Manish Butte

Allergy Asthma Clin Immunol. 2022 Mar 4;18(1):19. doi: 10.1186/s13223-022-00662-6.

ABSTRACT

BACKGROUND: Primary immunodeficiencies (PI), which include more than 450 single-gene inborn errors of immunity and may affect up to 1% of the population, are genetic disorders that impair the immune system. If not properly identified and treated, individuals with PI are subject to serious, prolonged, and sometimes life-threatening infections or autoimmunity. Despite advancements, awareness of PI remains a critical issue for physicians and the public alike, as this leads to the enhanced and expedited management of these conditions. To address this critical issue, the Jeffrey Modell Foundation (JMF) formed a global network of specialized centers. The goal of this endeavor was to raise awareness of PI to better identify, diagnose, and treat patients, reducing associated mortality and morbidity and improving quality of life (QOL). For more than two decades, the Jeffrey Modell Centers Network (JMCN) has served as the foundation upon which these goals have been pursued. The JMCN currently includes 909 Expert Physicians at 400 institutions, in 316 cities, and 86 countries spanning six continents.

METHODS: A survey was developed by JMF for members of the JMCN, following the most recent Classification of PI from the IUIS Expert Committee, to periodically describe the patient population, including treatment modalities and demographics. Physician-reported data from 2021 was compared to that from 2018 and 2013. Physicians in the JMCN also reported on select outcomes of their PI patients one year prior to and one year following diagnosis.

RESULTS: A total of 300 JMF Physician Surveys from 681 physicians were included in this analysis. This is a 75% physician response rate. From 2013 to 2021, there was a 96.3% increase in patients followed in the US and an 86.1% increase globally. During the same period, patients identified with a specific PI defect increased by 46.6% in the US and 47.9% globally. Patients receiving IgG and HSCT increased by 110% and 201% respectfully since 2013. Early diagnosis led to reported decreased morbidity and mortality and reduced calculated healthcare costs.

CONCLUSIONS: This global analysis of physician-reported data on patients with PI demonstrates an increase in both diagnosed and treated patients. This substantial increase from within the JMCN is a testament to its impact. In addition to building an extensive global patient database, the expanding JMCN serves as a unique and critical resource, providing the infrastructure for earliest diagnosis, optimized treatments, and implementation of standard-of-care and best practices. The JMCN provides a critical platform that facilitates the education of physicians and patients, awareness initiatives, and research advances, through collaboration and connectivity, ultimately resulting in improved outcomes and QOL for patients with PI. The JMCN has steadily and substantially grown for more than two decades and continues to substantively impact the field of Immunology globally.

PMID:35246253 | DOI:10.1186/s13223-022-00662-6

Arthritis Rheumatol. 2022 Mar 3. doi: 10.1002/art.42104. Online ahead of print.

ABSTRACT

OBJECTIVES: Systemic juvenile idiopathic arthritis (sJIA) is a systemic inflammatory disease of childhood-onset. sJIA is associated with neutrophilia, including immature granulocytes, potentially driven by the growth factor granulocyte-colony stimulating factor (G-CSF). This study aimed to unravel the role of G-CSF in the pathology of sJIA.

METHODS: Injection of complete Freund’s adjuvant (CFA) in BALB/c mice induces mild inflammation and neutrophilia in wild-type (WT) mice and a more pronounced disease, reminiscent to patients, in interferon-γ (IFN-γ) knock-out (KO) mice. Extramedullary myelopoiesis was studied in CFA-immunised mice by single-cell RNA-sequencing and the effect of G-CSFR-blockage on neutrophil development and sJIA pathology was evaluated. Additionally, in patients, plasma G-CSF-levels were measured.

RESULTS: Both in sJIA patients and in a corresponding mouse model, plasma levels of G-CSF are increased. Using the model, we demonstrate that G-CSF is responsible for the observed neutrophilia and extramedullary myelopoiesis and the induction of immature neutrophils and myeloid-derived suppressor-like cells. Administration of a G-CSF-receptor antagonising antibody blocked the maturation and differentiation of neutrophils in CFA-immunised mice. In IFN-γ KO mice, treatment was associated with almost complete inhibition of arthritis due to its reduced neutrophilia and osteoclast formation. Disease symptoms were ameliorated although slight increases in IL-6, TNF-α and IL-17 were detected upon G-CSFR inhibition in the IFN-γ KO mice, associated with mild increases in weight loss, tail damage and immature RBCs.

CONCLUSION: We described the role of G-CSF in a sJIA-like mouse model and point towards an important role for G-CSF-induced myelopoiesis and neutrophilia, regulating the development of arthritis.

PMID:35243819 | DOI:10.1002/art.42104

Front Pediatr. 2022 Feb 15;9:804912. doi: 10.3389/fped.2021.804912. eCollection 2021.

