Pigment Cell Research August 2007

I came across this very interesting and detailed medical study release. Some of it is a bit technical, but if you’ve read through as many medical journals as I have by now, from researching vitiligo, you’ll have no problem getting the gist of the article.

NALP1 and the inflammasomes: challenging our perception of vitiligo and vitiligo-related autoimmune disorders

  • Inserm U876, Universite Victor Segalen, Bordeaux, France
*Address correspondence to Alain Taïeb, e-mail: alain.taieb@chu-bordeaux.fr


When looking at vitiligo skin, the disease seems clinically at least simpler than other common chronic skin disorders, such as atopic dermatitis or psoriasis. There is only a visible loss of pigmentation, and opposite to these other chronic skin conditions, inflammation is lacking. When taking a biopsy of vitiliginous skin, the evidence of inflammation is usually scarce or absent, even though some reports support a marginal infiltration of T cells (Van den Wijngaard et al., 2000). The microscopic features are dominated by a loss of melanocytes, without clear destructive process targeting those cells, and foci of pigment cell loss without inflammatory infiltrates have been documented in normal looking skin in generalized (non-segmental) vitiligo (Pretti Aslanian et al., 2007). The next question is then: why do melanocytes leave the epidermis and/or hair follicles? This question has generated several speculations (reviewed in Dell’anna and Picardo, 2006; Gauthier et al., 2003; Taieb, 2000), based on clinical or experimental data, but without definitive supporting evidence. As a consequence of this absence of basic understanding of the disease, therapies do not meet the patient’s needs (Whitton et al., 2006).

The apparently simple problem of vitiligo is indeed one of the most challenging ones in dermatology and medicine. A good angle of attack to the problem is obviously lacking. Other common chronic disorders including skin disorders have benefited from the genetic angle. In 2006, a breakthrough was made in atopic dermatitis and related atopic disorders, a field also characterized by very contrasted opinions about pathophysiology and therapeutic options. A skin inherited basis, with a loss of function of a gene encoding filaggrin, a stratum corneum precursor protein, was found in 30–40% of cases of European descent individuals with the disorder (Palmer et al., 2006). Similar progress is expected to follow for psoriasis, which has a strong inherited component, and part of its heritability is probably also situated within the epidermal differentiation complex at 1q21 close to filaggrin (Cookson et al., 2001). However, when comparing common chronic skin disorders for monozygous twin concordance, an excellent marker of the inherited component in complex disorders, atopic dermatitis and psoriasis have definitely a more inherited profile than vitiligo: only 23% concordance for vitiligo (Alkhateeb et al., 2003), versus 35–56% in psoriasis (Brandrup et al., 1982; Duffy et al., 1993) and up to 72% in atopic dermatitis (Schultz Larsen, 1993). Furthermore, according to genome-wide linkage analyses for the generalized vitiligo phenotype performed in populations of various ethnic backgrounds, the major inherited loci are not the same (Chen et al., 2005; Fain et al., 2003).

Thus, the genetic angle of attack has certainly intrinsic weaknesses in vitiligo research but, in derivation of it, the recent paper by the group of Spritz (Jin et al., 2007) offers an unexpected research avenue for vitiligo-associated autoimmune/inflammatory disorders. This study is based on previous reports of the same group that have shown a linkage between a locus on chromosome 17p13 and multiple autoimmune disease associated with vitiligo. This locus is not linked with vitiligo occurring in isolation. Scanning with SNPs (single-nucleotide polymorphims) the 11.3 cM interval of 6.19 Mb containing the putative autoimmune vitiligo gene at 17p13, the authors found one haplotype encoding the proximal coding region and the extended promotor region of the NALP1 gene (encoding NACHT leucine-rich-repeat protein 1), which shows a significant but not considerable association with vitiligo and vitiligo-associated autoimmune diseases (odds ratio of less than 2). Further analyses led to the conclusion that two independent variants of the NALP1 region are associated with an increased risk of vitiligo-associated autoimmune/inflammatory diseases, one situated on the NALP1 gene, and the other upstream in a region involving the gene promoter. The functional significance of these genetic variants is still unknown.

