HLA-1-opathies and peptides

Abstract

James R Archer*

It is almost 50 years since it was realised that specific HLA molecules are associated with numerous chronic inflammatory diseases [1]. The HLA-1-opathies were subsequently defined as a subgroup of these, characterized genetically by three specific genes - a class I HLA which controls the particular disease, ERAP1, coding an endopeptidase trimming the peptides included in the class I heterotrimer and IL23R, coding part of the IL23 receptor, which affects the strength and nature of the inflammatory response [2]. Originally, the most obvious association was of the class I molecule HLA B27 with the arthritic disease ankylosing spondylitis (AS), which is now included in axial spondyloarthropathy (axSpa) [3,4]. As it was assumed that HLA molecules were involved in protection from infection, extensive efforts were made to identify microbial agents causing these diseases. Currently, however, although many associations are still being found, no foreign agent has been identified as a plausible explanation for the pathology. This paper offers an alternative hypothesis, questioning the assumption that cells invariably produce sufficient peptides to complete HLA class 1 heterotrimers and emphasising the role of self proteins, together with explanations for why the microbial data have caused so much confusion. It suggests new targets for the development of therapies.

HTML PDF