ABSTRACT

Severe combined immunodeficiencies (SCIDs) correspond to the most severe form of primary immunodeficiency. Allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy are curative treatments, depending on the donor’s availability and molecular diagnostics. A partially human leukocyte antigen (HLA)-compatible donor used has been developed for this specific HSCT indication in the absence of a matched donor. However, the CD34+ selected process induces prolonged post-transplant T-cell immunodeficiency. The aim here was to investigate a modeling approach to predict the time course and the extent of CD4+ T-cell immune reconstitution after CD34+ selected transplantation. We performed a Bayesian approach based on the age-related changes in thymic output and the cell proliferation/loss model. For that purpose, we defined specific individual covariates from the data collected from 10 years of clinical practice and then evaluated the model’s predicted performances and accuracy. We have shown that this Bayesian modeling approach predicted the time course and extent of CD4+ T-cell immune reconstitution after SCID transplantation.

PMID:35242727 | PMC:PMC8885722 | DOI:10.3389/fped.2021.804912

Front Immunol. 2022 Feb 15;13:815193. doi: 10.3389/fimmu.2022.815193. eCollection 2022.

ABSTRACT

BACKGROUND: Common Variable Immunodeficiency (CVID) is classified as a ‘Predominantly Antibody Deficiency’ (PAD), but there is emerging evidence of cellular immunodeficiency in a subset of patients. This evidence includes CVID patients diagnosed with cytomegalovirus (CMV) infection, a hallmark of ‘combined immunodeficiency’. CMV infection also has the potential to drive immune dysregulation contributing to significant morbidity and mortality in CVID. We aim to determine the extent of cellular immune dysfunction in CVID patients, and whether this correlates with CMV infection status.

METHODS: We conducted a single-center retrospective cohort study of individuals with CVID at the Royal Melbourne Hospital, and identified patients with and without CMV disease or viraemia. We then isolated T-cells from patient and healthy donor blood samples and examined T-cell proliferation and function.

RESULTS: Six patients (7.6%, 6/79) had either CMV disease (pneumonitis or gastrointestinal disease), or symptomatic CMV viraemia. A high mortality rate in the cohort of patients with CVID and CMV disease was observed, with 4 deaths in the period of analysis (66.6%, 4/6). Individuals with CMV infection showed reduced T-cell division in response to T-cell receptor (TCR) stimulation when compared with CMV-negative patients.

DISCUSSION: This study demonstrates the morbidity and mortality associated with CMV in CVID, and highlights the need for focused interventions for patients with CVID at risk of CMV disease.

PMID:35242131 | PMC:PMC8885594 | DOI:10.3389/fimmu.2022.815193

Front Immunol. 2022 Feb 15;13:805552. doi: 10.3389/fimmu.2022.805552. eCollection 2022.

ABSTRACT

Opa interacting protein 5 (OIP5), overexpressed in some types of human cancers, has been reported to be associated with the carcinogenesis of human cancer. However, its contribution to cancer immunity remains unknown. Furthermore, the relationship between OIP5 and cancer immunity remains uncertain. In our research, we explored the different expression of OIP5 between 539 ccRCC and 72 normal renal tissues base on TCGA data set. We analyzed the associations between OIP5 expression with ccRCC progression and survival. Next, we compared immune cell profiles in cancer tissues and normal tissues in the Cancer Genome Atlas (TCGA) ccRCC cohort. We found that the level of immune cell infiltration was correlated with the copy number of OIP5 gene in ccRCC. The effect of OIP5 on immune activity was verified by Gene Set Enrichment Analysis of RNA-seq data from 32 ccRCC cell lines in the public database. Moreover, a pathway enrichment analysis of 49 OIP5-associated immunomodulators demonstrated the involvement of the T cell receptor signaling pathway, the JAK-STAT signaling pathway, the NF-kappa B signaling pathway and the primary immunodeficiency pathway. In addition, using OIP5-associated immunomodulators, we constructed multiple-gene risk prediction signatures using the Cox regression model. Our results provided insights into the role of OIP5 in tumor immunity and revealed that OIP5 may be a potential immunotherapeutic target for ccRCC. Designated immune signature is a promising prognostic biomarker in ccRCC.

PMID:35242130 | PMC:PMC8886046 | DOI:10.3389/fimmu.2022.805552

Bone. 2022 Feb 28:116345. doi: 10.1016/j.bone.2022.116345. Online ahead of print.

NO ABSTRACT

PMID:35241400 | DOI:10.1016/j.bone.2022.116345

Front Immunol. 2022 Feb 14;13:827048. doi: 10.3389/fimmu.2022.827048. eCollection 2022.

