Model of pathogenesis of psoriasis. Part 2. Local processes

Analytical research of results of experimental and theoretical studies on pathogenesis of psoriatic disease is carried out. The new model of pathogenesis - skin reaction to systemic psoriatic process SPP is formulated. … Psoriatic inflammation is regarded as a reaction of the skin immune system to activity of Mo-R and DC-R involved in derma from blood flow. They contain Y-antigen and, getting to derma, can be transformed in mature maDC-Y and present this antigen to Y-specific T-lymphocytes as well as activate them. Y-antigen is a part of the interpeptide bridge IB-Y. Therefore, the skin immune system can incorrectly interpret Y-antigen presentation as a sign of external PsB-infection and switch one of mechanisms of protection against bacterial infection - epidermal hyperproliferation. Psoriatic plaque can be initiated only during action of local inflammatory process LP2 in derma causing not only innate, but also adaptive response. In particular, it is possible at LP2(IN) - open trauma of derma or at LP2(HPV) - HPV-carriage of keratinocytes. The level of Y-priming (presence and concentration of Y-specific T-lymphocytes in prepsoriatic derma and in lymph nodes) also determines possibility of psoriatic plaque initiation. Existence and severity of psoriatic plaque is determined by intensity of Y-antigen income into derma (inside Mo-R and DC-R). … Severity of plaque is aggravated by LP2-inflammation if it persists after this plaque initiation. New Mo-T, DC-T (incl. Mo-R, DC-R) and Y-specific T-lymphocytes are constantly attracted into plaques from blood flow, and so support vicious cycles. Only at decrease of SPP severity, these vicious cycles weaken and natural remission of plaques takes place, up to their complete disappearance. The detailed analysis comparing the new model of pathogenesis with five other previously published models is carried out. Part 1. arXiv:1110.0584

💡 Research Summary

The paper proposes a comprehensive, systems‑level model of psoriasis pathogenesis that integrates a systemic component—the Systemic Psoriatic Process (SPP)—with local skin events (LP2). In the SPP, circulating monocytes (Mo‑R) and dendritic cells (DC‑R) carry a bacterial‑derived Y‑antigen, which is a fragment of the inter‑peptide bridge (IB‑Y) found in bacterial cell walls. When these cells extravasate into the dermis, they mature into Y‑antigen‑presenting dendritic cells (maDC‑Y) that display the antigen to Y‑specific CD4⁺ and CD8⁺ T lymphocytes. The immune system interprets this presentation as a sign of an external bacterial infection, even though no pathogen is present. Consequently, Y‑specific T cells release IL‑17, IL‑22, IFN‑γ and other pro‑inflammatory cytokines that drive keratinocyte hyperproliferation and the characteristic epidermal thickening of psoriatic plaques.

Local processes (LP2) act as the trigger that allows the systemic signal to manifest as a skin lesion. Two LP2 scenarios are described: (1) physical trauma (LP2‑IN) that disrupts the epidermal barrier, and (2) carriage of human papillomavirus (HPV) within keratinocytes (LP2‑HPV). Both conditions provoke innate immune activation (e.g., via TLRs, cGAS‑STING) and simultaneously recruit adaptive immunity. HPV infection, in particular, amplifies interferon responses, synergizing with Y‑antigen presentation to accelerate plaque formation.

A critical determinant of whether a plaque will develop is “Y‑priming,” defined as the presence and concentration of Y‑specific T cells in pre‑psoriatic skin and draining lymph nodes. High Y‑priming lowers the threshold for plaque initiation; even minor trauma or low‑level HPV can precipitate a full‑blown lesion. Low Y‑priming, by contrast, renders the skin resistant to the same triggers.

The model emphasizes a vicious cycle: persistent SPP supplies a continual influx of Mo‑R and DC‑R into the skin, which in turn generate new maDC‑Y and sustain Y‑specific T‑cell activation. Activated T cells secrete cytokines that increase endothelial adhesion molecule expression, recruiting more monocytes and dendritic cells from the bloodstream. This feedback loop maintains chronic inflammation and plaque expansion. When systemic SPP activity wanes—through natural disease modulation, therapeutic intervention, or immunoregulatory mechanisms—the cycle weakens, allowing natural remission and eventual plaque resolution.

The authors compare their framework with five previously published models: (1) Th1/Th17‑centric cytokine models, (2) Koebner phenomenon (mechanical injury) models, (3) autoimmune auto‑antigen models, (4) dysbiosis‑related microbiome models, and (5) gene‑environment interaction models. While each of those explains specific aspects of psoriasis, none integrates a systemic antigen‑driven signal with a local trigger in a unified mechanistic pathway. By introducing the concrete molecular entity Y‑antigen and linking it to both systemic immune status and local skin injury or viral carriage, the new model offers a more holistic explanation.

Therapeutic implications are discussed. Targeting the Y‑antigen (e.g., neutralizing antibodies), blocking the migration of Mo‑R/DC‑R (e.g., CCR2/CCR5 antagonists), or modulating Y‑specific T‑cell priming (e.g., tolerogenic vaccines) could interrupt the pathogenic loop. Moreover, measuring Y‑antigen levels or Y‑specific T‑cell frequencies might serve as biomarkers for disease activity, risk stratification, and treatment monitoring, paving the way for personalized psoriasis management.

In summary, the paper advances a novel, integrative concept of psoriasis as a skin reaction to a systemic psoriatic process, mediated by Y‑antigen‑bearing myeloid cells and contingent upon local inflammatory events. This paradigm bridges gaps among existing theories and opens new avenues for research, diagnostics, and targeted therapy.