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Novel mutations in hyper-IgM syndrome type 2 and X-linked agammaglobulinemia detected in three patients with primary immunodeficiency disease.

Mol Genet Genomic Med. 2020 Dec 30;:e1552

Authors: Chen X, Liu F, Yuan L, Zhang M, Chen K, Wu Y

Abstract
BACKGROUND: Ambiguous or atypical phenotypes can make a definite diagnosis of primary immunodeficiency diseases based on biochemical indices alone challenging. Further, mortality in early life because of infections in patients with these conditions supports the use of genetic tests to facilitate rapid and accurate diagnoses.
METHODS: Genetic and clinical analyses of three unrelated Chinese children with clinical manifestations of recurrent infections, who were considered to have primary immunodeficiency diseases, were conducted. Patient clinical features and serum immunological indices were recorded. Next-generation sequencing was used to screen for suspected pathogenic variants. Family co-segregation and in silico analysis were conducted to evaluate the pathogenicity of identified variants, following the American College of Medical Genetics and Genomics guidance.
RESULTS: All three patients were found to have predominant antibody defects. Sequencing analysis revealed that one had two compound heterozygous variants, c.255C>A and c.295C>T, in the autosomal gene, activation-induced cytidine deaminase (AICDA). The other two patients were each hemizygous for the variants c.1185G>A and c.82C>T in the Bruton’s tyrosine kinase (BTK) gene on the X chromosome. In silico analysis revealed that identified substituted amino acids were highly conserved and predicted to cause structural and functional damage to the proteins.
CONCLUSION: Four pathogenic variants in AICDA and BTK were confirmed to cause different forms of hyper-IgM syndrome type 2 (HIGM2) and X-linked agammaglobulinemia (XLA); two were novel mutations that have never been reported previously. This is the first report of HIGM2 caused by AICDA deficiency in a patient from the Chinese mainland.

PMID: 33377626 [PubMed – as supplied by publisher]

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Invasive Nocardiosis: Disease Presentation, Diagnosis and Treatment – Old Questions, New Answers?

Infect Drug Resist. 2020;13:4601-4613

Authors: Lafont E, Conan PL, Rodriguez-Nava V, Lebeaux D

Abstract
Nocardia spp. is an environmental filamentous Gram-positive bacterium that may cause infections in humans and, despite recent progress, many challenges remain regarding the management of nocardiosis. This review aims at describing most recently published data regarding the diagnosis, treatment and follow-up of patients with invasive nocardiosis. As nocardiosis mainly affects patients with cell-mediated immunity defects, a comprehensive workup is mandatory in case of invasive nocardiosis occurring in “apparently healthy patients”. Indeed, invasive nocardiosis might reveal an unknown primary immunodeficiency or the presence of anti-GM-CSF autoantibodies. Even if the diagnosis of nocardiosis mostly relies on direct examination and bacterial culture, a genus-specific PCR may be used for the detection of Nocardia, when directly performed on a clinical sample. Brain imaging should always be performed, even in the absence of neurological symptoms. Cotrimoxazole (trimethoprim/sulfamethoxazole), linezolid, parenteral cephalosporins, carbapenems and amikacin may be used as initial antibiotics to treat nocardiosis. Cotrimoxazole or linezolid can be used as monotherapy in selected patients without brain involvement. Although treatment duration has historically been set to at least 6 months in the absence of central nervous system involvement, shorter durations (<120 days) seem to be associated with a favourable outcome.

PMID: 33376366 [PubMed]

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More severe than CVID: Combined immunodeficiency due to a novel NFKB2 mutation.

Pediatr Allergy Immunol. 2020 Dec 28;:

Authors: Bienias M, Gabrielyan A, Geberzahn L, Rösen-Wolff A, Huebner A, Jacobsen EM, Toepfner N, Fang M, Lee-Kirsch MA, Roesler J, Schuetz C

Abstract
The nuclear factor kappa-B (NF-κB) signaling pathway is crucial in inflammatory and immune responses. NF-κB2 plays a pivotal role in the noncanonical pathway important for peripheral lymphoid organ development, B-cell maturation and antibody production. 1 Heterozygous mutations in the NFKB2 gene have been identified as a molecular cause of primary immunodeficiency. Previously described NF-κB2-defective patients presented with hypogammaglobulinemia in early childhood and suffered from recurrent respiratory tract infections. 2 Clinical and immunological features are often compatible with common variable immunodeficiency (CVID), but additional defects in T and NK cells have been reported. 3-5,9 . Other typical symptoms such as ectodermal dysplasia with alopecia totalis and trachyonychia may be autoimmune manifestations. About half of the patients develop isolated ACTH deficiency with consecutive cortisol deficiency, an unusual feature in large cohorts of CVID patients. Susceptibility to herpes infections has also been described.

