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Streptococcus mutans UA159, the genome sequence reference strain, exhibits nonlantibiotic mutacin activity. In this study, bioinformatic and mutational analyses were employed to demonstrate that the antimicrobial repertoire of strain UA159 includes mutacin IV (specified by the nlm locus) and a newly identified bacteriocin, mutacin V (encoded by SMU.1914c).

The HLA-DRB1 locus is strongly associated with rheumatoid arthritis (RA) susceptibility, whereupon citrullinated selfpeptides bind to HLA-DR molecules bearing the shared epitope (SE) amino acid motif. However, the differing propensity for citrullinated/noncitrullinated self-peptides to bind given HLA-DR allomorphs remains unclear. Here, we used a fluorescence polarisation assay to determine a hierarchy of binding affinities of 34 self-peptides implicated in RA against three HLA-DRB1 allomorphs (HLA-DRB1*04:01/*04:04/*04:05) each possessing the SE motif. For all three HLA-DRB1 allomorphs, we observed a strong correlation between binding affinity and citrullination at P4 of the bound peptide ligand. A differing hierarchy of peptide-binding affinities across the three HLA-DRB1 allomorphs was attributable to the b-chain polymorphisms that resided outside the SE motif and were consistent with sequences of naturally presented peptide ligands. Structure determination of eight HLA-DR4-self-epitope complexes revealed strict conformational convergence of the P4-Cit and surrounding HLA b-chain residues. Polymorphic residues that form part of the P1 and P9 pockets of the HLA-DR molecules provided a structural basis for the preferential binding of the citrullinated selfpeptides to the HLA-DR4 allomorphs. Collectively, we provide a molecular basis for the interplay between citrullination of self-antigens and HLA polymorphisms that shape peptide-HLA-DR4 binding affinities in RA. Sources for the primary RA-associated autoantigens may be from the site of disease including articular cartilage and synovial fluids (12-14) but others may be derived from blood plasma or surrounding mucosal tissues that are susceptible to inflammation (2). These proteins could undergo PTMs during numerous physiologic processes including infection, apoptosis and cellular stress. Some of the best-characterised autoantigens that bind ACPAs are citrullinated vimentin, fibrinogen, α-enolase and Type II collagen, which are present at high levels in the joint synovium (3,15).One of the key inherited risk factors that contribute to ACPA positive RA is the human leukocyte antigen (HLA) class II loci, namely HLA-DRB1, which encodes the HLA class II antigen presenting molecules (16-21). The antigen-binding groove of the HLA class II molecule can accommodate peptide ligands that vary in length, but the main pockets that interact most strongly with the bound peptide are P1, P4, P6, P7 and P9, which can accommodate the side chains of the peptide residues 1, 4, 6, 7 and 9 (22,23). A conserved amino acid sequence QKRAA, QRRAA, or RRRAA in position 70-74 of the HLA-DRB1 chain, known as the shared epitope (SE) motif, is highly prevalent (~90%) among ACPA seropositive patients (11,16). This SE motif defines the P4 pocket of the high-risk HLA-DRB1 RA-associated allomorphs. Subsequent GWAS studies have shown that two polymorphisms encoding β-chain residues at positions 11 and 13 at the base of the P4 pocket are also strongly associated with RA susceptibility (16)....

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Objective: The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with ACPA-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the "shared susceptibility epitope (SE)".

The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4+ T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22α and HLA-DQ2.2-Phe22α) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5–mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance.

Staphylococcus aureus is an opportunistic pathogen that produces many virulence factors. Two major families of which are the staphylococcal superantigens (SAgs) and the Staphylococcal Superantigen-Like (SSL) exoproteins. The former are immunomodulatory toxins that induce a Vβ-specific activation of T cells, while the latter are immune evasion molecules that interfere with a wide range of innate immune defences. The superantigenic properties of Staphylococcal enterotoxin-like X (SElX) have recently been established. We now reveal that SElX also possesses functional characteristics of the SSLs. A region of SElX displays high homology to the sialyl-lactosamine (sLacNac)-specific binding site present in a sub-family of SSLs. By analysing the interaction of SElX with sLacNac-containing glycans we show that SElX has an equivalent specificity and host cell binding range to the SSLs. Mutation of key amino acids in this conserved region affects the ability of SElX to bind to cells of myeloid origin and significantly reduces its ability to protect S. aureus from destruction in a whole blood killing (WBK) assay. Like the SSLs, SElX is up-regulated early during infection and is under the control of the S. aureus exotoxin expression (Sae) two component gene regulatory system. Additionally, the structure of SElX in complex with the sLacNac-containing tetrasaccharide sialyl Lewis X (sLeX) reveals that SElX is a unique single-domain SAg. In summary, SElX is an ‘SSL-like’ SAg.