Manish Butte

Int J Mol Sci. 2022 Apr 20;23(9):4547. doi: 10.3390/ijms23094547.

ABSTRACT

Giant condyloma acuminatum, also known as Buschke-Lowenstein tumor (BLT), is a rare disease of the anogenital region. BLT is considered a locally aggressive tumor of benign histological appearance, but with the potential for destructive growth and high recurrence rates. BLT development is strongly associated with infection with low-risk human papillomaviruses (HPVs), mostly HPV-6 and -11. Immunity to HPVs plays a crucial role in the natural control of various HPV-induced lesions. Large condyloma acuminata are frequently reported in patients with primary (e.g., DOCK8 or SPINK5 deficiencies) and secondary (e.g., AIDS, solid organ transplantation) immune defects. Individuals with extensive anogenital warts, including BLT in particular, should therefore be tested for inherited or acquired immunodeficiency. Research into the genetic basis of unexplained cases is warranted. An understanding of the etiology of BLT would lead to improvements in its management. This review focuses on the role of underlying HPV infections, and human genetic and immunological determinants of BLT.

PMID:35562936 | DOI:10.3390/ijms23094547

Eur J Immunol. 2022 May 13. doi: 10.1002/eji.202149480. Online ahead of print.

ABSTRACT

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS, as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID. This article is protected by copyright. All rights reserved.

PMID:35562849 | DOI:10.1002/eji.202149480

J Clin Immunol. 2022 May 13. doi: 10.1007/s10875-022-01284-8. Online ahead of print.

NO ABSTRACT

PMID:35556195 | DOI:10.1007/s10875-022-01284-8

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R4476.

ABSTRACT

The prevalence of allergic diseases such as Asthma, Rhinitis, Anaphylaxis, Eczema, Urticaria, and Angioedema have been rising dramatically in low- and middle-income countries around the world. According to American College of Allergy, Asthma & Immunology, allergies are the 6th leading cause of chronic illness in the U.S. and more than 50 million Americans suffer from allergies each year. Extensive data suggest that food allergies affect up to 10% of the world population and have been increasing in the last two to three decades. Globally 300 million people have asthma and about 200 to 250 million people suffer from food allergies. Previously we have shown that a small molecule compound, formononetin have shown decreases IgE production from B cells. We hypothesize that formononetin will be a potential candidate for preventing food anaphylaxis in food allergy by regulating molecular pathways that involved in IgE production in B cells, mast cell activation and degranulation. The objective of this study is to reveal potential therapeutic mechanisms of formononetin in prevention and treatment of food anaphylaxis from food allergy, by using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analyses and in silico molecular docking to identify gene and protein targets that are regulated in food allergy and mast cells diseases. The targets identified were further validated using qRT-PCR in B cell multiple myeloma cell line. U266 cells were cultured to 1.0 × 10⁶ cells/mL and then incubated with formononetin at different concentrations of 20 μg/mL for 72 hours. Supernatants were collected for measuring IgE levels by ELISA and cell viability was determined using Trypan blue dye. mRNA expression was determined for the top targets identified and compared with GAPDH. Mining formononetin targets into obtained disease targets uncovers 25 targets for food allergy, 51 targets for IgE diseases and 19 targets for mast cell diseases. This targets where further used for gene ontology, KEGG pathway analysis, CTPD network and protein-protein interaction. Top regulated KEGG pathways include the primary immunodeficiency pathway, Epstein Barr virus infection pathway, Th17 cell differentiation, PI3K-Akt pathway. Regulated gene ontology biological processes include B cell proliferation, B cell differentiation, B cell activation and apoptotic process. Formononetin decreased IgE at after 72 hours, P < 0.05 without cytotoxicity. Formononetin decreased mRNA expression of P53, TYK2, CASP8 significantly (P < 0.05) and IgEH very significantly (P < 0.01) and increased the mRNA expression of BCL2, NFKBIA and BTK significantly (P < 0.05) after 72 hours in the culture group compared to the untreated group. These findings suggest that formononetin may be a novel therapeutic candidate for treatment and prevention of IgE/mast cell mediated food allergy and other allergic diseases.

PMID:35554259 | DOI:10.1096/fasebj.2022.36.S1.R4476

Front Pediatr. 2022 Apr 25;10:638549. doi: 10.3389/fped.2022.638549. eCollection 2022.

ABSTRACT

BACKGROUND: Patients with T cell deficiency <10% of normal proliferation are indicated to receive immune reconstruction by hematopoietic stem cell transplantation (HSCT). This study aimed to investigate whether non-radioactive assays can be used to quantitatively detect the lymphocyte proliferation <10% of normal as radioactive [³H]-thymidine.”

METHODS: Radioactive [³H]-thymidine, non-radioactive carboxyfluorescein diacetate succinimidyl ester (CFSE), and Ki-67 protein expressions were used to measure the lymphocyte proliferation as calculated using the stimulation index (SI), subtraction percentage, and proliferation index (FlowJo software). Normal references were established for comparison in the absence of parallel healthy controls.

