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Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., , , , , , , , , , and , in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. The reduced expression of downstream signaling molecules, specially and , confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.

Introduction: Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility to Staphylococcal skin and pulmonary infections, eczema, raised serum IgE (>2,000 IU/ml), craniofacial anomalies, and recurrent bone fractures. Data on HIES from the Indian subcontinent is scarce and restricted to small case series and case reports. This is the first compilation of national data on HIES. Materials and Methods: A total 103 cases clinically diagnosed and treated as HIES were analyzed from nine centers. Cases with clinical and/or molecular diagnosis of DOCK8 deficiency were not included. Patients were divided into two groups: group I for whom a heterozygous rare variant of STAT3 was identified, and group II, with clinical features similar to those of AD STAT3 deficiency, but without any genetic diagnosis. Results: Genetic diagnosis was available in 27 patients (26.2%) and all harbored rare variants in the STAT3 gene. Majority of these STAT3 HIES patients presented with recurrent skin abscesses (77.7%) or pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%). Mycobacterial infections were seen in a significant 18.5%. Mortality was seen in three subjects (11.1%). A similar trend in the clinical presentation was observed when all the 103 patients were analyzed together. Twenty percent of patients without a rare variant in the STAT3 gene had an NIH score of ≥40, whereas, 51.9% of STAT3 HIES subjects had scores below the cut off of ≥40. TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6, 16, 17, 19, 22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs * 8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12. Conclusions: The report includes seven novel STAT3 variants, including a rare linker domain nonsense variant and a CC domain variant. Mycobacterial diseases were more frequent, compared to western literature.

There is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with XLA from India. Data on XLA from all regional centers supported by the Foundation for Primary Immunodeficiency Diseases (FPID), USA and other institutions providing care to patients with PIDs were collated. Diagnosis of XLA was based on European Society for Immunodeficiencies (ESID) criteria. We received clinical details of 195 patients with a provisional diagnosis of XLA from 12 centers. At final analysis, 145 patients were included (137 'definite XLA' and eight 'probable/possible XLA'). Median age at onset of symptoms was 12.0 (6.0, 36.0) months and median age at diagnosis was 60.0 (31.5, 108) months. Pneumonia was the commonest clinical manifestation (82.6%) followed by otitis media (50%) and diarrhea (42%). Arthritis was seen in 26% patients while 23% patients developed meningitis. Bronchiectasis was seen in 10% and encephalitis (likely viral) in 4.8% patients. was the commonest bacterial pathogen identified followed by , and . Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in gene were the most common (36%) followed by frameshift (22%) and nonsense variants (21%). Most pathogenic gene variants (53%) were clustered in the distal part of gene encompassing exons 14-19 encoding for the tyrosine kinase domain. Follow-up details were available for 108 patients. Of these, 12% had died till the time of this analysis. The 5-year and 10-year survival was 89.9% and 86.9% respectively. Median duration of follow-up was 61 months and total duration of follow-up was 6083.2 patient-months. All patients received intravenous immunoglobulin (IVIg) replacement therapy. However, in many patients IVIg could not be given at recommended doses or intervals due to difficulties in accessing this therapy because of financial reasons and lack of universal health insurance in India. Hematopoietic stem cell transplant was carried out in four (2.8%) patients. There was a significant delay in the diagnosis and facilities for molecular diagnosis were not available at many centers. Optimal immunoglobulin replacement is still a challenge.

Hyper-IgE syndrome (HIES) caused by loss-of-function (LOF) mutations in STAT3 gene (STAT3 LOF HIES) is associated with dental and facial abnormalities in addition to immunological defects. The role of STAT3 in the pathogenesis of the dental/facial features is, however, poorly elucidated. Since mechanism of cellular resorption of mineralized tissues such as bone and teeth are similar, we attempted to study the expression of genes involved in bone homeostasis in STAT3 LOF HIES. Peripheral blood mononuclear cells from healthy controls (HCs), STAT3 LOF HIES patients, STAT3 PC-3 cells and STAT3 LNCaP cells were stimulated with IL-6 and quantitative PCR array was performed to study the relative mRNA expression of 43 pre-selected genes. PCR array finding were further evaluated after induced STAT3 inhibition. Osteopontin (OPN) gene was seen to be significantly upregulated after IL-6 stimulation in HC (mean fold change 18.6,  = 0.01) compared with HIES subjects. Inhibition of STAT3 signaling by followed by IL-6 stimulation abrogated the OPN response in HCs suggesting that IL-6-induced STAT3 signaling regulates expression. Bioinformatics analysis predicted the presence of STAT3 response element TTCCAAGAA at position -2005 of the OPN gene. Regulation of OPN gene through IL-6-mediated STAT3 activation and its significant dysregulation in STAT3 LOF HIES subjects could make OPN a plausible candidate involved in the pathogenesis of dental/facial manifestations in HIES.

