Altered Levels of Negative Costimulatory Molecule V-Set Domain-Containing T-Cell Activation Inhibitor-1 (VTCN1) and Metalloprotease Nardilysin (NRD1) are Associated with Generalized Active Vitiligo

ABSTRACT

Background

Vitiligo is characterized by depigmented macules on the skin caused due to autoimmune destruction of melanocytes. V-set domain-containing T-cell activation inhibitor-1 (VTCN1) is a negative costimulatory molecule that plays a vital role in suppressing autoimmunity and tuning immune response. Nardilysin (NRD1), a metalloproteinase, cleaves membrane-tethered VTCN1 resulting in the shedding of soluble-VTCN1 (sVTCN1). However, the role of VTCN1 and NRD1 in vitiligo pathogenesis is unexplored.

Objectives and methods

This study was aimed to (i) Investigate the association of VTCN1 intronic polymorphisms (rs10923223 T/C and rs12046117 C/T) with vitiligo susceptibility in Gujarat population by using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) (ii) Estimate VTCN1 & NRD1 transcript levels from peripheral blood mononuclear cells (PBMCs) and skin samples of vitiligo patients by real-time PCR, (iii) Estimate sVTCN1 and NRD1 protein levels from plasma by ELISA and (iv) Estimate VTCN1 protein levels in the skin samples of vitiligo patients by immunofluorescence.

Results

The analysis revealed increased VTCN1 and NRD1 transcript levels in the skin (p = .039, p = .021 respectively), increased sVTCN1 and NRD1 levels (p  = .026, p = .015 respectively) in the plasma, and decreased VTCN1 protein levels (p = .0002) in the skin of vitiligo patients as compared to healthy controls. The genetic analysis revealed no significant association of VTCN1 intronic polymorphisms rs10923223 T/C and rs12046117 C/T with vitiligo susceptibility in Gujarat population (p = .359, p = .937, respectively).

Conclusions

The present study revealed altered VTCN1 and NRD1 expressions in the blood and skin of vitiligo patients, suggesting their potential role in the development and progression of Vitiligo.

KEYWORDS:

• Autoimmunity
• Nardilysin (NRD1)
• polymorphisms
• vitiligo
• VTCN1 (B7-H4)

Acknowledgments

RB thanks the Science and Engineering Research Board (SERB), Government of India (Grant No. EMR/2016/001565) for the financial support. We sincerely thank all the vitiligo patients and control subjects for their participation in the study. We acknowledge the use of the DST-FIST fluorescent microscope facility at the Department of Biochemistry (SR/FST/LS-II/2017/87). SJ thanks the University Grants Commission (UGC), New Delhi for providing SRF (Senior Research Fellowship).

Author contributions

RB and MS formulated the idea. JV, SJ, and RB designed the experiments. JV performed the experiments. FK and MY helped with experiments and data collection. JV and SJ analyzed the data. JV has written the original draft. SJ reviewed and edited the draft. RB helped with critical revision and approval of the manuscript. All the authors have read and agreed to the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/08820139.2022.2097091

Additional information

Funding

This work was supported by a grant to RB [EMR/2016/001565] SERB, New Delhi, India.