Vitiligo and multiple autoimmune disease

Topic: V itiligo: a role for the innate immune system?

Title- NALP1 in vitiligo-associated multiple autoimmune disease.

Authors: Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, & Spritz RA.

Reference: New England Journal of Medicine 356: 1216-1225, 2007



Autoimmune thyroid disease is the commonest of a group of around eighty disorders which often occur together in either individual patients or their families more frequently than by chance. Almost all autoimmune disorders, with the notable exceptions of autoimmune polyglandular syndrome type 1 and IPEX syndrome, are multifactorial and are believed to result from a complex interplay between genetic and environmental factors. Different combinations of these factors may be responsible for the same disease. Identifying genetic factors which lead to autoimmune disease are likely to shed fresh light on pathogenesis and could at some stage be used in prediction of who is at risk of developing components in the autoimmune disease spectrum.


This research group has previously undertaken whole genome scanning to identify novel loci in families with vitiligo and other autoimmune diseases. One possible locus was identified on chromosome 17p13. To identify the exact gene responsible within this region, fine scale genetic association and DNA sequence analysis was undertaken.


The study comprised 114 families with multiple autoimmune disease, but with vitiligo as the key disorder. Each family had at least two members with generalised vitiligo and at least one having an additional autoimmune condition including thyroid disease. 177 single nucleotide polymorphisms (SNPs) spanning the 17p13 region were tested and NALP1 was identified as a strong candidate gene. Further sequence analysis of DNA around this gene identified further SNPs and a second round of association tests were performed with these additional SNPs to fully elucidate the association with the gene.


Association analysis resulted in identification of the candidate gene NALP1 . This gene encodes NACHT leucine-rich-repeat protein 1, which is a regulator of innate immunity. Further detailed analysis of NALP1 SNPs suggests that there are different variants of the gene which can contribute independently to disease susceptibility.


Polymorphism within the NALP1 region is associated with vitiligo and associated autoimmune diseases. Since the gene is involved in the regulation of the innate immune system, this study reveals an unsuspected role for this limb of the immune system in organ‑specific autoimmune disease.


Genome wide scanning in complex autoimmune diseases has been expensive, time consuming, and frustrating. One outstanding example of the success of this approach was the identification of NOD2 as a risk factor in Crohn-s disease (NOD stands for nucleotide oligomerization domain). NOD2, a protein that recognises bacterial components, is a member of a family of such proteins entitled NOD-like receptors. The NALP proteins are another group of these NOD-like receptors. Already there is a possible explanation for the autoimmune disease susceptibility conferred by NALP1 . NALP1 is part of a cascade of proteins which can regulate the activation of caspases 1 & 5 which, in turn, activate pro-inflammatory interleukins such as IL-1 and IL-18. Thus, polymorphism in NALP1 could lead to altered tissue levels of IL-1 and other inflammatory cytokines.

The study itself does not breakdown the disease components in the patients with vitiligo and so no comments can be made at present on the relationship between NALP1 polymorphisms and autoimmune thyroid disease. The odds ratio conferred by the disease associated SNPs was around 2, and this was the same for those with vitiligo and for those who had an additional autoimmune disease. No doubt many groups will already be studying patients with thyroid disease alone to see whether there is an association with Graves- disease or Hashimoto-s thyroiditis, when not complicated by vitiligo. This will certainly shed further light on the association between these common disorders, and if autoimmune thyroid disease alone is found to be associated with polymorphisms in NALP1 , there is a new role possible for the innate immune system in these disorders. In addition, the results offer the promise of treatment for vitiligo. Until now there has been no reliable therapy available for what can be severely psychologically disabling illness.

( Summary and commentary prepared by Anthony Weetman )

Present summary & commentary are related to Chapter N- 7 of the TDM

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