RESULTS: Normal ranges of mitogen-stimulated lymphocyte proliferation were established as a SI of 15-267 (CSFE 47-92%, Ki-67 42-79%) with phytohemagglutinin (PHA) 5 μg/ml stimulation; 19-139 (CFSE 62-83%, 45-74% Ki-67) with concanavalin-A (ConA) 5 μg/ml stimulation; 7-53 (CFSE 6-23%, Ki-67 10-24%) with pokeweed mitogen (PWM) 0.1 ug/ml stimulation; 3-28 (CFSE 4-10%, Ki-67 5-14%) with candida 10 ug/ml stimulation; and 2-27 (CFSE 6-41%, Ki-67 6-30%) with bacille Calmette-Guerin (BCG) 0.02 ng/ml stimulation. The normalized CFSE-proliferation index was between 2.1 and 3.0. Although there was no significant correlation between these three assays in the healthy controls, the SI value for <10% [³H]-thymidine proliferation in those with T cell deficiency was compatible with CFSE- and Ki-67-stained lymphocyte percentages, and validated in patients with IL2RG, RAG1, and ZAP70 mutations. When calculating [³H]-thymidine <10% of normal lymphocyte proliferation, the threshold of parallel controls was more reliable than previously established normal references.

CONCLUSION: The large quantitative value of radioactive [³H]-thymidine was more easily recognizable than that for non-radioactive CFSE and Ki-67. Even though the correlation was not significant, those identified to have <10% of normal proliferation by [³H]-thymidine could be consistently detected by CFSE and Ki-67, and consequently indicated for HSCT.

PMID:35547552 | PMC:PMC9082031 | DOI:10.3389/fped.2022.638549

J Clin Immunol. 2022 May 11. doi: 10.1007/s10875-022-01283-9. Online ahead of print.

ABSTRACT

Immunodeficient individuals often rely on donor-derived immunoglobulin (Ig) replacement therapy (IGRT) to prevent infections. The passive immunity obtained by IGRT is limited and reflects the state of immunity in the plasma donor population at the time of donation. The objective of the current study was to describe how the potential of passive immunity to SARS-CoV-2 in commercial off-the-shelf Ig products used for IGRT has evolved during the pandemic. Samples were collected from all consecutive Ig batches (n = 60) from three Ig producers used at the Immunodeficiency Unit at Karolinska University Hospital from the start of the SARS-CoV-2 pandemic until January 2022. SARS-CoV-2 antibody concentrations and neutralizing capacity were assessed in all samples. In vivo relevance was assessed by sampling patients with XLA (n = 4), lacking endogenous immunoglobulin synthesis and on continuous Ig substitution, for plasma SARS-CoV-2 antibody concentration. SARS-CoV-2 antibody concentrations in commercial Ig products increased over time but remained inconsistently present. Moreover, Ig batches with high neutralizing capacity towards the Wuhan-strain of SARS-CoV-2 had 32-fold lower activity against the Omicron variant. Despite increasing SARS-CoV-2 antibody concentrations in commercial Ig products, four XLA patients on IGRT had relatively low plasma concentrations of SARS-CoV-2 antibodies with no potential to neutralize the Omicron variant in vitro. In line with this observation, three out the four XLA patients had symptomatic COVID-19 during the Omicron wave. In conclusion, 2 years into the pandemic the amounts of antibodies to SARS-CoV-2 vary considerably among commercial Ig batches obtained from three commercial producers. Importantly, in batches with high concentrations of antibodies directed against the original virus strain, protective passive immunity to the Omicron variant appears to be insufficient.

PMID:35538387 | DOI:10.1007/s10875-022-01283-9

J Clin Immunol. 2022 May 10. doi: 10.1007/s10875-022-01282-w. Online ahead of print.

ABSTRACT

Although fatigue is a common symptom in adult patients with primary immunodeficiencies (PID), data in pediatric patients are limited. The goal of this study is to estimate the prevalence and impact of fatigue in children with PID as reported by patients, parents, and health-care providers. A retrospective single-center observational study was performed. Prevalence of fatigue was measured by reviewing medical charts of 54 children in our department who are on immunoglobulin replacement therapy. Both prevalence and impact were also measured by the PedsQL-Multidimensional Fatigue Scale (MFS) in 27 patients and 32 of their parents. This is an age-appropriate questionnaire for self-report of fatigue symptoms in patients aged 5-18 years and for parent proxy reports for patients aged 2-18 years. General, cognitive, and sleep-rest fatigue was measured, and a total fatigue score was calculated. Means, standard deviation and Z scores were calculated using age-specific reference values. Intraclass correlation coefficients (ICC) were calculated for comparison of scores provided by parents vs children’s self-reported scores. Both chart review data and PedsQL-MFS showed fatigue rates of 65%. Pediatric PID patients of all ages had significantly lower scores on all subscales and total score of the PedsQL-MFS compared to healthy children, indicating greater perceived symptoms of fatigue. General fatigue was the most affected subscale in PID patients, suggesting that fatigue in these patients is mainly physical. Seventy-four percent of PID patients had a Z score lower than – 1 on the general fatigue subscale indicating severe fatigue. Child-parent concordance varied between 0.24 and 0.93. Our results show the feasibility of the PedsQL-MFS survey to evaluate the prevalence and severity of fatigue in children with PID and underscore the importance of this issue in our patient care.

