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Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome

Charbit-Henrion, Fabienne*,†,‡,§; Jeverica, Anja K.||; Bègue, Bernadette*,†,§; Markelj, Gasper||; Parlato, Marianna*,†,§; Avčin, Simona Lucija; Callebaut, Isabelle#; Bras, Marc**; Parisot, Mélanie††; Jazbec, Janez; Homan, Matjaz§,‡‡; Ihan, Alojz§§; Rieux-Laucat, Frédéric†,||||; Stolzenberg, Marie-Claude†,||||; Ruemmele, Frank M.*,†,‡,§; Avčin, Tadej||,§§; Cerf-Bensussan, Nadine*,†,‡,§GENIUS Group

Journal of Pediatric Gastroenterology and Nutrition: March 2017 - Volume 64 - Issue 3 - p 378–384
doi: 10.1097/MPG.0000000000001262
Original Articles: Gastroenterology

Objective: Early-onset inflammatory bowel diseases can result from a wide spectrum of rare mendelian disorders. Early molecular diagnosis is crucial in defining treatment and in improving life expectancy. Herein we aimed at defining the mechanism of an immunodeficiency-polyendrocrinopathy and enteropathy-X-linked (IPEX)–like disease combined with a severe immunodeficiency in 2 siblings born from distantly related parents.

Methods: Whole exome sequencing was performed on blood-extracted genomic DNA from the 2 affected children and their parents on the genomic platform of Institut IMAGINE. Candidate gene mutation was identified using the in-house software PolyWeb and confirmed by Sanger sequencing. Protein expression was determined by western blot. Flow cytometry was used to assess consequences of the mutation on lymphocyte phenotype and nuclear factor-kappa B (NF-κB) activation at diagnosis and after treatment by hematopoietic stem cell transplantation.

Results: We identified a homozygous missense mutation in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1), which precluded protein expression. In keeping with the known function of MALT1, NF-κB–dependent lymphocyte activation was severely impaired. Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype. Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery. Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency.

Conclusions: Along with FOXP3, interleukin 2 receptor alpha chain (IL2RA), and cytotoxic T-lymphocyte protein 4 precursor (CTLA-4) mutations, MALT1 deficiency should now be considered as a possible cause of IPEX-like syndrome associated with immunodeficiency that can be cured by hematopoietic stem cell transplantation.

Supplemental Digital Content is available in the text

*INSERM, UMR1163, Laboratory of Intestinal Immunity

Université Paris Descartes-Sorbonne Paris Cité and Institut IMAGINE

Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Department of Pediatric Gastroenterology, Paris

§GENIUS Group (GENetically and/or ImmUne mediated enteropathieS) From ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition)

||Department of Allergology, Rheumatology and Clinical Immunology

Department of Haemato-oncology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia

#Institut de Minéralogie, de Physique des Matériaux, et de Cosmochimie, Sorbonne Universités—UMR CNRS 7590, UPMC Université Paris 6, Muséum National d’Histoire Naturelle, IRD UMR 206, IUC

**Bioinformatics Platform, Université Paris-Descartes-Paris Sorbonne Centre and Institut IMAGINE

††Genomic platform, Institut IMAGINE, Paris, France

‡‡Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital

§§Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

||||INSERM, UMR1163, Immunogenetics of Pediatric Autoimmunity, Paris, France.

Address correspondence and reprint requests to Nadine Cerf-Bensussan, Laboratory of Intestinal Immunity, Institut IMAGINE-INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité. 24, boulevard du Montparnasse, 75015 Paris, France (e-mail:

Received 19 February, 2016

Accepted 4 May, 2016

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (

This work was supported by Institutional grants from INSERM, by the European grant ERC-2013-AdG-339407-IMMUNOBIOTA, by the Investissement d’Avenir grant ANR-10-IAHU-01, by the Fondation Princesse Grace and by University Medical Centre Ljubljana Research Grant 20140208. FCH was supported by fellowships from Institut IMAGINE and from INSERM. NCB benefits from an Interface-Assistance Publique-Hôpitaux de Paris.

Drs Fabienne Charbit-Henrion and Anja Koren Jeverica shared first authorship.

Drs Frank M. Ruemmele, Tadej Avčin, and Nadine Cerf-Bensussan shared senior authorship.

For more information:;

The authors report no conflicts of interest.

