Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations

Dieli-Crimi, Romina; Martínez-Gallo, Mónica; Franco-Jarava, Clara; Antolı́n, Maria; Blasco, Laura Campello; Paramonov, Ida; Semidey, María Eugenia; Fernández, A.; Molero, Xavier; Velásquez, Julio; Martin‐Nalda, Andrea; Pujol-Borrell, Ricardo; Colobran, Roger

doi:10.1016/j.clim.2018.07.015

Cited by 32 publications

(23 citation statements)

References 48 publications

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“…We are currently using a custom‐designed next‐generation sequencing (NGS)‐based panel that targets 323 genes, including most of the known PID‐causing genes according to the 2015 IUIS (International Union of Immunological Societies) classification and other more recently described genes causing PID (Picard, Al‐Herz, Bousfiha, Casanova, & Chatila, ). This panel has been successfully used in our laboratory for genetic diagnosis of PID (Dieli‐Crimi, Martínez‐Gallo, Franco‐Jarava, Antolin, & Blasco, ). DNA copy‐number variations were investigated with array CGH using the CytoSure Constitutional v3 array 8 × 60K (Oxford Gene Technology) according to the manufacturer's recommendations.…”

Section: Methodsmentioning

confidence: 99%

Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency. Two years’ experience in Catalonia (Spain)

Martin‐Nalda

Cueto‐González

Ramírez

et al. 2019

Molec Gen & Gen Med

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BackgroundThe current scenario of newborn screening is changing as DNA studies are being included in the programs of several countries. Severe combined immunodeficiency (SCID) disorders can be detected using quantitative PCR assays to measure T‐cell receptor excision circles (TRECs), a byproduct of correct T‐cell development. However, in addition to SCID, other T‐cell‐deficient phenotypes such as 22q11.2 deletion syndrome 22q11.2 duplication syndrome, CHARGE syndrome, and trisomy 21 are detected.MethodsWe present our experience with the detection of 22q11.2 deletion syndrome and 22q11.2 duplication syndrome in a series of 103,903 newborns included in the newborn screening program of Catalonia (Spain).ResultsThirty newborns tested were positive (low TREC levels) and five were found to have copy number variations at the 22q11 region (4 deletions and 1 duplication) when investigated with array comparative genomic hybridization technology and MLPA.ConclusionNewborn screening for SCID enables detection of several conditions, such as 22q syndromes, which should be managed by prompt, proactive approaches with adequate counseling for families by a multidisciplinary team.

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Section: Methodsmentioning

confidence: 99%

Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency. Two years’ experience in Catalonia (Spain)

Martin‐Nalda

Cueto‐González

Ramírez

et al. 2019

Molec Gen & Gen Med

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“…Because ICOS activation is essential for terminal B cell differentiation and immune tolerance (96) both ICOS and NF-κB deficiencies result in CVID-like immunodeficiency syndromes and autoimmunity (77). NFKB1 mutation has also been linked with cytokine dysregulation, namely the elevation of type 1 cytokines that mirrors the immune profile characterizing the broader population of genetically-undefined CVID with non-infectious complications (97). Some with NFKB1 mutations have antibody deficiency without associated non-infectious complications (98).…”

Section: Genetics Of Cvid Autoimmunitymentioning

confidence: 99%

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

Gereige

Maglione

2019

Front. Immunol.

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Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency and comprises a group of disorders with similar antibody deficiency but a myriad of different etiologies, most of which remain undefined. The variable aspect of CVID refers to the approximately half of patients who develop non-infectious complications in addition to heightened susceptibility to infection. The pathogenesis of these complications is poorly understood and somewhat counterintuitive because these patients that are defined by their immune futility simultaneously have elevated propensity for autoimmune disease. There are numerous aspects of immune dysregulation associated with autoimmunity in CVID that have only begun to be studied. These findings include elevations of T helper type 1 and follicular helper T cells and B cells expressing low levels of CD21 as well as reciprocal decreases in regulatory T cells and isotype-switched memory B cells. Recently, advances in genomics have furthered our understanding of the fundamental biology underlying autoimmunity in CVID and led to precision therapeutic approaches. However, these genetic etiologies are also associated with clinical heterogeneity and incomplete penetrance, highlighting the fact that continued research efforts remain necessary to optimize treatment. Additional factors, such as commensal microbial dysbiosis, remain to be better elucidated. Thus, while recent advances in our understanding of CVID-associated autoimmunity have been exciting and substantial, these current scientific advances must now serve as building blocks for the next stages of discovery.