ABSTRACT

Previous studies on immune responses following COVID-19 vaccination in patients with common variable immunodeficiency (CVID) were inconclusive with respect to the ability of the patients to produce vaccine-specific IgG antibodies, while patients with milder forms of primary antibody deficiency such as immunoglobulin isotype deficiency or selective antibody deficiency have not been studied at all. In this study we examined antigen-specific activation of CXCR5-positive and CXCR5-negative CD4⁺ memory cells and also isotype-specific and functional antibody responses in patients with CVID as compared to other milder forms of primary antibody deficiency and healthy controls six weeks after the second dose of BNT162b2 vaccine against SARS-CoV-2. Expression of the activation markers CD25 and CD134 was examined by multi-color flow cytometry on CD4⁺ T cell subsets stimulated with SARS-CoV-2 spike peptides, while in parallel IgG and IgA antibodies and surrogate virus neutralization antibodies against SARS-CoV-2 spike protein were measured by ELISA. The results show that in CVID and patients with other milder forms of antibody deficiency normal IgG responses (titers of spike protein-specific IgG three times the detection limit or more) were associated with intact vaccine-specific activation of CXCR5-negative CD4⁺ memory T cells, despite defective activation of circulating T follicular helper cells. In contrast, CVID IgG nonresponders showed defective vaccine-specific and superantigen-induced activation of both CD4⁺T cell subsets. In conclusion, impaired TCR-mediated activation of CXCR5-negative CD4⁺ memory T cells following stimulation with vaccine antigen or superantigen identifies patients with primary antibody deficiency and impaired IgG responses after BNT162b2 vaccination.

PMID:35237272 | PMC:PMC8882590 | DOI:10.3389/fimmu.2022.827048

Cureus. 2022 Jan 26;14(1):e21624. doi: 10.7759/cureus.21624. eCollection 2022 Jan.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immunodeficiency caused by the lack of B cell differentiation into plasma cells, thereby leading to decreased serum immunoglobulins. Patients with this condition are predisposed to recurrent infections and are more likely to develop certain cancers and autoimmune diseases. We report the case of a 53-year-old female suffering from recurrent pulmonary infections and a history of non-Hodgkin lymphoma (NHL) who had a poor response to the measles, mumps, and rubella (MMR) and varicella vaccines as a child, and was infected with coronavirus disease 2019 (COVID-19) twice in 2020. Testing of her antibody titers in order to determine suitability for Streptococcus pneumoniae (S. pneumoniae) vaccination found an overall decrease in major immunoglobulin classes (IgG, IgM, and IgA) and B cells with normal morphology. The diagnosis of CVID was made, and prompt treatment with intravenous immunoglobulins (IVIG) brought her IgG levels up from 282 to 680 mg/dL within three months. This case highlights the importance for providers to keep immunological dysfunction on their differentials for patients with atypical presentations involving multiple organ systems.

PMID:35228973 | PMC:PMC8874879 | DOI:10.7759/cureus.21624

J Paediatr Child Health. 2022 Feb 26. doi: 10.1111/jpc.15924. Online ahead of print.

ABSTRACT

AIM: The recognition and diagnosis of primary immunodeficiency disorders (PIDs) is challenging in developing countries. This study aimed to describe the features of PID patients in a tertiary care setting in Egypt and analyse the distribution, clinical features and outcome of PID among paediatric patients.

METHODS: This cross-sectional retrospective study was conducted between January 2016 and January 2021, to evaluate all paediatric patients aged below 18 years with PID that were diagnosed according to the International Union of Immunological Societies 2017 classification. We retrospectively studied the clinical features, diagnostic spectrum, laboratory investigations and relevant immunological workup, and treatment options.

RESULTS: A total of 61 PID patients were enrolled in the current study. The median age at diagnosis was 22 months. The overall consanguinity rate was 49.2%, and the family history of PID was 19.7%. Among all PIDs, the combined immunodeficiency with syndromic features predominates with 17 cases, accounting for 27.9% of all cases of PIDs. The predominant antibody deficiency was the second common PID that was diagnosed in 14 patients (23%). Recurrent pneumonia was the most common initial presentation, occurring in 77% of patients, followed by failure to thrive (63.9%), and recurrent otitis media (55.7%). The total deaths were 18 patients (29.5%).

CONCLUSION: Paediatric patients with PIDs are not uncommon in Egypt. There is a need to improve PID diagnosis and treatment, for better estimation of PID and to decrease morbidity and mortality.

PMID:35218595 | DOI:10.1111/jpc.15924

Clin Genet. 2022 Feb 26. doi: 10.1111/cge.14125. Online ahead of print.

ABSTRACT

Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194* and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs*4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss-of-function variant c.1255_1259delAAGAA;p.Lys419Leufs*5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency which should be considered as one of the most important phenotypic characteristics of BS. This article is protected by copyright. All rights reserved.

PMID:35218564 | DOI:10.1111/cge.14125