What Is Known

  • Immunodeficiency polyendrocrinopathy and enteropathy-X–linked and IPEX-like syndromes can be caused by multiple monogenic defects.
  • Mutations in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1) have been described as a cause of severe combined immunodeficiency in 4 patients, 1 of whom improved by hematopoietic stem cell transplantation.

What Is New

  • MALT1 deficiency can lead to an IPEX-like syndrome combining autoimmune enteropathy, dermatitis, hyper immunoglobulin E in addition to a severe immune defect.
  • Hematopoietic stem cell transplantation is an effective cure in MALT1–deficient patients, correcting both the profound immune defect and the severe autoimmunity.

One rare but most severe group of inflammatory bowel diseases concerns extremely young children, for whom the early definition of the most pertinent treatment is crucial to reduce morbidity and increase life expectancy. Early age of onset and disease severity point out to mendelian genetic defects. Accordingly, mutations have been identified in an expanding number of genes (1). Inflammation can predominate in colon as in loss-of-function mutations in the interleukin-10 pathway or in the small intestine as in immunodeficiency polyendrocrinopathy and enteropathy-X-linked (IPEX) and IPEX-like syndromes because of mutations in genes indispensable for regulatory T cells differentiation or function (2,3). Herein we used whole exome sequencing (WES) and identified a loss-of-function mutation in mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) as the cause of an IPEX-like syndrome combining autoimmune enteropathy, dermatitis, and hyper immunoglobulin E (IgE) in 2 siblings also displaying severe immunodeficiency.

MALT1 is an intracellular protein constitutively associated with B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10). BCL10 and MALT1 genes were initially identified in recurring translocations that promoted constitutive activation of the canonical nuclear factor-kappa B (NF-κB) pathway in mucosa-associated B-cell lymphomas (4). It was then shown that BCL10 and MALT1 can bind 3 members of the caspase recruitment domain (CARD) family of adaptors, CARD9 in myeloid cells, CARD10 in epithelial cells, and CARD11 in lymphocytes and thereby form 3 complexes called CARD-Bcl10-Malt1 (CBM) signalosomes, which link a large spectrum of membrane receptors to the NF-κB pathway. The CARD9-containing signalosome is necessary for innate immune responses downstream C-type-lectin receptors and Toll-like-receptors and patients with CARD9 mutations develop severe fungal infections. The CARD11 signalosome is recruited downstream the B- (BCR) and T-cell (TCR) receptors and is indispensable for adaptive immunity. Accordingly, 2 patients with mutations in CARD11 displayed pulmonary infections with Pneumocystis jirovecii. Recently, loss of functions mutations in MALT1 have also been identified in 4 children as the cause of severe combined immunodeficiency (5–7). Herein we report the case of 2 siblings with MALT1 deficiency and discuss how this immune deficiency can cause IPEX-like syndrome despite profound impairment of lymphocyte activation. In keeping with a recent single report, we confirm that this severe disease can be cured by hematopoietic stem cell transplantation.

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Two siblings and their parents were studied after informed written consent was obtained for functional and genomic molecular studies. Written consent was obtained for publication of photographs.

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Lymphocyte Isolation and Cell Lines

Peripheral blood cells (PBMCs) were isolated on Ficoll HyPaque Plus (GE Healthcare, Velizy-Villacoublay, France). To obtain T-cell lines, PBMC (1 × 106 cells/mL) were stimulated for 3 days with phytohemagglutin A (PHA) (1 μg/mL; Sigma, Saint-Quentin Fallavier, France) in RPMI 1640 Glutamax supplemented with 1% non-essential amino acids, 1% sodium pyruvate, 1% HEPES (Invitrogen, Cergy Pontoise, France), and 10% inactivated human serum AB (PAA, Les Mureaux, France). PHA-stimulated PBMCs were next cultured with 50 U/mL recombinant IL2 (R&D Systems, Lille, France) for 2 to 3 weeks. Epstein-Barr virus (EBV) immortalized B cell lines were derived from PBMCs by the Necker Center for biological resources according to a standard procedure.

