EBV‐positive B‐cell lymphoma manifestation of the liver in an infant with RAG1 severe combined immunodeficiency disease

Maas, Constantin; Lüftinger, Roswitha; Krois, Wilfried; Matthes‐Martin, Susanne; Bayer, G.; Boztuğ, Kaan; Metzelder, Martin L.

doi:10.1002/pbc.27258

Cited by 7 publications

(15 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the GnomAD database, this deletion was found in heterozygous state in six people of European population (non-Finnish) of 282,486 individuals [https://gnomad.broadinstitute.org/variant/11-36595109-TAA-T]. Reviewing published cases, we established that patients with homo-and heterozygous p.K86Vfs * 33 RAG1 variants were detected in European cohorts (2,13,(37)(38)(39)(40). A recent Turkey study reported one patient with homozygous p.K86Vfs * 33 in RAG1 among the cohort of 44 SCID patients (32) and a SCID infant with EBV-positive B-cell lymphoma of the liver with homozygous p.K86Vfs * 33 was diagnosed in Austria (40).…”

Section: Discussionmentioning

confidence: 98%

“…Reviewing published cases, we established that patients with homo-and heterozygous p.K86Vfs * 33 RAG1 variants were detected in European cohorts (2,13,(37)(38)(39)(40). A recent Turkey study reported one patient with homozygous p.K86Vfs * 33 in RAG1 among the cohort of 44 SCID patients (32) and a SCID infant with EBV-positive B-cell lymphoma of the liver with homozygous p.K86Vfs * 33 was diagnosed in Austria (40). It should be noted that in all these previous studies, the ethnic origin of the patients was not documented.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

et al. 2020

View full text Add to dashboard Cite

Background: Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency.Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries.Methods: Demographic, clinical, and laboratory data were collected from RAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay.Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID (n = 20), OS (n = 37), and LS/CID (n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n = 47) of patients with RAG1 variants carried p.K86Vfs * 33 (c.256_257delAA) allele, either in homozygous (n = 18, 27%) or in compound heterozygous (n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs * 33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs * 33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion:We propose that RAG1 p.K86Vfs * 33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In PIDs in which T cell development is severely impaired (such as SCID with B cells but no T cells (SCID T‐B+), resulting from mutations in IL2RG , JAK3 , IL7RA or CD3 subunits) or combined immunodeficiency (CID) caused by mutations in ZAP70 (characterized by the almost total absence of CD8 T cells), few cases of severe EBV infections have been documented . Patients who carry hypomorphic mutations in genes causing SCID T‐B‐ (such as RAG1/2 , LIG4 and DCLRE1C ) may also experience severe B‐cell lymphoproliferative disorders in which B‐cell development is preserved to some extent . The fact that severe EBV infections are so rare in these conditions is somewhat surprising, given the severity of the T‐cell defects.…”

Section: Immunodeficiencies Causing Ebv‐driven B‐lymphoproliferative mentioning

confidence: 99%

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latour

Fischer

2019

Immunological Reviews

113

View full text Add to dashboard Cite

Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV -notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T-and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions. K E Y W O R D S B-cell lymphoproliferation, cell-cytotoxicity, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, primary immunodeficiency, T-cell proliferation | IMMUNE RE S P ON S E S TO EBV INFEC TI ONEpstein-Barr virus (EBV, also known as human herpesvirus 4) is a gamma herpes virus that only infects primates (primarily humans). 1,2 It is an encapsidated, double-stranded DNA virus with more than 100 genes. It is pandemic, since the great majority of human beings (>90%) have been infected by EBV. The main cell target is B lymphocytes that express CD21 -the membrane receptor for EBV entry through its 350 kDa major envelope glycoprotein. In immunocompetent adolescents and adults, EBV infection causes infectious mononucleosis (IM). Immunologically speaking, IM is characterized by a This article is part of a series of reviews covering Signaling and Signal Diversification in Immune

show abstract

“…[ 39 ] B cell lymphomas in the presence and absence of EBV infection with liver involvement has been described in multiple case reports. [ 40–42 ]…”

Section: Clinical Approach To Liver Disease In Ieismentioning

confidence: 99%

“…[39] B cell lymphomas in the presence and absence of EBV infection with liver involvement has been described in multiple case reports. [40][41][42] CD40 ligand deficiency Hyper IgM syndrome encompasses a group of rare genetic disorders in which there is a loss of T cell-driven immunoglobulin class switch recombination leading to normal/high IgM levels and low IgA, IgG, and IgE levels and/or defective somatic hypermutation and impaired T cell activation. [2] The most common subtype is CD40 ligand (CD40L) deficiency (previously known as X-linked hyper IgM syndrome [XHIM]), which results from genemutation encoding for the CD40L glycoprotein, which is expressed on the surface of T lymphocytes.…”

Section: Severe Combined Immunodeficiencymentioning

confidence: 99%

Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity

et al. 2022

View full text Add to dashboard Cite

Inborn errors of immunity (IEIs) consist of numerous rare, inherited defects of the immune system that affect about 500,000 people in the United States.As advancements in diagnosis through genetic testing and treatment with targeted immunotherapy and bone marrow transplant emerge, increasing numbers of patients survive into adulthood posing fresh clinical challenges.A large spectrum of hepatobiliary diseases now present in those with immunodeficiency diseases, leading to morbidity and mortality in this population. Awareness of these hepatobiliary diseases has lagged the improved management of the underlying disorders, leading to missed opportunities to improve clinical outcomes. This review article provides a detailed description of specific liver diseases occurring in various inborn errors of immunity.A generalized approach to diagnosis and management of hepatic complications is provided, and collaboration with hepatologists, immunologists, and pathologists is emphasized as a requirement for optimizing management and outcomes.

show abstract

EBV‐positive B‐cell lymphoma manifestation of the liver in an infant with RAG1 severe combined immunodeficiency disease

Cited by 7 publications

References 6 publications

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity

Contact Info

Product

Resources

About