Publications by authors named "Sudhir Gupta"

174 Publications

Interindividual immunogenic variants: Susceptibility to coronavirus, respiratory syncytial virus and influenza virus.

Rev Med Virol 2021 Mar 16:e2189. Epub 2021 Mar 16.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.
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http://dx.doi.org/10.1002/rmv.2234DOI Listing
March 2021

Update on Infections in Primary Antibody Deficiencies.

Front Immunol 2021 11;12:634181. Epub 2021 Feb 11.

Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA, United States.

Bacterial respiratory tract infections are the hallmark of primary antibody deficiencies (PADs). Because they are also among the most common infections in healthy individuals, PADs are usually overlooked in these patients. Careful evaluation of the history, including frequency, chronicity, and presence of other infections, would help suspect PADs. This review will focus on infections in relatively common PADs, discussing diagnostic challenges, and some management strategies to prevent infections.
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http://dx.doi.org/10.3389/fimmu.2021.634181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905085PMC
February 2021

Update on Infections in Primary Antibody Deficiencies.

Front Immunol 2021 11;12:634181. Epub 2021 Feb 11.

Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA, United States.

Bacterial respiratory tract infections are the hallmark of primary antibody deficiencies (PADs). Because they are also among the most common infections in healthy individuals, PADs are usually overlooked in these patients. Careful evaluation of the history, including frequency, chronicity, and presence of other infections, would help suspect PADs. This review will focus on infections in relatively common PADs, discussing diagnostic challenges, and some management strategies to prevent infections.
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http://dx.doi.org/10.3389/fimmu.2021.634181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905085PMC
February 2021

Progression of primary selective immunoglobulin M deficiency to common variable immunodeficiency.

Ann Allergy Asthma Immunol 2021 Feb 17. Epub 2021 Feb 17.

Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, California. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2021.02.012DOI Listing
February 2021

SARS-CoV-2-Associated T-Cell Responses in the Presence of Humoral Immunodeficiency.

Int Arch Allergy Immunol 2021 22;182(3):195-209. Epub 2021 Jan 22.

Division of Basic and Clinical Immunology, University of California, Irvine, California, USA.

We report perhaps the most comprehensive study of subsets of CD4+ and CD8+ and subsets of B cells in a mild symptomatic SARS-CoV-2+ immunocompetent patient and a common variable immunodeficiency disease (CVID) patient who had normal absolute lymphocyte counts and remained negative for SARS-CoV-2 IgG antibodies. Naïve (TN), central memory (TCM), effector memory (TEM), and terminally differentiated effector memory (TEMRA) subsets of CD4+ and CD8+ T cells, subsets of T follicular helper cells (cTFH, TFH1, TFH2, TFH17, TFH1/TFH17, and TFR), CD4 Treg, CD8 Treg, mature B cells, transitional B cells, marginal zone B cells, germinal center (GC) B cells, CD21low B cells, antibody-secreting cells (plasmablasts), and Breg cells were examined in patients and age-matched controls with appropriate monoclonal antibodies and isotype controls using multicolor flow cytometry. Different patterns of abnormalities (often contrasting) were observed in the subsets of CD4+ T, CD8+ T, B-cell subsets, and regulatory lymphocytes among the immunocompetent patient and CVID patient as compared to corresponding healthy controls. Furthermore, when data were analyzed between the 2 patients, the immunocompetent patient demonstrated greater changes in various subsets as compared to the CVID patient. These data demonstrate different immunological responses to SARS-CoV-2 infection in an immunocompetent patient and the CVID patient. A marked decrease in GC B cells and plasmablasts may be responsible for failure to make SARS-CoV-2 antibodies. The lack of SARS-CoV-2 antibodies with mild clinical disease suggests an important role of T-cell response in defense against SARS-CoV-2 infection.
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http://dx.doi.org/10.1159/000514193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900460PMC
March 2021

Next Generation Sequencing Based Forward Genetic Approaches for Identification and Mapping of Causal Mutations in Crop Plants: A Comprehensive Review.

Plants (Basel) 2020 Oct 14;9(10). Epub 2020 Oct 14.

Nuclear Agriculture and Biotechnology Division, Bhabha Atomic Research Centre, Mumbai 400085, India.

