A-DRB1*03:01 and HLA-DRB1*0401, which represent the principal AIH susceptibility alleles among Europeans and Americans, and in the context of alleles HLA-DRB1*04:05 and HLA-DRB1*04:04, which are instead linked to AIH susceptibility in Japan, Argentina and Mexico [12,13]. In particular, a positively charged residue at position 71 in the context of the area 67?2 on the DR polypeptide corresponding to the LLEQ [K/R]R motif, which can be shared among the above mentioned HLA alleles, has been indicated as crucial for AIH susceptibility [14]. Recently, HLA-DRB1*03:01 transgenic mice had been immunized with SLA/LP, using the aim of identifying auto-antigenic SLA/LP peptides that are targeted by CD4+ T cells, and restricted by the illness susceptibility gene HLA-DRB1 *03:01 [15]. Interestingly, the observation that the C-terminal area of SLA/LP spanning residues 452?65 (sequence NRLDRCLKAVRKER), which was identified because the optimal CD4+ T cell epitope, overlaps together with the SLA/LP sequence that is definitely recognized by antibodies of sufferers with AIH suggests that the C-terminal region of SLA/LP isn’t only targeted by humoral, but also by cellular immune responses [4,15].4-(4-Bromophenyl)-1-methyl-1H-pyrazole site To date, the exact molecular mechanisms that initiate and retain the production of autoantibodies in AIH are not clear, though the exceptional uniformity in epitope recognition shown by SLA/LP autoantibodies suggests a frequent mechanism [16].313052-18-5 web Molecular mimicry amongst self-antigens and antigens from infectious agents has been suggested as a mechanism for the generation of autoantibodies [17]. For that reason, it has been hypothesised that autoimmunity towards the SLA/LP protein might be driven by viral/bacterial antigens, as an alternative to by the SLA/LP antigen itself [16]. Nevertheless, earlier attempts to look for proof of cross-reactivity of the immunodominant area that’s specifically recognized by SLA/LP autoantibodies with microbial antigens have already been unsuccessful [16],Paiardini and Pascarella Theoretical Biology and Healthcare Modelling 2013, ten:25 http://tbiomed/content/10/1/Page 3 ofleading to the conclusion that SLA/LP autoimmunity is autoantigen-driven, as an alternative to being driven by molecular mimicry [18]. The present study suggests that local sequence similarity amongst SLA/LP and a non-homologous bacterial protein from Rickettsia spp. can drive autoimmunity to SLA/LP, by way of initial CD4+ T cell recognition and subsequent humoral response.PMID:33600139 MethodsSequence analysisResidues encompassed by positions 450?95 of SLA/LP autoantigen (O-phosphoserine (Sep)-tRNA:selenocysteine (Sec)-tRNA synthase) from Homo sapiens [UniProt:Q9HD40, sequence variant AAD33963.two as outlined by [4]] had been employed as query in the non-redundant (nr) protein sequence database (GenBank CDS translations [19], PDB [20] and UniProtKB/ Swiss-Prot [21]) search, by suggests in the BLAST server [22]. Algorithm parameters had been kept at their default values except for word size, which was set to two to improve search sensibility. Sequence show and alignment relied around the system Jalview [23]. Secondary structure and solvent accessibility were predicted with JPred3 [24]. Predictions of intrinsically disordered regions (IDRs) have been carried out as described previously [25].Modeling of the interaction HLA-DRB1*03:01-peptideThe crystal structure of HLA-DRB1*03:01 [UniProt:P01912] in complex using a 15 residues fragment (87?01) of invariant chain referred to as CLIP was obtained by PDB [PDB:1A6A; [26]]. The CLIP fragment was subsequently applied as structural templat.