Background: Various studies have implicated that plasma causing transfusion-related acute lung injury is from alloimmunized females. The frequency of sensitization to human leukocyte antigen (HLA) was found to correlate with their parity score. No literature on the prevalence of anti-HLA antibodies in Indian blood donors is available to date. Hence, this pilot study was done to know the frequency of HLA alloimmunization in Indian blood donors. Materials and Methods: A total of 192 consenting voluntary blood donors from blood donation camps were enrolled in the study. Test group: Parous female donors (n = 96) and control group: Nulliparous female donors (n = 48) and male donors (n = 48). HLA alloimmunization was tested on the Luminex platform by screening assay to detect IgG antibodies to HLA Class I and II molecules of human origin. A mean fluoresence index of more than 2000 was considered as a positive reaction, considering the high sensitivity of Luminex assay. Results: Sixty-three out of 192 donors (32.8%) tested positive for anti-HLA antibodies, out of which 23 donors were in the control group (23.9%), and 40 donors were in the test group (41.7%); P = 0.002. On gender-based comparison, 9 out of 48 male donors (18.7%), as compared to 54 out of 144 female donors (37.5%), tested positive for HLA antibodies (P = 0.02). Based on an increase in parity score, the frequency of HLA alloimmunization was found to be significantly correlated (P = 0.002). A decrease in the trend of HLA alloimmunization was observed as the duration from the last pregnancy increased. A higher frequency of HLA alloimmunization was observed in female donors with a history of transfusion and bad obstetric history. Conclusion: The present study substantiates that plasma from parous female donors has a higher chance of containing anti-HLA antibodies as compared to nulliparous female and male donors.

BackgroundAbility to predict the manner in which a recipient’s immune system would respond to a transplanted graft by analyzing cytokine profiles of the “allograft antigen sensitized” recipient lymphocytes in vitro might provide a means to identify patients at risk to adverse clinical endpoints.MethodsCytokine/chemokine gene expression profiles of peripheral blood mononuclear cells co-cultured with allograft antigen-pulsed macrophages were studied in 49 renal transplant recipients—12 with acute cellular rejection (ACR) with or without antibody-mediated rejection (AMR), 7 with AMR (without ACR), and 30 with stable allografts (SA). An 86-gene inflammatory cytokines and receptors PCR array was used to measure fold changes in gene expression between pulsed and un-pulsed cultures.ResultsOn linear discriminant analysis and multivariate analysis of variance, a gene set comprising C3, CCL3, IL1B, TOLLIP, IL10, CXCL5, ABCF1, CCR3, IL10RB, CXCL1, and IL1R1 differentiated the ACR–AMR from the SA group. Similarly, a gene set comprising IL10, C3, IL37, IL1B, CCL3, CARD18, and TOLLIP differentiated the AMR from the SA group. No significant difference was found between the ACR–AMR vs AMR groups.ConclusionDistinct post in vitro stimulation cytokine profiles at the time of transplantation thus correlated with the occurrence of post-transplantation rejection episodes which indicated feasibility of this in vitro model to assess the recipient’s anti-graft response at an early stage.

The initial precipitating injury such as SE progresses to chronic epilepsy through multiple epileptogenic processes. Early epileptogenic events are generally characterized by neuroinflammation, neurodegeneration and abnormal neurogenesis in the hippocampus. Metformin has exhibited anti-inflammatory and neuroprotective properties in numerous studies. The current study attempts to investigate the effect of metformin on seizure-induced inflammation and neuronal degeneration, and the involvement of the mTOR pathway. Status epilepticus (SE) was induced in male Wistar rats with systemic administration of Lithium (127 mg/kg) and Pilocarpine (30 mg/kg). In test rats, Metformin 100 mg/kg or 200 mg/kg was administered orally for 7 days, followed by SE induction. Results indicate that metformin did not alter the SE profile significantly which was evident by the behavioural scoring and electroencephalogram (EEG) recordings. However, metformin 200 mg/kg attenuated the SE-induced glial activation ( p  < 0.01), up regulated mRNA levels of proinflammatory cytokines ( p  < 0.001) and chemokines ( p  < 0.001) and enhanced BBB permeability ( p  < 0.05). In addition, metformin ameliorated the insult-induced region-specific neuronal damage ( p  < 0.01) and restored the hippocampal neuronal density. Metformin significantly inhibited phosphorylated S6 ribosomal protein (phospho-S6rp) ( p  < 0.05), thus demonstrating that the beneficial effects might be partly mediated by the mTOR pathway. The study thus reiterates that mTOR signalling is one of the mechanisms involved in inflammation and neurodegeneration in early epileptogenesis following SE.

