HLA-DM

HLA-DM (Human Leukocyte Antigen – DM), also known as MHC class II molecule, DM isoform, is an intracellular protein that plays a crucial role in antigen processing and presentation within the adaptive immune system. Specifically, HLA-DM is a non-classical MHC class II molecule, meaning it does not directly present antigenic peptides on the cell surface for T cell recognition. Instead, it functions as a chaperone molecule, facilitating the loading of antigenic peptides onto other MHC class II molecules, namely HLA-DR, HLA-DP, and HLA-DQ.

Function:

The primary function of HLA-DM is to edit the peptide repertoire of MHC class II molecules within endosomal compartments of antigen-presenting cells (APCs), such as B cells, macrophages, and dendritic cells. Here's a more detailed breakdown:

• Release of CLIP: Newly synthesized MHC class II molecules are associated with a protein called the class II-associated invariant chain peptide (CLIP) within the endoplasmic reticulum. CLIP blocks the peptide-binding groove, preventing premature binding of peptides in the ER. As the MHC class II/CLIP complex travels to the endosome, the invariant chain is degraded, leaving CLIP in the groove. HLA-DM facilitates the removal of CLIP from the MHC class II molecule.

• Peptide Exchange: Once CLIP is removed, the MHC class II molecule is now free to bind antigenic peptides derived from proteins that have been internalized by the APC. HLA-DM stabilizes the peptide-free MHC class II molecule, making it more receptive to binding peptides with high affinity. It also promotes the release of peptides with low affinity, ensuring that only stable peptide-MHC class II complexes are presented on the cell surface.

• Optimization of Peptide Presentation: By mediating peptide editing, HLA-DM ensures that MHC class II molecules present peptides that are most likely to elicit a strong and specific T cell response. This contributes to the efficiency and accuracy of adaptive immunity.

Structure and Expression:

HLA-DM is a heterodimer consisting of two subunits, HLA-DMA and HLA-DMB. These subunits are encoded by genes located within the major histocompatibility complex (MHC) region on chromosome 6. HLA-DM is primarily expressed in professional APCs, where it resides within endosomal compartments.

Clinical Significance:

Mutations or deficiencies in HLA-DM can lead to defects in antigen presentation and impaired T cell activation. This can result in increased susceptibility to infections and potentially contribute to the development of autoimmune diseases. Research suggests a role for HLA-DM polymorphisms in influencing the course and severity of certain autoimmune conditions. Studies also explore HLA-DM as a potential target for therapeutic interventions in immune-related disorders.