DR15 Associated Diseases
Autoimmune Disease Platform
Target Disease-Associated MHC Class II
Autoimmune diseases are genetically associated with specific MHC class II molecules
- Precision medicine concept: treat patients who carry disease-associated MHC with inhibitors of MHC-antigen binding
Autoimmune Disease
- Multiple Sclerosis
- Goodpasture’s disease
- Prodromal Parkinson’s
- D. Sulzer; D. Agalliu (Columbia) Prodromal Parkinson’s is linked to α-synuclein antigen binding to DR15 (Garretti et al., 2023, Neuron 111, 3397–3413)
- Lupus nephritis, PR3-ANCA
Associated MHC II
- DR15 (DRB1*15:01/DRB5*01:01)
- DR15 (DRB1*15:01/ DRB5*01:01)
- Rheumatoid arthritis, Pemphigus
- Celiac disease
- Type 1 diabetes
- Pemphigus vulgaris
- Lupus (SLE)
- DR4 DR1
- DQ2
- DQ2 DQB
- DR4
- DR3
Other Autoimmune Disease Targets
Disease association
HLA DR1 (DRB1*0101) and DR4 (DRB1*0401)
- Rheumatoid Arthritis (80+% of patients)
- Pemphigus vulgaris (DRB1*0402)
- Hashimoto thyroiditis (DR4), autoimmune hepatitis (DRB1*0401)
- Lyme arthritis (DRB1*0401), etc.
Celiac/Type 1 Diabetes (DQ)
- HLA DQ2 is highly associated with celiac disease (98% DQ2)
- DQ8 is associated with type 1 diabetes
Provid strategy to target disease-associated alleles
Differences in the binding site characteristics of several MHC class II molecules in complex with peptide antigens have been observed in X-ray crystal structures. These characteristics for DR1, DR4, DQ2 and DQ8 are evident in the pockets that interact with the peptide antigens. These offer opportunities for extension of the Provid strategy to additional autoimmune diseases.
References
HLA DRB1*01:01 DR1
–Stern LJ , Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide, Nature. 1994 Mar 17;368(6468):215-21.
HLA DRB1*04:01 DR4
–Dessen A, Lawrence CM, Cupo S, Zaller DM, Wiley DC. X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity. 1997 Oct;7(4):473-81.
–Bolin DR, Swain AL, Sarabu R, Berthel SJ, Gillespie P, Huby NJ, Makofske R, Orzechowski L, Perrotta A, Toth K, Cooper JP, Jiang N, Falcioni F, Campbell R, Cox D, Gaizband D, Belunis CJ, Vidovic D, Ito K, Crowther R, Kammlott U, Zhang X, Palermo R, Weber D, Guenot J, Nagy Z, Olson GL. Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures. J Med Chem. 2000 Jun 1;43(11):2135-48.
HLA DQB1*02:01 DQ2
–Structure of HLA-DQ2 with the gliadin epitope (QLQPFPQPELPY) Kim, C. Y., Quarsten, H., Bergseng, E., Khosla, C. & Sollid, L. M. (2004) Proc Natl Acad Sci U S A 101, 4175-9
HLA DQB1*03:02 DQ8
–Lee KH, Wucherpfennig KW, Wiley DC. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol. 2001 Jun;2(6):501-7. doi: 10.1038/88694. Erratum in: Nat Immunol 2001 Sep;2(9):889.