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Phenotyping of Regulatory T Cells and Anti-Enterocyte Antibodies

PBMCs (1 × 106) were surface stained with sCD3-BV510 (OKT3; Sony, San Jose, CA), CD4-FITC (Leu 3a+3b; BD Biosciences, Rungis, France), CD25-BV650 (MA 251, BD Biosciences), and then intracellularly stained with FoxP3-PE (PCH101; eBioscience, San Diego, CA) antibody according to manufacturer's instructions. Data were collected with a Fortessa cytometer (BD Biosciences) and analyzed with Flow Jo software (TreeStar, Ashland, OR). Detection of serum antibodies against enterocytes or against the 75 kDa harmonin antigen (8) was performed respectively by immunohistochemistry or radioimmunoassay as described (9).

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Genotypic Analysis

Genomic DNA from peripheral blood cells was isolated using the QIAamp DNA Blood Mini Kit (Qiagen, Courtaboeuf, France) according to manufacturer's instructions. WES was performed on the genomic platform of Institut IMAGINE's. Agilent SureSelect libraries were prepared from 3 μg of genomic DNA sheared with a Covaris S2 Ultrasonicator. Exon regions were captured using the Agilent Sure Select All Exon V5 (AGILENT, Les Ulis, France) and sequenced using a HiSeq2500 next-generation sequencer (Illumina, San Diego, CA). Depth of coverage obtained for each sample was around 100 times with >98% of the exome covered at least 15-fold. Paired-end sequences were then mapped on the human genome reference (NCBI build37/hg19 version) using the Burrows-Wheeler Aligner. Downstream processing was carried out with the Genome Analysis Toolkit (GATK), SAMtools, and Picard, following documented best practices ( Variant calls were made with the GATK Unified Genotyper. All variants were annotated using the in-house software (PolyWeb) developed by Paris Descartes University Bioinformatics platform as described in Figure 1 . All the annotation process was based on the 72 version of ENSEMBL database. Analysis of genome variations was made using PolyWeb. This software allows to filter variants and to eliminate irrelevant and common polymorphisms, to compare exomes of patients and relatives, to detect variations compatible with the different modes of inheritance. Variants were compared with the ones already present in US National Center for Biotechnology Information database (10) of SNP, 1000 Genome, and Exome Variant Server databases. The functional consequence of the mutation on the protein function was predicted using 3 algorithms: Polyphen2 (, Sift (Sorting Intolerant From Tolerant, J. Craig Venter Institute), and Mutation Taster ( To confirm the mutation by Sanger sequencing, genomic DNA was amplified by standard techniques using oligonucleotide primers flanking the exon 4 of MALT1 (forward 5′-TGGGGGAAAAATGTTGCACT-3′, lower 5′-CCCCATCCCA ACATTCAGCT) using TaqDNA Polymerase (Life Technologies, Saint-Aubin, France). After purification with theQIAquick PCR Purification kit (Qiagen), PCR fragments were sequenced using the same primers by Eurofins on the Genomic Platform of Université Paris Descartes.



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PCR and Western Blot

Total RNA (500 ng) extracted from T-cell lines (Rneasy Plus Kit; Qiagen) was retro-transcribed to cDNA with M-MLV retro-transcriptase and a mixture of oligo dT (18) and hexamers (Life Technologies) and amplified with primers for MALT1 (forward 5′-CAGTTGCCT AGACCTGGAGC-3′ in exon 2, reverse 5′-GCTTCCAACAGCAACACACT-3′ in exon 5) and for the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase (forward 5′-GAAGGTGAAGGTCGGA GTC-3′ in exon 2, reverse 5′-GAGGGATCTCGCTCC TGGAAGA-3′ in exon 5). To study Malt1 protein expression, 10 × 106 T cells or 4 × 106 EBV-immortalized B cells were lysed in radioimmunoprecipitation assay buffer (Sigma) and 20 μg of proteins were resolved on 4% to 15% sodium dodecyl sulfate–polyacrylamide gels and transferred to polyvinylidene fluoride membranes (Biorad, Marnes-la-Coquette, France). Membranes were immunoblotted with a monoclonal antibody against human MALT1 carboxy-terminus (imunogen part Asp701-Thr808, clone MALT1-C, 110 kDa, R&D Systems), and horseradish peroxidase-linked anti-mouse Ig1, or horseradish peroxidase-conjugated glyceraldehyde 3-phosphate dehydrogenase rabbit antibody (38 kDa, Ozyme, Montigny-le Bretonneux, France) and were revealed using ECL Prime Western Blotting Detection reagent, (GE Healthcare, Velizy-Villacoublay, France) and Molecular Imager Chemidoc (Biorad, Marnes-la-Coquette, France). Bands were analyzed with Image Lab software. To inhibit proteasome activity, EBV-immortalized B cells were incubated in 100 μmol/L of MG132 for 8 hours (Sigma) before western blot analysis.

