The aim of this study was to investigate the contribution of the different B27 subtypes to ankylosing spondylitis (AS) susceptibility. The polymerase chain reaction (PCR) in combination with the sequence-specific oligonucleotide probes (SSOs) was used to analyse the polymorphism in exon 2 and 3 of HLA-B27 in two Asian groups with different genetic HLA structures: Indian (I) and Thai (T) populations. The same number of AS patients (45) and healthy B27 positive donors (n = 17) from both populations were analysed in order to ascertain the B27 subtypes. Three different findings can be concluded from this study: 1) B*2707 has been found to be associated with AS in both populations. This association has not been previously reported in either ethnic group. 2) B*2704 is strongly associated with AS in the Thai patients (91% in AS vs. 47% in C; RR = 11.5; EF = 0.83). In contrast, B*2704 was found with similar frequency in Asian Indians AS patients and controls (41% in AS vs. 41% in C.). 3) B*2706 was found overrepresented in control populations and absent in AS patients (0% in AS vs. 47% in C.; pc < 10(-6)) showing the maximum value of protective fraction (PF = 1). The B*2706 negative association with AS has not been previously described in other ethnic groups and could indicate a protective effect of this subtype on AS susceptibility. The B*2706 allele has two changes relative to B*2704 at residue 114 (His to Asp) and 116 (Asp to Tyr) in the pockets D/E. The importance that these differences can play in the pathogenesis of AS are discussed.

Broad and potent neutralizing antibodies (bnAbs) with multiple epitope specificities evolve in HIV-1-infected children. Herein, we studied two antiretroviral-naive chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, with potent plasma bnAbs. Elite plasma neutralizing activity was observed since the initial sampling at 78 months of age in AIIMS_330 and persisted throughout, while in AIIMS_329 it was seen at 90 months of age, after which the potency decreased over time. We evaluated potential viral characteristics associated with the varied immune profiles by generating single genome-amplified pseudoviruses. The AIIMS_329 viruses generated from the 90-month time point were neutralization sensitive to bnAbs and contemporaneous plasma antibodies, while viruses from the 112-month and 117-month time points were resistant to most bnAbs and contemporaneous plasma. AIIMS_329 viruses developed resistance to plasma neutralizing antibodies (nAbs) plausibly by N160 glycan loss and V1 and V4 loop lengthening. The viruses generated from AIIMS_330 (at 90 and 117 months) showed varied susceptibility to bnAbs and autologous contemporaneous plasma antibodies, while the viruses of the 112-month time point, at which the plasma nAb specificities mapped to the V2 glycan, V3 glycan, and CD4 binding site (CD4bs), were resistant to contemporaneous plasma antibodies as well as to most bnAbs. Chimeric viruses were constructed from 90-month-time-point PG9-sensitive AIIMS_329 and AIIMS_330 viruses with swapped V1V2 regions of their respective evolved viruses (at 112 and 117 months), which led to higher resistance to neutralization by PG9 and autologous plasma antibodies. We observed the evolution of a viral pool in the AIIMS_330 donor comprising plasma antibody neutralization-sensitive or -resistant diverse autologous viruses that may have contributed to the development and maintenance of elite neutralizing activity. IMPORTANCE Herein, we report the longitudinal development of bnAbs in a pair of chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, who acquired the infection by vertical transmission. The plasma from both donors, sharing a similar genetic makeup and infecting virus, showed the evolvement of bnAbs targeting common epitopes in the V2 and V3 regions of the envelope, suggesting that bnAb development in these twins may perhaps be determined by specific sequences in the shared virus that can guide the development of immunogens aimed at eliciting V2 and V3 bNAbs. Characterization of the neutralization-sensitive and -resistant viruses coevolving with bNAbs in the contemporaneous AIIMS_330 plasma provides information toward understanding the viral alterations that may have contributed to the development of resistance to bnAbs. Further longitudinal studies in more monozygotic and dizygotic twin pairs will help in delineating the role of host and viral factors that may contribute to the development of bnAbs.

