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Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency

Kotlarz, Daniela; Ziętara, Nataliab; Milner, Joshua D.c; Klein, Christopha

doi: 10.1097/MOP.0000000000000160

Purpose of review This review highlights the recent identification of human interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) deficiencies as novel entities of primary immunodeficiency.

Recent findings We recently described the first patients with IL-21R deficiency who had cryptosporidial infections associated with chronic cholangitis and liver disease. All IL-21R-deficient patients suffered from recurrent respiratory tract infections. Immunological work-up revealed impaired B cell proliferation and immunoglobulin class-switch, reduced T cell effector functions, and variable natural killer cell dysfunctions. Recently, these findings have been extended by the discovery of one patient with a mutation in the IL21 gene. This patient predominantly manifested with very early onset inflammatory bowel disease and recurrent respiratory infections. Laboratory examination showed reduced circulating B cells and impaired B cell class-switch.

Summary Human IL-21 and IL-21R deficiencies cause severe, primary immunodeficiency reminiscent of common variable immunodeficiency. Early diagnosis is critical to prevent life-threatening complications, such as secondary liver failure. In view of the critical role of IL-21 in controlling immune homeostasis, early hematopoietic stem cell transplantation might be considered as therapeutic intervention in affected children.

aDepartment of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich

bInstitute of Immunology, Hannover Medical School, Hannover, Germany

cLaboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

Correspondence to Christoph Klein, MD, PhD, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Lindwurmstr. 4, D-80337 Munich, Germany. Tel: +49 89 4400 57701; fax: +49 89 4400 57702; e-mail:

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