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BACKGROUND: Human leukocyte antigen (HLA) restriction plays an important role in the susceptibility to alloimmunization against red blood cell (RBC) antigens. The prevalence of anti-D alloimmunization in RhD negative pregnancy is still quite high in our population. Thus, we planned this study to determine the association of HLA-DRB1 alleles with anti-D alloimmunization in RhD negative pregnant women. MATERIAL AND METHODS: RBC antibody screen (ABS) was performed for RhD negative pregnant women attending the antenatal clinic our institute. Those with a negative result were included in the 'non-alloimmunized' (NAL) group ('Control' group), while those with anti-D alloantibody on performing antibody identification were included in the alloimmunized (AL) group of the study (n = 50 each). ABS and identification were done using column agglutination technique. The HLA-DRB1 typing was done by Luminex based reverse sequence specific oligonucleotide probing (SSOP) using commercial kits. The HLA-DRB1 allele frequency was compared in both the groups. RESULTS: There was a significant difference between the two groups in terms of gravida (p < 0.001) and history of anti-D immunoprophylaxis (p < 0.001). The frequency of HLA-DRB1*03 and HLA-DRB1*04 alleles was significantly higher in the AL group than the NAL group: 40 % versus 18 % [Odds Ratio (OR): 3.04, 95 % CI: 1.21-7.6; p = 0.015] for HLA-DRB1*03 alleles and 18 % versus 4 % (OR: 5.27, 95 % CI: 1.08-25.78, p = 0.025) for HLA-DRB1*04 alleles. CONCLUSION: The frequency of HLADRB1*03 and HLADRB1*04 alleles was significantly higher in RhD negative pregnant women alloimmunized with anti-D alloantibody.
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Mujeres Embarazadas , Globulina Inmune rho(D) , Humanos , Femenino , Embarazo , Cadenas HLA-DRB1/genética , Alelos , Isoanticuerpos , Frecuencia de los GenesRESUMEN
Human cytomegalovirus (HCMV) infection is associated with renal allograft failure. Allograft damage in animal models is accelerated by CMV-induced T helper 17 (Th17) cell infiltrates. However, the mechanisms whereby CMV promotes Th17 cell-mediated pathological organ inflammation are uncharacterized. Here we demonstrate that murine CMV (MCMV)-induced intragraft Th17 cells have a Th1/17 phenotype co-expressing IFN-γ and/or TNF-α, but only a minority of these cells are MCMV specific. Instead, MCMV promotes intragraft expression of CCL20 and CXCL10, which are associated with recruitment of CCR6+ CXCR3+ Th17 cells. MCMV also enhances Th17 cell infiltrates after ischemia-reperfusion injury, independent of allogeneic responses. Pharmacologic inhibition of the Th17 cell signature cytokine, IL-17A, ameliorates MCMV-associated allograft damage without increasing intragraft viral loads or reducing MCMV-specific Th1 cell infiltrates. Clinically, HCMV DNAemia is associated with higher serum IL-17A among renal transplant patients with acute rejection, linking HCMV reactivation with Th17 cell cytokine expression. In summary, CMV promotes allograft damage via cytokine-mediated Th1/17 cell recruitment, which may be pharmacologically targeted to mitigate graft injury while preserving antiviral T cell immunity.
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Infecciones por Citomegalovirus , Trasplante de Riñón , Muromegalovirus , Nefritis , Insuficiencia Renal , Aloinjertos/metabolismo , Animales , Antivirales , Citocinas/metabolismo , Humanos , Inflamación/patología , Interleucina-17/metabolismo , Trasplante de Riñón/efectos adversos , Ratones , Insuficiencia Renal/complicaciones , Células TH1 , Células Th17 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, which is known to be associated with HLA-DRB1 and Epstein-Barr virus (EBV) infection. In the Indian subcontinent where there is high seroendemicity of EBV, we postulated that the association of this virus in adult SLE (aSLE) and pediatric SLE (pSLE) patients would be different and differentially associate with the HLA-DRB1 susceptibility and protective genes. METHODS: A total of 109 aSLE, 52 pSLE, 215 adult healthy and 63 pediatric healthy controls were recruited. HLA-DRB1 genotyping by PCR-SSP, EBV load estimation by real-time PCR and antibody profiling (IgG & IgM) to EBV antigens by line blot assay were performed. RESULTS: DRB1*15 was found predominant in pSLE patients and DRB1*03 in aSLE patients. DRB1*15/X heterozygous was predominant in overall SLE patients, although disease severity, like hypocomplementemia, higher autoantibody levels and more organ involvement was observed in *15/*15 homozygous state. EBV strongly associated with pSLE patients showing higher percent of EA-D IgG (p < 0.0001) and p22 IgG (p = 0.035) along with higher viral load (p = 0.001) as compared to healthy controls. In addition, the higher EBV DNA load significantly associated with anti-EA-D IgG (p = 0.013) and DRB1*15/*15 (p = 0.007) in pSLE patients as compared to aSLE patients. CONCLUSIONS: This study therefore indicates that different HLA-DRB1 allotypes confer susceptibility to SLE in children and adults and disease may be triggered by increased EBV reactivation.