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Intracellular Signaling Assays

PHA-T-cell lines were analyzed after a 4-hour rest without interleukin 2 (IL-2). To study IL-2 induction, T-cell lines were stimulated with 32 nmol/L phorbol-12-myristate-13-acetate (PMA) and 0.5 μmol/L ionomycin for 18 hours and 10 μg/mL of Brefeldin A (Sigma) were added for the last 3 hours. Cells (106) were then surface labeled with CD3Pe-Cy7 antibody (BD Biosciences), fixed and permeabilized with BDCytofix/Cytoperm Plus Fixation/PermeabilizationSolution Kit (BD Biosciences), and intracellularly stained with Alexa Fluor 488 anti-human IL-2 (clone MQ1–17H12; Biolegend, San Diego, CA, and Ozyme, Montigny-le-Bretonneux, France). To study IκBα degradation, T-cell lines were stimulated with 162 nmol/L PMA and (0.5 μmol/L) Ionomycin for 15 minutes at 37°C, and 106 cells were fixed and permeabilized with PhosFlow CytoFix buffer and PermII buffer (BD Biosciences) and then stained with a mixture of anti-IκBα-PE(clone 25/IκBα/MAD-3) or isotype control and anti-CD3-BV510 (BD Biosciences). Cells were analyzed on a CANTO II instrument (BD Biosciences) and with Flow Jo software (TreeStar Inc).

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Description of Patients

Patient 1 (P1), a 7-year-old girl, and P2, her 4-year-old brother, were born from distantly related parents. Facial dysmorphy was noted from birth (Fig. 1A) and chronic eczema-like dermatitis since the first months of life. After 16 months, P1 experienced multiple severe or even life-threatening bacterial, viral, and fungal infections (Supplementary Table 1, At 2.5 years, she developed severe chronic diarrhea with subtotal villous atrophy, massive duodenal T-cell lymphocyte infiltration (Fig. 1B), and moderate colonic inflammation. Methylprednisolone and tacrolimus induced good clinical response and partial histological recovery, suggesting autoimmune enteropathy despite the absence of harmonin serum autoantibodies that are frequently elevated in autoimmune enteropathy, either caused by or not caused by loss-of-function mutations in Forkhead box P3 (FOXP3) (9,11). P2 also presented with chronic dermatitis and repeated infections that were, however, less frequent and less severe than his sister. Because he had no clinical signs of intestinal disease and no anti-harmonin autoantibodies, intestinal biopsy was not performed.

Both patients displayed low IgM, normal IgG and IgA levels, normal CD20+ but reduced CD21 B+ cells. Counts of CD4+ and CD8+ cells, activated (human leukocyte antigen-DR+) and memory (CD45RA-) T cells were elevated. Proliferative response to PHA was normal, whereas proliferation induced through TCR by CD3/CD28 stimulation was markedly reduced (Supplementary Table 1, Strikingly, both patients showed blood eosinophilia, high IgE, and only 0.7% to 1% of CD4+ T cells displayed a CD25+FoxP3+ phenotype, pointing out to a severe quantitative defect in FoxP3+ regulatory T cells (Treg) (Fig. 1C and Supplementary Table 1, Overall these data suggested that the patients had an inborn immunodeficiency combining increased sensitivity to all types of infections and an IPEX-like syndrome.

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Identification of a MALT1 Homozygous Mutation