Aim This study was undertaken to explicate the shared and distinctive genetic susceptibility and immune dysfunction in patients with T1D alone and T1D with CD (T1D + CD). Methods A total of 100 T1D, 50 T1D + CD and 150 healthy controls were recruited. HLA-DRB1/DQB1 alleles were determined by PCR-sequence-specific primer method, SNP genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP-array and genotyping for INS-23 Hph1 A/T was done by RFLP. Autoantibodies and cytokine estimation was done by ELISA. Immune-regulation was analysed by flow-cytometry. Clustering of autoantigen epitopes was done by epitope cluster analytical tool. Results Both T1D alone and T1D + CD had a shared association of DRB1*03:01, DRB1*04, DRB3*01:07/15 and DQB1*02. DRB3*01:07/15 confers the highest risk for T1D with relative risk of 11.32 (5.74–22.31). Non-HLA gene polymorphisms PTPN22 and INS could discriminate between T1D and T1D + CD. T1D + CD have significantly higher titers of autoantibodies, expression of costimulatory molecules on CD4 and CD8 cells, and cytokine IL-17A and TGF-β1 levels compared to T1D patients. Epitopes from immunodominant regions of autoantigens of T1D and CD clustered together with 40% homology. Conclusion Same HLA genes provide susceptibility for both T1D and CD. Non-HLA genes CTLA4, PTPN22 and INS provide further susceptibility while different polymorphisms in PTPN22 and INS can discriminate between T1D and T1D + CD. Epitope homology between autoantigens of two diseases further encourages the two diseases to occur together. The T1D + CD being more common in females along with co-existence of thyroid autoimmunity, and have more immune dysregulated state than T1D alone.

Genetic variation in HLA genes influence the immune response and may thus contribute to differential development of tuberculosis (TB) in HIV-infected individuals. The study was designed to determine whether HLA polymorphisms influence the development of Mycobacterium tuberculosis infection in HIV-infected individuals. Fifty HIV-positive individuals without TB (HIV+TB-), 50 HIV patients co-infected with TB (HIV+TB+) and 50 control subjects (HIV-TB-) were analyzed for HLA Class I and II polymorphisms. In HLA Class II, frequency of occurrence of DRB1*13 (OR 3.165, CI 1.176-8.518, P value 0.019), DRB5 (OR 2.253, CI 1.011-5.019, P value 0.045) and DQB1*06 (OR 2.705, CI 1.197-6.113, P value 0.016) were increased in HIV+TB+compared to HIV+TB-. HLA DQB1*02 (OR 0.436, CI 0.185-1.029, P value 0.05) on the other hand conferred a protective role. In HLA Class I, frequency of B*15 (OR 2.705, CI 1.040-7.036, P value 0.038) was increased, whereas B*51 (OR 0.148, CI 0.031-0.706, P value 0.007) was decreased in HIV+TB+group compared to HIV+TB-. These differences however were not significant when compared with healthy controls. HLA polymorphisms independently did not account for the susceptibility to either of the disease mostly, although they seem to play a role once the infection(s) has established in a particular individual. Further studies are needed on a larger sample size to confirm these observations.

Sjogren’s syndrome (SS) is a multisystem disorder of autoimmune etiology, which can be primary or secondary. Quality of life in SS depends on severity of involvement of different systems. The aims of this study are to analyze peripheral nervous system involvement in primary and secondary SS and its impact on quality of life (QOL). In this cross-sectional observational study conducted between January 2020 and June 2021, 67 patients of SS attending to this tertiary care center were included. Nerve conduction study and sympathetic skin response test were done in all cases. QOL was assessed with SF-36 questionnaire. Out of 67 cases, 50 had primary and 17 had secondary SS. 50.7% of cases had peripheral neuropathy. In primary SS, prevalence of peripheral neuropathy was 56% as against 35.3% in secondary. 50% of peripheral neuropathy were asymptomatic and were diagnosed after electrodiagnostic tests. Polyneuropathy was the most common pattern. There was no difference of other system involvement or immunological markers among those with and without peripheral neuropathy in either primary or secondary SS. Cases with peripheral neuropathy in the primary Sjogren’s group and in the cohort as a whole scored significantly lower in 7 domains of SF-36. Peripheral nervous system involvement is common in Sjogren’s syndrome, and most of them are asymptomatic. Peripheral neuropathy has significant impact on QOL in people with SS. Early detection and halting the progression of asymptomatic cases can be helpful in improving QOL.