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Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency

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Abstract

Purpose

MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency.

Methods

The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation.

Results

The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03).

Conclusion

This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.

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Data Availability

The data generated during the study are included in this published article and its supplementary file.

The study was approved by the Ethics Committee of Marmara University, School of Medicine (09.2018.624).

References

  1. Thome M. Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol. 2008;8(7):495–500.

    Article  CAS  PubMed  Google Scholar 

  2. Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM, Abazeed ME, Chen FF, et al. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem. 2001;276(22):19012–9.

    Article  CAS  PubMed  Google Scholar 

  3. Lu HY, Bauman BM, Arjunaraja S, Dorjbal B, Milner JD, Snow AL, et al. The CBM-opathies-a rapidly expanding spectrum of human inborn errors of immunity caused by mutations in the CARD11-BCL10-MALT1 complex. Front Immunol. 2018;9:2078.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Thome M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nat Rev Immunol. 2004;4(5):348–59.

    Article  CAS  PubMed  Google Scholar 

  5. Ruland J, Hartjes L. CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nat Rev Immunol. 2019;19(2):118–34.

    Article  CAS  PubMed  Google Scholar 

  6. Thome M, Charton JE, Pelzer C, Hailfinger S. Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol. 2010;2(9):a003004.

  7. Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J Clin Immunol. 2020;40(1):66–81.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. The ever-increasing array of novel inborn errors of immunity: an interim update by the IUIS committee. J Clin Immunol. 2021;41(3):666–79.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jabara HH, Ohsumi T, Chou J, Massaad MJ, Benson H, Megarbane A, et al. A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J Allergy Clin Immunol. 2013;132(1):151–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McKinnon ML, Rozmus J, Fung SY, Hirschfeld AF, Del Bel KL, Thomas L, et al. Combined immunodeficiency associated with homozygous MALT1 mutations. J Allergy Clin Immunol. 2014;133(5):1458–62, 62 e1–7.

  11. Punwani D, Wang H, Chan AY, Cowan MJ, Mallott J, Sunderam U, et al. Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation. J Clin Immunol. 2015;35(2):135–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Frizinsky S, Rechavi E, Barel O, Najeeb RH, Greenberger S, Lee YN, et al. Novel MALT1 mutation linked to immunodeficiency, immune dysregulation, and an abnormal T cell receptor repertoire. J Clin Immunol. 2019;39(4):401–13.

    Article  CAS  PubMed  Google Scholar 

  13. Wiegmann H, Reunert J, Metze D, Marquardt T, Engel T, Kunde V, et al. Refining the dermatological spectrum in primary immunodeficiency: mucosa-associated lymphoid tissue lymphoma translocation protein 1 deficiency mimicking Netherton/Omenn syndromes. Br J Dermatol. 2020;182(1):202–7.

    CAS  PubMed  Google Scholar 

  14. Kutukculer N, Seeholzer T, O'Neill TJ, Grass C, Aykut A, Karaca NE, et al. Human immune disorder associated with homozygous hypomorphic mutation affecting MALT1B splice variant. J Allergy Clin Immunol. 2021;147(2):775–8 e8.

  15. Charbit-Henrion F, Jeverica AK, Begue B, Markelj G, Parlato M, Avcin SL, et al. Deficiency in mucosa-associated lymphoid tissue lymphoma translocation 1: a novel cause of IPEX-like syndrome. J Pediatr Gastroenterol Nutr. 2017;64(3):378–84.

    Article  PubMed  Google Scholar 

  16. Shirmast P PK, Moeini shad T. Case report- MALT 1 mutation in a patient with severe combined immunologic Immunol Genet J 2020. 2020;3:47–52.

  17. Lu HY, Turvey SE. Human MALT1 deficiency and predisposition to infections. Curr Opin Immunol. 2021;72:1–12.

    Article  CAS  PubMed  Google Scholar 

  18. Abolhassani H, Aghamohammadi A, Fang M, Rezaei N, Jiang C, Liu X, et al. Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency. Genet Med. 2019;21(1):243–51.

    Article  CAS  PubMed  Google Scholar 

  19. Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, et al. Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency. J Allergy Clin Immunol. 2018;141(4):1450–8.

    Article  CAS  PubMed  Google Scholar 

  20. Abolhassani H, Hammarstrom L, Cunningham-Rundles C. Current genetic landscape in common variable immune deficiency. Blood. 2020;135(9):656–67.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Fang M, Abolhassani H, Lim CK, Zhang J, Hammarstrom L. Next generation sequencing data analysis in primary immunodeficiency disorders - future directions. J Clin Immunol. 2016;36(Suppl 1):68–75.

    Article  CAS  PubMed  Google Scholar 

  22. Kolukisa B, Baser D, Akcam B, Danielson J, Bilgic Eltan S, Haliloglu Y, et al. Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency. Allergy. 2021.

  23. Abolhassani H, Kiaee F, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, et al. Fourth update on the Iranian National Registry of Primary Immunodeficiencies: integration of molecular diagnosis. J Clin Immunol. 2018;38(7):816–32.

