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 several loci associated with disease susceptibility. Much work remains to integrate these loci into the functional pathogenic pathways that characterize the disease. Our working hypothesis is that many genetic variations linked to SLE and autoimmunity mediate the risk of disease by altering cytokine profiles or responses to cytokine signaling. Genetic polymorphisms that affect cytokine signaling could alter thresholds for immune responses, resulting in proinflammatory 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 genotype-cytokine-phenotype relationships will increase our understanding of both initial disease pathogenesis as well as subsequent response/nonresponse 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.

Figure 1

Diagram of mean serum IFN-α at different ages in female and male SLE patients, healthy family members, and unrelated healthy controls. Y-axis represents relative serum IFN-α levels measured as a functional activity, and X-axis shows age in years of the subject at the time of donation of the serum sample.

Figure 2

Schematic diagram illustrating proposed functional locations of SLE-risk loci described and their proposed influence upon cytokine production and responses in SLE. Nucleic acid immune complexes can activate endosomal Toll-like receptors, and downstream signaling via the MyD88 adaptor leads to IFN-α production. This TLR/MyD88 signaling could be augmented by increases in OPN, as determined by OPN risk genotype. TNF-α can inhibit IFN-α production in dendritic cells, and PTPN22 alleles could influence IFN-α production via modulation of TNF-α production or TNF-α responses in macrophages or dendritic cells. After IFN-α has been produced, the STAT4 autoimmune disease risk allele results in increased sensitivity and downstream signaling following type I IFN receptor ligation.

Figure 3

Diagram of serum IFN-α and TNF-α when measured simultaneously in SLE serum showing an overall inverse correlation between the two cytokine levels and the typical location of PTPN22 risk allele carriers within this continuum.