Manish Butte

Cells. 2022 Jan 28;11(3):464. doi: 10.3390/cells11030464.

ABSTRACT

The altered wiring of signaling pathways downstream of antigen receptors of T and B cells contributes to the dysregulation of the adaptive immune system, potentially causing immunodeficiency and autoimmunity. In humans, the investigation of such complex systems benefits from nature’s experiments in patients with genetically defined primary immunodeficiencies. Disturbed B-cell receptor (BCR) signaling in a subgroup of common variable immunodeficiency (CVID) patients with immune dysregulation and expanded T-bet^highCD21^low B cells in peripheral blood has been previously reported. Here, we investigate PI3K signaling and its targets as crucial regulators of survival, proliferation and metabolism by intracellular flow cytometry, imaging flow cytometry and RNAseq. We observed increased basal but disturbed BCR-induced PI3K signaling, especially in T-bet^highCD21^low B cells from CVID patients, translating into impaired activation of crucial downstream molecules and affecting proliferation, survival and the metabolic profile. In contrast to CVID, increased basal activity of PI3K in patients with a gain-of-function mutation in PIK3CD and activated PI3K delta syndrome (APDS) did not result in impaired BCR-induced AKT-mTOR-S6 phosphorylation, highlighting that signaling defects in B cells in CVID and APDS patients are fundamentally different and that assessing responses to BCR stimulation is an appropriate confirmative diagnostic test for APDS. The active PI3K signaling in vivo may render autoreactive T-bet^highCD21^low B cells in CVID at the same time to be more sensitive to mTOR or PI3K inhibition.

PMID:35159274 | DOI:10.3390/cells11030464

Blood Adv. 2022 Feb 14:bloodadvances.2021006018. doi: 10.1182/bloodadvances.2021006018. Online ahead of print.

ABSTRACT

Primary central nervous system large B-cell lymphoma (PCNS-LBCL) occurs typically in older adults and only rarely in the pediatric population. The genomic landscape of PCNS-LBCL in children and young adults (YA) is not well-characterized. In this multi-institutional study, targeted next-generation DNA sequencing and chromosomal copy number analysis was performed on a cohort of 12 pediatric and YA (age<40 years) PCNS-LBCL patients without known immunodeficiency and correlated with clinicopathologic data. Based on genomic features, we identified two subgroups: a unique “Pediatric type, MYD88-wildtype” group (median age 14 years, range 7-25 years) was characterized by absence of MYD88 mutations but frequent genetic alterations in TP53 (6/8, 75%), NFKBIE (4/8, 50%), and GNA13 (4/8, 50%); and an “adult type, MYD88-mutant” group (median age 35 years, range 25-38 years) was defined by MYD88 hotspot mutations (4/4, 100%), with frequent PRDM1 mutation/deletion (3/4, 75%), CDKN2A/B homozygous deletion (3/4, 75%), and deletions of the HLA gene cluster (2/4, 50%). Kaplan-Meier analysis demonstrated that patients with pediatric type, MYD88-wildtype PCNS-LBCL had favorable outcomes (median survival: >100 months; 5-year-overall survival: 100%). In conclusion, we have identified a new pediatric type of PCNS-LBCL that is molecularly distinct from PCNS-LBCL occurring in adults, based on an absence of MYD88 mutation, CDKN2A/B homozygous deletion, deletion of HLA gene cluster, and paucity of CD79B and PRDM1 mutations, along with an enrichment for TP53, NFKBIE, and GNA13 mutations. Patients with pediatric type, MYD88-wildtype PCNS-LBCL often have long-term survival compared to their adult counterparts.

PMID:35157770 | DOI:10.1182/bloodadvances.2021006018

Front Immunol. 2022 Jan 26;13:799564. doi: 10.3389/fimmu.2022.799564. eCollection 2022.

ABSTRACT

The study of inborn errors of immunity (IEI) provides unique opportunities to elucidate the microbiome and pathogenic mechanisms related to severe viral infection. Several immunological and genetic anomalies may contribute to the susceptibility to develop Human Papillomavirus (HPV) pathogenesis. They include different acquired immunodeficiencies, EVER1-2 or CIB1 mutations underlying epidermodysplasia verruciformis (EV) syndrome and multiple IEI. Whereas EV syndrome patients are specifically unable to control infections with beta HPV, individuals with IEI show broader infectious and immune phenotypes. The WHIM (warts, hypogammaglobulinemia, infection, and myelokathexis) syndrome caused by gain-of-CXCR4-function mutation manifests by HPV-induced extensive cutaneous warts but also anogenital lesions that eventually progress to dysplasia. Here we report alterations of B and NK cells in a female patient suffering from cutaneous and mucosal HPV-induced lesions due to an as-yet unidentified genetic defect. Despite no detected mutations in CXCR4, B but not NK cells displayed a defective CXCR4-dependent chemotactic response toward CXCL12. In addition, NK cells showed an abnormal distribution with an expanded CD56^bright cell subset and defective cytotoxicity of CD56^dim cells. Our observations extend the clinical and immunological spectrum of IEI associated with selective susceptibility toward HPV pathogenesis, thus providing new insight on the immune control of HPV infection and potential host susceptibility factors.