    Article  PubMed  Google Scholar 

  24. Aghamohammadi A, Rezaei N, Yazdani R, Delavari S, Kutukculer N, Topyildiz E, et al. Consensus Middle East and North Africa Registry on inborn errors of immunity. J Clin Immunol. 2021.

  25. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human Inborn errors of immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24–64.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Thalhammer J, Kindle G, Nieters A, Rusch S, Seppanen MRJ, Fischer A, et al. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol. 2021.

  27. Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, et al. Abatacept as a long-term targeted therapy for LRBA deficiency. J Allergy Clin Immunol Pract. 2019;7(8):2790–800 e15.

  28. Eken A, Cansever M, Somekh I, Mizoguchi Y, Zietara N, Okus FZ, et al. Genetic deficiency and biochemical inhibition of ITK affect human Th17, Treg, and innate lymphoid cells. J Clin Immunol. 2019;39(4):391–400.

    Article  PubMed  Google Scholar 

  29. Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A, et al. Severe early-onset combined immunodeficiency due to heterozygous gain-of-function mutations in STAT1. J Clin Immunol. 2016;36(7):641–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen Y, Lu H, Zhang N, Zhu Z, Wang S, Li M. PremPS: predicting the impact of missense mutations on protein stability. PLoS Comput Biol. 2020;16(12):e1008543.

  31. Zhang Z, Wang L, Gao Y, Zhang J, Zhenirovskyy M, Alexov E. Predicting folding free energy changes upon single point mutations. Bioinformatics. 2012;28(5):664–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gehring T, Erdmann T, Rahm M, Grass C, Flatley A, O'Neill TJ, et al. MALT1 phosphorylation controls activation of T lymphocytes and survival of ABC-DLBCL tumor cells. Cell Rep. 2019;29(4):873–88 e10.

  33. Ancien F, Pucci F, Godfroid M, Rooman M. Prediction and interpretation of deleterious coding variants in terms of protein structural stability. Sci Rep. 2018;8(1):4480.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Redler RL, Das J, Diaz JR, Dokholyan NV. Protein Destabilization as a common factor in diverse inherited disorders. J Mol Evol. 2016;82(1):11–6.

    Article  CAS  PubMed  Google Scholar 

  35. Brustle A, Brenner D, Knobbe-Thomsen CB, Cox M, Lang PA, Lang KS, et al. MALT1 is an intrinsic regulator of regulatory T cells. Cell Death Differ. 2017;24(7):1214–23.

    Article  CAS  PubMed  Google Scholar 

  36. Bornancin F, Renner F, Touil R, Sic H, Kolb Y, Touil-Allaoui I, et al. Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation. J Immunol. 2015;194(8):3723–34.

    Article  CAS  PubMed  Google Scholar 

  37. Guckel E, Frey S, Zaiss MM, Schett G, Ghosh S, Voll RE. Cell-intrinsic NF-kappaB activation is critical for the development of natural regulatory T cells in mice. PLoS One. 2011;6(5):e20003.

  38. Oh H, Grinberg-Bleyer Y, Liao W, Maloney D, Wang P, Wu Z, et al. An NF-kappaB transcription-factor-dependent lineage-specific transcriptional program promotes regulatory T cell identity and function. Immunity. 2017;47(3):450–65 e5.

  39. Rozmus J, McDonald R, Fung SY, Del Bel KL, Roden J, Senger C, et al. Successful clinical treatment and functional immunological normalization of human MALT1 deficiency following hematopoietic stem cell transplantation. Clin Immunol. 2016;168:1–5.

    Article  CAS  PubMed  Google Scholar 

  40. Ruland J, Duncan GS, Wakeham A, Mak TW. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity. 2003;19(5):749–58.

    Article  CAS  PubMed  Google Scholar 

  41. Gross O, Grupp C, Steinberg C, Zimmermann S, Strasser D, Hannesschlager N, et al. Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-kappaB and MAPK activation to selectively control cytokine production. Blood. 2008;112(6):2421–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Grinberg-Bleyer Y, Oh H, Desrichard A, Bhatt DM, Caron R, Chan TA, et al. NF-kappaB c-Rel is crucial for the regulatory T cell immune checkpoint in cancer. Cell. 2017;170(6):1096–108 e13.

  43. Oh H, Ghosh S. NF-kappaB: roles and regulation in different CD4(+) T-cell subsets. Immunol Rev. 2013;252(1):41–51.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Demeyer A, Van Nuffel E, Baudelet G, Driege Y, Kreike M, Muyllaert D, et al. MALT1-deficient mice develop atopic-like dermatitis upon aging. Front Immunol. 2019;10:2330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Alroqi FJ, Charbonnier LM, Baris S, Kiykim A, Chou J, Platt CD, et al. Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018;141(3):1050–9 e10.

