Autoimmunity and Autoinflammation: Relapsing Polychondritis and VEXAS Syndrome Challenge

Abstract

Relapsing polychondritis is a chronic autoimmune inflammatory condition characterized by recurrent episodes of inflammation at the level of cartilaginous structures and tissues rich in proteoglycans. The pathogenesis of the disease is complex and still incompletely elucidated. The data support the important role of a particular genetic predisposition, with HLA-DR4 being considered an allele that confers a major risk of disease occurrence. Environmental factors, mechanical, chemical or infectious, act as triggers in the development of clinical manifestations, causing the degradation of proteins and the release of cryptic cartilage antigens. Both humoral and cellular immunity play essential roles in the occurrence and perpetuation of autoimmunity and inflammation. Autoantibodies anti-type II, IX and XI collagens, anti-matrilin-1 and anti-COMPs (cartilage oligomeric matrix proteins) have been highlighted in increased titers, being correlated with disease activity and considered prognostic factors. Innate immunity cells, neutrophils, monocytes, macrophages, natural killer lymphocytes and eosinophils have been found in the perichondrium and cartilage, together with activated antigen-presenting cells, C3 deposits and immunoglobulins. Also, T cells play a decisive role in the pathogenesis of the disease, with relapsing polychondritis being considered a TH1-mediated condition. Thus, increased secretions of interferon γ, interleukin (IL)-12 and IL-2 have been highlighted. The "inflammatory storm" formed by a complex network of pro-inflammatory cytokines and chemokines actively modulates the recruitment and infiltration of various cells, with cartilage being a source of antigens. Along with RP, VEXAS syndrome, another systemic autoimmune disease with genetic determinism, has an etiopathogenesis that is still incompletely known, and it involves the activation of the innate immune system through different pathways and the appearance of the cytokine storm. The clinical manifestations of VEXAS syndrome include an inflammatory phenotype often similar to that of RP, which raises diagnostic problems. The management of RP and VEXAS syndrome includes common immunosuppressive therapies whose main goal is to control systemic inflammatory manifestations. The objective of this paper is to detail the main etiopathogenetic mechanisms of a rare disease, summarizing the latest data and presenting the distinct features of these mechanisms.

Keywords: VEXAS syndrome; anti-collagen antibodies; cartilage; inflammation; relapsing polychondritis.

Figure 1

Pathogenic mechanisms involved in the occurrence of inflammation and cartilage damage in RP.

Figure 2

The main autoantibodies in RP. COMP = cartilage oligomeric matrix protein, ANCA = antineutrophil cytoplasmic antibody, ANA = antinuclear antibody, RP = relapsing polychondritis.

Figure 3

The main cells and molecules with a pro-inflammatory role involved in the initiation of inflammation and cartilage destruction in RP. Th = T helper lymphocyte, IL = interleukin, INFγ = interferon γ, NKT = natural killer T cell, Treg = regulatory T cell, TREM-1 = triggering receptor expressed on myeloid cells-1, MMP = matrix metalloproteinase, VEGF = vascular endothelial growth factor, CCL4 = C-C motif ligand 4, MIF = macrophage migration inhibitory factor, ↑—increased secretion, ↓—decreased secretion.