Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency

Alazami, Anas M.; Al-Helale, Maryam; Alhissi, Safa; Al‐Saud, Bandar; Alajlan, Huda; Monies, Dorota; Shah, Zeeshan Ali; Abouelhoda, Mohamed; Arnaout, Rand; Al-Dhekri, Hasan; Al‐Numair, Nouf S.; Ghebeh, Hazem; Sheikh, Farrukh; Al‐Mousa, Hamoud

doi:10.3389/fimmu.2018.00203

Cited by 57 publications

(55 citation statements)

References 21 publications

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“…Similar observations have been made for mammalian sterile 20‐like one deficiency, a rare form of combined immunodeficiency, where high IgE levels were found only in three of 10 patients described to date . Recessive defects in the cytoskeletal regulator CARMIL2 manifest with dermatitis and combined immunodeficiency, but only two of seven patients had IgE >1000 IU/mL . A novel somatic STAT5b gain of function has been associated with nonclonal eosinophilia, atopic dermatitis, urticaria and diarrhoea in two paediatric patients; however, serum IgE was only elevated in one .…”

Section: Ii: Infantile Eczema and Recurrent Infectionssupporting

confidence: 72%

Hyper‐IgE in the allergy clinic––when is it primary immunodeficiency?

Ponsford¹,

Klocperk

Pulvirenti

et al. 2018

Allergy

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The 2017 International Union of Immunological Societies (IUIS) classification recognizes 3 hyper-IgE syndromes (HIES), including the prototypic Job's syndrome (autosomal dominant STAT3-loss of function) and autosomal recessive PGM3 and SPINK5 syndromes. Early diagnosis of PID can direct life-saving or transformational interventions; however, it remains challenging owing to the rarity of these conditions. This can result in diagnostic delay and worsen prognosis. Within increasing access to "clinical-exome" testing, clinicians need to be aware of the implication and rationale for genetic testing, including the benefits and limitations of current therapies. Extreme elevation of serum IgE has been associated with a growing number of PID syndromes including the novel CARD11 and ZNF341 deficiencies. Variable elevations in IgE are associated with defects in innate, humoral, cellular and combined immunodeficiency syndromes. Barrier compromise can closely phenocopy these conditions. The aim of this article was to update readers on recent developments at this important interface between allergy and immunodeficiency, highlighting key clinical scenarios which should draw attention to possible immunodeficiency associated with extreme elevation of IgE, and outline initial laboratory assessment and management.

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Section: Ii: Infantile Eczema and Recurrent Infectionssupporting

confidence: 72%

Hyper‐IgE in the allergy clinic––when is it primary immunodeficiency?

Ponsford¹,

Klocperk

Pulvirenti

et al. 2018

Allergy

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“…Previous studies found that T cell proliferation was also impaired in patients with CARMIL2 deficiencies [6,8,11]. Based on those results, we evaluated T cell proliferation in our cohort.…”

Section: Resultsmentioning

confidence: 89%

“…The fundamental value of CARMIL2 for immune defense was also recently proven as patients with bi‐allelic CARMIL2 mutations were diagnosed. Although rare, reports of affected patients have recently been accumulating [1,4,6‐12]. CARMIL2 deficiency is characterized by the reduced regulatory T cell (T reg ) counts and impaired T cell activation, which is attributed to a defect in CD28‐mediated co‐stimulation [4,7‐9].…”

Section: Introductionmentioning

confidence: 99%

Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation

Shamriz

Simon

Lev

et al. 2020

Clinical &Amp; Experimental Immunology

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Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28-mediated co-signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)-2 on in-vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5-10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25-base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in-vitro with the addition of IL-2 in different concentrations. CD25 and interferon (IFN)-γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8 + and CD4 + T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8 + T cells from all patients demonstrated signifi-cantly reduced IFN-γ production. When cells derived from CARMIL2deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL-2. In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients. Thus, IL-2 should be further studied as a potential therapeutic modality for these patients.

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“…Similarly, an RLTPR deficiency that caused a selective defect in CD28 co‐stimulation in T cells was recently reported in more than 20 patients, whom none of them has developed EBV‐driven B cell lymphoproliferative disorders. Nevertheless, two patients had EBV viremia, and five developed EBV‐associated smooth muscle tumors . RLTPR‐deficient T‐cells were found to be defective in proliferation and effector functions through TCR‐dependent CD28 co‐stimulation.…”

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

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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

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Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency

Cited by 57 publications

References 21 publications

Hyper‐IgE in the allergy clinic––when is it primary immunodeficiency?

Hyper‐IgE in the allergy clinic––when is it primary immunodeficiency?

Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation

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

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