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Infecciones por Virus de Epstein-Barr , Lupus Eritematoso Sistémico , Adulto , Niño , Cadenas HLA-DRB1/genética , Herpesvirus Humano 4/genética , Humanos , Inmunidad , Inmunoglobulina G , Lupus Eritematoso Sistémico/complicaciones , Carga ViralRESUMEN
Antinuclear antibody (ANA) pattern and autoantibody (autoAb) profiling of 150 adult systemic sclerosis (SSc) patients concerning their clinical association and diagnostic significance were analyzed by indirect immunofluorescence (IIF), immunoblot, and fluorescence enzyme immunoassay. One hundred and forty-three (95.3%) patients had positive ANA: DNA topoisomerase I (topo I)-like pattern-84(56%); speckled pattern-44(29.3%);centromere pattern-7(4.6%); and nucleolar pattern-4(2.6%). Three distinct topo I-like immunofluorescence patterns were detected at 1:40 dilution. Topo I-like pattern (32/75-limited cutaneous systemic sclerosis (lcSSc) vs. 52/75-diffuse cutaneous systemic sclerosis (dcSSc); p < 0.001) was found to be associated with dcSSc subset and speckled pattern (lcSSc 28/75 vs. dcSSc 16/75; p < 0.03) with lcSSc subset. One hundred and thirty-eight (92%) patients were positive for SSc-associated autoAbs. The frequency distribution of autoAbs to topo I, centromere A (CENP A) and centromereB (CENP B), RNA polymerase III (RP11, RP155), fibrillarin (U3RNP), nucleolus organizer region (NOR)-90, Th/To, PM-Scl75, PM-Scl100, Ku, platelet-derived growth factor receptor (PDGFR) and Ro-52, were 87(58%), 9(6%), 8(5.3%), 6(4%), 9(6%), 0, 6(4%), 6(4%), 8(5.3%), 5(3.3%), 11(7.3%),0 and 46(30.6%), respectively. Topo I autoAb was strongly associated with dcSSc (35/75 lcSSc vs. 52/75 dcSSc; p < 0.004), Raynaud's (p < 0.003), interstitial lung disease (ILD) (p < 0.001) and pulmonary arterial hypertension (PAH) (p < 0.04). This study helps in defining SSc clinical subset, prognostic markers of disease severity, characterization of the topo I-like ANA pattern, and provides a definite association between the ANA patterns and corresponding autoAb.
