What are the current theories of psoriasis pathogenesis?

Current Theories of Psoriasis Pathogenesis

The IL-23/Th17 Axis as the Central Pathogenic Mechanism

Psoriasis is fundamentally an immune-mediated inflammatory disease driven by the IL-23/Th17 axis, representing the dominant pathogenic model that has revolutionized our understanding and treatment of this condition. 1, 2

The disease mechanism operates through a well-characterized inflammatory cascade:

• Dendritic cells produce TNF-α and IL-23, which promote T cell differentiation toward Th17 cells that subsequently produce the key psoriatic cytokines IL-17, IFN-γ, and IL-22 1, 3
• Th17 cells secrete IL-22, which directly promotes keratinocyte proliferation and augments production of antimicrobial peptides 1
• IL-17 activation in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin 2

The Pathogenic Triad: Dendritic Cells, Th17 Cells, and Keratinocytes

Emerging evidence indicates that dendritic cells, Th17 cells, and keratinocytes constitute a pathogenic triad in psoriasis, with each component amplifying the inflammatory response 3:

• Keratinocytes respond to cytokines with hyperproliferation and production of antimicrobial peptides, chemokines, and additional inflammatory mediators that further recruit immune cells 1
• This creates a vicious cycle in which cytokines continuously activate T cells and antigen-presenting cells within the psoriatic plaque 4

Complementary Role of Th1 Cells

While the IL-23/Th17 axis is dominant, Th1 cells and their cytokines (TNF-α, interferon-γ) work in concert with the IL-23/Th17 pathway to maintain disease activity 1, 5:

• The disease involves altered levels of chemokines and integrins, affecting migration of T cells, dermal dendritic cells, macrophages, and neutrophils into plaques 5
• Increased expression of TNF-α, interferon-γ, and IL-12/23-dependent genes occurs in lesional skin 5

Genetic Architecture and Susceptibility

The HLA-Cw6 allele (PSORS1) remains the strongest genetic determinant of psoriasis, but over 80 susceptibility loci have now been identified 1, 5:

• At least 8 chromosomal loci (PSORS I-VIII) show statistically significant linkage to psoriasis, confirming a polygenic inheritance pattern 1
• The low penetrance of these genetic factors indicates that environmental triggers are required for disease expression 1, 5
• A shared susceptibility region on chromosome 16 links psoriasis with Crohn disease and ulcerative colitis, indicating overlapping genetic risk 1

Environmental Triggers and Modifying Factors

Multiple environmental factors interact with genetic susceptibility to trigger disease expression 1, 5:

• Mechanical stress (Koebner phenomenon), infections (particularly streptococcal), medications (lithium, antimalarials, beta-blockers, NSAIDs, paradoxically TNF inhibitors), psychological stress, smoking, alcohol, and obesity 1, 5
• Streptococcal infections act as a potent environmental trigger, particularly for guttate psoriasis, implicating bacterial superantigens in disease activation 1
• Obesity is a strong risk factor for developing psoriasis, with a severity-dependent relationship and pooled odds ratio of 1.66, increasing to 2.23 in moderate-to-severe disease 1, 5

Role of Innate Immunity

The role of innate immunity in psoriasis pathogenesis is increasingly recognized 6:

• Neutrophils, γδ T cells, innate lymphoid cells (ILCs), mast cells, and other innate immune cells contribute to disease initiation and maintenance 3
• Prominent neutrophil collections define pustular psoriasis variants, reflecting strong activation of innate immunity 1

Systemic Inflammatory Disease Concept

Psoriasis is now recognized as a systemic inflammatory disease with far-reaching health implications beyond the skin 1:

• Chronic systemic inflammation contributes to increased cardiovascular disease, metabolic syndrome, type 2 diabetes, obesity, and depression 1
• Patients with severe psoriasis have increased mortality risk, dying on average 5 years younger than those without psoriasis, largely due to cardiovascular death 1
• Incidence of Crohn disease and ulcerative colitis is 3.8–7.5 times higher than in the general population 1

Integration of Immune and Epithelial Abnormalities

It is unlikely that psoriasis originates from an exclusive disorder of the immune system or an isolated primitive change of epithelial cells 6:

• Various combinations of selective abnormalities of both immune and epithelial compartments give rise to the psoriatic phenotype 6
• Some psoriasis susceptibility genes are linked to immunity, while others relate to primitive abnormalities of keratinocytes 6

Clinical Validation Through Therapeutic Response

The elucidation of the IL-23/IL-17 axis has revolutionized treatment, with biologics targeting IL-23p19 (guselkumab, risankizumab, tildrakizumab) and IL-17 signaling (secukinumab, ixekizumab, brodalumab) demonstrating superior efficacy 1, 2:

• Immunosuppressive agents and biologics targeting immune pathways are effective, confirming the disease's immune-driven nature 1
• Successful treatment reduces expression of TNF-α, IFN-γ, and IL-12/23-dependent genes in lesional skin 1