A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant

Kurolap, Alina; Adiv, Orly Eshach; Konnikova, Liza; Werner, Lael; Gonzaga‐Jauregui, Claudia; Steinberg, M.; Mitsialis, Vanessa; Mory, Adi; Nunberg, M; Wall, Sarah; Shaoul, Ron; Overton, John D.; Shuldiner, Alan R.; Zohar, Yaniv; Paperna, Tamar; Snapper, Scott B.; Shouval, Dror S.; Feldman, Hagit Baris

doi:10.1007/s10875-019-00631-6

Cited by 19 publications

(27 citation statements)

References 29 publications

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“…Consistent with these findings, other mutations that led to CARMIL2 deficiencies were reported to confer a similar immune phenotype [4,6–12,26]. In our study, we demonstrated that CARMIL2‐deficient naive T cells expressed diminished levels of surface CD28.…”

Section: Discussionsupporting

confidence: 90%

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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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Section: Discussionsupporting

confidence: 90%

“…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%

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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“…Our study confirms that CARMIL2 deficiency can manifest only with isolated IBD. Unlike more recent studies 17,18 reporting a very early IBD onset (6 out of 6 patients), two of our patients shared a later age of onset of IBD symptoms, namely at 11 and 15 years of age. Although the majority of studies on monogenic IBD have focused on the very early onset population, running the risk of selection bias, recent findings have pointed out that a genetic disorder should be considered in all patients with pediatric onset IBD 29 www.nature.com/scientificreports/ Supplementary Fig.…”

Section: Discussioncontrasting

confidence: 94%

“…In Patient 4, carrying the homozygous missense variant p.D623E, CARMIL2 expression in the mucosal layer was significantly weaker in comparison to controls, while infiltrated blood cells located in the stromal area showed focally positive staining. This range of staining intensity in different cell types is consistent with previously published immunohistochemistry images, showing stronger staining in lymphocytes than in intestinal epithelium 18 . Cytokeratin 18 staining pattern in all samples was as expected based on previous reports 35 , indicating a preserved tissue architecture.…”

Section: Immunostaining Of Bowel Biopsies In Biallelic Carmil2 Variansupporting

confidence: 92%

“…CARMIL2 deficiency has been associated with an autosomal recessive primary immunodeficiency (Immunodeficiency 58 IMD58 [MIM: 618131]), characterized by recurrent and/or chronic bacterial, viral, and fungal infections, cutaneous manifestations including eczematous dermatitis, and disseminated Epstein-Barr virus-associated smooth muscle tumors [9][10][11][12][13][14] . Recently, biallelic loss-of-function (LoF) variants of CARMIL2 have been linked to very early onset inflammatory bowel disease (IBD) or IBD-like inflammatory gastrointestinal disorder, with or without clinical manifestations of immunodeficiency 11,13,[15][16][17][18] .…”

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confidence: 99%

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Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease

Bosa

Batura

Colavito³

et al. 2021

Sci Rep

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CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.

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Genetic susceptibility to EBV infection: insights from inborn errors of immunity

Tangye

2020

Hum Genet

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A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant

Cited by 19 publications

References 29 publications

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

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

Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease

Genetic susceptibility to EBV infection: insights from inborn errors of immunity

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