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9.A.75.  The MHC II Receptor (MHC2R) Family 

This family consists of a complex of 3 proteins, DQ α-1, DQ β-1, which together comprise a heterodimer, and CD74, a homotrimer that forms a nanomeric complex with three DQ α/β dimers.  CD74 plays a role in MHC class II antigen processing by stabilizing the peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis, and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II (DG α-1/DG β-1) takes place. CD74 also serves as cell surface receptor for the cytokine MIF.  MHC II binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. The removal of the CD74-derived CLIP peptide is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO (Jiang et al. 2019; Santambrogio et al. 2019; Jurewicz and Stern 2019; Dijkstra and Yamaguchi 2019).

As noted above, an alpha and a beta subunit, also referred as MHC class II molecule, forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases, leaving a small fragment termed CLIP  (see above) on each MHC class II molecule. An MHC class II molecule interacts with HLA_DM, and HLA_DO in the B-cells, in order to release CLIP and facilitate the binding of antigenic peptides (Lee et al. 2001; Siebold et al. 2004; Kim et al. 2004; Henderson et al. 2007).

References associated with 9.A.75 family:

Dijkstra, J.M. and T. Yamaguchi. (2019). Ancient features of the MHC class II presentation pathway, and a model for the possible origin of MHC molecules. Immunogenetics 71: 233-249. 30377750
Harvey, I.B., X. Wang, and D.H. Fremont. (2019). Molluscum contagiosum virus MC80 sabotages MHC-I antigen presentation by targeting tapasin for ER-associated degradation. PLoS Pathog 15: e1007711. 31034515
Henderson, K.N., J.A. Tye-Din, H.H. Reid, Z. Chen, N.A. Borg, T. Beissbarth, A. Tatham, S.I. Mannering, A.W. Purcell, N.L. Dudek, D.A. van Heel, J. McCluskey, J. Rossjohn, and R.P. Anderson. (2007). A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. Immunity 27: 23-34. 17629515
Jiang, J., K. Natarajan, and D.H. Margulies. (2019). MHC Molecules, T cell Receptors, Natural Killer Cell Receptors, and Viral Immunoevasins-Key Elements of Adaptive and Innate Immunity. Adv Exp Med Biol 1172: 21-62. 31628650
Jurewicz, M.M. and L.J. Stern. (2019). Class II MHC antigen processing in immune tolerance and inflammation. Immunogenetics 71: 171-187. 30421030
Kim, C.Y., H. Quarsten, E. Bergseng, C. Khosla, and L.M. Sollid. (2004). Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc. Natl. Acad. Sci. USA 101: 4175-4179. 15020763
Lee, K.H., K.W. Wucherpfennig, and D.C. Wiley. (2001). Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol 2: 501-507. 11376336
Peng, F., H. Zhang, X. He, and Z. Song. (2023). Early flora colonization affects intestinal immunoglobulin G uptake in piglets, which may be mediated by NF-κB-FcRn pathway. Front Microbiol 14: 1136513. 36865776
Petersen, J.L., H.D. Hickman-Miller, M.M. McIlhaney, S.E. Vargas, A.W. Purcell, W.H. Hildebrand, and J.C. Solheim. (2005). A charged amino acid residue in the transmembrane/cytoplasmic region of tapasin influences MHC class I assembly and maturation. J Immunol 174: 962-969. 15634919
Sadegh-Nasseri, S., M. Chen, K. Narayan, and M. Bouvier. (2008). The convergent roles of tapasin and HLA-DM in antigen presentation. Trends Immunol 29: 141-147. 18261958
Salnikov, E.S., C. Aisenbrey, B. Pokrandt, B. Brügger, and B. Bechinger. (2019). Structure, Topology, and Dynamics of Membrane-Inserted Polypeptides and Lipids by Solid-State NMR Spectroscopy: Investigations of the Transmembrane Domains of the DQ Beta-1 Subunit of the MHC II Receptor and of the COP I Protein p24. Front Mol Biosci 6: 83. 31608287
Santambrogio, L., S.J. Berendam, and V.H. Engelhard. (2019). The Antigen Processing and Presentation Machinery in Lymphatic Endothelial Cells. Front Immunol 10: 1033. 31134089
Saunders, P.M. and P. van Endert. (2011). Running the gauntlet: from peptide generation to antigen presentation by MHC class I. Tissue Antigens 78: 161-170. 21736566
Siebold, C., B.E. Hansen, J.R. Wyer, K. Harlos, R.E. Esnouf, A. Svejgaard, J.I. Bell, J.L. Strominger, E.Y. Jones, and L. Fugger. (2004). Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc. Natl. Acad. Sci. USA 101: 1999-2004. 14769912
Wosen, J.E., D. Mukhopadhyay, C. Macaubas, and E.D. Mellins. (2018). Epithelial MHC Class II Expression and Its Role in Antigen Presentation in the Gastrointestinal and Respiratory Tracts. Front Immunol 9: 2144. 30319613