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Anticuerpos Antinucleares , Esclerodermia Sistémica , Adulto , Autoanticuerpos , Humanos , ARN Polimerasa III , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Centros de Atención TerciariaRESUMEN
The objective of the study is to report the outcomes of COVID-19 in ANCA-associated vasculitis (AAV) patients. This was a registry-based observational study conducted at a tertiary care center in north India. AAV patients with at least one follow-up visit between March 2020 and September 2021 were included. Demographic features, clinical manifestations, disease activity, and treatment details of underlying AAV were noted in all patients. Details of COVID-19 infection including severity, treatment, and outcomes were noted. Predictors of COVID-19 severity were determined using univariate analysis. A total of 33 (18.3%) out of 180 AAV patients contracted COVID-19 infection. Moderate COVID-19 infection was seen in 33.3% and severe or critical infection was seen in 36.3% of patients. Seventeen patients (51.5%) required supplemental oxygen therapy. Nine patients had active disease at the time of COVID-19 infection and three of them died due to COVID-19 infection. The risk of COVID-19 infection and its severity did not differ between patients receiving different immunosuppressants including rituximab induction. Hypothyroidism (p = 0.046) and ocular (p = 0.038) involvement due to AAV predicted the development of moderate to severe/critical COVID-19. Three (9.1%) patients died from COVID-19 and the rate of AAV flare after COVID-19 was similar to that in non-COVID-19 patients (15.3/100 person-year vs. 15.6/100 person-year, p = 0.95). Majority of the patients with AAV had moderate to severe or critical COVID-19 infection. The rate of death due to COVID-19 in AAV is higher than in general population. Use of standard remission induction regimens did not lead to increased risk of COVID-19 infection in our AAV cohort.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , COVID-19 , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Anticuerpos Anticitoplasma de Neutrófilos , COVID-19/epidemiología , Estudios Transversales , Humanos , Inmunosupresores/uso terapéutico , Oxígeno , Pandemias , Inducción de Remisión , Rituximab/uso terapéuticoRESUMEN
BACKGROUND: There is paucity of literature on long-term follow-up of patients with hereditary angioedema (HAE) from developing countries. OBJECTIVE: This study was carried out to analyze the clinical manifestations, laboratory features, and genetic profile of 32 patients (21 male and 11 female) from 23 families diagnosed with HAE between January 1996 and December 2019. METHODS: Data were retrieved from medical records of Paediatric Immunodeficiency Clinic, Postgraduate Institute of Medical Education and Research, Chandigarh, India. RESULTS: Median age at onset of symptoms was 6.25 years (range 1-25 years), and median age at diagnosis was 12 years (range 2-43 years). Serum complement C4 level was decreased in all patients. All patients had low C1-esterase inhibitor (C1-INH) quantitative level (type 1 HAE). SERPING1 gene sequencing could be carried out in 20 families. Of these, 11 were identified to have a pathogenic disease-causing variant in the SERPING1 gene. While 2 of these families had a previously reported mutation, remaining 9 families had novel pathogenic variants in SERPING1 gene. Because of non-availability of C1-INH therapy in India, all patients were given long-term prophylaxis (attenuated androgens or tranexamic acid (TA) or a combination of the 2). Life-threatening episodes of laryngeal edema were managed with fresh-frozen plasma (FPP) infusions. We recorded one disease-related mortality in our cohort. This happened in spite of long-term prophylaxis with stanozolol and TA. CONCLUSIONS: We report largest single-center cohort of patients with HAE from India. Attenuated androgens, fibrinolytic agents, and FPP may be used for management of HAE in resource-limited settings.
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Angioedemas Hereditarios , Proteína Inhibidora del Complemento C1 , Adolescente , Adulto , Edad de Inicio , Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/epidemiología , Niño , Preescolar , Proteína Inhibidora del Complemento C1/genética , Complemento C4 , Femenino , Humanos , Lactante , Masculino , Mutación , Adulto JovenRESUMEN
The 1990 American College of Rheumatology (ACR) criteria for the classification of polyarteritis nodosa (PAN) have many pitfalls and performed poorly when used for diagnostic purposes. Recently, a provisional seven-item diagnostic criteria for PAN was proposed. To validate the provisional seven-item diagnostic criteria for PAN in a cohort of PAN patients from a tertiary care centre in India. Clinical details of patients diagnosed as PAN as per the European Medicines Agency algorithm between 2005 and 2020 were collected retrospectively. Age and sex-matched anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) patients were included in the non-PAN group. Patients with a deficiency of adenosine deaminase 2 (DADA2) were included as a separate group. The sensitivity, specificity, positive and negative predictive values (PPV and NPV) for ACR criteria, the Ministry of Health, Labour and Welfare (MHLW) in Japan diagnostic criteria and the seven-item diagnostic criteria were calculated. Thirty-seven PAN, 14 DADA2 and 37 AAV patients were included in the analysis. The sensitivity, specificity, PPV and NPV of the seven-item criteria were 83.7%, 96.8%, 97.3% and 81.1% respectively. For the ACR criteria, sensitivity was 82.9% and specificity was 79.5%. The sensitivity, specificity for MHLW criteria were 77.3% and 90% respectively. The sensitivity and specificity of seven-item criteria for DADA2 patients were 58.8% and 88.2% respectively. There was very poor agreement between the ACR criteria and the seven-item and MHLW criteria and fair agreement between seven-item and MHLW criteria (κ = 0.279). The provisional seven-item criteria for PAN performed well with high specificity and PPV.
