Non-HLA antigens include antigens expressed on endothelial, epithelial cells, parenchymal cells and circulating immune cells . Non HLA abs can be directed against auto- or allo-antigens and be either present pre-transplant or de novo formed post transplantation. Furthermore, The most reported Non-HLA abs include those directed against Angiotensin II Type 1 Receptor (AT1R-Ab), Endothelin Type A Receptor (ETAR), MHC Class I Chain-Related Antigen A (MICA-Ab), Vimentin (AVA), Tubulin (anti-Ka1 tubulin), Collagens (anti-Col) Anti Endothelial Cell Antibodies (AECA), anti-heat shock protein, and antiphospholipid. 

Moreover, the triggers of activation or transition of these Non-HLA abs toward pathogenicity are likely acute rejection, hypoperfusion, ischemia reperfusion, calcineurin toxicity, infection, and recurrent diseases. 

Non-HLA abs have a stronger role in graft dysfunction and rejection; Antibody-Mediated Rejection (AMR) or C4d deposition in the absence of circulating donor specific Non-HLA abs than previously thought . The aim of this review is to shed light on Non-HLA abs development, mechanism of action, clinical relevance, and treatment.