  46. Shamriz O, Patel K, Marsh RA, Bleesing J, Joshi AY, Lucas L, et al. Hypogammaglobulinemia with decreased class-switched B-cells and dysregulated T-follicular-helper cells in IPEX syndrome. Clin Immunol. 2018;197:219–23.

    Article  CAS  PubMed  Google Scholar 

  47. Hamilton KS, Phong B, Corey C, Cheng J, Gorentla B, Zhong X, et al. T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10. Sci Signal. 2014;7(329):ra55.

  48. Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, et al. Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet. 2017;49(8):1192–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Corvilain E, Casanova JL, Puel A. Inherited CARD9 deficiency: invasive disease caused by ascomycete fungi in previously healthy children and adults. J Clin Immunol. 2018;38(6):656–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Professor Dr. Figen Cullu Cokugras from Istanbul-Cerrahpasa University, Department of Pediatric Gastroenterology, Hepatology and Nutrition for her support during the data collection.

Funding

This work was supported by grants from the Scientific and Technological Research Council of Turkey (318S202) to S.B. and from National Institutes of Health (R01AI085090 and R01AI128976) to T.A.C. H.A. was supported by Jonas Söderquist scholarship and Åke Wibergs foundation. D.K. was supported by Deutsche Forschungsgemeinschaft (ID 360372040—SFB 1335 P07).

Author information

Authors and Affiliations

  1. Division of Pediatric Allergy/Immunology, Marmara University, Istanbul, Turkey

    Asena Pinar Sefer, Sevgi Bilgic Eltan, Burcu Kolukisa, Elif Karakoc-Aydiner, Ahmet Ozen & Safa Baris

  2. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey

    Asena Pinar Sefer, Sevgi Bilgic Eltan, Burcu Kolukisa, Elif Karakoc-Aydiner, Ahmet Ozen & Safa Baris

  3. Marmara University, The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey

    Asena Pinar Sefer, Sevgi Bilgic Eltan, Burcu Kolukisa, Elif Karakoc-Aydiner, Ahmet Ozen & Safa Baris

  4. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Hassan Abolhassani, Samaneh Delavari & Nima Rezaei

  5. Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden

    Hassan Abolhassani

  6. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden

    Hassan Abolhassani

  7. Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany

    Franziska Ober & Daniel Krappmann

  8. Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

    Basak Kayaoglu, Naz Surucu Yilmaz & Mayda Gursel

  9. TUBITAK Marmara Research Center, Gene Engineering and Biotechnology Institute, Gebze, Turkey

    Altan Kara

  10. Institute of Child Health, Hacettepe University, Ankara, Turkey

    Baran Erman

  11. Can Sucak Research Laboratory for Translational Immunology, Center for Genomics and Rare Diseases, Hacettepe University, Ankara, Turkey

    Baran Erman

  12. Division of Pediatric Allergy and Immunology, University of Health Sciences, Basaksehir Cam Sakura City Hospital, Istanbul, Turkey

    Cigdem Aydogmus

  13. Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Sezin Aydemir, Ayca Kiykim & Haluk Cokugras

  14. Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Division of Immunology, Boston, MA, USA

    Louis-Marie Charbonnier & Talal A. Chatila

  15. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran

    Gholamreza Azizi

  16. Department of Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

    Tooba Momen

  17. Faculty of Medicine, Department of Pediatrics, Marmara University, Istanbul, Turkey

    Simuzar Aliyeva

  18. Division of Pediatric Genetics, University of Health Sciences, Umraniye Education and Research Hospital, Istanbul, Turkey

    Yasemin Kendir Demirkol

  19. Hamidiye Faculty of Medicine, Department of Basic Medical Sciences, Division of Medical Biology, University of Health Sciences, Istanbul, Turkey

    Saban Tekin

  20. Faculty of Medicine, Pediatric Gastroenterology, Hepatology and Nutrition, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Omer Faruk Baser

  21. Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Nima Rezaei

Authors
  1. Asena Pinar Sefer
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  2. Hassan Abolhassani
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  3. Franziska Ober
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  4. Basak Kayaoglu
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  5. Sevgi Bilgic Eltan
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  6. Altan Kara
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  8. Naz Surucu Yilmaz
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  28. Safa Baris
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Contributions

S.B. conceptualized and supervised the study. F.O., B.K., A.K., B.E., N.S.Y, L.M.C., Y.K.D., and S.T. performed the experiments. A.P.S., H.A., S.B.E., C.A., S. Aydemir, B. Kolukisa, S. Aliyeva, A.K., O.F.B., H.C., E.K.A., G.A., S.D., T.M., N.R., and A.O. provided patient care, collected samples, and clinical data. S.B. and A.P.S. wrote the paper. M.G., H.A., D.K., and T.A.C. edited the paper. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Safa Baris.

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Sefer, A.P., Abolhassani, H., Ober, F. et al. Expanding the Clinical and Immunological Phenotypes and Natural History of MALT1 Deficiency. J Clin Immunol 42, 634–652 (2022). https://doi.org/10.1007/s10875-021-01191-4

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