PMID: 33369776 [PubMed – as supplied by publisher]

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Prenatal Diagnosis for Primary Immunodeficiency Disorders-An Overview of the Indian Scenario.

Front Immunol. 2020;11:612316

Authors: Yadav RM, Gupta M, Dalvi A, Bargir UA, Hule G, Shabrish S, Aluri J, Kulkarni M, Kambli P, Uppuluri R, Seshadri S, Jagadeesh S, Suresh B, Raja J, Taur P, Malaischamy S, Ghosh P, Mahalingam S, Kadam P, Lashkari HP, Tamhankar P, Tamhankar V, Mithbawkar S, Bhattad S, Jhawar P, Makam A, Bansal V, Prasad M, Govindaraj G, Guhan B, Bharadwaj Tallapaka K, Desai M, Raj R, Madkaikar MR

Abstract
Prenatal Diagnosis (PND) forms an important part of primary preventive management for families having a child affected with primary immunodeficiency. Although individually sparse, collectively this group of genetic disorders represents a significant burden of disease. This paper discusses the prenatal services available for affected families at various centers across the country and the challenges and ethical considerations associated with genetic counseling. Mutation detection in the index case and analysis of chorionic villous sampling or amniocentesis remain the preferred procedures for PND and phenotypic analysis of cordocentesis sample is reserved for families with well-characterized index case seeking PND in the latter part of the second trimester of pregnancy. A total of 112 families were provided PND services in the last decade and the presence of an affected fetus was confirmed in 32 families. Post-test genetic counseling enabled the affected families to make an informed decision about the current pregnancy.

PMID: 33365035 [PubMed – in process]

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NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing.

iScience. 2021 Jan 22;24(1):101900

Authors: Dang AT, Strietz J, Zenobi A, Khameneh HJ, Brandl SM, Lozza L, Conradt G, Kaufmann SHE, Reith W, Kwee I, Minguet S, Chelbi ST, Guarda G

Abstract
BTN3A molecules-BTN3A1 in particular-emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g. with Mycobacterium tuberculosis, or by alterations in cellular metabolism. Despite the growing interest in the BTN3A genes and their high expression in immune cells and various cancers, little is known about their transcriptional regulation. Here we show that these genes are induced by NLRC5, a regulator of MHC class I gene transcription, through an atypical regulatory motif found in their promoters. Accordingly, a robust correlation between NLRC5 and BTN3A gene expression was found in healthy, in M. tuberculosis-infected donors’ blood cells, and in primary tumors. Moreover, forcing NLRC5 expression promoted Vγ9Vδ2 T-cell-mediated killing of tumor cells in a BTN3A-dependent manner. Altogether, these findings indicate that NLRC5 regulates the expression of BTN3A genes and hence open opportunities to modulate antimicrobial and anticancer immunity.

PMID: 33364588 [PubMed]

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Two patients with chronic mucocutaneous candidiasis caused by TRAF3IP2 deficiency.

J Allergy Clin Immunol. 2020 Dec 23;:

Authors: Shafer S, Yao Y, Comrie W, Cook S, Zhang Y, Yesil G, Karakoç-Aydiner E, Baris S, Cokugras H, Aydemir S, Kiykim A, Ozen A, Lenardo M