The recent advancements in forward genetics have expanded the applications of mutation techniques in advanced genetics and genomics, ahead of direct use in breeding programs. The advent of next-generation sequencing (NGS) has enabled easy identification and mapping of causal mutations within a short period and at relatively low cost. Identifying the genetic mutations and genes that underlie phenotypic changes is essential for understanding a wide variety of biological functions. To accelerate the mutation mapping for crop improvement, several high-throughput and novel NGS based forward genetic approaches have been developed and applied in various crops. These techniques are highly efficient in crop plants, as it is relatively easy to grow and screen thousands of individuals. These approaches have improved the resolution in quantitative trait loci (QTL) position/point mutations and assisted in determining the functional causative variations in genes. To be successful in the interpretation of NGS data, bioinformatics computational methods are critical elements in delivering accurate assembly, alignment, and variant detection. Numerous bioinformatics tools/pipelines have been developed for such analysis. This article intends to review the recent advances in NGS based forward genetic approaches to identify and map the causal mutations in the crop genomes. The article also highlights the available bioinformatics tools/pipelines for reducing the complexity of NGS data and delivering the concluding outcomes.
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http://dx.doi.org/10.3390/plants9101355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602136PMC
October 2020

Reconstitution of IgG Subclasses Following Immunoglobulin Administration in Adult Patients with Common Variable Immune Deficiency.

Int Arch Allergy Immunol 2021 14;182(3):243-253. Epub 2020 Oct 14.

Division of Basic and Clinical Immunology, University of California at Irvine, Irvine, California, USA,

Background: Immunoglobulin (Ig) therapy reduces the frequency and severity of infection among patients with antibody deficiency disorders. However, a subset of patients lacks adequate clinical response.

Objective: The purpose of this study was to determine in adult common variable immune deficiency (CVID) patients (A) if lack of clinical response to Ig therapy correlates with lack of reconstitution of IgG subclass (es), (B) correlation between Ig dosing and/or IgG trough levels and IgG subclass reconstitution, (C) and most common impaired Streptococcus pneumoniae (S. pneumoniae) serotype antibody response.

Methods: Single-institution, retrospective chart review for CVID patients at immunology clinics from 2015 to 2019. Patients were monitored every 3-6 months for IgG dosage, IgG trough levels, IgG subclass reconstitution, infectious episodes (chronic sinusitis, bronchitis, upper respiratory, and lower respiratory tract infections), urinary tract infections, and antibiotic use. Follow-up was calculated in patient years.

Results: Twenty-five of 41 patients achieved complete reconstitution of all IgG subclasses, and 16/41 demonstrated intermittent or lack of reconstitution. There were significantly less (p < 0.001) infections among fully reconstituted patients (0.66 ± 0.19 infections per patient year) as compared to those with intermittent or lack of reconstitution (1.26 ± 0.13 infections per patient year). There was a significant correlation between IgG trough levels and IgG subclass reconstitution. Most common impaired S. pneumoniae serotype included 3, 4, 9n, 10a, 11a, 12f, and 15b.

Conclusions: Incomplete IgG subclass reconstitution was associated with increased frequency of infections. IgG trough levels correlate with IgG subclass reconstitution. A limited number of S. pneumoniae serotype antibodies are commonly impaired in CVID.
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http://dx.doi.org/10.1159/000510790DOI Listing
October 2020

Human pregnancy levels of estrogen and progesterone contribute to humoral immunity by activating T /B cell axis.

Eur J Immunol 2021 01 21;51(1):167-179. Epub 2020 Oct 21.

Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.

Circulating T (cT ) cells express CXCR5, PD-1, and, when activated, ICOS, and release IL-21. According to the production of IFN-γ, IL-4, and IL-17 and expression of FoxP3, these cells are also classified as cT 1, cT 2, cT 17, and cT cells, respectively. This CD4 T-cell subset is pivotal to efficient humoral immunity, and pregnancy appears to favor IgG production. Here, not only pregnancy amplified the in vivo production of anti-HBsAg IgG in HBV immunized women, but the frequency of cT cells was directly correlated with estradiol levels. In vitro, pregnancy-related dose of 17-β-estradiol (E2) directly increased the percentage of different cT subsets. While E2 and progesterone (P4) increased the proportion of differentiated T cells derived from naïve CD4 T-cells, only E2 amplified the release of IL-21 in those cell cultures. In addition, E2 and P4 increased the proportion of memory B cells and plasma cells, respectively. In SEB-activated B/T cell co-cultures, E2, in the presence of P4, increased the production of total IgG. Finally, among the hormones, P4 was stronger in upregulating the percentage of IL-10 T cells. Collectively, our findings suggested that E2 and P4 cooperate in the humoral immune response by favoring the expansion of different cT and B cell subsets.
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http://dx.doi.org/10.1002/eji.202048658DOI Listing
January 2021

Assessment of Occult Pulmonary Involvement in Ulcerative Colitis.

Inflamm Intest Dis 2020 Aug 1;5(3):144-150. Epub 2020 Jul 1.

Department of Gastroenterology, Government Medical College and Super Specialty Hospital, Nagpur, India.

