Abstract
Classical MHC class II (MHCII) proteins present peptides for CD4+ T-cell surveillance and are by far the most prominent risk factor for a number of autoimmune disorders. To date, many studies have shown that this link between particular MHCII alleles and disease depends on the MHCII's particular ability to bind and present certain peptides in specific physiological contexts. However, less attention has been paid to the non-classical MHCII molecule human leucocyte antigen-DM, which catalyses peptide exchange on classical MHCII proteins acting as a peptide editor. DM function impacts the presentation of both antigenic peptides in the periphery and key self-peptides during T-cell development in the thymus. In this way, DM activity directly influences the response to pathogens, as well as mechanisms of self-tolerance acquisition. While decreased DM editing of particular MHCII proteins has been proposed to be related to autoimmune disorders, no experimental evidence for different DM catalytic properties had been reported until recently. Biochemical and structural investigations, together with new animal models of loss of DM activity, have provided an attractive foundation for identifying different catalytic efficiencies for DM allotypes. Here, we revisit the current knowledge of DM function and discuss how DM function may impart autoimmunity at the organism level.
Highlights
The major histocompatibility complex (MHC), known as human leucocyte antigen (HLA), stands out in genome-wide association studies as the most prominent genetic locus for a number of human autoimmune disorders [1,2]
This study showed a clear decrease in the numbers of CD4þ T cells, as well as lowered MHC class II (MHCII) expression levels and structural differences between the MHCII molecules expressed in the wt nonobese diabetogenic (NOD) model versus the DM2/– mutant [15]
To what extent are our in vitro results translated into a proper cellular model of DM function, and, second to what extent do DM variants result in different levels of CD4þ T-cell activation? DM has an enzyme-like behaviour, it is essential to keep in mind that, in order to properly address this question, a system must be designed with as few differences in the natural DM/MHCII expression ratios as possible
Summary
The major histocompatibility complex (MHC), known as human leucocyte antigen (HLA), stands out in genome-wide association studies as the most prominent genetic locus for a number of human autoimmune disorders [1,2]. We have recently demonstrated the reduced activity of a particular polymorphism of a DMA allele (DMA*0103) relative 2 to the most abundant allele (DMA*0101), providing, for the first time, evidence for differential editing activity of natural variants of HLA-DM [12] In this context, while genetic association studies have failed to make a clear connection between natural variants of DM and disease, reduced levels of DM activity in certain cellular compartments [13], modulation by other nonclassical MHCII protein in murine models (HLA-DO [14]) and total loss of DM activity in an autoimmune-predisposing genetic background [15] have all been directly related to autoimmune conditioning. Difficulties in understanding the functional mechanism of HLA-DM, its low degree of polymorphism, and the complexity of the genetics of the MHC locus are likely to have hindered progress in investigating these topics, the putative contribution of DM natural variants to autoimmune disorders has been touched upon by several reviews in the field [16,17,18]
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