Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects

J Allergy Clin Immunol. 2018 Dec;142(6):1818-1830.e6. doi: 10.1016/j.jaci.2018.03.014. Epub 2018 Apr 26.


Background: Regulatory T (Treg) cells play a crucial role in peripheral immune tolerance in multiple organs, including the skin. Thus far, the effect of peripheral immune tolerance failure on autoantibody-related autoimmune reactions to the skin is unclear.

Objective: We sought to elucidate the target autoantigens in the skin under the condition of Treg cell dysfunction caused by forkhead box P3 (Foxp3) gene mutations in scurfy mice and patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.

Methods: Sera and skin from scurfy mice and sera from patients with IPEX syndrome were analyzed to detect target autoantigens by using immunofluorescence studies, ELISAs, and immunoblotting. The pathogenicity of scurfy IgG was examined by using a passive transfer experiment. CD4+ T cells from scurfy mice were transferred to immunodeficient mice to examine their pathogenicity. Signal transducer and activator of transcription 6 (Stat6)-/- scurfy mice were analyzed to further clarify the molecular pathway of autoantibody production. Follicular helper T-cell counts are measured in Stat6-/- scurfy mice and scurfy mice.

Results: Scurfy mice spontaneously generated IgG autoantibodies to the dermal-epidermal junction, which had been class-switched from IgM within 12 days after birth. The target autoantigens were murine BP230 and type XVII collagen (COL17). The scurfy polyclonal autoantibodies did not induce skin fragility in neonatal mice. Autoantibody production was induced by CD4+ T cells from scurfy mice and was ameliorated by Stat6 gene knockout in association with a decrease of follicular helper T cells. We also identified autoantibodies to COL17 and BP230 in patients with IPEX syndrome and found an association between production of autoantibodies to COL17 and an eczematous skin phenotype.

Conclusions: Dysregulation of Treg cells generates autoantibodies to COL17 and BP230 in vivo.

Keywords: BP230; Regulatory T cell; X-linked syndrome; bullous pemphigoid; enteropathy; immunodysregulation; polyendocrinopathy; scurfy mouse; signal transducer and activator of transcription 6; type XVII collagen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology*
  • Autoantigens / immunology*
  • Collagen Type VII / immunology*
  • Diabetes Mellitus, Type 1 / congenital*
  • Diabetes Mellitus, Type 1 / immunology
  • Diarrhea / immunology*
  • Dystonin / immunology*
  • Female
  • Forkhead Transcription Factors / genetics
  • Genetic Diseases, X-Linked / immunology*
  • Humans
  • Immune System Diseases / congenital*
  • Immune System Diseases / immunology
  • Immunoglobulin G / immunology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • STAT6 Transcription Factor / genetics
  • T-Lymphocytes, Regulatory / immunology*


  • Autoantibodies
  • Autoantigens
  • Collagen Type VII
  • DST protein, human
  • Dystonin
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Immunoglobulin G
  • STAT6 Transcription Factor

Supplementary concepts

  • Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome