A Psoriasis Gene Emerges: IL-36–Receptor Antagonist Deficiency Causes Generalized Pustular Psoriasis
The first single-gene mutation to be directly implicated in psoriasis presents a potential target for intervention.
Generalized pustular psoriasis (GPP) is an episodic, multisystem, inflammatory disorder characterized by fever, leukocytosis, disseminated pustules, and considerable mortality. To identify the disease's genetic basis, researchers studied nine Tunisian families with an autosomal recessive predisposition to GPP.
The investigators identified an area of homozygosity at chromosome 2q13-14 in all affected individuals. In this area of the genome, which contains many genes governing cytokine function and regulation, they identified a mutation that affects the interleukin (IL)-36–receptor antagonist IL-36Ra, weakening the protein and compromising its function.
IL-36Ra is an endogenous antagonist of the IL-36α, β, and inflammatory cytokines that normally activate nuclear factor-B and mitogen-activated protein kinase pathways. Keratinocytes from affected patients produced more IL-8 in response to diverse immune- activating stimuli, and lesional patient skin had elevated levels of multiple inflammatory cytokines.
Comment: The long search for psoriasis susceptibility genes has pointed to variants at several genetic loci that are overrepresented in people with psoriasis vulgaris. This first, well-characterized, single-gene mutation to be directly implicated in psoriasis presents a potential target for intervention. Increased interleukin-8 expression is relevant in psoriasis because this cytokine recruits neutrophils, which have a role in the pathogenesis of psoriasis. The inability to dampen innate immune responses may explain why infections trigger flares. Presence of plaque psoriasis in patients with generalized pustular psoriasis suggests that dysregulation of IL-36 signaling may be involved in the more common psoriasis variants and, combined with overexpression of antimicrobial peptides, may explain alterations in the microbiological environment of psoriatic lesions.
Published in Journal Watch Dermatology August 17, 2011
Marrakchi S et al. Interleukin-36–receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011 Aug 18; 365:620.
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