title: Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity.
abstract: More than one third of patients with chronic lung disease undergoing lung transplantation have pre-existing Abs against lung-restricted self-Ags, collagen type V (ColV), and k-α1 tubulin (KAT). These Abs can also develop de novo after lung transplantation and mediate allograft rejection. However, the mechanisms leading to lung-restricted autoimmunity remain unknown. Because these self-Ags are normally sequestered, tissue injury is required to expose them to the immune system. We previously showed that respiratory viruses can induce apoptosis in CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), the key mediators of self-tolerance. Therefore, we hypothesized that lung-tissue injury can lead to lung-restricted immunity if it occurs in a setting when Tregs are impaired. We found that human lung recipients who suffer respiratory viral infections experienced a decrease in peripheral Tregs. Pre-existing lung allograft injury from donor-directed Abs or gastroesophageal reflux led to new ColV and KAT Abs post respiratory viral infection. Similarly, murine parainfluenza (Sendai) respiratory viral infection caused a decrease in Tregs. Intratracheal instillation of anti-MHC class I Abs, but not isotype control, followed by murine Sendai virus infection led to development of Abs against ColV and KAT, but not collagen type II (ColII), a cartilaginous protein. This was associated with expansion of IFN-γ-producing CD4(+) T cells specific to ColV and KAT, but not ColII. Intratracheal anti-MHC class I Abs or hydrochloric acid in Foxp3-DTR mice induced ColV and KAT, but not ColII, immunity, only if Tregs were depleted using diphtheria toxin. We conclude that tissue injury combined with loss of Tregs can lead to lung-tissue-restricted immunity.
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Stephen
authors.identifier: 0000-0003-2759-9394
authors.initials: S
authors.lastname: Chiu
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Ramiro
authors.identifier: 0000-0002-0590-3773
authors.initials: R
authors.lastname: Fernandez
authors.affiliation: Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Vijay
authors.initials: V
authors.lastname: Subramanian
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Malcolm M
authors.initials: MM
authors.lastname: DeCamp
authors.affiliation: Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kreisel
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.affiliation: Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and abharat@nm.org.
authors.forename: Ankit
authors.initials: A
authors.lastname: Bharat
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008168:Lung / Q000276:immunology*; D055370:Lung Injury / Q000276:immunology*; D016040:Lung Transplantation; D051379:Mice; D010253:Respirovirus Infections / Q000276:immunology*; D029082:Sendai virus / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; C508017:IL2RA protein, human; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma