HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis

Abstract

Summary The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4 + T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4 + T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila ), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4 + T cells in MS.

An Overview of the Crystallized Structures of the SARS-CoV-2

“…Moreover, the authors advance the hypothesis of the “hotspot” region in S for receptor binding. Further experiments with the polyclonal antibodies, confirm the differences between SARS-CoV-2 and SARS-CoV’ S glycoprotein [ 36 ].…”

“…The structural studies greatly advance the selection of the best immunogens for SARS-CoV-2 prophylaxis. A comparison of the HCoV suggests that the spike’s SARS-CoV-2-CTD domain could be a valid immunogen for a future vaccine [ 36 ]. The viral immune evasion depends on more than one factor and structural work of many research teams greatly advances the understanding of immune response.…”

“…The recent structural works provide insight into the nucleotide analog inhibitors’ ability to hamper SARS-CoV-2 RNA replication. The pre-translocated and post-translocated RdRp complex structures (PDB ID(s) 7C2K and 7BZF) show that an efficient inhibitory strategy could be the blocking of the interaction between nsp8 and nsp12 [ 45 ]. The biochemical and structural works of Peng et al .…”

Cross-reactivity between cancer and microbial antigens

“… 6 Multiple sclerosis (MS) has been epidemiologically associated with the presence of Akkermansia muciniphila in the gut, and HLA-DR15-restricted CD4 + T cells from MS patients can recognize peptides encoded by the A. muciniphila genome. 7 Finally, in the context of systemic lupus erythematosus (SLE), HLA-DR3 and HLA-DR15-restricted human Ro60 autoantigen–specific CD4 memory T cell clones are activated by bacteria that express an Ro60 orthologue. 9 As an alternative, bacteria may interact with host cells to elicit the expression of autoimmunity-relevant autoantigens, as documented for rheumatoid arthritis, in which leukotoxic Aggregatibacter actinomycetemcomitans strains involved in periodontitis cause neutrophils to produce and release citrullinated proteins, 8 and SLE, in which Enterococcus gallinarum translocates from the gut into the liver and causes hepatocytes to express the autoantigens ERV gp70 and β2GPI ( Table 1 ).…”

“… B. thetaiotaomicron monocolonization expressing the β-galactosidase epitope favors myocarditis development in mice expressing a MYH6- specific T cell receptor on more than 95% of their CD4 + T cells. 6 Multiple sclerosis (MS) Akkermansia muciniphila Epstein Barr virus (EBV) HLA-DR15 DR2a and Dr2b presenting peptides derived from themselves HLA-DR15 cross-reactive responses between autoreactive CD4 + T cells from an MS patients and peptides derived from A. muciniphila or EBV, which are both epidemiologically associated with MS 7 Rheumatoid arthritis (RA) Citrullination of host proteins following periodontitis by leukotoxic Aggregatibacter actinomycetemcomitans (Aa) strains Citrullinated host proteins in neutrophils Shared epitope (SE)-containing HLA-DRB1 alleles. Epidemiological association between anti-Aa antibodies, anti-citrullinated protein antibodies and rheumatoid factor 8 Systemic lupus erythematosus (SLE) Skin and mucosal bacteria expressing Ro60, in particular species of Corynebacterium, Propionibacterium , and Bacteroides Ro60 autoantigen HLA-DR3 and HLA-DR15 Human Ro60 autoantigen–specific CD4 memory T cell clones from lupus patients are activated by Ro60-containing bacteria.…”