Association and expression of antigen processing gene PSMB8 coding for Low Molecular Mass Protease 7 (LMP7) with Vitiligo in North India: case-control study

Summary

Background

Vitiligo is a multifactorial, autoimmune, depigmenting disorder of the skin where aberrant presentation of auto antigens may have a role to play.

Objectives

To study the association of antigen processing genes, PSMB8 and PSMB9 with vitiligo.

Methods

1320 vitiligo cases (1050 generalized and 270 localized) and 752 normal healthy controls were studied for PSMB9 exon 3 G/A SNP, PSMB8 exon 2 C/A SNP and PSMB8 Intron 6 G/T at 37360 site using PCR-RFLP. Real time PCR was used for transcriptional expression of PSMB8 and cytokines. Expressions of ubiquitinated proteins and phosphorylated-p38 (P-p38) were studied by western blotting.

Results

Significant increase in PSMB8 exon 2 allele A (p < 2.07x10^-16, Odds Ratio (OR) =1.93) and genotypes AA (p< 1.03X10^-6, OR=2.51) and AC (p< 1.29X10^-6, OR=1.63) were observed in vitiligo. IFN-γ stimulation induced lower expression of PSMB8 in PBMCs of cases compared with controls suggesting impaired antigen processing which was confirmed by accumulation of ubiquitinated proteins in both lesional and non-lesional skin of vitiligo patients. Expression of pro-inflammatory cytokines, IL-6, IL-1β and IL-8 was higher in the lesional skin. P-p38 expression was variable but correlated with the amount of ubiquitinated proteins in the lesional and non-lesional skin, suggesting that the inflammatory cytokine responses in the lesional skin could be a result of both P-p38 and P-p38 independent pathways.

Conclusions

PSMB8 exon 2 SNP is significantly associated with vitiligo. Accumulation of ubiquitinated proteins in skin of vitiligo cases suggests their aberrant processing which may be promoting the development of the disease.

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