title: B-cell memory and primary immune deficiencies: interleukin-21 related defects.
abstract: OBJECTIVE
  The purpose of this study is to describe recent advances in our understanding of the role of interleukin-21 (IL-21) in B-cell maturation, and how defects in IL-21 receptor (IL-21R) signalling pathways (IL-21R/γc/JAK3/STAT3) are related to primary immune deficiencies.
  
  
  RESULTS
  Abnormal signalling through IL-21R/γc/JAK3/STAT3 pathway has been related to decreased specific antibody responses following vaccination, and to increased susceptibility to encapsulated bacterial infections. This is manifested in the hyper-IgE syndrome, X-linked and JAK3-related severe combined immunodeficiency (SCID) and loss-of-function mutations in the IL-21R gene. Common variable immunodeficiency is associated with impaired in-vitro development of peripheral blood mononuclear cells or purified B-cells into memory or CD38 B-cells following addition of IL-21.
  
  
  CONCLUSIONS
  IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting cells. Abnormal signalling through the IL-21R/γc/JAK3/STAT3 pathway leads to defective humoral immune responses to both T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell memory. Studies involving patients with hyper-IgE syndrome demonstrated the nonredundant role of STAT3 in B-cell production of high-affinity specific antibodies, while total serum immunoglobulins could be maintained through STAT3-independent activation of AID (activation-induced cytidine-deaminase). IL-21 related defects may also be associated with reduced natural killer (NK)-cell cytotoxicity and TH17 cytokine production, indicating that abnormalities in the IL-21-IL-21R pathway have profound effects on crucial immune responses.
authors.affiliation: aDivision of Pediatric Allergy and Clinical Immunology, Department of Pediatrics bMeakins-Christie Laboratories, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Marylin
authors.initials: M
authors.lastname: Desjardins
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Mazer
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000276:immunology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007156:Immunologic Memory / Q000235:genetics*; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D053616:Janus Kinase 3 / Q000235:genetics / Q000276:immunology; D007589:Job Syndrome / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics*; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D000098546:Interleukin-21; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C508117:IL21R protein, human; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507933:JAK3 protein, human; D053616:Janus Kinase 3; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D000098546:Interleukin-21