Molecular dynamics simulations provide molecular insights into the role of HLA-B51 in Behçet's disease pathogenesis.

Behçet's disease is an inflammatory disorder of unknown etiology. Genetic tendency has an important role in its pathogenesis, and HLA-B51, a class I MHC antigen, has been recognized as the strongest susceptibility factor for Behçet's disease. Despite the confirmation of the association of HLA-B51 with Behçet's disease in different populations, its pathogenic mechanisms remain elusive. HLA-B51 differs in only two amino acids from HLA-B52, other split antigen of HLA-B5, which is not associated with Behçet's disease. These two amino acids are located in the B pocket of the antigen-binding groove, which occupies the second amino acids of the bound peptides. To understand the nature of the HLA-peptide interactions, differences in structure and dynamics of two HLA alleles were investigated by molecular dynamics simulations using YAYDGKDYI, LPRSTVINI, and IPYQDLPHL peptides. For HLA-B51, all bound peptides fluctuated to larger extent than HLA-B52. Free energy profiles of unbinding process for YAYDGKDYI by steered molecular dynamics simulations showed that unbinding from HLA-B52 results in greater free energy differences than HLA-B51. These results suggest the possibility of an instability of HLA-B51 associated with the repertoire of peptides, and this finding may provide significant insight to its pathogenic role in Behçet's disease.

Reduced Risk of BK Polyomavirus Infection in HLA-B51-positive Kidney Transplant Recipients.

BACKGROUND: Identification of specific HLA alleles and T-cell epitopes that influence the course of BK polyomavirus (BKPyV) infection after kidney transplantation (KTx), including development of BKPyV-associated nephropathy (BKPyVAN), can be useful for patient risk stratification and possibly vaccine development. METHODS: In a retrospective cohort of 407 living kidney donor-recipient pairs, donor and recipient HLA class I and II status were correlated with the occurrence of recipient BKPyV viremia and BKPyVAN in the first year after KTx. Relevant HLA alleles were systematically analyzed for candidate peptide epitopes in silico. RESULTS: Although none of the 78 HLA alleles analyzed increased the risk of BKPyV viremia and BKPyVAN, a considerable reduction of BKPyV viremia and BKPyVAN cases was observed in HLA-B51-positive KTx recipients. Multivariate analysis showed that HLA-B51 positivity, found in 36 (9%) recipients, reduced the risk of viremia approximately fivefold (hazard ratio, 0.18; 95% confidence interval, 0.04-0.73; P = 0.017). Four HLA-B51-restricted putative cytotoxic T lymphocyte epitopes were identified, including a previously described HLA-B supermotif-containing peptide (LPLMRKAYL), encoded by 2 relevant T-antigens (small T and large T) and previously shown to be highly immunogenic. CONCLUSIONS: In conclusion, HLA-B51-positive kidney transplant recipients were less susceptible to BKPyV infection, which might be explained by efficient presentation of a particular BKPyV-derived immunogenic peptide.

Is Behçet's disease a 'class 1-opathy'? The role of HLA-B*51 in the pathogenesis of Behçet's disease.

The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the 'MHC-I-opathies'. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies.

HLA-B*51:01 is strongly associated with clindamycin-related cutaneous adverse drug reactions.

Clindamycin causes cutaneous adverse drug reactions (cADRs), sometimes with the mechanisms of pathogenicity or risk factors unknown. This study aims to assess whether HLA alleles are associated with clindamycin-related cADRs in the Han Chinese population. We performed an association study of 12 subjects with clindamycin-related cADRs, 279 controls and 26 clindamycin-tolerant subjects. Subjects who received clindamycin through intravenous drip were analyzed separately. Unbiased, in silico docking was conducted. We found 6 out of 12 clindamycin-induced cADR patients carried HLA-B*51:01, and all of them received clindamycin via intravenous drip (6/9). The carrier frequency of HLA-B*51:01 is significantly higher compared with the control group (P=0.0006; OR=9.731, 95% CI: 2.927-32.353) and the clindamycin-tolerant group (OR=24.000, 95% CI: 3.247-177.405). In silico docking showed clindamycin is potentially more stable inside HLA-B*51:01 protein. Our results suggested, for the first time, that HLA-B*51:01 is a risk allele for clindamycin-related cADRs in Han Chinese, especially when clindamycin is administered via intravenous drip.

Molecular Dynamics Simulation Reveals the Selective Binding of Human Leukocyte Antigen Alleles Associated with Behçet's Disease.

