B-cell memory and primary immune deficiencies: interleukin-21 related defectsDesjardins, Marylin; Mazer, Bruce D.Current Opinion in Allergy and Clinical Immunology: December 2013 - Volume 13 - Issue 6 - p 639–645 doi: 10.1097/ACI.0000000000000009 PRIMARY IMMUNE DEFICIENCY DISEASE: Edited by Ramsay L. Fuleihan and Bruce D. Mazer Abstract Author Information Purpose of review 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. Recent findings 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. Summary 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. aDivision of Pediatric Allergy and Clinical Immunology, Department of Pediatrics bMeakins-Christie Laboratories, McGill University Health Centre, Montreal, Quebec, Canada Correspondence to Bruce D. Mazer, Meakins Christie Laboratories, McGill University Health Center Research Istitute, 3626 St. Urbain, Montreal, QC H2X 2P2, Canada. Tel: +1 514 398 3664; fax: +1 514 398 7483; e-mail: firstname.lastname@example.org Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.