HLA-Association Drives Cytokine Shifts in Two Autoimmune Skin Diseases: Pemphigus Vulgaris and Alopecia Areata

Summary: Background: Autoimmune diseases (AID) are defined by immune dysregulation characterized by specific humoral and/or cell mediated responses directed against the body's own tissues. Cytokines in particular play a pivotal role in the pathogenesis of AID, with pro-inflammatory cytokines contributing to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate regression of inflammation and recovery from acute phases of the disease. Methods: Parallel work in our group evaluated a comprehensive set of pro- and anti-inflammatory serum cytokines in 130 Pemphigus Vulgaris (PV) as well as 64 Alopecia Areata (AA) patients via Luminex Cytokine Assay and ELISAs respectively. Results: We uncovered a similar pattern of inheritance specific immune dysregulation in these two distinct autoimmune skin diseases. In AA, we found healthy control subjects who are blood related to AA patients exhibit the same cytokine dysregulation in Th1 and Th17 pathways as do patients with AA. In PV, patients as well as individuals who are healthy but carry specific PV-associated HLA alleles (HLA-matched controls) demonstrate cytokine upregulations similar to each other, but distinct from healthy controls who do not express these alleles. More specifically, HLA-matched controls and PV patients share immunological activation of pro-inflammatory cytokines IL-1a, IL-1b, IL-6, and TNF-a, Th17 cytokines IL-21 and IL-23, the Th2 cytokine IL-13, and the chemokine IL-8. Conclusions: In both AA and PV, we see cytokine profiles that are linked to genetic background. Our data underscore the known tendency of AID to cluster in families and support the notion of the shared genetic/ common cause hypothesis across multiple AID. The presence of disease promoting pathways in not only patients, but also genetically related, but healthy control individuals evokes the further hypothesis that there may be coexisting disease counteracting immune protective mechanisms at play in thwarting the threat of disease in genetically predisposed individuals who remain healthy.