PMID:35154113 | PMC:PMC8825485 | DOI:10.3389/fimmu.2022.799564

Front Immunol. 2022 Jan 28;13:791522. doi: 10.3389/fimmu.2022.791522. eCollection 2022.

ABSTRACT

Ataxia-telangiectasia (A-T) is a neurodegenerative and primary immunodeficiency disorder (PID) characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient’s needs. Besides the classical ataxia-telangiectasia (classical A-T) phenotype, a variant phenotype (variant A-T) exists with partly overlapping but some distinctive disease characteristics. Here we present a case series of 6 patients with classical A-T and variant A-T, which illustrates the phenotypic variability of A-T that can present in childhood with prominent extrapyramidal features, with or without cerebellar ataxia. We report the clinical data, together with a detailed genotype description, immunological analyses, and related expression of the ATM protein. We show that the presence of some residual ATM kinase activity leads to the clinical phenotype variant A-T that differs from the classical A-T. Our data illustrate that the diagnosis of the variant form of A-T can be delayed and difficult, while early recognition of the variant form as well as the classical A-T is a prerequisite for providing a correct prognosis and appropriate rehabilitation and support, including the avoidance of diagnostic X-ray procedures, given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment.

PMID:35154108 | PMC:PMC8831727 | DOI:10.3389/fimmu.2022.791522

Pharmacotherapy. 2022 Feb 11. doi: 10.1002/phar.2671. Online ahead of print.

ABSTRACT

Inactivated vaccines are generally considered safe in immunocompromised patients but the ability of immunocompromised patients to generate an effective immune response to vaccines is uncertain. Although recent reviews have focused on the effects of vaccines in patients who are immunocompromised due to various disease states (primary immunodeficiency), the effects of immunosuppressive drug therapy (secondary immunodeficiency) has received relatively less attention. This review evaluates evidence regarding the efficacy of inactivated vaccines against influenza, COVID-19, and other diseases in patients treated with immunosuppressive oncologic agents, immunosuppressants used for transplant recipients, and immunosuppressants used for autoimmune disorders. Although evidence is mixed for many immunosuppressive agents and vaccines, most studies have found an attenuated immune response to inactivated vaccines, although the majority of data indicate anti-B cell antibodies have a more severe and prolonged negative effect on vaccine efficacy.

PMID:35146780 | DOI:10.1002/phar.2671

Front Genet. 2022 Jan 25;13:768000. doi: 10.3389/fgene.2022.768000. eCollection 2022.

ABSTRACT

X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect (XMEN) disease is a primary immunodeficiency caused by loss-of-function variants in the MAGT1 gene. Only two patients from one family have been diagnosed with XMEN in China. In this study, we retrospectively analyzed the genetic, clinical, and immunological characteristics of six pediatric patients in a Chinese cohort. Medical records were retrieved, immunological phenotypes were assessed, and infectious microbes in patients were detected. Six male patients (mean age, 6.3 years) from five unrelated families were genetically diagnosed as XMEN. Five patients presented with a major complaint of elevated liver enzymes, while one patient was referred for recurrent fever, cough and skin rash. Five patients developed EBV viremia, and one patient developed non-Hodgkin’s lymphoma. Histopathological findings from liver biopsy tissues showed variable hepatic steatosis, fibrosis, inflammatory infiltration, and glycogenosis. Immune phenotypes included CD4 T-cell lymphopenia, elevated B cells, inverted CD4/CD8 ratios, and elevated αβDNTs. No pathogenic microbes other than EBV were identified in these patients. This study reports the clinical and molecular features of Chinese patients with XMEN. For patients with transaminase elevation, chronic EBV infection and EBV-associated lymphoproliferative disease, the possibility of XMEN should be considered in addition to isolated liver diseases.

PMID:35145548 | PMC:PMC8821886 | DOI:10.3389/fgene.2022.768000

Bone Marrow Transplant. 2021 Jun;56(6):1483-1484. doi: 10.1038/s41409-020-01175-9.

