HLA-DMA

HLA-DMA encodes the alpha subunit of the HLA-DM heterodimer, a non-classical MHC class II molecule essential for peptide loading onto classical MHC class II molecules in antigen-presenting cells (PMID:8139690). HLA-DMA and HLA-DMB are both required for MHC class II/peptide complex formation; somatic cell mutants lacking functional DMA show defective class II/peptide assembly that is reversed by DMA cDNA transfection (PMID:8139690). Polymorphic residues in HLA-DMA directly modulate the catalytic rate of DM-mediated peptide exchange: the DMA*0103 variant (G155A) attenuates peptide release from MHC class II, increasing the half-life of preloaded peptide complexes and altering the antigenic peptide repertoire (PMID:25505276).

1. 1994 High

   The fundamental question of whether HLA-DMA encodes a functional gene product required for antigen presentation was resolved: DMA is an essential subunit of a heterodimer needed for MHC class II peptide loading.

   Evidence Somatic cell mutagenesis and cDNA complementation/rescue in antigen-presenting cell lines

   PMID:8139690

   Open questions at the time

   • Catalytic mechanism of DM-mediated peptide exchange not yet defined
   • Functional significance of DMA polymorphisms unknown
   • Subcellular site of DM action not resolved in this study
2. 1994 Medium

   Genomic characterization established that HLA-DMA shares the exon-intron organization of classical MHC class II genes but carries unique structural features in the membrane-proximal domain, positioning DM as an ancient divergent class II family member.

   Evidence Genomic sequencing and comparative gene organization analysis

   PMID:8034636

   Open questions at the time

   • Evolutionary timing of DM divergence from classical class II loci not precisely dated
   • Functional consequence of the exon 3 deletion/insertion not tested experimentally
3. 2014 High

   The open question of whether natural DMA polymorphisms affect DM catalytic function was answered: the DMA*0103 allele (G155A) reduces peptide exchange velocity approximately twofold, demonstrating that DMA variation tunes the peptide repertoire presented to CD4+ T cells.

   Evidence In vitro reconstituted peptide exchange and dissociation kinetics assays with site-specific DMA variants and HLA-DR/peptide complexes

   PMID:25505276

   Open questions at the time

   • Structural basis for how G155A attenuates catalytic activity not determined
   • In vivo impact of DMA polymorphisms on CD4+ T cell responses and autoimmunity susceptibility not directly demonstrated
   • Whether DMA polymorphisms affect interactions with HLA-DO (the endogenous DM inhibitor) is untested

• A structural mechanism explaining how DMA polymorphisms modulate the conformational rearrangement of MHC class II molecules during peptide exchange remains undefined, and the in vivo immunological consequences of DMA allelic variation have not been established.
• No high-resolution structure of DMA variant heterodimers in complex with MHC class II
• No in vivo studies linking DMA allelic variation to altered immune repertoire or disease susceptibility
• Interplay between DMA polymorphisms and HLA-DO regulation unexplored