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Poliarteritis Nudosa/diagnóstico , Adolescente , Adulto , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Poliarteritis Nudosa/clasificación , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
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.
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Hipocampo/efectos de los fármacos , Metformina/farmacología , Fármacos Neuroprotectores/farmacología , Estado Epiléptico/tratamiento farmacológico , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipocampo/patología , Inflamación/tratamiento farmacológico , Inflamación/patología , Masculino , Metformina/administración & dosificación , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Estado Epiléptico/fisiopatología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND/OBJECTIVE: This study was done to examine the role of CD40 ligand (CD40L) in children with Kawasaki disease (KD). There is paucity of literature on this aspect of KD. METHODS: This was a case-control study of patients with KD diagnosed at the Allergy Immunology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India. CD40L expression on activated CD3+ T cells was measured using flow cytometry, and soluble CD40L (sCD40L) was measured using enzyme-linked immunosorbent assay. RESULTS: We included 14 children with KD, 14 healthy controls, and 12 febrile controls for the purpose of this study. Mean percentage CD40L expression was higher in patients with KD (before administration of intravenous immunoglobulin [IVIg]) as compared with normal and febrile controls. This difference was statistically significant when compared with normal control (p = 0.00; confidence interval [CI], 8.92-20.30), but was not statistically significant when compared with febrile controls (p = 0.138; CI, -3.50 to 22.08). CD40L expression decreased after giving IVIg, but the difference was not statistically significant (p = 0.073; CI, -1.04 to 19.73). Mean sCD40L values increased significantly after giving IVIg (when repeated after a median period of 11 days; p = 0.001; CI, -0.77 to -0.29). There was no statistically significant difference between mean sCD40L in patients with KD (before giving IVIg) as compared with normal and febrile controls (p = 0.42; CI, -1.11 to -0.51 and p = 0.641; CI, -0.37 to 0.57, respectively). CONCLUSIONS: CD40L may have important role in the pathogenesis of KD. However, these results need to be validated in larger multicenter studies.
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Ligando de CD40 , Síndrome Mucocutáneo Linfonodular , Estudios de Casos y Controles , Niño , Humanos , India/epidemiología , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Linfocitos TRESUMEN
BACKGROUND & OBJECTIVES: : Celiac disease (CD) can exist in various forms in type 1 diabetes (T1D) patients and can remain undetected, leading to severe complications. This study was aimed to evaluate five commercially available anti-tissue transglutaminase (tTG) ELISA kits with distinct formats for the detection of CD and potential CD in T1D patients. Clinical and demographic profiles of the patients with different disease subsets were also studied. METHODS: : Fifty T1D patients with classical and non-classical symptoms of CD and 100 T1D patients without any symptoms of CD were included in this study. Anti-tTG autoantibody levels were estimated by five ELISA kits followed by histological examination of duodenal biopsy. HLA DQ2-DQ8 and DRB1-DQB1 typing was done, and serum levels for transforming growth factor (TGF)-ß1 were also estimated. RESULTS: : Assay format detecting anti-tTG IgA antibodies against recombinant antigens along with neopeptides of gliadin was most efficient in the detection of CD in symptomatic patients, and assay format detecting IgA+IgG helped in the detection of potential CD in asymptomatic T1D patients. These findings were supported by histological examination and human leucocyte antigen analysis. Patients with potential CD were found to have markedly deranged glycaemic control parameters and also had significantly raised serum levels of TGF-ß1, (P <0.05) compared to T1D patients. INTERPRETATION & CONCLUSIONS: : Potential CD can be frequently seen in T1D patients. This can be attributed to the dietary patterns prevalent in the subcontinent and the genetic basis of the disease. Anti-tTG IgA+IgG antibodies can be useful in the detection of these potential CD cases in T1D patients. Early intervention with gluten-free diet can be considered in these patients for better disease management.