Background: Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury (AKI), is characterized by dysregulation of the alternative complement pathway. Autoantibodies to factor H (FH), a chief regulator of this pathway, account for a distinct subgroup. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required. Methods: Of 781 patients <18-year-old of aHUS in the nationwide database from 2007 to 2018, 436 (55.8%) had anti-FH antibodies. Clinical features and outcome of patients managed in the last 6-year ( n = 317) were compared to before ( n = 119). In plasma samples of 44 patients, levels of serial circulating FH immune complexes (CIC), free FH, soluble terminal complement complex (sC5b-9), sheep red blood cell (SRBC) lysis and epitope specificity ( n = 8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH), and proteinuria were evaluated in a subset. Results: Patients presented with markedly elevated anti-FH titers (10,633.2 ± 998.5 AU/ml). Management varied by center, comprising plasma exchange (PEX; 77.5%) and immunosuppression (73.9%). Patients managed in the last 6-year showed better renal survival at mean 28.5 ± 27.3 months (log rank P = 0.022). Mean anti-FH titers stayed 700–1,164 AU/ml during prolonged follow-up, correlating with CIC. Patients with relapse had lower free-FH during remission [Generalized estimating equations (GEE), P = 0.001]; anti-FH levels ≥1,330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; P = 0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8,000 AU/ml (HR 2.23; P = 0.024), time to PEX ≥14 days (HR 2.09; P = 0.071) and PEX for <14 days (HR 2.60; P = 0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; P = 0.026); maintenance therapy reduced risk of relapses (HR 0.11; P < 0.001). At 4.4±2.5 year, median renal reserve was 15.9%; severe ambulatory, masked and pre-hypertension were found in 38, 30, and 18%, respectively. Proteinuria and LVH occurred in 58 and 28% patients, respectively. Conclusion: Prompt recognition and therapy with PEX and immunosuppression, is associated with satisfactory outcomes. Free-FH predicts early relapses in patients with high anti-FH titers. A significant proportion of impaired functional reserve, ambulatory hypertension, proteinuria and LVH highlight the need for vigilant long-term follow-up.

BackgroundRole of Th9 cells and interleukin-9 (IL-9) in human autoimmune diseases such as psoriasis and ulcerative colitis has been explored only very recently. However, their involvement in human rheumatoid arthritis (RA) is not conclusive. Pathogenesis of RA is complex and involves various T cell subsets and neutrophils. Here, we aimed at understanding the impact of IL-9 on infiltrating immune cells and their eventual role in synovial inflammation in RA.MethodsIn vitro stimulation of T cells was performed by engagement of anti-CD3 and anti-CD28 monoclonal antibodies. Flow cytometry was employed for measuring intracellular cytokine, RORγt in T cells, evaluating apoptosis of neutrophils. ELISA was used for measuring soluble cytokine, Western blot analysis and confocal microscopy were used for STAT3 phosphorylation and nuclear translocation.ResultsWe demonstrated synovial enrichment of Th9 cells and their positive correlation with disease activity (DAS28-ESR) in RA. Synovial IL-9 prolonged the survival of neutrophils, increased their matrix metalloprotienase-9 production and facilitated Th17 cell differentiation evidenced by induction of transcription factor RORγt and STAT3 phosphorylation. IL-9 also augmented the function of IFN-γ + and TNF-α + synovial T cells.ConclusionsWe provide evidences for critical role of IL-9 in disease pathogenesis and propose that targeting IL-9 may be an effective strategy to ameliorate synovial inflammation in RA. Inhibiting IL-9 may have wider impact on the production of pathogenic cytokines involved in autoimmune diseases including RA and may offer better control over the disease.Electronic supplementary materialThe online version of this article (10.1186/s13075-017-1505-8) contains supplementary material, which is available to authorized users.

The aim of this study was to determine whether a common diabetic haplotype, including human leukocyte antigen (HLA)-B8 and HLA-DR3, in Northern India is the same haplotype as the European HLA-B8-DR3 haplotype. DNA samples from Northern Indian subjects selected on the basis of HLA-B8 and HLA-DR3 were tested for microsatellite and single nucleotide polymorphism alleles throughout the major histocompatibility complex (MHC). It was found that the Indian samples represent a conserved haplotype in which all alleles were shared by Indian subjects with HLA-B8 and HLA-DR3, but were different to those that are characteristic of the European 8.1 ancestral haplotype. The Indian and European haplotypes share HLA-B*0801, HLA-DRB1*0301 and HLA-DQB1*02 but differ for subtypes of HLA-Cw*07 and HLA-DRB3 and all central MHC alleles tested. In contrast, Indian subjects selected on the basis of HLA-B58 ( 1-17) and HLA-DR3 shared the same alleles at other MHC loci as have been described in the common Chinese haplotype with HLA-B58/17 and HLA-DR3. A third haplotype, HLA-B50/21 and HLA-DR3, was also found to be highly conserved but shares little in common with the other two HLA-DR3-containing Indian haplotypes.