Introduction: Nearly 50% of patients with inflammatory bowel disease (IBD) experience at least one extraintestinal manifestation. Bronchopulmonary involvement is rare in IBD. Pulmonary function test (PFT) abnormality in cases of ulcerative colitis (UC) has been reported to be 17-55%. Occult pulmonary disease may be diagnosed using variables of the PFT. Hence, we aim to evaluate the frequency and type of pulmonary dysfunction in patients with UC in remission.

Methods: Eighty-three patients of UC in remission and 48 controls underwent the PFT including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), Tiffeneau value (FEV1/FVC), and midexpiratory flow (MEF 25-75%) rate with a spirometer. The patients were divided based on the age of onset of UC into A1 (<16 years), A2 (16-40 years), and A3 (>40 years) and based on the extent of disease into E1 (proctitis), E2 (left-sided colitis), and E3 (extensive colitis).

Results: Patients with UC had significantly abnormal PFT compared with controls (51 [61.5%] vss. 8 [16.67%]; = 0.000). Patients with UC commonly had a restrictive pattern (33 [64.47%]) of PFT followed by small airway disease (11 [21.56%]) and obstructive pattern (7 [13.72%]). Pulmonary involvement in cases of UC was more in E3 followed by E2 and E1. Pulmonary involvement was more in the late age of onset of disease. BMI was positively and significantly correlated with FEV1 and FVC. Hemoglobin had a positive and significant correlation with FEV1 while a negative correlation with FEV1/FVC and MEF 25-75%. All predictors except for age were found to contribute in higher risk (OR > 1) for PFT abnormality.

Conclusion: Patients with UC have chronic pulmonary inflammation leading to different patterns of lung involvement in the form of restrictive, obstructive airway, and small airway disease. Patients with UC commonly have a restrictive pattern of pulmonary involvement. Impairment of the PFT is related to the disease extent and the age of onset of disease. Assessment of the PFT using a spirometer is a noninvasive, simple, cost-effective, and reliable method for early detection of occult pulmonary involvement in patients of UC.
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http://dx.doi.org/10.1159/000508772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506263PMC
August 2020

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, Australia. Electronic address:

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

CD8 Treg Cells Inhibit B-Cell Proliferation and Immunoglobulin Production.

Int Arch Allergy Immunol 2020 14;181(12):947-955. Epub 2020 Aug 14.

Division of Basic and Clinical Immunology, Department of Medicine, School of Medicine, University of California, Irvine, California, USA.

Aim: The role of CD4+ Treg in immune responses has been well established. More recently, a role of CD8+ T regulatory cells (CD8 Treg) in the regulation of immune responses in health and autoimmune diseases has been investigated. Furthermore, different investigators have used different markers to define CD8 Treg. Finally, regulatory effects of CD8 Treg have been studied against T-cell responses; however, their role in regulating B-cell proliferation and immunoglobulin production has not been evaluated. Therefore, in this study we examined the effect of two types of CD8 Treg on B-cell proliferation and immunoglobulin production.

Methods: Purified CD8+ T cells were activated with anti-CD3/CD28 for 48 h and then sorted into two different types of CD8 Treg as defined by two different sets of markers, CD8+CD183+CD197+CD45RA- and CD8+CD183+CD25highCD278+. Purified B cells were cocultured with sorted CD8 Treg at 1:1, 1:1/2, and 1:1/4 ratios and activated with anti-CD40 and CpG. B-cell proliferation was assessed by the CFSE dye dilution assay and immunoglobulin production by the ELISA assay.

Results: Our data show CD183+CD197+CD45RA-CD8 Treg significantly inhibited B-cell proliferation and inhibited IgM and IgG production but not IgA production at 1:1 ratio only. However, CD183+CD25highCD278+CD8 Treg inhibited significantly B-cell proliferation at 1:1 and 1:1/2 ratios and IgM, IgG, and IgA production at all ratios.

Conclusion: CD8 Treg regulate B-cell responses, and CD183+CD25highCD278+CD8 Treg are more powerful regulators of B-cell proliferation and immunoglobulin production than CD183+CD197+CD45RA-CD8 Treg and, therefore, may be used as preferred markers for CD8 Treg.
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http://dx.doi.org/10.1159/000509607DOI Listing
January 2021

Phenotypic analysis of T follicular helper and T follicular regulatory cells in primary selective IgM deficiency.

Hum Immunol 2020 Oct - Nov;81(10-11):625-633. Epub 2020 Aug 7.

Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA, United States. Electronic address:

Selective IgM deficiency (SIgMD) is a rare immunodeficiency characterized by serum IgM below two standard of mean, and normal IgG and IgA levels. Both in human and mice with selective IgM deficiency, germinal centers cells are decreased. The development of germinal center and humoral immunity are regulated in part by follicular helper T (T) and follicular regulatory T (T) cells. However, the analysis of circulating T (cT) and T (cT) cells in the pathogenesis of SIgMD has not been explored. We observed lower percentage of cT cells in SIgMD patients than in control group. However, we did not observe any significant difference in the percentage of cT cells and their subsets between both experimental groups. When data were analyzed according to specific antibody response to pneumococcal polysaccharide, we observed a higher percentage of cT cells in SIgMD patients with specific antibody deficiency than in SIgMD patients with normal specific antibody response. Our results suggest that cT cells and their subsets are preserved in SIgMD patients. However, the role of lower percentage of cT cells in the pathogenesis of this immunodeficiency is not clear.
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http://dx.doi.org/10.1016/j.humimm.2020.07.008DOI Listing
August 2020

Phenotypically defined subpopulations of circulating follicular helper T cells in common variable immunodeficiency.

Immun Inflamm Dis 2020 09 2;8(3):441-446. Epub 2020 Jul 2.

Division of Basic and Clinical Immunology, University of California, Irvine, California.

Background: Common variable immunodeficiency (CVID) is characterized by low immunoglobulin G and IgA/IgM, decreased switched memory B cells, impaired response to vaccine, and an increased susceptibility to infections and autoimmunity. T cells play an important role in germinal center reaction where it supports isotype switching, somatic hypermutation, generation of memory B cells, and differentiation of B cells to plasma cells. The objective was to study the distribution of three subsets of T cells and their relationship with autoimmune diseases associated with CVID.

Methods: T cells have been divided into T 1 (interleukin 21 [IL-21] and interferon γ), T 2 (IL-21 and IL-4), and T 17 (IL-21 and IL-17) cells. Mononuclear cells from 25 patients with CVID and age and gender-matched controls were stained with various monoclonal antibodies (anti-CD4 APC, anti-CXCR5 FITC, anti-CCR6 PerCP, and anti-CXCR3 PE) and isotype controls and analyzed for T 1 (CD4 CXCR5 CXCR3 CCR6 ), T 2 (CD4 CXCR5 CXCR3 CCR6 ), and T 17 (CD4 CXCR5 CXCR3 CCR6 ) cells by multicolor flow cytometry. Twenty thousand cells were acquired and analyzed by FlowJo software. Statistical analysis of comparison of patients and healthy controls was performed by paired t test using PRISM 7 software.

Results: T 2 and T 17 cells subpopulations of T cells were significantly decreased (P < .003 and P < .006, respectively) in CVID as compared with controls. No significant difference was observed in any of T cell subpopulations between CVID with and those without autoimmunity group.

Conclusion: Alterations in T cell subpopulation may play a role in defects in B cell compartment in CVID.
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http://dx.doi.org/10.1002/iid3.326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416056PMC
September 2020

Abscess in a Patient with Common Variable Immunodeficiency.

Pathogens 2020 Jun 22;9(6). Epub 2020 Jun 22.

Division of Basic and Clinical Immunology, and Department of Pathology and Laboratory Medicine, University of California at Irvine, Irvine, CA 92660, USA.

is an anaerobic, gram-positive commensal organism of the urogenital tract. typically causes urinary tract infections, predominantly in the elderly. Here, we describe the first case of infection presenting as cellulitis and abscess in a patient with common variable immunodeficiency. The patient was successfully treated with an incision and drainage and a prolonged antibiotic course. infection should be considered in sterile abscesses, and anaerobic cultures should be requested in the absence of positive routine cultures.
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http://dx.doi.org/10.3390/pathogens9060494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350303PMC
June 2020

Phenotypic and Functional Analysis of T Follicular Cells in Common Variable Immunodeficiency.

Int Arch Allergy Immunol 2020 3;181(8):635-647. Epub 2020 Jun 3.

Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, California, USA.

Introduction: One of the most frequent abnormalities of B cells in common variable immunodeficiency (CVID) is reduced number of class-switched memory B cells, suggesting an impaired germinal center response. Therefore, due to its pivotal role in regulating the development of humoral immunity, the objective of this study was to evaluate the role of circulating T follicular helper (cTFH) and circulating T follicular regulatory (cTFR) cells in the pathogenesis of CVID.

Methods: cTFH and cTFR cells from CVID patients and healthy subjects were phenotypically characterized by flow cytometry. cTFH and memory B cells from CVID patients and healthy subjects were isolated and cocultured.

Results: Our results showed a reduced proportion of cTFH17 cells in patients with CVID and an increased ratio of cTFH/cTFR cells in CVID patients with autoimmune diseases. Furthermore, the proportion of IL-21-producing cTFH cells was directly related to the proportion of CD27+ IgD- B cells. Interestingly, coculture assay showed that CVID-derived cTFH cells are able to help memory B cells from healthy controls to produce immunoglobulins.

