Pathobiology of Non-HLA immunity in renal transplantation

Conventionally, major histocompatibility complex (MHC)-encoded human leukocyte antigens (HLAs) of a donor are considered as the principal targets of the recipient's immune system in renal transplantation (RT), and the clinical significance of anti-HLA allo-antibodies (Abs) is well established. In contrast, the importance of non-HLA immunity in RT is being increasingly recognized. Majority of non-HLA immune targets are the non-MHC-encoded proteins on vascular endothelial cells and exist as cryptic autoantigens. The synergistic triad of tissue injury, anti-HLA, and non-HLA immunity is involved in many cases of graft rejection and loss. The exact mechanisms by which the non-HLA auto-Abs are produced and induce graft injury are still speculative and under research. Understanding them enables the development of novel diagnostic assays and therapeutic strategies and thereby improves long-term graft outcomes. In this review, we discuss the pathobiology and novel mechanisms of non-HLA immunity in RT.