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Enfermedad Celíaca/sangre , Diabetes Mellitus Tipo 1/sangre , Transglutaminasas/aislamiento & purificación , Adolescente , Adulto , Anticuerpos Antiidiotipos/inmunología , Autoanticuerpos/inmunología , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/dietoterapia , Enfermedad Celíaca/inmunología , Niño , Preescolar , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 1/inmunología , Dieta Sin Gluten , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Persona de Mediana Edad , Factor de Crecimiento Transformador beta1/sangre , Transglutaminasas/inmunología , Adulto JovenRESUMEN
X-linked hyper IgM Syndrome (XLHIGM), the most frequent form of the Hyper IgM syndromes is a primary immune deficiency resulting from a mutation in the CD40 ligand gene (CD40LG). We analyzed the clinical and laboratory features of ten patients with XLHIGM, who were diagnosed at a tertiary care hospital in North India. Most common infections were sinopulmonary infections (80%) and diarrhea (50%). Sclerosing cholangitis and necrotising fasciitis were noted in one patient each. Three novel mutations in CD40LG (c.429_429 delA, p. G144DfsX5; c.500â¯Gâ¯>â¯A, p.G167E and c.156â¯Gâ¯>â¯C, p.K52â¯N) were detected. In addition, we found one missense mutation, two splice site mutations and two large deletions, which have been previously reported. Four (4) patients had expired at the time of analysis. We report the first series of XLHIGM from North India where we have documented unique features such as pulmonary alveolar proteinosis and infections with Mycobacterium sp.
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Ligando de CD40/genética , Diarrea/genética , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/genética , Mutación/genética , Infecciones por Mycobacterium/genética , Mycobacterium/fisiología , Proteinosis Alveolar Pulmonar/genética , Infecciones del Sistema Respiratorio/genética , Células Cultivadas , Niño , Preescolar , Citometría de Flujo , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/fisiopatología , India , Lactante , Masculino , FenotipoRESUMEN
BACKGROUND: A complex interplay between genetic and environmental factors contributes to disease etiology of most of the autoimmune disorders. Type 1 diabetes mellitus (T1DM) and celiac disease (CD) are polygenic autoimmune diseases that have high propensity to coexist due to shared etiological factors like genetics and clinico-pathological overlaps. SUMMARY: The mean prevalence rate for coexistence of these diseases is 8%, and this value is a gross underestimation as reported from biopsy-proven symptomatic cases. The prevalence rate will rise when studies will excavate bottom layers of the "celiac iceberg" to detect potential and silent celiac cases. The concomitant presence of both these disorders is a complex situation immunologically as well as clinically. There is an accentuated breakdown of tolerance and proinflammatory cytokine storm that leads to the progression of organ-specific autoimmunity to systemic. No immunomodulating drugs are advocated as exogenous insulin supplementation and gluten exclusion are recommended for T1DM and CD respectively. Nevertheless, these pose certain challenges to both the clinicians and the patients, as gluten free diet (GFD) has been described to have an impact on glycemic control, bone health, and vascular complications. Also intermittent gluten intake by these patients due to non-compliance with GFD also stimulates the autoreactive immune cells that result in an augmented immune response. Key Messages: Large public health studies are needed to estimate the prevalence of all forms of CD in T1DM patients. Strict global guidelines need to be formulated for the disease management and prognosis, and there is also a need for an extensive research on each front to thoroughly understand the co-occurrence of these diseases.
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Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/terapia , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/terapia , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/genética , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: Ability 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. METHODS: Cytokine/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. RESULTS: On 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. CONCLUSION: Distinct 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.
