Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been... more
Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our f...
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An alarming increase in the number of patients with chronic and recurrent dermatophytosis has invoked the need to study the immunological parameters of the host.
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Supplemental digital content is available in the text. 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.... more
Supplemental digital content is available in the text. 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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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. The primary objective was to assess the efficacy of rituximab... more
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. 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. 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-β secreting Th3 regulatory cells was performed. Clinical evaluation and flow cytometric analysis of Tregs was performed periodical...
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X-linked agammaglobulinemia (XLA) is an X-linked genetic defect in maturation of B lymphocytes that results in the absence of B lymphocytes in the peripheral blood and profound hypogammaglobulinemia. It is caused by a mutation in the BTK... more
X-linked agammaglobulinemia (XLA) is an X-linked genetic defect in maturation of B lymphocytes that results in the absence of B lymphocytes in the peripheral blood and profound hypogammaglobulinemia. It is caused by a mutation in the BTK gene located on the X chromosome. There are no large series describing XLA from the developing world. To analyze the clinical features, immunologic and genetic characteristics, and outcomes of 36 patients with XLA diagnosed and managed for a period of 2 decades. Diagnosis of XLA was made on the basis of presence of BTK gene mutation or marked reduction of B lymphocytes in peripheral blood with a family history of an affected male relative. The diagnosis was confirmed by genetic mutation studies in 28 patients with 25 unique mutations in the BTK gene. There was a significant delay in diagnosis in most of the patients. The mean (SD) delay in the diagnosis was 4.2 (3.5) years. Point mutations were the most common mutations detected, accounting for 68% of all mutations. Deletions and insertions were also seen in a few cases. Four of the mutations are novel mutations that have not been previously reported. Seven of the 36 patients (19%) were dead at the time of analysis in the present cohort. The mean survival was 137 months (95% confidence interval, 13-163 months). The present study is perhaps the largest series of patients with XLA from any developing country so far.
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Common variable immunodeficiency (CVID) is the most common primary immunodeficiency of young adolescents and adults which also affects the children. The disease remains largely under-diagnosed in India and Southeast Asian countries.... more
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency of young adolescents and adults which also affects the children. The disease remains largely under-diagnosed in India and Southeast Asian countries. Although in majority of cases it is sporadic, disease may be inherited in a autosomal recessive pattern and rarely, in autosomal dominant pattern. Patients, in addition to frequent sino-pulmonary infections, are also susceptible to various autoimmune diseases and malignancy, predominantly lymphoma and leukemia. Other characteristic lesions include lymphocytic and granulomatous interstitial lung disease, and nodular lymphoid hyperplasia of gut. Diagnosis requires reduced levels of atleast two immunoglobulin isotypes: IgG with IgA and/or IgM and impaired specific antibody response to vaccines. A number of gene mutations have been described in CVID; however, these genetic alterations account for less than 20 % of cases of CVID. Flow cytometry aptly demonstr...
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Autoantibody testing forms an important part of diagnostic workup of patients in Pediatric rheumatology practice. However it is important to understand that the mere presence of autoantibodies does not necessarily mean the presence of an... more
Autoantibody testing forms an important part of diagnostic workup of patients in Pediatric rheumatology practice. However it is important to understand that the mere presence of autoantibodies does not necessarily mean the presence of an underlying autoimmune disease. Autoantibodies may be present decades before the development of clinical manifestations of an autoimmune disease and may be viewed as harbingers of Autoimmune disease. On the other hand, low-affinity autoantibodies may be present in normal healthy individuals; these natural autoantibodies serve an important function in immune regulation and tolerance. Autoantibody testing in pediatric practice mainly includes testing for anti-nuclear antibodies, anti-dsDNA antibodies, anti-neutrophil cytoplasmic autoantibodies and antiphospholipid antibodies. Rheumatoid factor and anti-CCP do not have much significance in the diagnostic schema in pediatric rheumatology, except perhaps for classification of juvenile idiopathic arthritis (JIA) and prognostication in late-onset polyarticular JIA. The positive predictive value (PPV) of any laboratory test depends on the prevalence of the disease in the population being tested. Hence, test ordering practices greatly impact the performance characteristics and positive predictive value of any laboratory test. A restricted test ordering only in patients with clinical signs and symptoms suggestive of autoimmune disease would thus greatly increase the PPV of tests such as antinuclear antibody used for diagnosing autoimmunity.
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The study was conducted with an aim to assess the efficacy of recombinant HBV vaccination in untreated HBV seronegative HIV/AIDS subjects as compared to normal controls. The second objective was to identify differences in CD4 and CD8 T... more
The study was conducted with an aim to assess the efficacy of recombinant HBV vaccination in untreated HBV seronegative HIV/AIDS subjects as compared to normal controls. The second objective was to identify differences in CD4 and CD8 T cell numbers/kinetics/functions and levels of TH2 cytokines (IL4 and IL10) in different groups during the three-dose vaccination regimen. 40 HIV/AIDS patients were subdivided into groups 1A where patients had a high CD4 (> 200/mm3) count and IB where patients had a low CD4 (< 200/mm3) count. Twenty normal healthy control subjects were also recruited in the study (group II). Patients received 40 micro and controls received 20 micro of recombinant HBV vaccine in each dose. All subjects received 3 doses of the vaccine. Detection of CD4 and CD8 cells was done by flowcytometry. TH2 type of cytokines IL4 and IL10 were estimated in the culture supernatant of PHA stimulated leukocyte rich plasma by sandwich ELISA. Anti-HBs levels were estimated in the s...