Behçet's disease (BD), a multi-organ inflammatory disorder, is associated with the presence of the human leukocyte antigen (HLA) HLA-B*51 allele in many ethnic groups. The possible antigen involvement of the major histocompatibility complex class I chain related gene A transmembrane (MICA-TM) nonapeptide (AAAAAIFVI) has been reported in BD symptomatic patients. This peptide has also been detected in HLA-A*26:01 positive patients. To investigate the link of BD with these two specific HLA alleles, molecular dynamics (MD) simulations were applied on the MICA-TM nonapeptide binding to the two BD-associated HLA alleles in comparison with the two non-BD-associated HLA alleles (B*35:01 and A*11:01). The MD simulations were applied on the four HLA/MICA-TM peptide complexes in aqueous solution. As a result, stabilization for the incoming MICA-TM was found to be predominantly contributed from van der Waals interactions. The P2/P3 residue close to the N-terminal and the P9 residue at the C-terminal of the MICA-TM nonapeptide served as the anchor for the peptide accommodated at the binding groove of the BD associated HLAs. The MM/PBSA free energy calculation predicted a stronger binding of the HLA/peptide complexes for the BD-associated HLA alleles than for the non-BD-associated ones, with a ranked binding strength of B*51:01 > B*35:01 and A*26:01 > A*11:01. Thus, the HLAs associated with BD pathogenesis expose the binding efficiency with the MICA-TM nonapeptide tighter than the non-associated HLA alleles. In addition, the residues 70, 73, 99, 146, 147 and 159 of the two BD-associated HLAs provided the conserved interaction for the MICA-TM peptide binding.

Pathogenesis of Behçet's disease: autoinflammatory features and beyond.

Behçet's disease (BD) is an inflammatory disorder of unknown aetiology characterised by recurrent attacks affecting the mucocutaneous tissues, eyes, joints, blood vessels, brain and gastrointestinal tract. It is a multifactorial disease classified as a variable vessel vasculitis, and several environmental triggers may induce inflammatory episodes in genetically susceptible individuals. BD has several autoinflammatory features including recurrent self-limited clinical manifestations overlapping with monogenic autoinflammatory disorders, significant host predisposition and abnormally increased inflammatory response, with a robust innate component. Human leukocyte antigen (HLA)-B*51 is the strongest susceptibility factor described so far affecting the disease risk and typical phenotype. Non-HLA genetic associations such as endoplasmic reticulum aminopeptidase 1 (ERAP1), interleukin 23 receptor (IL23R) and IL10 variations suggest that BD shares susceptibility genes and inflammatory pathways with spondyloarthritis. Although genomewide association studies revealed an increased risk associated with recessively inherited ERAP1 variations in HLA-B*51 positive patients, it is not clear yet whether certain peptide-HLA allele combinations result in an adaptive response by a self-antigen-directed cytotoxic response or an innate response by modulating an NK cell activity or causing an unfolded protein response. Understanding of major histocompatibility complex (MHC) Class I-driven inflammatory response is expected to provide insights for the development of better treatment and remission-induction options in BD as well as in ankylosing spondylitis (AS) and psoriasis.

Treatment and functional outcome of patients with cystoid macular edema: a single-center experience.

The aim of this study was to describe a single-center experience in the treatment and follow-up of cystoid macular edema patients. Clinical records of all patients with cystoid macular edema followed up in the Rheumatologic and Ophthalmological Unit of our center between 1993 and 2013 were retrospectively evaluated. The outcome was assessed by visual acuity and optical coherence tomography status during follow-up. Comparisons were made by Fisher's exact test (p < 0.05 significant). In this study 16 eyes in 9 patients were analyzed. Our study includes mainly post-uveitic (78 %) cases with a high prevalence of human leukocyte antigen B51 (67 %). Systemic immunosuppressive therapy was prescribed in 87 % of cases. The most frequently used drugs were cyclosporine, interferon-α, and infliximab. The first two molecules appeared respectively the most used as the first option and the one with the longest survival on treatment. Interferon-α was the most effective drug in contrasting visual acuity loss compared to the majority of drugs, but significantly more effective than mycophenolate (p = 0.01) in reducing macular edema. At the end of follow-up, 50 % of patients showed a significant visual loss, while 88 % did not present macular edema. In our small cohort, interferon-α is the most promising drug in contrasting visual acuity loss in cystoid macular edema. Visual prognosis remains severe in these patients.