Human Leukocyte Antigen-Class I Alleles and the Autoreactive T Cell Response in Psoriasis Pathogenesis

Abstract

Psoriasis is a complex immune-mediated inflammatory skin disease characterized by T-cell-driven epidermal hyperplasia. It occurs on a strong genetic predisposition. The human leukocyte antigen (HLA)-class I allele HLA-C*06:02 on psoriasis susceptibility locus 1 (PSORS1 on 6p21.3) is the main psoriasis risk gene. Other HLA-class I alleles encoding HLA molecules presenting overlapping peptide repertoires show associations with psoriasis as well. Outside the major histocompatibility complex region, genome-wide association studies identified more than 60 psoriasis-associated common gene variants exerting only modest individual effects. They mainly refer to innate immune activation and the interleukin-23/Th/c17 pathway. Given their strong risk association, explaining the role of the HLA-risk alleles is essential for elucidating psoriasis pathogenesis. Psoriasis lesions develop upon epidermal infiltration, activation, and expansion of CD8+ T cells. The unbiased analysis of a paradigmatic Vα3S1/Vβ13S1-T-cell receptor from a pathogenic epidermal CD8+ T-cell clone of an HLA-C*06:02+ psoriasis patient had revealed that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation, and it identified a peptide form ADAMTS-like protein 5 as an HLA-C*06:02-presented melanocyte autoantigen. These data demonstrate that psoriasis is an autoimmune disease, where the predisposing HLA-class I alleles promote organ-specific inflammation through facilitating a T-cell response against a particular skin-specific cell population. This review discusses the role of HLA-class I alleles in the pathogenic psoriatic T-cell immune response. It concludes that as a principle of T-cell driven HLA-associated inflammatory diseases proinflammatory traits promote autoimmunity in the context of certain HLA molecules that present particular autoantigens.

Imiquimod-Induced Psoriasis in Mice Depends on the IL-17 Signaling of Keratinocytes

“…What exactly triggers the inflammation in the skin of psoriasis patients is not clear. One possibility is that T cells recognize an autoantigen in the skin, and after their activation, they secrete key cytokines such as IL-17A, IL-22, and TNFa (Prinz, 2018). These cytokines trigger the local cells, such as the KCs, leading to the production of chemokines that initiate neutrophil infiltrations to the skin.…”

Psoriasis Pathogenesis: Keratinocytes Are Back in the Spotlight

“…Early danger signals induce T helper type 17 (or ILC3) differentiation. These cells migrate into skin, recognize autoantigens that are presented by distinct major histocompatibility complex class I molecules (Prinz, 2018), and secrete IL-17A/F, IL-21, and IL-22. Keratinocytes respond to IL-17 homo-or heterodimers via a dimeric receptor that includes IL-17RA (Eyerich et al, 2017).…”

Risk of acute infections in psoriatic patients during biologic therapies is linked to gender

“…3 Psoriatic patients carrying the HLA-C*06:02 allele have improved response to ustekinumab compared to those without, 4-6 and aside from HLA-C*06:02, psoriasis is associated with HLA-C*12:03, HLA-C*07:01, HLA-C*07:02 and HLA-C*07:04. 7 Here, we have used high-resolution HLA typing to evaluate the role of HLA-C antigen variants on effectiveness and drug survival of ustekinumab in patients with moderate-severe psoriasis over 2 years.…”

“…6 Further studies have reported that low-dose bexarotene can be effective either as monotherapy or as combination treatment. 2,6,7 The Cutaneous Lymphoma Italian Study Group (CLISG) investigated the efficacy of low-dose bexarotene as adjuvant therapy. 7 Despite its heterogeneous population consisting of MF/SS and peripheral T-cell lymphoma patients, the overall response rate was 75% and median progression-free survival was 25 months.…”

“…2,6,7 The Cutaneous Lymphoma Italian Study Group (CLISG) investigated the efficacy of low-dose bexarotene as adjuvant therapy. 7 Despite its heterogeneous population consisting of MF/SS and peripheral T-cell lymphoma patients, the overall response rate was 75% and median progression-free survival was 25 months. The aim of the present study was to assess whether low-dose bexarotene as maintenance treatment could increase the time to next treatment (TTNT) in advanced MF/SS patients, after a first course of non-skin-directed treatment (Data S1 and are shown in Table 1).…”