Antibodies to MHC Class II Molecules Induce Autoimmunity: Critical Role for Macrophages in the Immunopathogenesis of Obliterative Airway Disease

Abstract

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.

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

“…A number of studies have suggested possible mechanistic effects of HLA-specific antibodies in the development of obstructive airway disease. [37][38][39][40][41] The majority of these studies utilized W6/32, a monoclonal antibody directed against a monomorphic determinant on HLA Class I molecules. Ligation of W6/32 to epithelial cells has been shown to cause cell proliferation, production of growth factors and chemotactic factors, as well as cell death through apoptosis.…”

“…However, the majority of DSA detected after lung transplantation are directed against HLA Class II molecules. A recent study by Takenaka et al 41 demonstrated that administration of a monoclonal antibody to Class II antigens led to the development of obstructive airway disease in a mouse model. Further work is required to understand the effects of antibodies to Class II antigens on epithelial cells and development of BOS.…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…While the mechanisms of AMR are not firmly established, de novo donor-specific antibodies against HLA have been shown to predispose to the development of immune responses to lung self-antigens and BOS (69)(70)(71). To define mechanisms leading to anti-MHC-mediated development of rejection, a preclinical murine model was developed in which exogenous anti-MHC was administered into the native lungs and elicited production of antibodies and T cell responses specific for lung-associated self-antigens, type V collagen [col(V)], and K-α 1 tubulin, culminating in fibrotic pathology (72,73). Human lung transplant recipients develop antibodies against col(V), a protein mainly located in the lung interstitium and not ordinarily exposed to the immune system.…”

CYP2J2 attenuates metabolic dysfunction in diabetic mice by reducing hepatic inflammation via the PPARγ

“…The infiltration of activated macrophages in liver tissue was assessed by immunohistochemistry staining of established macrophage markers, including F4/80 for mature macrophages, CD11C for classically activated (M1) macrophages, and CD206 for alternatively activated (M2) macrophages (6,21,50) to illustrate the hepatic inflammation response to diabetic pathology (27). Immunohistochemistry was performed as usual (63).…”