Research Interests: Virology, Medicine, Hepatitis B, Humans, Female, and 6 moreMale, Vaccination, Adult, Hepatitis B Vaccines, Interleukin, and HIV infections
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The cut-off values of immunological tests employed in diagnosis of allergic bronchopulmonary aspergillosis (ABPA) have never been validated. Herein, we compare the immunological findings in patients with ABPA and asthma using receiver... more
The cut-off values of immunological tests employed in diagnosis of allergic bronchopulmonary aspergillosis (ABPA) have never been validated. Herein, we compare the immunological findings in patients with ABPA and asthma using receiver operating characteristic analysis. Consecutive asthmatic subjects underwent all the following investigations: Aspergillus skin test, IgE levels (total and A. fumigatus-specific), Aspergillus precipitins, eosinophil count, chest radiograph and CT chest. There were 372 subjects (179 men, mean age 35.9 years) with a mean asthma duration of 8 years. ABPA was diagnosed in 76 patients (64 bronchiectasis, 12 without bronchiectasis). ABPA was separated from asthma using the best cut-off values of total IgE, A. fumigatus IgE and total eosinophil count of 2347 IU ml(-1) , 1.91 kUA l(-1) and 507 cells per μl respectively. The sensitivity/specificity of these parameters were 87/81%; 99/87%; and, 79/76% respectively. The corresponding AUC values were 0.95, 0.90 and 0.82 respectively. The combination of these three tests at the aforementioned cut-offs provided 100% specificity. Our study provides evidence-based cut-off values of IgE (total and A. fumigatus-specific) and eosinophil counts in differentiating ABPA from asthma. As this is a single centre retrospective study, further studies from different centres are required, as these values could vary by ethnicity and environmental exposure.
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1. J Otolaryngol. 2002 Jun;31(3):184-6. Metastatic bone marrow involvement by squamous cell carcinoma of the tonsil. Saikia B, Varma N, Mohan C, Radotra BD, Sharma SC. Department of Hematology, Post Graduate Institute ...
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Immunoglobulin G4 subclass deficiency is the most common IgG subclass deficiency, followed by immunoglobulin G2 deficiency. However, IgG2 deficiency is the most common IgG subclass deficiency associated with recurrent infections.... more
Immunoglobulin G4 subclass deficiency is the most common IgG subclass deficiency, followed by immunoglobulin G2 deficiency. However, IgG2 deficiency is the most common IgG subclass deficiency associated with recurrent infections. Immunoglobulin G4 subclass deficiency occurs in association with other isotype deficiencies. Isolated IgG4 deficiency, however, is much less common. Although respiratory tract infections are the most common manifestation in isolated IgG4 deficiency, other mucosal surfaces may also be affected in IgG4 deficiency leading to diarrhea and recurrent giardiasis. The authors herein report a case of isolated immunoglobulin G4 subclass deficiency in a young girl presenting with bronchiectasis. The diagnosis was established after ruling out other causes of secondary and primary immunodeficiency.
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Research Interests: Immunology, Computed Tomography, Medicine, Allergic bronchopulmonary aspergillosis, Aspergillus, and 15 moreAllergy, Humans, Female, Male, Prednisolone, Immunoglobulin E, Recurrence, Clinical Sciences, IGE, High, Adult, Attenuation, Glucocorticoids, Clinical evaluation, and Cardiovascular medicine and haematology
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Research Interests: Allergic bronchopulmonary aspergillosis, Humans, Female, Infection, Male, and 15 moreYoung Adult, Immunoglobulin E, Lung, Aspergillus fumigatus, Middle Aged, Eosinophils, Spirometry, Adult, Public health systems and services research, Retrospective Studies, Bronchiectasis, Mucus, Cohort Studies, Peripheral blood, and leukocyte Count
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Research Interests: Magnetic Resonance Imaging, Medicine, Brain, Humans, Child, and 15 moreFluorescence in situ hybridization, Female, Male, Infant, Differential Diagnosis, Clinical Sciences, Adult, Neck, Adrenocortical Carcinoma, Brain Neoplasms, Lymph nodes, Chromosome deletion, Liver neoplasms, Medical and Health Sciences, and Diagnostic errors
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... more
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. To report clinical and molecular analyses of patients with Hyper IgE syndrome from a single tertiary care center in India. Four patients with suspected HIES were studied. Flowcytometry for T(H)17 cell numbers and phosphoSTAT3, and STAT3 gene sequencing were performed. 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...