Vitiligo pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Vitiligo is the most common human pigmentation disorder and is characterized by a lost of skin melanocytes. The exact mechanism is not well understood jet but apparently involves genetic predisposition, autoimmune factors, oxidative stress and sympathetic neurogenic disturbance.[1][2]
Pathophysiology
Genetics
Jin in the New England Journal of Medicine reported a study comparing 656 people with and without vitiligo in 114 families, which found several mutations (single-nucleotide polymorphisms) in the NALP1 gene.[3][4] The NALP1 gene, which is on chromosome 17 located at 17p13, is on a cascade that regulates inflammation and cell death, including myeloid and lymphoid cells, which are white cells that are part of the immune response. NALP1 is expressed at high levels in T cells and Langerhan's cells, white cells that are involved in skin autoimmunity.
Among the inflammatory products of NALP1 are caspase 1 and caspase 5, which activate the inflammatory cytokine interleukin-1β. Interleukin-1β is expressed at high levels in patients with vitiligo. There are compounds which inhibit caspase and interleukin-1β, and so might be useful drugs for vitiligo and associated autoimmune diseases.
Of the 656 people, 219 had vitiligo only, 70 had vitiligo with autoimmune thyroid disease, and 60 had vitiligo and other autoimmune diseases. Addison's disease (typically an autoimmune destruction of the adrenal glands) may cause vitiligo.
In one of the mutations, the amino acid leucine in the NALP1 protein was replaced by histidine (Leu155->His). The original protein and sequence is highly conserved in evolution, and found in humans, chimpanzee, rhesus monkey, and bush baby, which means that it's an important protein and an alteration is likely to be harmful.
The following is the normal DNA and protein sequence in the NALP1 gene:
| TCA | CTC | CTC | TAC | CAA |
| Ser | Leu | Leu | Tyr | Gln |
| S | L | L | Y | Q |
In some cases of vitiligo the first leucine is altered to histidine, by a Leu155→His mutation:
| TCA | CAC | CTC | TAC | CAA |
| Ser | His | Leu | Tyr | Gln |
| S | H | L | Y | Q |
(Leucine is nonpolar and hydrophobic; histidine is positively charged and hydrophilic, so it is unlikely to serve the same function.[5] [6])
The normal sequence of the DNA code for NALP1 of TCACTCCTCTACCAA is replaced in some of these vitiligo families by the sequence TCACACCTCTACCAA,[7] which respectively code for the amino acid sequence of the normal NALP1 protein SLLYQ being replaced by SHLYQ.[8]
Associated Conditions
Vitiligo is associated with autoimmune and inflammatory diseases, commonly thyroid overexpression and underexpression.
Gross Pathology
Microscopic Pathology
References
- ↑ Gauthier Y, Cario Andre M, Taïeb A (2003). "A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocytorrhagy?". Pigment Cell Res. 16 (4): 322–32. PMID 12859615.
- ↑ Dell'anna ML, Picardo M (2006). "A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo". Pigment Cell Res. 19 (5): 406–11. doi:10.1111/j.1600-0749.2006.00333.x. PMID 16965269.
- ↑ Gregersen PK (2007). "Modern genetics, ancient defenses, and potential therapies". N. Engl. J. Med. 356 (12): 1263–6. doi:10.1056/NEJMe078017. PMID 17377166.
- ↑ Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA (2007). "NALP1 in vitiligo-associated multiple autoimmune disease". N. Engl. J. Med. 356 (12): 1216–25. doi:10.1056/NEJMoa061592. PMID 17377159.
- ↑ List of Amino Acids and Their Abbreviations
- ↑ The Genetic Code (DNA)
- ↑ Ensembl Transcript Report Ensembl Transcript ID: NST00000262467
- ↑ Ensembl Protein Report Ensembl Peptide: ID ENSP00000262467