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Citocinas/genética , Citocinas/inmunología , Perfilación de la Expresión Génica/métodos , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Prueba de Histocompatibilidad/métodos , Isoantígenos/inmunología , Trasplante de Riñón/efectos adversos , Linfocitos/inmunología , Adulto , Aloinjertos , Estudios de Casos y Controles , Células Cultivadas , Técnicas de Cocultivo , Análisis Discriminante , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/diagnóstico , Humanos , Inmunidad Celular , Inmunidad Humoral , Modelos Lineales , Macrófagos/inmunología , Masculino , Análisis Multivariante , Análisis de Secuencia por Matrices de Oligonucleótidos , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Transcriptoma , Resultado del TratamientoRESUMEN
BACKGROUND: Cytomegalovirus (CMV) results in significant morbidity and mortality in Human Immunodeficiency Virus (HIV)-infected individuals. There is paucity of literature on paediatric CMV disease, especially from developing countries. METHODS: A retrospective review of records of all HIV-infected children with evidence of CMV disease was done. RESULTS: A total of 15 children were found to have CMV disease (retinitis in all, pneumonia in two and invasive gastrointestinal disease in one). Median CD4+ T cell count and percentage at diagnosis of CMV disease was 64.5 cells/µl and 3.6%, respectively. Intravenous ganciclovir was used in patients with active CMV disease. Of the 15 children, three died while two were lost to follow-up. Symptomatic patients had poor visual outcome and almost all children who were diagnosed on active screening attained normal vision. CONCLUSION: Retinitis is the most common CMV disease in HIV-infected children. Early detection by active screening and initiation of systemic ganciclovir reduces the morbidity.
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Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Antivirales/administración & dosificación , Infecciones por Citomegalovirus/tratamiento farmacológico , Citomegalovirus/aislamiento & purificación , Ganciclovir/administración & dosificación , Infecciones por VIH/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Administración Intravenosa , Terapia Antirretroviral Altamente Activa , Antivirales/uso terapéutico , Recuento de Linfocito CD4 , Niño , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/mortalidad , Infecciones por Citomegalovirus/virología , Retinitis por Citomegalovirus/diagnóstico , Retinitis por Citomegalovirus/tratamiento farmacológico , Retinitis por Citomegalovirus/mortalidad , Retinitis por Citomegalovirus/virología , Femenino , Ganciclovir/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , India/epidemiología , Masculino , Neumonía por Pneumocystis/tratamiento farmacológico , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Psoriasis is a multisystem, immune-mediated inflammatory disease. Some authors have proposed an autoimmune basis for psoriasis; however, till date, it has not been definitely established. This study was conducted to explore the autoimmune nature of psoriasis. MATERIALS AND METHODS: This was a prospective study in which 43 psoriasis patients were assessed for detailed clinical, histopathological and immunopathological features to explore the diagnostic utility of subtypes, intensity and number of immunoreactants in lesional and non-lesional skin in these patients. In addition, the sera of these patients were analyzed for the presence of various autoantibodies. RESULTS: The patients' age ranged from 14 to 75 years with a male-to-female ratio of 1.52:1. Nine patients (20.93%) were positive for antinuclear and 2 (4.65%) for antismooth muscle antibodies. Direct immunofluorescence (DIF) was positive in 31 (72%) biopsies from the lesional and 27 (63%) biopsies from non-lesional skin. In all these DIF positive cases, granular deposits of C5b-9 were detected at the dermoepidermal junction. No significant difference was observed on comparing the type and pattern of immunoreactant positivity, among lesional and non-lesional skin biopsies (P > .05). CONCLUSION: No significant association between psoriasis and immunoreactant deposition as well as autoantibody seroprevalence was observed, thereby refuting a definite autoimmune basis for psoriasis.
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Autoanticuerpos/metabolismo , Enfermedades Autoinmunes , Psoriasis , Piel , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Femenino , Humanos , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Psoriasis/metabolismo , Psoriasis/patología , Piel/metabolismo , Piel/patologíaRESUMEN
BACKGROUND: Robust evidence for the efficacy of rituximab monotherapy in pemphigus is lacking. The effects of rituximab on T-regulatory cells (Tregs) in pemphigus have not been studied. OBJECTIVE: The primary objective was to assess the efficacy of rituximab monotherapy in severe pemphigus vulgaris. The secondary objectives were to assess whether counts of different subsets of Tregs in the peripheral blood correlate with baseline clinical severity and whether clinical response in severe pemphigus is associated with an alteration in the Treg count. METHODS: Eighteen eligible subjects with severe pemphigus vulgaris were recruited and were treated with 1 g of intravenous rituximab on days 0 and 15. Efficacy was assessed in terms of disease control, time to disease control, complete remission off therapy, and relapse. Flow cytometric analysis of CD4+CD25+FoxP3, IL-10-secreting Tr1, and TGF-ß secreting Th3 regulatory cells was performed. Clinical evaluation and flow cytometric analysis of Tregs was performed periodically until follow-up at 26 weeks. RESULTS: Rituximab monotherapy was able to induce complete remission in all but 5 (68.75%) patients and was well tolerated. No direct relationship between clinical severity and CD4+CD25+FoxP3 cell counts was found. There were inverse correlations between serially measured values of the cutaneous and mucosal Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Th3 cell count. CONCLUSION: Rituximab is a safe and effective monotherapy option for severe pemphigus. As the immunological findings were somewhat different from those observed in other autoimmune conditions treated with rituximab, further studies are required to substantiate the findings of our study in pemphigus patients.
