October 21, 2011 (Montreal, Quebec) — A mutation in the interleukin-36 receptor antagonist (IL-36Ra) has been identified as a cause of the unregulated secretion of inflammatory cytokines and generalized pustular psoriasis (GPP) by a multicenter consortium.
Their research was presented here at the 12th International Congress of Human Genetics and the 61st American Society of Human Genetics Annual Meeting.
Asma Smahi, PhD, from Hôpital Necker-Enfants Malades, Paris, France, and colleagues identified a highly significant linkage to an interval of 1.2 Mb on chromosome 2q13-q14.1, as well as a homozygous missense mutation in the IL-36Ra, an antiinflammatory cytokine gene.
"We performed homozygosity mapping and direct sequencing on 9 Tunisian multiplex families with autosomal recessive GPP," Dr. Smahi reported, "and results reveal a key role for IL-36Ra-regulated autoinflammation in the pathogenesis of GPP via unregulated IL-1 family inflammatory cytokine secretion in the skin."
Chromosome Region Pinpointed
As Dr. Smahi told Medscape Medical News, they first identified a chromosome region in which the mutation was implicated, and then sequenced the gene located in that region. "What we found specifically was a mutation in the gene that encodes for the IL-36Ra, and in vitro studies on keratinocytes from our patients showed that this mutation was responsible for loss of function of this receptor."
Because this receptor functions as an inhibitor, "inflammation is not regulated," she added, "and this leads to GPP and potentially other forms of psoriasis."
Importantly, a separate group of researchers from London have identified another mutation in the same gene in another group of families with GPP living in the United Kingdom — suggesting that there is a common pathway giving rise to GPP, and psoriatic diseases in general.
These observations could have direct therapeutic implications. As Dr. Smahi explained, they previously identified another autoinflammatory syndrome — deficiency of IL-1 Ra, which has been shown to respond to treatment with a targeted IL-1 Ra, restoring the phenotype in patients with this deficiency.
"This gives us good reason to believe that IL-36Ra treatment will restore the impaired function of this receptor [giving rise to GPP] and stop the upregulation of inflammatory cytokines," she said.
Hervé Bachelez, MD, PhD, from teh service de dermatologie, Hôpital Saint-Louis, Paris, France, told Medscape Medical News that from its initial description in 1910, the GPP form of psoriasis has been shown to be a rare, life-threatening variant displaying a filiation with plaque-type psoriasis — the most frequent form of psoriasis — with which it is combined in a single patient in roughly one quarter of cases.
"Likewise, studying genetic and molecular mechanisms underlying these rare variants may identify new key pathogenic mechanisms and therapeutic targets shared by GPP and plaque-type psoriasis (also called psoriasis vulgaris)," he said. Our results and those from the London team support the therapeutic targeting of the IL-36 receptor pathway as an appealing strategy in familial and sporadic cases of GPP, he explained.
Furthermore, Dr. Bachelez added, even though genetic abnormalities of IL-Ra have not been shown in patients with psoriasis vulgaris so far, "there have been convincing demonstrations that both IL-36 and its receptor are activated in psoriatic plaques from patients with psoriasis vulgaris. Altogether, these recent insights emphasize the key role of innate immunity in psoriatic inflammation."
Dr. Smahi and Dr. Bachelez have disclosed no relevant financial relationships.
12th International Congress of Human Genetics (ICHG) and the 61st American Society of Human Genetics (ASHG) Annual Meeting: Abstract 63. Presented October 12, 2011.
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Cite this: IL-36 Receptor Antagonist Mutation Cause of Psoriasis Type - Medscape - Oct 21, 2011.