Model of pathogenesis of psoriasis. Part 1. Systemic psoriatic process

Analytical study of results of experimental and theoretical works on pathogenesis of psoriatic disease was conducted. Psoriasis is dermal implication of systemic psoriatic process (SPP). New SPP model explaining results of clinical and laboratory experiments was formulated. According to Y-model there are two main factors: hyperpermeability of small intestine for bacterial products and colonization of its walls by Gram+ bacteria (incl. psoriagenic bacteria PsB) and Gram(-) TLR4-active bacteria. Inside SPP there is a vicious cycle which is supported by disturbance of production and-or circulation of bile acids. SPP central subprocess is PAMP-nemia, namely chronic kPAMP-load on blood phagocytes (neutrophiles, monocytes and dendritic cells). The load results in increase of blood kPAMP level. The major key PAMP (kPAMP) are LPS and PG (incl. PG-Y - peptidoglycan of psoriagenic bacteria). Chronically increased kPAMP-load possibly provides tolerization of some neutrophils Neu, monocytes Mo and dendritic cells DC in blood flow. The chemostatus of tolerized blood Neu-T in process of their aging changes similarly to chemostatus nonactivated Neu and, hence, they carry endocytosed content from blood flow into the bone marrow. Chemostatuses of tolerized Mo-T and DC-T are similar to nonactivated ones. So they don’t bring endocytosed content to lymph nodes or spleen and remain in blood. Tolerized phagocytes degrade endocytosed fragments of bacterial products containing kPAMP slowly and incompletely, Tolerized phagocytes appeared to be (PG-Y)-carriers are named by R-phagocytes and are designated as Neu-R, Mo-R and DC-R. SPP severity predetermines possibility of psoriasis initialization and maintenance because Mo-R and DC-R along with normal Mo and DC participate in homeostatic and inflammatory renewal of pool of dermal macrophages and DC of non-resident origin. Part 2 - arXiv:1201.2900

💡 Research Summary

The paper presents a comprehensive re‑examination of psoriasis pathogenesis, proposing that the disease is a cutaneous manifestation of a broader systemic condition termed the Systemic Psoriatic Process (SPP). By analytically reviewing experimental and theoretical studies, the author formulates the “Y‑model,” which integrates four inter‑related components: (1) hyper‑permeability of the small intestine, (2) colonisation of the intestinal wall by specific Gram‑positive (including so‑called psoriagenic bacteria, PsB) and Gram‑negative TLR4‑activating bacteria, (3) chronic “PAMP‑nemia” – a sustained load of key pathogen‑associated molecular patterns (kPAMPs) such as lipopolysaccharide (LPS) and peptidoglycan (PG‑Y) in the bloodstream, and (4) a disturbance of bile‑acid production or circulation that further amplifies intestinal permeability and bacterial overgrowth.

Under continuous kPAMP exposure, circulating phagocytes—neutrophils, monocytes, and dendritic cells—undergo a process termed “tolerisation.” Tolerised neutrophils (Neu‑T) retain a chemokine‑receptor profile similar to non‑activated cells, allowing them to traffic back to the bone marrow while carrying endocytosed bacterial fragments. Tolerised monocytes (Mo‑T) and dendritic cells (DC‑T) remain in the bloodstream without migrating to lymph nodes or spleen, effectively acting as silent carriers. Because these cells degrade internalised kPAMPs only slowly and incompletely, a subset becomes “R‑phagocytes” (Neu‑R, Mo‑R, DC‑R) that retain intact PG‑Y fragments.

R‑phagocytes travel via the blood to the dermis, where they participate in the homeostatic renewal of resident macrophage and dendritic‑cell pools. Their presence introduces bacterial PAMPs directly into the skin microenvironment, priming local immune cells, promoting cytokine release, and sustaining the characteristic hyper‑proliferative, inflammatory plaque of psoriasis. Consequently, the severity of SPP—reflected by the quantity and activity of R‑phagocytes—determines both the initiation and chronicity of cutaneous lesions.

The model also highlights the role of bile‑acid dysregulation. Bile acids normally limit Gram‑negative bacterial overgrowth and maintain mucosal integrity; when their synthesis or enterohepatic circulation is impaired, intestinal permeability rises, Gram‑negative LPS‑producing bacteria proliferate, and the PAMP load intensifies, creating a self‑reinforcing vicious cycle.

Clinical and laboratory observations cited in the paper support the Y‑model: psoriasis patients frequently exhibit increased intestinal permeability, detectable colonisation by specific Gram‑positive PsB strains, elevated serum LPS and PG‑Y levels, and higher frequencies of tolerised phagocytes in peripheral blood. Skin biopsies often reveal macrophages containing bacterial peptidoglycan fragments, consistent with the hypothesised migration of R‑phagocytes.

While the Y‑model offers a unifying framework that connects gut microbiota, systemic immune tolerance, and skin pathology, several gaps remain. Direct identification and functional validation of R‑phagocytes are required, as is quantitative profiling of gut microbiota composition, permeability indices, and bile‑acid metabolites in psoriasis cohorts. Moreover, the molecular mechanisms by which tolerisation preserves chemokine‑receptor expression yet suppresses antimicrobial functions need elucidation.

In summary, the paper redefines psoriasis from a purely dermatological disorder to a systemic disease driven by gut‑derived PAMPs, tolerised immune cells, and disrupted bile‑acid homeostasis. This reconceptualisation opens new therapeutic avenues: restoring intestinal barrier integrity, modulating specific bacterial populations, correcting bile‑acid metabolism, and targeting tolerised R‑phagocytes to prevent their skin infiltration. Future interventional studies testing these strategies could substantially advance the management of psoriasis.