To identify the putative gene defect, WES was performed on genomic DNA from P1, P2, and their parents (Fig. 2A). WES identified 1 single missense c.550G>T variation in exon 4 of the MALT1 gene, that was homozygous in both affected siblings and heterozygous in their parents (Fig. 2B). MALT1 is an 824 amino acids intracellular protein, containing an N-terminal death domain, 3 immunoglobulin-like domains and 1 paracaspase domain (Fig. 2C). The missense c.550G>T variation resulted in an aspartic acid to tyrosine substitution at amino-acid position 184 (p.Asp184Tyr) in the first immunoglobulin-like domain of MALT1. Asp184 is highly conserved as the sixth amino acid (EF6) of the E-F helix in proteins of the Immunoglobulin superfamily (12,13) and stabilizes this helix by creating a hydrogen bond with EF3. Its substitution by a tyrosine residue removes the hydrogen bond necessary for proper folding of the immunoglobulin-like domain (Fig. 3A), and should therefore impair protein stability. In keeping with this prediction, the MALT1 D184Y protein was undetectable in PHA-T or EBV cell lines from the patients compared with control and parents, but its expression was restored in the presence of proteasome inhibitor (Fig. 3B and Supplementary Fig. 1A and 1B,





As discussed above, MALT1 associates with B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL-10) and, in lymphocytes, with CARD11 to form 1 CBM signalosome that links the TCR and B-cell receptor to the canonical NF-κB pathway (14). Upon lymphocyte activation, the CBM signalosome stimulates the IκB kinase complex, leading to phosphorylation and proteosomal degradation of the IκBα inhibitor and to the release of NF-κB that can translocate into the nucleus and activate its transcriptional targets. MALT1 has also a paracaspase activity that cleaves negative regulators of NF-κB and thereby further promotes IL-2 production (15). Confirming the loss-of-function mutation in MALT1, degradation of IκBα and induction of IL-2 in response to PMA and ionomycin were drastically impaired in PHA-T cell lines from both siblings compared with a control cell line and to cell lines from their parents (Fig. 3C and Supplementary Fig. 1C,

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Treatment of MALT1 Deficiency by Hematopoietic Stem Cell Transplantation

Both patients underwent hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning according to EBMT/ESID guidelines for HSCT for primary immunodeficiencies, consisting of fludarabin (180 mg/m2), busulfan (13–15 mg/kg), and alemtuzumab (0.6 mg/kg). They received peripheral mobilized CD34+ cells from two 10/10 human leukocyte antigen-matched unrelated donors. Graft-versus-host disease prophylaxis included cyclosporine and mycophenolate mofetil in both patients. Owing to severe allergic reaction to cyclosporine, graft-versus-host disease prophylaxis was changed to tacrolimus in P2. Post-HSCT cytomegalovirus reactivation was observed in both children and was successfully treated with foscarnet (because of resistance to gancyclovir). Both patients had reactivation despite antiviral prophylaxis that resolved with short-term therapy. P1, who experienced life-threatening infections and severe auto-immune enteropathy, is now free of symptoms and has resumed growth. P2 is also free of symptoms. Chimerism on total blood was 100% in P1 on day 300 and 75% in P2 on day 250 after graft. In both patients, IgM serum levels and T-cell counts were nearly normal, except for a moderate CD4+ lymphopenia likely secondary to conditioning by fludarabin (Supplementary Table 1, Frequency of CD25+ FoxP3+ T cells among peripheral CD4+ T cells was comparable with that of control at day 170 and day 400 post-BMT in P1 (Fig. 1C and data not shown). Moreover, IκBα underwent normal degradation in PHA blasts stimulated by PMA and ionomycin and the later cells produced substantial amounts of IL-2 (Fig. 3C and data not shown). Partial recovery of the studied parameters was observed in P2 at day 120 and at day 300 (Figs. 1C and 3C and data not shown).

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Past studies have demonstrated that IPEX and IPEX-like syndromes can be caused by loss-of-function mutations in FOXP3, interleukin 2 receptor alpha chain (IL2RA), STAT5b, and cytotoxic T-lymphocyte protein 4 precursor (CTLA-4) genes that are indispensable for Treg generation, homeostasis or function, or from gain-of-function mutations in STAT3 and STAT1 that induce T-cell hyperactivation (2,3). In all the latter diseases, effector T cells are not impaired or only moderately impaired in their function. Herein, we highlight how severe defect in Treg in patients with MALT1 loss-of-function can cause IPEX-like symptoms despite profound impairment of lymphocyte activation.