PMID:35536474 | DOI:10.1007/s10875-022-01282-w

Allergy Asthma Clin Immunol. 2022 May 9;18(1):38. doi: 10.1186/s13223-022-00679-x.

ABSTRACT

BACKGROUND: Patients with primary immunodeficiency (PID) are at increased risk for infections such as SARS-CoV-2 (COVID-19), due to the nature of their diseases and being immunocompromised. At this time, four vaccines against COVID-19 (Pfizer-BioNtech’s Comirnaty^®, Moderna’s Spikevax^®, AstraZeneca’s Vaxzevria^®, Johnson & Johnson’s Janssen^®) have been approved for use by Health Canada. Due to the novelty of these vaccines, clinical studies in patients with PID are ongoing. Despite limited evidence, Canada’s National Advisory Committee on Immunization (NACI) recommend that patients with PID without any contraindications should be vaccinated with any of the approved vaccines as the potential benefits of being immunized against the virus likely outweigh the risks of contracting a severe infection. The aim of this study was to understand the perceptions regarding COVID-19 vaccination among patients with PID and to identify specific factors related to vaccine hesitancy.

METHODS: The Canadian Immunodeficiencies Patient Organization (CIPO) conducted an online survey of its members to evaluate uptake of the COVID-19 vaccines by patients with PID. Data was collected using a self-administered online questionnaire. The survey was conducted between March and April 2021.

RESULTS: At the time of survey, among 370 respondents who had not received the COVID-19 vaccine, 302 respondents (81.6%) indicated they were very or somewhat likely to get vaccinated against COVID-19; and 68 respondents (18.4%) indicated they were somewhat or very unlikely, undecided, or not planning to get vaccinated. A large majority of respondents indicated they had a diagnosis of PID (67.8%) and/or specified their type of PID (27.7%). The most common reason for vaccine hesitancy was primarily due to uncertainty about immune response given an underlying immunodeficiency. Other concerns included unknown long-term side effects of COVID-19 vaccination, pre-existing history of allergic reactions, limited amount of data, lack of investigation of safety and effectiveness of COVID-19 vaccines in those with medical conditions, and skepticism of the underlying science and/or the medical system.

CONCLUSIONS: The results point to the importance of ongoing patient outreach, education, and up-to-date information on the rapidly evolving scientific knowledge and evidence on COVID-19 relevant to the PID community, from clinical trials to real-world evidence and observational studies.

PMID:35534860 | DOI:10.1186/s13223-022-00679-x

Expert Rev Clin Immunol. 2022 May 9. doi: 10.1080/1744666X.2022.2074400. Online ahead of print.

ABSTRACT

INTRODUCTION: Wiskott-Aldrich syndrome (WAS) serves as the prototype of how variants in a gene which encodes a protein central to actin cytoskeletal homeostasis can manifest clinically in a variety of ways including infection, atopy, autoimmunity, inflammation, bleeding, neutropenia, non-malignant lymphoproliferation, and malignancy. Despite the discovery of the WAS gene almost 30 years ago, our understanding of the pathophysiological mechanisms underlying WAS continues to unfold.

AREAS COVERED: This review will provide an overview of the approach to the diagnosis of WAS as well as the management of its associated complications. Advances in the use of allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy as well as the associated challenges unique to WAS will be discussed.

EXPERT OPINION: Basic research, combined with clinical research focusing on longitudinal analysis of WAS patients, will help clarify determinants that influence WAS pathogenesis as well as clinical complications and outcomes. Advances in curative approaches including the use of alternative donor HSCT for WAS continue to evolve. Gene therapy employing safer and more effective protocols ensuring full correction of WAS will provide life-saving benefit to WAS patients that are unable to undergo HSCT.

PMID:35533396 | DOI:10.1080/1744666X.2022.2074400

Arch Argent Pediatr. 2022 Jun;120(3):e127-e131. doi: 10.5546/aap.2022.e127.

ABSTRACT

Microsporum gypseum is a geophilic fungus that can cause inflammatory skin lesions in heathy people. More extensive lesions have been described in immunocompromised patients. We present a patient with extensive dermatophytosis, which mycological examination led the identification of Candida sp, Epidermophyton Floccosum and Trichophyton tonsurans and showed poor response to treatment with griseofulvina and itraconazol at usual doses. When skin biopsy was performed, it had positive culture for M. gypseum. Due to the extension and poor response to treatment, immunological assessment was performed and it showed a defect of STAT1 with gain of function (STAT 1-GOF). Patients with primary immunodeficiency are susceptible to fungal infections, especially Candida but also virus and bacteria, although to a lesser extent. The patient received long-term treatment with systemic imidazole antifungal recovering for the lesions.

PMID:35533125 | DOI:10.5546/aap.2022.e127