Conclusions: The proportions of cTFH17 and cTFR cells are altered in CVID patients; however, the cTFH function in assisting B cells to produce antibodies in vitro is preserved.
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http://dx.doi.org/10.1159/000507995DOI Listing
January 2021

The urgent need for integrated science to fight COVID-19 pandemic and beyond.

J Transl Med 2020 05 19;18(1):205. Epub 2020 May 19.

Universal Scientific Education and Research Network (USERN), , .

The COVID-19 pandemic has become the leading societal concern. The pandemic has shown that the public health concern is not only a medical problem, but also affects society as a whole; so, it has also become the leading scientific concern. We discuss in this treatise the importance of bringing the world's scientists together to find effective solutions for controlling the pandemic. By applying novel research frameworks, interdisciplinary collaboration promises to manage the pandemic's consequences and prevent recurrences of similar pandemics.
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http://dx.doi.org/10.1186/s12967-020-02364-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236639PMC
May 2020

In vitro Effects of CD8+ Regulatory T Cells on Human B Cell Subpopulations.

Int Arch Allergy Immunol 2020 3;181(6):476-480. Epub 2020 Apr 3.

Division of Basic and Clinical Immunology, Department of Medicine, School of Medicine, University of California at Irvine, Irvine, California, USA.

Background: CD8+ regulatory T cells (CD8+ Tregs) are relatively recently described T cell subsets that have been shown to regulate various T cell responses and appear to play a role in autoimmunity. However, their effects on B cells have not been explored.

Objectives: In this investigation we examine the effect of CD8+ Tregs on various subsets of peripheral B cells include naïve B cells, transitional B cells, marginal zone B cells, IgM memory B cells, class switched memory B cells, and plasmablasts, and on the expression of B cell-activating factor receptor (BAFF-R).

Methods: CD8+ T cells were first purified and then activated with anti-CD3/CD28 beads to generate CD8+ Tregs. Purified CD19+ B cells were cultured alone or with sorted CD8+ Tregs (CD8+CD183+CCR7+CD45RA-) and activated with anti-CD40 monoclonal antibody and CpG. B cell subsets and the expression of BAFF-R on naïve and memory B cells were analyzed using various monoclonal antibodies and corresponding control isotypes. Ten thousand cells were acquired and analyzed by FACSCalibur using the FlowJo software.

Results: CD8+ Tregs selectively and significantly suppressed plasmablasts without any significant effect on other B cell subsets or on the expression of BAFF-R.

Conclusion: CD8+ Tregs may play a role in autoimmunity by regulating antibody production via suppression of plasmablasts.
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http://dx.doi.org/10.1159/000506806DOI Listing
November 2020

Comprehensive clinical and immunological features of 62 adult patients with selective primary IgM deficiency.

Am J Clin Exp Immunol 2019 25;8(6):55-67. Epub 2019 Dec 25.

Division of Basic and Clinical Immunology, University of California Irvine, California, USA.

Selective IgM Deficiency (SIgMD) is a recently incorporated disorder in the classification of primary immunodeficiency diseases. The purpose of this study was to present detailed clinical and immunological features in a cohort of 62 adult patients with SIgMD. A retrospective chart review of 62 patients between 2009 and 2017 with a diagnosis of SIgMD was performed for clinical and immunological features, and response to immunoglobulin therapy in symptomatic patients who also exhibited specific antibody deficiency. The majority of patients presented with recurrent and chronic upper and lower respiratory tract infections (73%), most often with recurrent sinusitis (29%), bronchitis (33%), pneumonia (21%), and recurrent urinary tract infections (16%). Forty three percent of patients had associated autoimmune diseases including Hashimoto's thyroiditis, and systemic lupus erythematosus. Approximately 35% of patients had atopic diseases, including allergic rhinitis and asthma. CD3+ T, CD4+ T, CD8+ T, and CD19+ B cells were normal in the majority of patients. IgG subclass deficiency was observed in approximately 22% of cases. Forty seven percent of patients exhibited specific anti-pneumococcal antibody deficiency. The six most common pneumococcal serotypes that were impaired in majority (>70%) of subjects included 3, 4, 9V, 9N, 12F, 23F. Eighteen (66%) of 27 patients with specific antibody deficiency received immunoglobulin therapy and almost all subjects responded to immunoglobulin therapy by decreased frequency of infections. No correlation was observed in immunological features, clinical manifestations, or response to therapy with serum IgM levels.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971419PMC
December 2019

Transition of Macrophages to Fibroblast-Like Cells in Healing Myocardial Infarction.

