as well as subsequent response/non-response to various therapies. In this review we summarize some recent work in the area of SLE cytokine genetics, and describe the implications for SLE, autoimmunity, and immune system homeostasis which are revealed by these investigations.

Interleukin-10 receptor expression and signalling were down-regulated in CD4+ T cells of lupus nephritis patients

“…SLE is clinically heterogeneous, and individual cytokine patterns will be more or less important to different disease manifestations and subtypes of patients [24]. In this study we investigated the expression and signalling of IL-10R1 in SLE patients to elucidate the role of the IL-10 signalling pathway in the pathogenesis of SLE.…”

Activation of the type I interferon pathway in primary Sjogren’s syndrome

“…TLR7 duplication in the Yaa locus in the Y chromosome of BXSB lupus mice is associated with more severe disease activity, providing a clue for the male predominance of this animal model. Of interest, polymorphisms in a number of genes involved in the type I IFN pathway have been correlated with levels of type I activity in lupus patients (reviewed in [6,52,53]). …”

Familial Aggregation of Autoimmune Disease in Juvenile Dermatomyositis

“…14,38 We present an important corollary to these data, demonstrating that a family history of SLE is associated with higher serum IFN-␣ in newly diagnosed JDM patients. These data support the idea that increased IFN-␣ signaling is important in the initiation of multiple autoimmune diseases, including JDM, and some shared genetic risk factors in this pathway would be expected.…”