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Factores Inmunológicos/uso terapéutico , Pénfigo/tratamiento farmacológico , Pénfigo/inmunología , Rituximab/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Antígenos CD4/análisis , Factores de Transcripción Forkhead/análisis , Humanos , Factores Inmunológicos/farmacología , Interleucina-10/metabolismo , Subunidad alfa del Receptor de Interleucina-2/análisis , Recuento de Linfocitos , Inducción de Remisión , Rituximab/farmacología , Índice de Severidad de la Enfermedad , Brote de los Síntomas , Linfocitos T Reguladores/química , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVE: We compared levels of Th1/Th2/Th17 cytokines and T-regulatory cells in active and remitting granulomatosis with polyangiitis (GPA). METHODOLOGY: Twenty-one cases of GPA in active state as well as in remitting state and 20 healthy controls (HC) were enrolled in the study. Cytokines were detected in culture supernatants of PBMCs after stimulation with proteinase-3 (PR3) and phytohemagglutinin antigen (PHA). Serum IL-17 cytokine was studied by ELISA. T-regulatory cells (Tregs) were analyzed by flow cytometry. Gene expression of FOXP3 and ROR-γt was compared by Real Time PCR. RESULTS: We observed significantly increased level of IL-17 in serum as well in culture supernatants of PBMCs after PR3 stimulation along with ROR-γt gene expression in active disease state of GPA as compared to HC. Importantly, remitting state showed low levels of serum IL-17 with decreased ROR-γt gene expression and increased FOXP3 expression. Using PR3 as an immunostimulant, we could demonstrate the generation of IL-17 and TNF-α secreting effector memory cells during remission. Reduced FOXP3 expression with reduced IL-10 levels in active disease indicated the reduced function of Tregs in active disease. CONCLUSION: We observed Th17 dominant environment in peripheral blood of patients in active state of disease, with "hyporesponsiveness", in, in vitro stimulated PBMC-in their ability to secrete TNF-α and IL-6. Treg numbers were unaltered but function was compromised. Targeting PR3 specific effector memory cells, to prevent relapse, and instituting anti IL-17 therapy, or modulating Tregs could be newer forms of therapy for this serious autoimmune disease.
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Citocinas/inmunología , Granulomatosis con Poliangitis/inmunología , Mieloblastina/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adolescente , Adulto , Anciano , Células Cultivadas , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Expresión Génica/inmunología , Granulomatosis con Poliangitis/tratamiento farmacológico , Granulomatosis con Poliangitis/genética , Granulomatosis con Poliangitis/metabolismo , Humanos , Interleucina-10/inmunología , Interleucina-10/metabolismo , Interleucina-17/sangre , Interleucina-17/inmunología , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Estudios Prospectivos , Inducción de Remisión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T Reguladores/metabolismo , Células Th17/metabolismo , Adulto JovenRESUMEN
PURPOSE: Prevalence data of herpes simplex virus (HSV) in oral mucositis in children on treatment for cancer is limited. Quantitative polymerase chain reaction (PCR) has been seldom utilized for detection of HSV-1/2 in oral mucosa. METHODS: Children on treatment for cancer with oral mucositis were enrolled as cases and healthy children as controls. An oral swab from the lesion in cases and mucosal scraping in controls were obtained. Both qualitative and real-time quantitative PCR for HSV-1/2 were performed. Serum ELISA-IgG/IgM for HSV-1/2 antibodies (NovaLisa™-Dietzenbach-Germany) were measured. RESULTS: Thirty-two cases (Age, 6.3±3.4 years) and 30 controls were enrolled. Majority (69%) of cases had ALL. All patients had febrile neutropenia, except two. ELISA-IgM-HSV-1/2 was not positive in any case or control. ELISA-IgG-HSV-1/2 was positive in 11 (34%) cases and nine (30%) controls (p=1.0). Qualitative PCR for HSV-1 detected the virus in eight (25%) cases and nil controls (p=0.009). HSV-2 was not detected in any case/control by qualitative PCR. Quantitative PCR detected HSV-1 in 21 (66%) and HSV-2 in 22 (69%) cases. In controls, quantitative PCR detected HSV-1 in three (10%) and HSV-2 in none. In patients, the mean viral load of HSV-1 (5,500±15,987×10(4) copies/nanogram DNA) was more than HSV-2 (4.03±8.5×10(4)) (p=0.11). There was no correlation of HSV-1/2 with grading of mucositis. CONCLUSIONS: Both HSV-1/2 are commonly shed from oral mucosal lesions in children receiving chemotherapy. In a novel finding, real-time PCR detected copies of HSV-2 in 69% cases, all missed by conventional PCR. Implication for morbidity, if any, or treatment needs to be determined.
