HLA and kidney disease: from associations to mechanisms

Abstract

Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases.

Revisiting the association between human leukocyte antigen and end-stage renal disease

“…In the majority of the previous works, ESRD patients waiting for kidney transplantation were examined. Nonetheless, there are several contradictions in these studies, and no consistent trend on the association between different HLA alleles and ESRD was observed [1]. It has been suggested that a few HLA alleles may affect the severity of kidney disease or risk of progression [1].…”

“…Nonetheless, there are several contradictions in these studies, and no consistent trend on the association between different HLA alleles and ESRD was observed [1]. It has been suggested that a few HLA alleles may affect the severity of kidney disease or risk of progression [1]. For instance, specific HLA alleles could promote a more generalized pro-fibrogenic T cell phenotype that may contribute to disease progression or onset [1].…”

“…A wide array of research works have indicated associations between human leukocyte antigen (HLA) status and various kidney diseases [1]. Few of these disorders are immune-mediated, while, in others, the pathogenesis is unclear or the relevance of HLA is not entirely understood.…”

Cathepsin S and Protease-Activated Receptor-2 Drive Alloimmunity and Immune Regulation in Kidney Allograft Rejection

“…Presentation of alloantigen's is a central path mechanism of alloimmunity and involves MHC class II molecules on professional antigen-presenting cells (Borges et al, 2016;Robson et al, 2018). Within antigen-presenting cells, the maturation of MHC class II molecules is tightly regulated, whereby the invariant chain covers the peptide-binding domain up to when peptide loading occurs and the molecule is shuttled to the cell surface (Roche and Frusta, 2015;Robson et al, 2018).…”

“…Presentation of alloantigen's is a central path mechanism of alloimmunity and involves MHC class II molecules on professional antigen-presenting cells (Borges et al, 2016;Robson et al, 2018). Within antigen-presenting cells, the maturation of MHC class II molecules is tightly regulated, whereby the invariant chain covers the peptide-binding domain up to when peptide loading occurs and the molecule is shuttled to the cell surface (Roche and Frusta, 2015;Robson et al, 2018). Cathepsin (Cat-) S is one of several proteases that chop the invariant chain in a stepwise process (Shi et al, 1999;Roche and Frusta, 2015); hence, Cat-S deficiency or pharmaceutical Cat-S inhibition prevents MHC class II-mediated (auto)antigen presentation (Rise et al, 1996(Rise et al, , 1998Dresden et al, 1999;Saugus et al, 2002;Stickle et al, 2012).…”