J Am Coll Cardiol 2019 12;74(25):3124-3135

Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content.

Objectives: This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis.

Methods: Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre);ROSA26(EYFP) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI.

Results: Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3Col1A1 cells in the heart after MI.

Conclusions: The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.
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http://dx.doi.org/10.1016/j.jacc.2019.10.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425814PMC
December 2019

Role of non-invasive markers in prediction of esophageal varices and variceal bleeding in patients of alcoholic liver cirrhosis from central India.

Turk J Gastroenterol 2019 Dec;30(12):1036-1043

Department of Gastroenterology, Government Medical College - Superspeciality Hospital, Nagpur, Maharashtra, India.

Background/aims: Alcohol is the leading cause of liver cirrhosis, which results in portal hypertension and subsequently, culminates into esophageal varices and esophgeal variceal bleeding. Esophagogastroduodenoscopy is gold standard for diagnosis of varices. Non-invasive markers based on clinical, laboratory - ultrasonographic parameters can be utilised for prediction of risk of esophageal varices - variceal bleed in alcoholic cirrhosis from central India.

Materials And Methods: This was a cross sectional observational study. Child Turcot Pugh scores, MELD, AST ALT Ratio(AAR), AST Platelet Ratio Index(APRI), FIB-4 index and Platelet count-Spleen diameter(PC/SD) ratio were calculated for all patients and correlated with esophagogastroduodenoscopy findings. Short term follow up was done for variceal bleeding.

Results: Total 202 male patients were included with mean age of 43.77±9.95 years. 188(93%) patients had esophageal varices. 61(30.19%) patients had variceal bleeding. On univariate analysis platelet count, APRI, spleen bipolar diameter, and PC/SD ratio were significantly associated with varices. For prediction of esophageal varices, only PC/SD ratio was significant and showed area under the curve of 65.6% at cut-off of <997. CTP score, FIB-4, APRI, and PC/SD ratio were significant for variceal bleeding. At cut-off <985 PC/SD ratio had sensitivity of 82% and specificity of 63% with AUC of 78% for prediction of variceal bleeding. Also, FIB-4 and APRI had diagnostic accuracy of 64% and 61% with AUC of 74% and 72% respectively for bleed.

Conclusion: FIB-4 and PC/SD may be useful among armamentarium of non-invasive markers for predicting esophageal varices and risk of variceal bleeding in alcoholic liver cirrhosis.
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http://dx.doi.org/10.5152/tjg.2019.18334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924602PMC
December 2019

Biochemical findings in sudden unexpected death in epilepsy: Hospital based case-control study.

J Forensic Leg Med 2020 Jan 9;69:101884. Epub 2019 Nov 9.

Department of Forensic Medicine, All India Institute of Medical Sciences, New Delhi, India.

Purpose: A review study on the biochemistry of epilepsy showed that in epileptic patients, serum glucose and cholesterol concentrations are low, sodium is unaffected, potassium increases, glucose is high and mild hypocalcemia. We have conducted a biochemical study on sudden unexpected death in epilepsy (SUDEP) cases in an attempt to establish the characteristic biochemical values to diagnose these deaths.

Methods: This was a hospital based case-control study done at All India Institute of Medical Sciences, New Delhi for one year. Twenty SUDEP cases and 20 age- and sex-matched controls were included in the study. Femoral blood, cerebrospinal fluid, vitreous humor, and pericardial fluid were biochemically analyzed for sodium, potassium, calcium, glucose, N-acetyl- cysteine activated creatine kinase (CK-NAC) and isoenzyme CK-MB.

Result: Serum sodium, CK-MB and CK-NAC level was found significantly increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. Likewise, in CSF, sodium and CK-NAC was found increased and potassium level was found decreased in SUDEP cases. In vitreous humor, sodium and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. In pericardial fluid, sodium, CK-NAC and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths.

Conclusion: It concludes that high sodium level and low potassium level could be associated with SUDEP. However, this is a small size study, a larger study is needed to verify the findings. Furthermore, it is difficult to conclude whether these findings are exclusive to SUDEP.
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http://dx.doi.org/10.1016/j.jflm.2019.101884DOI Listing
January 2020

Pregnancy favors circulating IL-21-secreting T -like cell recovery in ARV-treated HIV-1-infected women.

Am J Reprod Immunol 2020 02 17;83(2):e13204. Epub 2019 Nov 17.

Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.

Problem: Pregnancy appears to favor maternal antibody production. In contrast, by damaging follicular helper T cells (T ), HIV-1 infection compromises protective humoural immune response. Therefore, we aimed to investigate the frequency of different T -like cells in HIV-infected pregnant women (PW) before and after antiretroviral (ARV) therapy.

