title: The effects of RelB deficiency on lymphocyte development and function.
abstract: Multiple receptors that control cell growth and inflammation activate the NFκB pathway that comprises of two pathways. Dysfunction of the classical pathway leads to impaired adaptive and innate immunity in humans. In contrast the exact role of the alternative NFκB pathway mediated by RelB in humans remains largely elusive. We have recently identified deleterious mutations in RelB in patients with combined immunodeficiency and autoimmunity. We studied here the biological effects of RelB deficiency on the immune system. We show that the thymus in this patient is dysplastic and consequently new thymus emigrants are rare and there is an accumulation of CD45 RO(+) T cells with an increase in CD62L(+) central memory cells. The TCR repertoire of these cells appears skewed with selective clonal expansion. In vitro responses to T cell mitogens were markedly depressed and so were PHA induced IL2 and IFNγ production. In addition, the TH1 promoting T bet and STAT1 were reduced. In contrast, hyper-activation was seen in response to anti-CD3 and CD28. T cell dependent antibody responses were low to absent in all patients. We found that BAFF-R was reduced and CD40 signaling aberrant. Critically, CD27(+) memory cells were absent. We have shown here for the first time the role of RelB on lymphocyte development in humans. In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies. T cell maturation in the thymus appears altered with reduced output and production of a skewed T cell repertoire with expansion of clones which are likely the cause of the autoimmune features observed in these patients.
authors.affiliation: The Canadian Centre for Primary Immunodeficiency, Immunogenomic Laboratory, Division of Immunology/Allergy, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, 555 University Ave., Toronto, On M5G 1X8, Canada.
authors.forename: Nigel
authors.initials: N
authors.lastname: Sharfe
authors.affiliation: Centre for Applied Genomics, The Hospital for Sick Children and the University of Toronto, 555 University Ave., Toronto, On M5G 1X8, Canada.
authors.forename: Daniele
authors.initials: D
authors.lastname: Merico
authors.affiliation: The Canadian Centre for Primary Immunodeficiency, Immunogenomic Laboratory, Division of Immunology/Allergy, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, 555 University Ave., Toronto, On M5G 1X8, Canada.
authors.forename: Ariana
authors.initials: A
authors.lastname: Karanxha
authors.affiliation: The Canadian Centre for Primary Immunodeficiency, Immunogenomic Laboratory, Division of Immunology/Allergy, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, 555 University Ave., Toronto, On M5G 1X8, Canada.
authors.forename: Carly
authors.initials: C
authors.lastname: Macdonald
authors.affiliation: The Canadian Centre for Primary Immunodeficiency, Immunogenomic Laboratory, Division of Immunology/Allergy, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, 555 University Ave., Toronto, On M5G 1X8, Canada.
authors.forename: Harjit
authors.initials: H
authors.lastname: Dadi
authors.affiliation: Division of Pathology, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children and the University of Toronto, 555 University Ave., Toronto, On M5G 1X8, Canada.
authors.forename: Bo
authors.initials: B
authors.lastname: Ngan
authors.affiliation: Centre for Applied Genomics, The Hospital for Sick Children and the University of Toronto, 555 University Ave., Toronto, On M5G 1X8, Canada.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Herbrick
authors.affiliation: The Canadian Centre for Primary Immunodeficiency, Immunogenomic Laboratory, Division of Immunology/Allergy, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, 555 University Ave., Toronto, On M5G 1X8, Canada. Electronic address: chaim.roifman@sickkids.ca.
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
mesh_terms: D015551:Autoimmunity; D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007376:Interleukin-2 / Q000276:immunology; D008297:Male; D052002:NF-kappa B p50 Subunit / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013950:Thymus Gland / Q000002:abnormalities* / Q000276:immunology / Q000473:pathology; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology*
chemical_list: D007376:Interleukin-2; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C497593:RELB protein, human; D051841:Transcription Factor RelB
keywords: Autoimmunity; Lymphocyte; NFκB; RelB; Rheumatoid arthritis