MHC class I signaling: new functional perspectives for an old molecule

Abstract

Donor specific antibodies are associated with refractory rejection episodes and poor allograft outcomes in solid organ transplantation. Our understanding of antibody mediated allograft injury is expanding beyond complement deposition. In fact, unique mechanisms of alloantibodies are advancing our knowledge about transplant vasculopathy and antibody mediated rejection. These include direct effects on the endothelium, resulting in the recruitment of leukocytes, chemokine and cytokine production, and stimulation of innate and adaptive alloresponses. These effects will be the focus of the following review.

Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation

“…[21][22][23] Furthermore, MHC ligation of endothelial cells with and without the help of integrin-β4 can lead to a vasculopathy through complementindependent mechanisms that include: (a) signaling cascades, such as FAK, SCR, PI3k, AKT, mTORC1 [(Raptor) GbL (mTOR)], S6k and S6RP, which cause endothelial/smooth muscle cells to proliferate and release inflammatory mediators; (b) exocytosis of granules containing von Willebrand factor (vWF) and P-selectin, which cause platelet activation and inflammation; (c) up-regulation of fibroblastlike growth factor receptor (FGFR)/FGF biology and its downstream MEK and ERK pathways leading to endothelial/ smooth muscle cell proliferation; and (d) up-regulation of endothelial cell expression of chemokines, which recruit NK cells that express IFN-γ-inducing cells to express more MHC Class I and II, generating further alloimmunity. 3,[21][22][23][24][25][26][27][28][29][30][31] Alternatively, the Fc portion of antibodies can interact with leukocytes via Fc-receptors (FcR) initiating antibodydependent cellular cytotoxicity (ADCC), opsonization and cytokine/chemokine expression, all of which exaggerate allograft damage. 3,[21][22][23][24][25][26][27][28][29] Last, autoantibodies (e.g., vimentin, collagen V, perlecan, Kα1-tubulin, AT1R and MICA) can also cause significant allograft damage as well as amplify alloantibody damage.…”

Donor-specific HLA Antibodies Are Associated With Late Allograft Dysfunction After Pediatric Liver Transplantation

“…DSA also promote allograft damage via complement independent mechanisms. Crosslinking of HLA class I antigens by antibodies triggers intracellular signaling pathways resulting in endothelial cell and smooth muscle cell proliferation (12). HLA ligation also induces Weibel Palade Body exocytosis, p-Selectin expression, and recruitment of leukocytes to the allograft (13).…”

Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types

“…The role of reverse MHC-I signaling in endothelial cells has been reviewed extensively in the context of transplant vasculopathy and concomitant tissue rejection. Specifically, alloantibodies generated by the transplant recipient against MHC-I and MHC-II alloantigens present in the transplanted tissue have been linked to endothelial cell proliferation, survival and migration that can be accompanied by recruitment of inflammatory cells into the transplanted tissue (5,7,10,100,101). The organ recipient develops antibodies not only against MHC-I, but also against different types of alloantigens.…”

“…MHC-I reverse signaling has been observed in multiple cell types, ranging from immune cells, such as macrophages, NK cells, T cells, and B cells, to non-immune cells like endothelial and smooth muscle cells (7,8). Furthermore, reverse MHC-I signaling has been investigated in the context of viral and bacterial infections (6,9), transplantation immunity (10), malignancies (11), and brain development (12). Here, we review the evidence for the alternative role of MHC-I as reverse signaling molecules across immune and non-immune cells.…”