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Herpes Simple/virología , Herpesvirus Humano 1/aislamiento & purificación , Herpesvirus Humano 2/aislamiento & purificación , Neoplasias/tratamiento farmacológico , Neoplasias/virología , Estomatitis/virología , Anticuerpos Antivirales/análisis , Estudios de Casos y Controles , Niño , ADN Viral/análisis , Ensayo de Inmunoadsorción Enzimática , Femenino , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/inmunología , Humanos , Masculino , Mucosa Bucal/virología , Reacción en Cadena en Tiempo Real de la Polimerasa , Esparcimiento de VirusRESUMEN
BACKGROUND: Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by the triad of elevated IgE and eosinophilia, eczema and recurrent skin and pulmonary infections. Mutation in the STAT3 gene accounts for majority of the autosomal dominant and sporadic forms of HIES. OBJECTIVE: To report clinical and molecular analyses of patients with Hyper IgE syndrome from a single tertiary care center in India. METHODS: Four patients with suspected HIES were studied. Flowcytometry for T(H)17 cell numbers and phosphoSTAT3, and STAT3 gene sequencing were performed. RESULTS: T(H)17 cells were significantly reduced. Mutations were found in the DNA-binding domain in three and a mutation in the transactivation domain in one patient. One of the mutations detected was a novel mutation (g54792 c.1018A> C p.K340Q) in the DNA binding domain. Mycobacterial infection, which is usually not commonly associated with HIES was found in two of our cases, one with a cutaneous abscess in the shoulder, and the other with BCG site reactivation. CONCLUSIONS: A novel mutation in the STAT3 is reported. Mycobacterial infections can be seen in the spectrum of HIES related infections.
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Síndrome de Job/genética , Factor de Transcripción STAT3/genética , Adulto , Preescolar , Análisis Mutacional de ADN , Citometría de Flujo , Humanos , India , Lactante , Síndrome de Job/inmunología , Masculino , Mutación , Linaje , Células Th17/inmunologíaRESUMEN
Cognitive impairment is a prevalent co-morbidity associated with epilepsy. Emerging studies indicate that neuroinflammation could be a possible link between epilepsy and its comorbidities, including cognitive impairment. In this context, the roles of glial activation, proinflammatory mediators, and neuronal death have been well studied and correlated with epilepsy-associated cognitive impairment in animal studies. While recent reports have demonstrated the anti-epileptogenic and anti-convulsant actions of metformin, its effect on epilepsy associated cognitive deficit remains unknown. Therefore, the current study investigated the effect of metformin treatment on neuroinflammation, neurodegeneration, and cognitive deficits after inducing status epilepticus (SE) with lithium-pilocarpine in rats. Metformin treatment improved the hippocampal-dependent spatial and recognition memory in Morris water maze and Novel object recognition tasks, respectively. Further, metformin treatment attenuated microglial and astroglial activation, accompanied by reduced IL-1ß, COX-2 and NF-Ä¸ß gene expression. Additionally, metformin conferred neuroprotection by inhibiting the neuronal death as assessed by Nissl staining and transmission electron microscopy. These findings suggest that metformin holds promise as a therapeutic intervention for cognitive impairment associated with epilepsy, possibly through its modulation of glial activation and neuronal survival. Further research is needed to elucidate the precise mechanisms and to assess the long-term effect of metformin in epilepsy-associated cognitive impairment.