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Psoriasis as netopathy. Model of pathogenesis with unique netosis role.

Mikhail Peslyak; Nikolay Korotky

Creative Commons License CC-BY-NC-ND.
 

An analytical survey of results of experimental and theoretical works on psoriatic disease has been carrried out. A new YN-model of pathogenesis of psoriasis as skin manifestation of systemic psoriatic process SPPN is formulated.

The central subprocess of systemic psoriatic process SPPN is PAMP-nemia, namely chronic kPAMP-load on blood phagocytes, also leading to increased kPAMP-level in blood.The key PAMP (kPAMP) are LPS (lipopolysaccharide), PG (peptidoglycan), including PG-Y (peptidoglycan of presumed psoriagenic PsB) and bacDNA (bacterial DNA).

The main reasons of PAMP-nemia are increased small intestine permeability for bacterial products and/or increased level of specific SIBO (small intestine bacterial overgrowth).

PAMP-nemia causes increased kPAMP-carriage of phagocytes and growth of prenetotic neutrophil fraction in blood. SPPN severity is proportional to total kPAMP-load on blood phagocytes and to their total (PG-Y)-carriage. SPPN severity predetermines possibility of initiating and supporting psoriasis.

PsB – bacteria presumed psoriagenic – are given a definition based on existence of genes responsible for forming peptidoglycan interpeptide bridges, similar to Str.pyogenes. All known such species are identified.

Because of PAMP-nemia senescent kPAMP+ blood neutrophils do not completely degrade kPAMP as they preserve the latter for delivery into bone marrow. Many of such neutrophils become attracted into inflamed skin, undergo netosis, and kPAMP (including PG-Y) appear in extracellular space.

Dermal monocytes and dendritic cells endocyte PG-Y, then they transform to maDC-Y (mature DC processing and presenting Y‑antigen) and carry out Y-antigen presentation to specific TL-Y, activating them. Skin immune system interprets Y-antigen presentation as a sign of dermal PsB expansion and turns on one of its protection mechanisms – epidermal hyperproliferation.

Pinpoint psoriatic plaque is initiated during dermal inflammatory process L2, causing innate response, particularly at L2(DEMP) - dermal expansion of commensal microbiome with PsB. For L2(DEMP), a phase-by-phase initiation of pinpoint plaque and of its subsequent growth is constructed. Y-priming level (presence and concentration of Y-specific T-lymphocytes in prepsoriatic dermis and lymphnodes) determines possibility of plaque initiation.

Severity and growth of plaque is determined by intensity of Y-antigen income to dermis inside kPAMP+ phagocytes. New kPAMP+ phagocytes and Y-specific T-lymphocytes are constantly attracted into plaques, which supports inflammatory reaction. With decrease of SPPN severity, natural remission of plaques occurs, up to their total disappearance.

Psoriasis is regarded as reaction of skin immune system to imaginary dermal PsB expansion supported by netosis of (PG-Y)+ neutrophils. Within YN-model, psoriasis is classified as netopathy.

The given book is authorized translation of the book, published in Russian:
ISBN 978-5-905504-07-5, DOI: 10.5281/zenodo.4065535.
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Edition r1.3 corrects the typos and inaccuracies found in edition r1.2a.
Section 5.1. Subprocess SP1. is corrected and supplemented..
Added Table 7. Hypotheses in YN-model (partially repeats Table A12 from Supplements).
For each of processes, the text  indicates whether it is a hypothesis (in addition to the information from Table 7).
Bibliography is supplemented.

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