Pathophysiology of Psoriasis
Psoriasis is a chronic inflammatory, immune-mediated skin disease driven by inappropriate activation of cutaneous T cells and dendritic cells, which release cytokines that trigger keratinocyte hyperproliferation and the characteristic scaly plaques. 1
Core Immunologic Mechanisms
The pathogenesis centers on dysregulated immune responses involving both innate and adaptive immunity:
- T-cell subsets play central roles, with TH1 cells historically implicated and TH17 cells now recognized as critically important in driving inflammation 1, 2, 3
- Dendritic cells become inappropriately activated alongside T cells, initiating the inflammatory cascade 1
- Cytokine networks are profoundly altered, with increased expression of TNF-α, interferon-γ, and IL-12/IL-23-dependent genes in lesional skin 2, 3
- IL-17 and IL-22 secreted by TH17 cells promote keratinocyte proliferation and production of antimicrobial peptides 1
The immune-mediated nature is strongly supported by the efficacy of immunosuppressive drugs (methotrexate, cyclosporine) and biologics targeting TNF-α and the IL-12/23 pathway 2. Disease resolution correlates with decreased infiltration of T cells, dermal dendritic cells, Langerhans cells, and neutrophils 2.
Keratinocyte Dysfunction
While immune cells drive the process, keratinocytes are not passive victims but active participants:
- Hyperproliferation of epidermal keratinocytes results from cytokine signaling, manifesting as the characteristic thickened plaques with silvery scale 1
- Altered differentiation and maturation of skin cells contribute to the abnormal epidermal architecture 4, 5
- Keratinocyte-intrinsic defects may serve as key drivers of inflammation, not merely responses to immune signals 4, 6
- Keratinocytes participate in self-perpetuating inflammatory loops that maintain disease activity 6
Vascular Changes
Angiogenesis is a critical but often underappreciated component:
- Increased dermal vascularity and dilation of blood vessels cause the characteristic erythema 1, 7
- New blood vessel formation begins with early psoriatic changes and resolves with disease clearance 7
- Pro-angiogenic factors including VEGF, hypoxia-inducible factors, angiopoietins, TNF, IL-8, and IL-17 are upregulated 7
Genetic Susceptibility
Genetic factors establish disease predisposition but require environmental triggers:
- HLA-Cw6 (PSORS1) is the major susceptibility gene and strongest genetic determinant 2, 3
- At least 8 chromosomal loci (PSORS I-VIII) show statistically significant linkage to psoriasis 2, 3
- Low penetrance of these genetic factors indicates that environmental triggers are necessary for disease expression 3
Environmental Triggers
Multiple factors can precipitate or exacerbate disease in genetically susceptible individuals:
- Medications including lithium, antimalarials, beta-blockers, and NSAIDs 3
- Skin trauma (Koebner's phenomenon) 2
- Infections and systemic illness 2, 3
- Psychological stress 2, 3
- Obesity is both a risk factor and severity modifier, with pooled odds ratio of 1.66 overall and 2.23 in moderate-to-severe disease 3
Clinical Manifestations of Pathophysiology
The underlying mechanisms produce the characteristic clinical features:
- Well-demarcated red plaques with silvery scale result from keratinocyte hyperproliferation and vascular dilation 1
- Typical distribution (scalp, elbows, knees, presacral region) reflects areas prone to trauma and mechanical stress 1
- Systemic inflammation extends beyond the skin, contributing to comorbidities including cardiovascular disease, metabolic syndrome, and psoriatic arthritis 1, 2
Associated Immune-Mediated Conditions
The shared pathophysiology explains disease associations:
- Psoriatic arthritis develops in 25-30% of patients with psoriasis 2
- Crohn's disease occurs 3.8-7.5 times more frequently than in the general population 1, 2
- Multiple sclerosis appears more common in families with psoriasis 1, 2
These associations suggest shared genetic susceptibility and inflammatory mechanisms rather than classical autoimmunity 2.