Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

Abstract

Complement inhibition has been identified as a potential therapeutic target for multiple inflammatory disorders including Hidradenitis Suppurativa (HS). It is currently unclear how complement integrates into our current model of molecular pathogenesis in HS and whether it represents a central component of pathogenesis, or a neutrophil-associated bystander. Levels of C5a in serum and tissue correlate with disease activity and degree of neutrophilic infiltrates in HS. C5a has been associated with Th17 immune axis activation in psoriasis, rheumatoid arthritis and Crohn's disease with strong similarities to TH17 activation in HS. Porphyromonas species (which are identified in the HS microbiome) are able to cleave inactive C5 into C5a implicating the cutaneous microbiome as an activator of complement. C3a and C5a are associated with activation of the NLRP3 inflammasome, implicated in the inflammatory drive in HS. Complement receptors are present upon dendritic cells, monocytes, fibroblasts and adipocytes, which may broaden the potential contribution of complement to multiple aspects of HS pathogenesis. Dysregulation of complement receptor pathways has been documented in obesity, insulin resistance and polycystic ovarian syndrome leading to the possibility that complement may explain the epidemiological associations between these conditions and HS. The therapeutic potential of complement inhibitors in HS may be related to the therapeutic target (complement receptor or complement subunit) and the presence of alternate receptors (such as C5aR2) or ligands (including C3a, PAMPs and DAMPs). Integrating complement into the known pathogenesis of HS may aid in explaining the contradictory results between Phase 2 studies of C5a antagonists. It also allows for the identification of existing knowledge gaps to target further clinical investigation and research.

Hidradenitis suppurativa is an autoinflammatory keratinization disease: A review of the clinical, histologic, and molecular evidence

“…The inflammatory signature of established hidradenitis suppurativa has been well characterized in multiple histologic 26,41 and molecular studies. 26,[42][43][44][45] Similarities and parallels with psoriasis 26 have been observed in lesional and perilesional hidradenitis suppurativa tissue, 26,46 with lesional nodules demonstrating mixed inflammatory infiltrates comprising T cells, dendritic cells, plasma cells, neutrophils, [47][48][49][50] and monocytes. 51 Chronic long-…”

What causes hidradenitis suppurativa ?—15 years after

“…Complement split products, like complement 5a (C5a), mediate neutrophil chemotaxis and may play some role in HS pathogenesis. 79,80 Indeed, C1q, C2 and factor B were found to be up-regulated and factor H, factor D and C7 downregulated in HS. In recent months, we have witnessed the spread of the novel coronavirus, SARS-CoV-2, which resulted in a global health emergency.…”

“…Complement split products, like complement 5a (C5a), mediate neutrophil chemotaxis and may play some role in HS pathogenesis 79,80 . Indeed, C1q, C2 and factor B were found to be up‐regulated and factor H, factor D and C7 downregulated in HS.…”

A Systematic Review of Promising Therapeutic Targets in Hidradenitis Suppurativa: A Critical Evaluation of Mechanistic and Clinical Relevance

“…The localization of complements (especially C5a) has not been assessed in HS tissue. Evidence from other inflammatory disorders identifies complement receptors as present on neutrophils, DCs, and monocytes (reviewed in [Ghias et al, 2020;Grand et al, 2020]). In vitro functional studies with anticomplement agents are limited.…”