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Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2.

Front Immunol. 2019 Mar 19;10:297. doi:10.3389/fimmu.2019.00297. eCollection 2019
Christian Klemann 1 , Nadezhda Camacho-Ordonez 2 , Linlin Yang 1 , Zoya Eskandarian 1 , Jessica L Rojas-Restrepo 1 , Natalie Frede 1 , Alla Bulashevska 1 , Maximilian Heeg 3 , Moudjahed Saleh Al-Ddafari 4 , Julian Premm 1 , Maximilian Seidl 5 , Sandra Ammann 6 , Roya Sherkat 7 , Nita Radhakrishnan 8 , Klaus Warnatz 9 , Susanne Unger 9 , Robin Kobbe 10 , Anja Hüfner 11 , T Ronan Leahy 12 , Winnie Ip 13 , Siobhan O Burns 14 , Manfred Fliegauf 15 , Bodo Grimbacher 15
Christian Klemann 1 , Nadezhda Camacho-Ordonez 2 , Linlin Yang 1 , Zoya Eskandarian 1 , Jessica L Rojas-Restrepo 1 , Natalie Frede 1 , Alla Bulashevska 1 , Maximilian Heeg 3 , Moudjahed Saleh Al-Ddafari 4 , Julian Premm 1 , Maximilian Seidl 5 , Sandra Ammann 6 , Roya Sherkat 7 , Nita Radhakrishnan 8 , Klaus Warnatz 9 , Susanne Unger 9 , Robin Kobbe 10 , Anja Hüfner 11 , T Ronan Leahy 12 , Winnie Ip 13 , Siobhan O Burns 14 , Manfred Fliegauf 15 , Bodo Grimbacher 15
+ et al

[No authors listed]

Author information
  • 1 Faculty of Medicine, Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Freiburg, Germany.
  • 2 Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 3 Faculty of Medicine, Center for Pediatrics, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany.
  • 4 Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Tlemcen, Algeria.
  • 5 Faculty of Medicine, Institute for Surgical Pathology, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany.
  • 6 Cambridge Institute for Medical Research, Cambridge, United Kingdom.
  • 7 Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
  • 8 Department of Pediatric Hematology Oncology, Super Speciality Pediatric Hospital and PG Teaching Institute, Noida, India.
  • 9 Faculty of Medicine, Division Immunodeficiency (CCI), Department of Rheumatology and Clinical Immunology, Medical Center, University of Freiburg, Freiburg, Germany.
  • 10 Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 11 Infectious Disease Unit, Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 12 Department of Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
  • 13 Department of Immunology, Great Ormond Street Hospital, London, United Kingdom.
  • 14 Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom.
  • 15 CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.

摘要

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency.

KEYWORDS: ACTH-deficiency, CID, CVID, DAVID-syndrome, NF-kappaB signaling, NF-kappaB2 clinical cases, autoimmunity, deficiency of anterior pituitary function and variable immunodeficiency

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