Method Of Study: Peripheral blood mononuclear cells, CD4 T and B cells, were obtained from asymptomatic HIV-1-infected non-PW and PW just before and after ARV therapy. In some experiments, healthy HIV-1-negative PW were also tested. The frequency of different T -like cell subsets was determined by flow cytometry. The plasma titers of IgG anti-tetanus toxoid (TT), anti-HBsAg, and anti-gp41 were determined by ELISA. The in vitro production of total IgG, IL-21, and hormones (estrogen and progesterone) was quantified also by ELISA.

Results: Our results demonstrate that antiretroviral (ARV) therapy was more efficient in elevating the percentage of circulating IL-21-secreting T cells in HIV-1-infected pregnant women (PW) than in non-pregnant patients (nPW). Moreover, in co-culture systems, CD4 T cells from ART-treated PW were more efficient in assisting B cells to produce IgG production. The in vivo anti-HBsAg IgG titers after ARV therapy were also significantly higher in PW, and their levels were directly associated with both IL-21 T frequency and plasma concentration of estrogen.

Conclusion: In summary, our results suggest that pregnancy favors the recovery of T -like cells after ARV therapy in HIV-1-infected women, which could help these mothers to protect their newborns from infectious diseases by transferring IgG across the placenta.
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http://dx.doi.org/10.1111/aji.13204DOI Listing
February 2020

Reconstitution of IgG Subclasses following Immunoglobulin Therapy in Adult Primary Hypogammaglobulinemia.

Int Arch Allergy Immunol 2019 11;180(3):221-232. Epub 2019 Sep 11.

Division of Basic and Clinical Immunology, University of California at Irvine, Irvine, California, USA,

Background: Immunoglobulin (Ig) therapy is highly effective in reducing the frequency and severity of infections. However, a subset of patients does not respond adequately.

Objective: To determine in adult patients with primary hypogammaglobulinemia (a) if failure to reconstitute IgG subclass(es) is associated with inadequate clinical response, (b) whether reconstitution of IgG subclasses differs between routes of Ig administration, (c) which subclasses contribute to low total IgG, and (d) what are the most commonly impaired Streptococcus pneumoniae serotypes.

Methods: A retrospective review of the records of patients with primary hypogammaglobulinemia followed up at the Immunology Clinic between 2010 and 2018 was conducted. Demographic, clinical, and laboratory data were collected.

Results: Seventy-one patients with primary hypogammaglobulinemia were included. All subclasses were reconstituted in 85% of the patients. IgG3 and IgG4 were most commonly not reconstituted. Reconstitution occurred in 85% of the patients on intravenous Ig (IVIG), 81% of the patients on conventional subcutaneous Ig (SCIG), and 100% of the patients on enzyme-facilitated subcutaneous Ig (fSCIG). The annual infection rate was 0.87 with IVIG, 0.88 with conventional SCIG, and 0.6 with fSCIG. IgG subclasses contributing to low total IgG included IgG1 (61%), IgG2 (49%), IgG3 (23%), and IgG4 (28%). In patients with concomitant specific antibody deficiency (n = 47), the most commonly impaired antibody responses were against pneumococcal serotypes 3, 4, 6b, 12f, and 23f.

Conclusions: Failure to reconstitute subclasses does not correlate with an inadequate clinical response to immunoglobulin therapy in primary hypogammaglobulinemia. Full reconstitution of IgG subclasses was observed with fSCIG. A smaller panel of pneumococcal antibody responses may be used to define specific antibody deficiency.
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http://dx.doi.org/10.1159/000502742DOI Listing
December 2019

IgAλ monoclonal gammopathy of undetermined significance (MGUS) associated with primary selective IgM deficiency.

Am J Clin Exp Immunol 2019 15;8(4):37-46. Epub 2019 Aug 15.

Basic Clinical Immunology, University of California Irvine, California, USA.

Selective IgM deficiency (SIgMD) and IgA MGUS in a young woman are two rare disorders. IgA MGUS has not been described in patients with SIgMD. We present the first comprehensive analysis of various subsets of CD4+ T, CD8+ T cells, and B cells in a young woman with SIgMD and IgAλ MGUS. Analysis of B cell subsets revealed increased proportions of transitional B cells, germinal center (GC) B cells, B regulatory cells (Breg), and plasmablasts (PB), and decreased proportions of marginal zone (MZ) B cells. BAFF-R expression on both naïve and memory B cells was increased. CD4+ and CD8+ effector memory cells were decreased, whereas CD4+ and CD8+ naïve T cells were increased. These abnormalities in B cell subsets and plasmablasts are not observed in SIgMD, therefore appears be influenced by MGUS. No correlation was observed with changes in the levels of monoclonal IgA and serum IgM levels over nine years follow-up suggesting that SIgMD is likely to be primary rather than secondary to MGUS. These observations also suggest that IgAλ MGUS and perhaps other MGUS may occur at a young age in association with selective IgM deficiency. The abnormalities in B cell subsets may have a predictive value for progression to multiple myeloma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726973PMC
August 2019

Granuloma-like lesion at subcutaneous immunoglobulin site in a common variable immunodeficiency patient.