MALT1 missense mutations have been recently reported in 2 siblings and 2 unrelated children as a cause of severe combined immunodeficiency without lymphopenia (5–7). Mutations were localized in the N-terminal CARD domain of MALT1, in its C-terminus or affected splicing, but all abrogated or drastically reduced protein expression (Fig. 2C). Herein, we have identified 2 siblings with a novel missense homozygous mutation that is predicted to prevent correct folding of the first immunoglobulin domain of the protein. We confirmed that, as a consequence, MALT1 was unstable and rapidly degraded by the proteasome. MALT1 has a dual function in lymphocytes. As a scaffold protein, it combines with BCL-10 and CARD11 in lymphocytes and forms a CBM signalosome that is indispensable to activate NF-κB downstream the T- and B-cell receptors (4). Accordingly, PMA and ionomycin failed to stimulate IκBα degradation and IL-2 production in T blasts from the 2 patients. In keeping with the profound functional lymphocyte defect and as previously reported in the 4 other cases of MALT1 deficiency, our 2 patients developed a wide spectrum of severe infections. One striking feature of the disease was, however, an IPEX-like syndrome combining severe eczema-like dermatitis, hyper-IgE and, in 1 sibling, intestinal inflammation with villous atrophy and massive hyperplasia of CD3+CD8+ intraepithelial lymphocytes. Moreover, both siblings had extremely low counts of FoxP3+ Treg. No IPEX syndrome has been formally described in the 4 other reported cases of MALT1 deficiency, but 2 unrelated children had severe exfoliating dermatitis. Inflammation of the upper digestive tract was noted in the 4 patients and 2 had villous atrophy with increased number of intraepithelial lymphocytes. Increased IgE levels were observed in only 1 case, whereas numbers of FoxP3+ Treg were found normal in 1 patient and extremely low in another (Table 1 and Supplementary Table 2, (5–7).



Interestingly, intrathymic but not peripheral generation of natural Treg was found to be profoundly impaired in Malt1 −/− mice, resulting in drastically reduced numbers of Treg in the peripheral blood of young mice, while this defect was masked by the progressive expansion of peripheral Treg in aged Malt1 −/− mice (16). Reduced numbers of Tregs were also observed in mice selectively lacking MALT1 paracaspase activity (Malt1 PM/PM), which is necessary for fine-tuning NF-κB activation (10,17,18). Despite the lack of natural Treg indispensable to protect against autoimmunity, no IPEX-like symptoms were observed in Malt1 −/− mice but Malt1 PM−/− mice, which, in contrast to Malt1 −/− mice, had normal effector T-cell functions, developed hyper-IgE, lymphadenopathy, multiorgan lymphocyte infiltration, and severe autoimmune gastritis alike Foxp3−/− mice (19). We suggest that, in MALT1-deficient humans, activation of effector T cells may be less impaired than in Malt1 −/− mice and therefore be sufficient, if not inhibited by natural Treg, to induce IPEX-like symptoms. Of note anti-enterocyte (harmonin) autoantibodies, which are present in FOXP3 −/− patients developing an autoimmune enteropathy, were absent in our MALT1 −/− patient (8). This negative result is in keeping with the profound B cell defect associated with MALT1 deficiency and confirms that these antibodies are dispensable for intestinal damage.

MALT1 expression is not restricted to the hematopoietic compartment and can form with BCL-10 and CARD10 a signalosome that participates in NF-κB activation downstream G protein-coupled receptors outside the immune system, notably in epithelial cells (20). The absence of MALT1 in other cell types may thus perhaps account for the dysmorphia observed in the 2 siblings in this study and in 1 previously reported MALT1 −/− patient (6). Yet MALT1 deficiency seems to affect most dramatically immune cells, highlighting a key nonredundant role of MALT1 in the hematopoietic compartment and pointing out to HSCT as a possible curative treatment. Accordingly, 1 of the 4 reported cases of MALT1 deficiency was successfully treated by HSCT (7). Confirming that HSCT is a pertinent therapeutic option in MALT1 deficiency, human leukocyte antigen-matched HSCT corrected lymphocyte dysfunction and allowed clinical recovery in both siblings in the present study.

In conclusion, our observations confirm and extend previous findings in MALT1 deficient children and highlight the unusual presentation of this extremely rare condition, which combines severe immunodeficiency and IPEX-like syndrome. Analysis of IκBα degradation after lymphocyte activation provides a simple diagnosis test to orientate genetic testing. Early recognition of this extremely severe disease is indispensable as it can be cured by HSCT.

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auto-immune enteropathy; CBM signalosome; intestinal immunity; extremely early-onset inflammatory bowel disease

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© 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,