A shift in the collagen V antigenic epitope leads to T helper phenotype switch and immune response to self-antigen leading to chronic lung allograft rejection

V. Tiriveedhi, N. Angaswamy, David Brand, J. Weber, A. G. Gelman, R. Hachem, E. P. Trulock, B. Meyers, G. Patterson, T. Mohanakumar

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Abstract

Immune responses to human leucocyte antigen (HLA) and self-antigen collagen V (Col-V) have been proposed in the pathogenesis of chronic rejection (bronchiolitis obliterans syndrome, BOS) following human lung transplantation (LTx). In this study, we defined the role for the shift in immunodominant epitopes of Col-V in inducing T helper phenotype switch leading to immunity to Col-V and BOS. Sera and lavage from BOS + LTx recipients with antibodies to Col-V were analysed. Two years prior to BOS, patients developed antibodies to both Col-V,α1(V) and α2(V) chains. However, at clinical diagnosis of BOS, antibodies became restricted to α1(V). Further, lung biopsy from BOS(+) patients bound to antibodies to α1(V), indicating that these epitopes are exposed. Fourteen Col-V peptides [pep1-14, pep1-4 specific to α1(V), pep5-8 to α1,2(V) and pep9-14 to α2(V)] which bind to HLA-DR4 and -DR7, demonstrated that prior to BOS, pep 6, 7, 9, 11 and 14 were immunodominant and induced interleukin (IL)-10. However, at BOS, the response switched to pep1, 4 and 5 and induced interferon (IFN)-γ and IL-17 responses, but not IL-10. The T helper (Th) phenotype switch is accompanied by decreased frequency of regulatory T cells (T regs) in the lavage. LTx recipients with antibodies to α1(V) also demonstrated increased matrix metalloproteinase (MMP) activation with decreased MMP inhibitor, tissue inhibitor of metalloproteinase (TIMP), suggesting that MMP activation may play a role in the exposure of new Col-V antigenic epitopes. We conclude that a shift in immunodominance of self-antigenic determinants of Col-V results in induction of IFN-γ and IL-17 with loss of tolerance leading to autoimmunity to Col-V, which leads to chronic lung allograft rejection.

Original languageEnglish (US)
Pages (from-to)158-168
Number of pages11
JournalClinical and Experimental Immunology
Volume167
Issue number1
DOIs
StatePublished - Jan 1 2012

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Bronchiolitis Obliterans
Autoantigens
Allografts
Epitopes
Collagen
Phenotype
Lung
Antibodies
Interleukin-17
Therapeutic Irrigation
HLA Antigens
Matrix Metalloproteinases
Interleukin-10
Interferons
Tissue Inhibitor of Metalloproteinases
Immunodominant Epitopes
Matrix Metalloproteinase Inhibitors
Lung Transplantation
Regulatory T-Lymphocytes
Autoimmunity

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

A shift in the collagen V antigenic epitope leads to T helper phenotype switch and immune response to self-antigen leading to chronic lung allograft rejection. / Tiriveedhi, V.; Angaswamy, N.; Brand, David; Weber, J.; Gelman, A. G.; Hachem, R.; Trulock, E. P.; Meyers, B.; Patterson, G.; Mohanakumar, T.

In: Clinical and Experimental Immunology, Vol. 167, No. 1, 01.01.2012, p. 158-168.

Research output: Contribution to journalArticle

Tiriveedhi, V. ; Angaswamy, N. ; Brand, David ; Weber, J. ; Gelman, A. G. ; Hachem, R. ; Trulock, E. P. ; Meyers, B. ; Patterson, G. ; Mohanakumar, T. / A shift in the collagen V antigenic epitope leads to T helper phenotype switch and immune response to self-antigen leading to chronic lung allograft rejection. In: Clinical and Experimental Immunology. 2012 ; Vol. 167, No. 1. pp. 158-168.
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AU - Weber, J.

AU - Gelman, A. G.

AU - Hachem, R.

AU - Trulock, E. P.

AU - Meyers, B.

AU - Patterson, G.

AU - Mohanakumar, T.

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