How much will this change our current (absence of) understanding of vitiligo? NALP1 is a NOD (nucleotide-binding oligomerization domain protein)-like receptor, a family of pattern recognition receptors for microorganisms, apoptotic fragments or cell debris, which also includes NOD2. Interestingly, variants of NOD2 are associated with Crohn’s disease, an inflammatory intestinal barrier disease (Hugot et al., 2001). In Crohn’s disease, variant NOD2 alleles cause a loss of physiological tolerance to commensal bacteria. As a consequence, immune responses develop that activate immunocompetent cells, resulting in the secretion of proinflammatory mediators that cause mucosal breaks and ulcerations. If NALP1 is physiologically close, its still unknown role in skin barrier is unlikely to provoke such a dramatic scenario causing a loss of pigment cells, because this would be clinically and histologically detectable. NALP1 is immunohistochemically found in epidermis within Langerhans cells (Kummer et al., 2007), but more precise studies focusing on pigment cells are lacking. NALP1 and 3 are part of cytoplasmic complexes called inflammasomes that regulate the activation of caspases which in turn convert proinflammatory cytokines into their active forms. Mutant NAPL3 phenotypes are known and are also clearly inflammatory causing disorders such as Muckle–Wells syndrome (Agostini et al., 2004).

Several lines of evidence suggest that the skin itself is important in the primary pathogenesis of vitiligo such as Koebner’s phenomenon, the more severe presentation of segmental vitiligo when associated with generalized vitiligo, so that to sum up our current perception, some fragility in the epidermal melanin unit, which may have an inherited component, leads to a chronic melanocytorrhagy (Gauthier et al., 2003). However, as stated before, inflammation is clearly not a major part of the disease. Thus, if the inflammasome story holds true in vitiligo in the context of a personal or family history of autoimmune disorders, my guess is that it could help trigger or enhance the autoimmune part of the disease, which may involve initial contacts between melanocytes or melanocyte fragments and NALP1-positive Langerhans, rather than being an initial factor in which a systemically dysregulated innate immunity would get rid of epidermal melanocytes as a priority. As noted by the authors of the NEJM paper (Jin et al., 2007), the NALP1 discovery is important to test new treatment options such as interleukin-1 (IL-1) receptor antagonists in autoimmune vitiligo and the group of vitiligo-related autoinflammatory disorders. This would be possible via the possible impairment of the NALP1-dependent regulation of the activity of caspases 1 and 5 which in turn modulate IL-1β activity.

However, it is tempting to speculate that for the more common non-segmental vitiligo phenotype occurring in isolation, without demonstrated autoimmunity, there is an intervention of a low key activation of the huge reservoir of IL-1β which is found in the stratum corneum. For instance, mechanical trauma might be such an environmental candidate factor leading to events that could subsequently destabilize the anchoring of basal melanocytes, without creating clinical or histological inflammation. In the epidermis, IL-1β is produced as a biologically inactive 31-kDa precursor, which is converted to the active 18-kDa form by proteolytic processing. Keratinocytes do not express the active form of the specific IL-1β-converting enzyme. Thus, the activation in situ of IL-1β remains elusive. Nylander-Lundqvist and Egelrud (1997) have already shown that IL-1β activation in human epidermis can occur via an alternative mechanism involving stratum corneum chymotryptic enzyme (SCCE or kallikrein 7), a serine protease specifically expressed in keratinizing squamous epithelia.

I would thus propose to take a look at this proposed alternative pathway of activation in vitiligo, which, if implicated, would support the view that many events occurring in skin physiology and disease are under the control of the most differentiated part of the epidermis, the stratum corneum (Elias et al., 1999). This would also fit the idea applicable to common skin disorders that the evidence is frequently closer to our eyes than expected due to complex speculations, as highlighted in Edgar Allan Poe’s famous short story, the purloined letter (Taieb, 2007).

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