Immunotherapy 2019 10 3;11(14):1177-1180. Epub 2019 Sep 3.

Department of Medicine, Division of Basic & Clinical Immunology, CA 92663, USA.

Immunoglobulin therapy is the main stay in the treatment of primary antibody deficiencies. Granulomatous lesions are common complication in patients with common variable immunodeficiency (CVID). We present the first case of cutaneous granuloma-like lesion at site of subcutaneous immunoglobulin injections in a patient with CVID. These lesions resolve overtime following switching treatment to intravenous immunoglobulin. Unlike granulomas associated with CVID, granulomatous lesion in this patient did not require any specific therapy, and resolved over a period of 4 weeks following switching subcutaneous immunoglobulin to intravenous immunoglobulin.
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http://dx.doi.org/10.2217/imt-2019-0109DOI Listing
October 2019

Clinical and Immunological Features of 78 Adult Patients with Primary Selective IgG Subclass Deficiencies.

Arch Immunol Ther Exp (Warsz) 2019 Oct 30;67(5):325-334. Epub 2019 Jul 30.

Program in Primary Immunodeficiency and Aging, Division of Basic and Clinical Immunology, University of California at Irvine, Irvine, CA, USA.

The purpose of this study is to describe both clinical and immunological features in large cohort of adult patients with IgG subclass deficiency, and response to immunoglobulin therapy. This is a retrospective study of data obtained from electronic medical records and paper charts of 78 patients with IgG subclass deficiency seen and followed at our immunology clinics from 2010 to 2016. Both isolated selective IgG subclass deficiency as well as combined (two) subclass deficiencies were observed. IgG3 subclass deficiency, isolated and in combination with other IgG subclass deficiency, is the most frequent of IgG subclass deficiency. A majority of patients presented with upper and lower respiratory tract infections, especially chronic sinusitis. Both allergic and autoimmune manifestations are common; however, there is no subclass preference. The proportions and absolute numbers of CD3 T cells, CD4 T and CD8 T cells, CD19 B cells, and CD3CD16CD56 NK cells were normal in the majority of patients in all IgG subclass deficiencies. Total serum IgG levels did not correlate with IgG subclass levels across all IgG subclass deficiencies. Anti-pneumococcal polysaccharide antibody responses were impaired in 56% of patients. IgG3 subclass deficiency is the most common IgG subclass deficiency, and anti-polysaccharide antibody responses are distributed among IgG subclasses with modest preference in IgG2 subclass. The majority of patients treated with immunoglobulin responded by reduction in frequency of infections and requirement of antibiotics.
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http://dx.doi.org/10.1007/s00005-019-00556-3DOI Listing
October 2019

Editorial: Immunology of Aging.

Front Immunol 2019 10;10:1614. Epub 2019 Jul 10.

Division of Basic and Clinical Immunology, University of California, Irvine, Irvine, CA, United States.

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http://dx.doi.org/10.3389/fimmu.2019.01614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636427PMC
June 2020

Diet and inflammatory bowel disease: The Asian Working Group guidelines.

Indian J Gastroenterol 2019 06 27;38(3):220-246. Epub 2019 Jul 27.

Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India.

Introduction: These Asian Working Group guidelines on diet in inflammatory bowel disease (IBD) present a multidisciplinary focus on clinical nutrition in IBD in Asian countries.

Methodology: The guidelines are based on evidence from existing published literature; however, if objective data were lacking or inconclusive, expert opinion was considered. The conclusions and 38 recommendations have been subject to full peer review and a Delphi process in which uniformly positive responses (agree or strongly agree) were required.

Results: Diet has an important role in IBD pathogenesis, and an increase in the incidence of IBD in Asian countries has paralleled changes in the dietary patterns. The present consensus endeavors to address the following topics in relation to IBD: (i) role of diet in the pathogenesis; (ii) diet as a therapy; (iii) malnutrition and nutritional assessment of the patients; (iv) dietary recommendations; (v) nutritional rehabilitation; and (vi) nutrition in special situations like surgery, pregnancy, and lactation.

Conclusions: Available objective data to guide nutritional support and primary nutritional therapy in IBD are presented as 38 recommendations.
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http://dx.doi.org/10.1007/s12664-019-00976-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675761PMC
June 2019