Human leukocyte Antigen-DM polymorphisms in autoimmune diseases

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.

Quantification of HLA-DM-Dependent Major Histocompatibility Complex of Class II Immunopeptidomes by the Peptide Landscape Antigenic Epitope Alignment Utility

“…Given the importance of DM expression in the display of epitopes related to autoimmunity ( 19 ), we inspected whether any autoimmune-related epitopes were found in our dataset, and how DM expression influences their display (Table 4 ). High expression levels of DM increase three previously reported autoimmune-related epitopes from the cytoplasmic actin 1 (actin B; epitope: AEREIVRDIKEKL), the GTP-binding nuclear protein Ran (epitope: APPEVVMDPALAAQYEH), and from the Lysosome-associated membrane glycoprotein 1 (LAMP1; epitope: LNTILPDARDPAFK) ( 32 – 34 ).…”

“…In this context, the development of LFQ-based approaches to group and quantify nested consensus epitopes would help to overcome such limitations ( 17 ). Here, we introduce a Python algorithm to define sets of nested peptides from MHCII-eluted peptides identified and quantified by MS. We apply this algorithm to determine the impact of different expression levels of the MHCII master peptide editor HLA-DM ( 18 , 19 ) on the immunopeptidome presented by HLA-DR3. Nested peptides are used to retrieve the core antigenic sequences based on per -residue summed intensities.…”

Immunoglobulin Binding Protein 1 as a Potential Urine Biomarker in Patients with Lupus Nephritis

“…IL-7R is a T-cell activation-related molecule and may function as a surrogate marker of LN activity [40]. Among the genes upregulated by siRNA-mediated silencing, HLA-DM plays a key role in MHC class II antigen presentation and CD4 + T-cell epitope selection [41]. Further, polymorphisms of HLA-DM alleles were found frequently in SLE patients [42,43].…”

Revisiting nonclassical HLA II functions in antigen presentation: Peptide editing and its modulation

“…The function of DM and DO has been evaluated and correlated to clinical conditions mostly upon investigation in settings restricted to specific peptides. The influence of DM has been studied in the context of the editing of epitopes related to autoimmunity, allergy or infection (eg, GAD65, CII, Insulin, BetV1, MTB) and for DO, on the display of self‐antigens related to allogenic stem cell transplantation (reviewed in Reference 93). While extremely appealing, the sometimes‐contradictory effects of DM and/or DM/DO complicate the assessment of a preferential function on editing epitopes related to a particular disease.…”

“…Of note, the MHCII locus in the mouse shows relevant differences with regard to humans. Mice only have H2‐A , or H2‐A and H2‐E genes (orthologues of DQ and DR, respectively), and there are two H2‐DMb genes which seems to be differentially expressed in response to cytokines but yield functionally active H2‐DM heterodimers (reviewed in Reference 93).…”