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“…Increased production of pro-inflammatory cytokines including interferon-γ (IFNγ) and tumor necrosis factor (TNF) has also been reported. These mice have increased susceptibility to infection and gut inflammation, which has also been seen in patients with NFKB1 haploinsufficiency (Stanic et al 2004;de Valle et al 2016;Schipp et al 2016;Kaustio et al 2017;Dieli-Crimi et al 2018). To further delineate the biological implications of this novel mutation in our patient, additional functional studies are warranted to ascertain the degree of p50 protein expression, activation of downstream signaling elements such as phosphorylation, and production of cytokines.…”

Section: Discussionmentioning

confidence: 85%

“…We report a novel mutation of NFKB1 in a pediatric patient with cytopenias, lymphadenopathy, and splenomegaly. To the best of our knowledge, this variant has not been reported in previously described NFKB1 cases (Boztug et al 2016;Maffucci et al 2016;Schipp et al 2016;Kaustio et al 2017;Lougaris et al 2017;Dieli-Crimi et al 2018;Fliegauf and Grimbacher 2018;Tuijnenburg et al 2018).…”

Section: Introductionmentioning

confidence: 72%

“…Multiple recent studies have identified variants in NFKB1 as a monogenic cause of immunodeficiency/ immune dysregulation (Table 2) (Maffucci et al 2016;Schipp et al 2016;Kaustio et al 2017;Lougaris et al 2017;Dieli-Crimi et al 2018;Fliegauf and Grimbacher 2018;Tuijnenburg et al 2018). Patients display a wide range of phenotypic heterogeneity including recurrent sinopulmonary infections, viral and fungal infections, autoimmunity, lymphoproliferation, and malignancy.…”

Section: Discussionmentioning

confidence: 99%

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Novel heterozygous NFKB1 mutation in a pediatric patient with cytopenias, splenomegaly, and lymphadenopathy

Duan

Feanny

2019

LymphoSign Journal

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Background: The nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) signaling pathway is a critical regulator of many important adaptive and innate immune responses. The NF-κB transcription factor family consists of 5 structurally related core proteins, one of which is NFKB1. Mutations in the NFKB1 gene has been reported in patients with common variable immune deficiency (CVID) as well as with a large spectrum of clinical features including recurrent viral, bacterial, and fungal infections, autoimmunity, inflammation, and malignancy. Aim: We describe the clinical characteristics of a pediatric patient with a novel mutation in NFKB1. Methods: Patient informed consent was obtained in accordance with approved protocols from the Research Ethics Board at the Hospital for Sick Children. Gene panel testing was employed to identify the immune aberration. Results: Our patient, a previously well 18-month-old boy of Philippines descent, presented with multi-lineage cytopenias (thrombocytopenia, hemolytic anemia, neutropenia), splenomegaly, and lymphadenopathy. He did not have prior history of recurrent infections. Immunological work-up showed normal numbers of T and B cells, normal quantitative immunoglobulins, and adequate vaccination titres. Gene panel testing revealed a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene. Due to persistent cytopenias unresponsive to steroids and IVIG, he was started on Sirolimus with improvement in symptoms. Conclusion: NFKB1 encodes for p105, which is processed to generate the active p50 transcription factor that can interact with different proteins to activate or inhibit downstream signaling. Our patient was found to have a missense mutation in the Rel homology domain (RHD) of p50, which has distinct functions including DNA binding, protein dimerization, and inhibitory protein binding. The clinical presentation described here broadens the scope of characteristics associated with heterozygous NFKB1 mutations. Statement of novelty: We report a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene in a pediatric patient with cytopenias, lymphadenopathy, and splenomegaly. To the best of our knowledge, this variant has not been previously reported.

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Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations

Cited by 32 publications

References 48 publications

Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency. Two years’ experience in Catalonia (Spain)

Identification of 22q11.2 deletion syndrome via newborn screening for severe combined immunodeficiency. Two years’ experience in Catalonia (Spain)

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

Novel heterozygous NFKB1 mutation in a pediatric patient with cytopenias, splenomegaly, and lymphadenopathy

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