NO ABSTRACT

PMID:35145239 | DOI:10.1038/s41409-020-01175-9

Front Immunol. 2022 Jan 24;12:803763. doi: 10.3389/fimmu.2021.803763. eCollection 2021.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI), characterised by recurrent bacterial and fungal infections. It is inherited either in an X-linked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of phenotypes expressed, and its study allows us to generate new knowledge of the disease. The objective of the study is to reveal the phenomic differences between XL and AR-CGD by using Human Phenotype Ontology (HPO) terms.

METHODS: We collected data on 117 patients with genetically diagnosed CGD from Asia and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only 90 patients with sufficient clinical information were included for phenomic analysis. We used HPO terms to describe all phenotypes manifested in the patients.

RESULTS: XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and genetic diagnosis compared with AR-CGD patients. The integument and central nervous system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as their first manifestation. Among our CGD patients, lung was the most frequently infected organ, with gastrointestinal system and skin ranking second and third, respectively. Aspergillus species, Mycobacterium bovis, and Mycobacteirum tuberculosis were the most frequent pathogens to be found.

CONCLUSION: Phenomic analysis confirmed that XL-CGD patients have more recurrent and aggressive infections compared with AR-CGD patients. Various phenotypic differences listed out can be used as clinical handles to distinguish XL or AR-CGD based on clinical features.

PMID:35140711 | PMC:PMC8818666 | DOI:10.3389/fimmu.2021.803763

Clin Rev Allergy Immunol. 2022 Feb 8. doi: 10.1007/s12016-022-08927-z. Online ahead of print.

ABSTRACT

Improved genetic testing has led to recognition of a diverse group of disorders of inborn errors of immunity that present as primarily T-cell defects. These disorders present with variable degrees of immunodeficiency, autoimmunity, multiple organ system dysfunction, and neurocognitive defects. 22q11.2 deletion syndrome, commonly known as DiGeorge syndrome, represents the most common disorder on this spectrum. In most individuals, a 3 Mb deletion of 22q11 results in haploinsufficiency of 90 known genes and clinical complications of varying severity. These include cardiac, endocrine, gastrointestinal, renal, palatal, genitourinary, and neurocognitive anomalies. Multidisciplinary treatment also includes pediatrics/general practitioners, genetic counseling, surgery, interventional therapy, and psychology/psychiatry. Chromosome 10p deletion, TBX1 mutation, CHD7 mutation, Jacobsen syndrome, and FOXN1 deficiency manifest with similar overlapping clinical presentations and T-cell defects. Recognition of the underlying disorder and pathogenesis is essential for improved outcomes. Diagnosing and treating these heterogenous conditions are a challenge and rapidly improving with new diagnostic tools. Collectively, these disorders are an example of the complex penetrance and severity of genetic disorders, importance of translational diagnostics, and a guide for multidisciplinary treatment.

PMID:35133619 | DOI:10.1007/s12016-022-08927-z

Endocr Metab Immune Disord Drug Targets. 2022 Feb 8. doi: 10.2174/1871530322666220208111837. Online ahead of print.

ABSTRACT

BACKGROUND: Specific Antibody Deficiency (SAD) is a primary immunodeficiency disease (PID) characterized by the occurrence of recurrent infections and inadequate antibody response to polysaccharide new antigens.

OBJECTIVE: This study aims to determine the titer of specific antibodies against unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV-23), the presence of SAD, and its association with clinical and laboratory findings in Ataxia-telangiectasia (A-T) and selective immunoglobulin A deficiency (SIgAD) patients.

METHODS: 32 A-T patients and 43 SIgAD patients were included in the study. Samples of the patients were obtained before and three weeks after vaccination with PPSV-23. Specific immunoglobulin G (IgG) directed towards pneumococcal capsular antigen and specific antibodies against whole pneumococcal antigens was measured.

RESULTS: Comparison of the response to vaccination revealed that 81.3% of A-T patients and 18.6% of the SIgAD patients had an inadequate response to PPSV-23 (p<0.001). The prevalence of recurrent infection (p=0.034) and pneumonia (p=0.003) in SIgAD patients was significantly higher in non-responders than responders. Likewise, the number of marginal zone B cells (p=0.037), transitional B cells (p=0.019), plasmablasts (p=0.019), CD8+ naïve T cells (p=0.036), and percentage of CD8+ T cells (p=0.047), switched memory B cells (SMB) (p=0.026) and immunoglobulin M (IgM) memory B cells (p=0.022) in SIgAD patients were significantly lower in non-responder group than responder group. In contrast, the percentage of CD4 T+ cells in A-T patients was lower in the non-responder group than responders (p=0.035).

CONCLUSION: SAD is more frequent in A-T patients than SIgAD patients. The role of SMB and T cells should not be underestimated in SAD.

PMID:35135457 | DOI:10.2174/1871530322666220208111837