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Review
. 2017 Dec;49:1-8.
doi: 10.1016/j.coi.2017.07.007. Epub 2017 Jul 22.

Psoriasis: A Mixed Autoimmune and Autoinflammatory Disease

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Free PMC article
Review

Psoriasis: A Mixed Autoimmune and Autoinflammatory Disease

Yun Liang et al. Curr Opin Immunol. .
Free PMC article

Abstract

In recent years marked progress has been made in our understanding of the critical biologic and immunologic pathways involved in psoriasis. Genetic studies have demonstrated that susceptibility to psoriasis involves components of both the adaptive and innate immune system and not surprisingly activation of both of these arms of the immune system is found in psoriatic skin. While adaptive immune responses predominate in chronic plaque psoriasis, innate and autoinflammatory responses dominate in pustular forms of psoriasis, with other clinical subtypes extending on a spectrum between plaque and pustular psoriasis. This makes psoriasis a unique disease where both autoimmune and autoinflammatory responses co-exist, with the balance between the two being critical in shaping its clinical presentation.

Conflict of interest statement

Conflict of Interests: The authors have no conflicts of interest with this manuscript and its contents.

Figures

Figure 1
Figure 1
Identified genetic risk loci in psoriasis since 2006. To date over 60 genetic risk loci have been identified in psoriasis. These involve distinct biological processes such as antigen presentation, cytokines and receptors, epidermal function, cell signaling, and transcriptional regulation.
Figure 2
Figure 2
Risk loci in context of adaptive vs. innate immune system function. This is a simplified view of the biologic function of psoriasis associated genetic risk loci in terms of adaptive (red) vs. innate (blue) immune system role. The risk loci highlighted by a red outline (IL36RN, CARD14 and AP1S3) have been implicated as risk factors for pustular psoriasis. Other loci (white) are not easily classified in terms of role in adaptive vs. innate immune system responses. The adaptive and innate immune system are closely integrated in psoriasis with activation of one generally leading to the activation of the other. Both systems contribute to all clinical subtypes of psoriasis but to a variable degree depending on the subtype.
Figure 3
Figure 3
Autoimmune vs. inflammatory responses in psoriasis. A) Antigen presentation plays a key role in psoriasis. Two endoplasmic aminopeptidases involved in processing of peptide antigens; ERAP1 and ERAP2, are established susceptibility genes in psoriasis along with HLA-Cw6 (highlighted in red). These have a role in processing and presenting antigens to CD8+ T cells, which on activation release pro-inflammatory cytokines including IL-17, TNF-α and IFN-γ. Another antigen presenting pathway involved in psoriasis involves presentation of lipid antigens to T and NKT cells through surface CD1 molecules. No susceptibility genes have yet been identified in that pathway. B) keratinocytes are the principal producer of IL-36 cytokines. Their expression is induced by pro-inflammatory cytokines including IL-1, IL-17 and TNF-α. Release of IL-36 cytokines from keratinocytes is triggered by danger signals such as ATP. Secreted IL-36 cytokines are found in full-length form (fIL-36), and have minimal biologic activity. When exposed to neutrophil nets, neutrophil proteases, or keratinocyte derived proteases (cathepsin S), fIL-36 is converted into a shorter, more active form (truncated IL-36; tIL-36). Truncated IL-36 (tIL-36) has approximately 500-fold increase (500×) in biologic activity. IL-36 cytokines act on the IL-36 receptor and induce expression of more IL-36 thereby promoting a self-sustaining cycle of inflammation that brings in additional leukocytes. Keratinocytes may regulate this process through secretion of serine-protease inhibitors such as serpin A1 and serpin A3, or the IL-36 receptor antagonist (IL-36RA). The three genetic variants associated with pustular psoriasis (IL36RN, CARD14, and AP1S3, highlighted in red) are involved in this process.
Figure 4
Figure 4
Autoimmune vs autoinflammatory responses in psoriasis. Plaque psoriasis and generalized pustular psoriasis are located on opposite ends of the balance between autoimmune and autoinflammatory responses. Thus, plaque psoriasis is characterized and enriched in biologic categories such as “adaptive immune response”, “antigen processing and presentation” as well as leukocyte-mediated immunity”. In contrast, generalized pustular psoriasis is characterized by massive neutrophil infiltration and enriched in biological categories including “granulocyte chemotaxis”, “positive regulation of chemotaxis”, and “antimicrobial humoral response”. Expression of the two principal autoinflammatory mediators; IL1B and IL36G across different clinical subtypes (plaque psoriasis vs erythrodermic vs. inverse, vs. generalized pustular psoriasis (GPP) vs. localized pustular psoriasis (PPP)) (mRNA expression of IL1B was only detectable in a subset of patients).

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