For this study, researchers wanted to discuss recent improvements in the knowledge of the function of interleukin-21 (IL-21) in B-cell maturation, as well as how abnormalities in IL-21R signaling pathways (IL-21R/c/JAK3/STAT3) are linked to primary immunological deficiencies. Reduced specific antibody responses following vaccination and higher susceptibility to encapsulated bacterial infections were linked to abnormal signaling through the IL-21R/c/JAK3/STAT3 pathway. Hyper-IgE syndrome, X-linked and JAK3-related severe combined immunodeficiency (SCID), and loss-of-function mutations in the IL-21R gene were all examples of this. Following the addition of IL-21, poor in-vitro growth of peripheral blood mononuclear cells or purified B-cells into memory or CD38+ B-cells was linked to common variable immunodeficiency. 

IL-21 was an important cytokine for B-cell maturation into immunoglobulin-secreting cells. Defective humoral immune responses to both T-dependent and T-independent antigens were caused by abnormal signaling through the IL-21R/c/JAK3/STAT3 pathway, which also hindered the development of long-lasting B-cell memory. The nonredundant involvement of STAT3 in B-cell synthesis of high-affinity specific antibodies was established in studies involving individuals with hyper-IgE syndrome, although total serum immunoglobulins may be maintained by STAT3-independent activation of AID (activation-induced cytidine deaminase). Reduced natural killer (NK)-cell cytotoxicity and TH17 cytokine production may be linked to IL-21-IL-21R pathway deficiencies, suggesting that anomalies in the IL-21-IL-21R pathway have a significant impact on critical immune responses.