Abstract
Autosomal dominant gain of function mutations in the gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Here we describe three patients in two families who were diagnosed with HIGM at a young age and were recently found to carry heterozygous mutations in PIK3CD. These patients had an abnormal circulating B cell distribution featuring a preponderance of early transitional (T1) B cells and plasmablasts. When stimulated in vitro, PIK3CD mutated B cells were able to secrete class-switched immunoglobulins. This finding implies that the patients’ elevated serum IgM levels were unlikely a product of an intrinsic B cell functional inability to class switch. All three patients developed malignant lymphoproliferative syndromes that were not associated with EBV. Thus, we identified a novel subset of patients with PIK3CD mutations associated with HIGM, despite indications of preserved in vitro B cell class switch recombination, as well as susceptibility to non-EBV-associated malignancies.
Similar content being viewed by others
Abbreviations
- AID:
-
Activated cytidine deaminase
- AML:
-
Acute myeloid leukemia
- HIGM:
-
Hyper IgM syndrome
- IVIG:
-
Intravenous immunoglobulin
- GC:
-
Germinal center
- MALT:
-
Mucosal associated lymphoid tissue
- PI(3)K:
-
Phosphoinositide 3 kinase
- PIK3CD :
-
Phosphatidylinositol-4,5-Bisphosphonate 3-Kinase, Catalytic subunit delta
- R-CHOP:
-
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Vrednisone
- UNG:
-
uracyl-N-glycosylase
References
Davies EG, Thrasher AJ. Update on the hyper immunoglobulin M syndromes. Br J Haematol. 2010;149(2):167–80.
Notarangelo LD, Duse M, Ugazio AG. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3(2):101–21.
Angulo I, Vadas O, Garcon F, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.
Lucas CL, Kuehn HS, Zhao F, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2013;15(1):88–97.
Kotlarz D, Zietara N, Uzel G, et al. Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J Exp Med. 2013;210(3):433–43.
Zhong M, Bian Z, Wu Z. miR-30a suppresses cell migration and invasion through downregulation of PIK3CD in colorectal carcinoma. Cell Physiol Biochem. 2013;31(2–3):209–18.
Zhang J, Grubor V, Love CL, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110(4):1398–403.
Xing Y, Hogge DE. Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110delta subunit and mitogen-extracellular activated protein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors. Leuk Res. 2013;37(6):697–704.
Zlotogora J. Germ line mosaicism. Hum Genet. 1998;102(4):381–6.
Moir S, Fauci AS. Insights into B cells and HIV-specific B-cell responses in HIV-infected individuals. Immunol Rev. 2013;254(1):207–24.
Acknowledgments
This research was supported by the Intramural Research Program of the NIH. The content of this publication does not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Author information
Authors and Affiliations
Corresponding author
Additional information
M. C. Crank and J. K. Grossman contributed equally to this work.
Rights and permissions
About this article
Cite this article
Crank, M.C., Grossman, J.K., Moir, S. et al. Mutations in PIK3CD Can Cause Hyper IgM Syndrome (HIGM) Associated with Increased Cancer Susceptibility. J Clin Immunol 34, 272–276 (2014). https://doi.org/10.1007/s10875-014-0012-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-014-0012-9