Antibodies to MHC class II molecules induce autoimmunity: critical role for macrophages in the immunopathogenesis of obliterative airway disease

PLoS One. 2012;7(8):e42370. doi: 10.1371/journal.pone.0042370. Epub 2012 Aug 10.


Previous studies have shown that intrabronchial administration of antibodies (Abs) to MHC class I resulted in development of obliterative airway disease (OAD), a correlate of chronic human lung allograft rejection. Since development of Abs specific to mismatched donor HLA class II have also been associated with chronic human lung allograft rejection, we analyzed the role of Abs to MHC class II in inducing OAD. Administration of MHC class II Abs (M5/114) to C57BL/6 mice induced the classical features of OAD even though MHC class II expression is absent de novo on murine lung epithelial and endothelial cells. The induction of OAD was accompanied by enhanced cellular and humoral immune responses to self-antigens (Collagen V and K- α1Tubulin). Further, lung-infiltrating macrophages demonstrated a switch in their phenotype predominance from MΦ1 (F4/80(+)CD11c(+)) to MΦ2 (F4/80(+)CD206(+)) following administration of Abs and prior to development of OAD. Passive administration of macrophages harvested from animals with OAD but not from naïve animals induced OAD lesions. We conclude that MHC class II Abs induces a phenotype switch of lung infiltrating macrophages from MΦ1 (F4/80(+)CD11c(+)) to MΦ2 (F4/80(+)CD206(+)) resulting in the breakdown of self-tolerance along with an increase in autoimmune Th17 response leading to OAD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoantibodies / administration & dosage
  • Autoantibodies / immunology*
  • Autoantigens / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology*
  • Bronchiolitis Obliterans / genetics
  • Bronchiolitis Obliterans / immunology*
  • Bronchiolitis Obliterans / pathology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation / immunology
  • Chemokines / immunology
  • Disease Models, Animal
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology*
  • Immunity, Cellular
  • Immunity, Humoral
  • Immunophenotyping
  • Lung / immunology
  • Lung / pathology
  • Macrophage Activation / immunology
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Chemokine / immunology
  • Th17 Cells / cytology
  • Th17 Cells / immunology


  • Autoantibodies
  • Autoantigens
  • Chemokines
  • Histocompatibility Antigens Class II
  • Receptors, Chemokine