Abstract
BACKGROUND: TRAF3IP2 (Act1) is an adapter protein that interacts with IL-17R via its SEF/IL-17R (SEFIR) domain and coordinates two separate pro-inflammatory pathways following IL-17 cytokine stimulation.
OBJECTIVE: To elucidate the immunological consequences of TRAF3IP2 homozygous mutations to improve treatments for immunodeficiency patients with chronic mucocutaneous candidiasis.
METHODS: We describe two patients presenting with chronic mucocutaneous candidiasis that harbor biallelic nonsense mutations in TRAF3IP2. The cellular and molecular features of this genetic defect were assessed using in vitro cytokine assays and protein analysis.
RESULTS: We show the homozygous mutation causes complete loss of protein expression. We also show that the absence of TRAF3IP2 was associated with a defective response to combined IL-2/IL-25 (IL-17E) stimulation.
CONCLUSION: Failure to initiate normal signaling downstream of IL-17R engagement likely contributes to the patients’ recurrent fungal infections. These findings add to our molecular understanding of genetic defects affecting this critical pathway of anti-fungal immunity.

PMID: 33359359 [PubMed – as supplied by publisher]

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[Analysis of Gene Variation in Thymoma by Microarray].

Zhongguo Fei Ai Za Zhi. 2020 Dec 20;23(12):1073-1079

Authors: Wang L, Yu L, Du X, Huo C

Abstract
BACKGROUND: Thymoma is the most common malignant tumor in anterior mediastinum, and its specific pathogenesis is still unclear. This limits the study of targeted drugs for thymoma. The aim of the study is to investigate the genes and signal pathways of thymoma, and provide help for the research of thymic tumor pathogenesis using the technology of second-generation genechip to analyze thymoma.
METHODS: From January 2015 to December 2017, we analyzed 31 cases of thymoma by CapitaBio mRNA expression profile genechip technology, and then confirmed the genes by reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS: We found some genes with different expression levels between thymoma and surrounding thymus tissue. Among them, six driving genes (FANCI, CAPD3, NCAPG, OXCT1, EPHA1 and MCM2) were significantly abnormal in thymoma. Some specific genes affected by copy-number variation were detected: E2F2, EphA1, CCL25 and MCM2 were significantly up-regulated, while IL-6, CD36, FABP4, SH2D1A and MYOC genes were significantly down-regulated. KEGG database analysis showed that the expression of 10 signaling pathway genes was generally up-regulated or down-regulated, such as systemic lupus erythematosus, viral oncogenes, primary immunodeficiency, cell cycle genes and p53 signaling pathway, which may be related to occurrence of thymoma.
CONCLUSIONS: We found a variety of genes abnormally expressed in thymoma, which will provide reference for the study of pathogenesis and biomarkers of thymoma in the future.

PMID: 33357314 [PubMed – in process]

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Antithyroid Drug-Induced Lupus Erythematosus and Immunoglobulin A Deficiency.

Am J Case Rep. 2020 Dec 22;21:e927929

Authors: Beernaert L, Vanderhulst J

Abstract
BACKGROUND Antithyroid drugs, namely methimazole, are well-known causes of drug-induced lupus erythematosus. This is, however, an infrequent adverse effect. Selective Immunoglobulin A (IgA) deficiency, in contrast, is the most common primary immunodeficiency. Patients with IgA deficiency are at risk of developing infectious diseases, but also autoimmune diseases such as Grave’s disease or systemic lupus erythematosus. CASE REPORT We report a case of methimazole-induced lupus erythematosus in a 32-year-old man with renal involvement and concomitant selective IgA deficiency. Symptoms promptly resolved after treatment with hydroxychloroquine and corticosteroids after discontinuation of methimazole. Lupus nephritis required treatment with cyclophosphamide followed by maintenance therapy with mycophenolate mofetil. CONCLUSIONS Drug-induced lupus erythematosus usually develops after a few months or years of exposure to the causative agent. No specific symptoms exist. The diagnosis is not based on particular specific tests, but relies on a set of arguments evoking the role of the medication inducing the condition. The first step in treatment is to stop the causative drug. The therapeutic management of the various manifestations does not differ from that of idiopathic systemic lupus erythematosus. We briefly discuss the relationship between drug-induced lupus erythematosus, Grave’s disease, and IgA deficiency, and suggest that IgA deficiency may act as a potential risk factor. Testing for IgA deficiency could be helpful in patients being treated with drugs known to be associated with drug-induced lupus erythematosus.

PMID: 33349625 [PubMed – in process]

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