한빛사 논문
A Reum Kim, DVM, PhD,a Dawoon Han MS,b Ji Young Choi MD,b Joon Seok MD,c SongEe Kim MS,b Seong-Hoon Seo MD,b Hayato Takahashi MD, PhD,d Masayuki Amagai MD, PhD,d Su-Hyung Park PhD,c Soo-Chan Kim MD, PhD,b,* Eui-Cheol Shin MD, PhD,a,* Jong Hoon Kim MD, PhD,b,*
aLaboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea;
bDepartment of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea;
cLaboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea;
dDepartment of Dermatology, Keio University School of Medicine, Tokyo, Japan;
*Corresponding author
Abstract
Background
Pemphigus vulgaris (PV) is an autoimmune bullous disease mediated by autoantibodies against desmoglein 3 (DSG3). Inducible T-cell costimulator (ICOS) is a costimulatory receptor expressed on T cells and influences the activity of T follicular helper (Tfh) cells in various autoimmune diseases, but the roles of ICOS and Tfh cells in PV remain unclear.
Objective
We examined the immunological characteristics, antigen specificity, and pathogenicity of CD4+ T cell subpopulations, and the therapeutic effect of anti-ICOS blocking antibodies in PV.
Methods
A mouse model of PV was established by adoptive transfer of immune cells from the skin-draining lymph nodes or spleens of DSG3-expressing skin-grafted DSG3–/– mice into RAG1–/– mice. The Tfh cells and CD4+ T cells in peripheral blood mononuclear cells from PV patients were examined by flow cytometry.
Results
Among CD4+ T cells from the mouse model, ICOS-positive Tfh cells were associated with B cell differentiation and required for disease induction. Using a major histocompatibility complex class II tetramer, DSG3-specific ICOS+ Tfh cells were found to be associated with anti-DSG3 antibody production and expanded in the absence of B cells. In human PV, the frequency of ICOS+CXCR5+PD-1+ memory CD4+ T cells correlated with the autoantibody level. Treatment with anti-ICOS blocking antibodies targeting ICOS+ Tfh cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo.
Conclusion
Mouse DSG3-specific ICOS+ Tfh cells and human ICOS+CXCR5+PD-1+ T helper cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5+PD-1+ T helper cells may be a therapeutic target for PV.
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TOP52020년 후보
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