Biology of HLA class I associated inflammatory diseases

Abstract

Human leukocyte antigen (HLA) class I association is a well-established feature of common and uncommon inflammatory diseases, but it is unknown whether it impacts the pathogenesis of these disorders. The "arthritogenic peptide" hypothesis proposed initially for HLA-B27-associated ankylosing spondylitis (AS) seems the most intuitive to serve as a model for other HLA class I-associated diseases, but evidence supporting it has been scarce. Recent technological advances and the discovery of epistatic relationships between disease-associated HLA class I and endoplasmic reticulum aminopeptidase (ERAP) coding variants have led to the generation of new data and conceptual approaches to the problem requiring its re-examination. Continued success in these endeavors holds promise to resolve a Gordian Knot in human immunobiology. It may ultimately benefit patients by enabling the development of new therapies and precision tools for assessing disease risk and predicting treatment responses.

Keywords: Ankylosing spondylitis; Behçet disease; HLA association; HLA class I; HLA restriction; Psoriasis; Rheumatic disease; Uveitis.

Figure 1.

HLA (MHC) class I antigen presentation pathway. Proteins fragmented by the proteasome in the cytoplasm are translocated into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP). There, the aminopeptidase ERAP1 trims peptides from the N-terminal end for loading onto the major histocompatibility complex class I (MHC I). Peptide-MHC I complexes reach the cell surface through the secretory pathway, where they become visible to the T cell receptors (TCR) on CD8+ T cells. Canonical α/β TCR require specific peptide-MHC combinations for recognition – a phenomenon called MHC restriction.