Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells

doi:10.1073/pnas.0901984106

Circulating CD21^low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells

^aCentre of Chronic Immunodeficiency and
^bDivision of Rheumatology and Clinical Immunology, University Medical Center Freiburg, 79106 Freiburg, Germany;
^cChildren's Hospital, University Hospital Ulm, 89075 Ulm, Germany;
^dDepartment of Immunology, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands;
^eInstitute for Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany;
^fDepartment of Clinical Immunology, University of Rome La Sapienza, 00185 Rome, Italy;
^gDepartment of Pneumology, University Medical Center Freiburg, 79106 Freiburg, Germany; and
^hInstitute for Transfusion Medicine, University of Ulm and Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, 89081 Ulm, Germany

Edited by Dennis A. Carson, University of California at San Diego School of Medicine, La Jolla, CA, and approved June 23, 2009
↵¹B.K. and S.G. contributed equally to this work. (received for review February 24, 2009)

Abstract

The homeostasis of circulating B cell subsets in the peripheral blood of healthy adults is well regulated, but in disease it can be severely disturbed. Thus, a subgroup of patients with common variable immunodeficiency (CVID) presents with an extraordinary expansion of an unusual B cell population characterized by the low expression of CD21. CD21^low B cells are polyclonal, unmutated IgM⁺IgD⁺ B cells but carry a highly distinct gene expression profile which differs from conventional naïve B cells. Interestingly, while clearly not representing a memory population, they do share several features with the recently defined memory-like tissue, Fc receptor-like 4 positive B cell population in the tonsils of healthy donors. CD21^low B cells show signs of previous activation and proliferation in vivo, while exhibiting defective calcium signaling and poor proliferation in response to B cell receptor stimulation. CD21^low B cells express decreased amounts of homeostatic but increased levels of inflammatory chemokine receptors. This might explain their preferential homing to peripheral tissues like the bronchoalveolar space of CVID or the synovium of rheumatoid arthritis patients. Therefore, as a result of the close resemblance to the gene expression profile, phenotype, function and preferential tissue homing of murine B1 B cells, we suggest that CD21^low B cells represent a human innate-like B cell population.

Footnotes

²To whom correspondence should be addressed. E-mail: klaus.warnatz{at}uniklinik-freiburg.de
Edited by Dennis A. Carson, University of California at San Diego School of Medicine, La Jolla, CA, and approved June 23, 2009
Author contributions: H.-H.P. and K.W. designed research; M.R., B.K., S. Gutenberger, C.F., M.H., G.D., M.v.d.B., E.W., M.V., N.V., and U.S. performed research; M.R., J.J.v.D., I.Q., A.P., U.S., S. Goldacker, P.F., H.E., K.S., and K.W. analyzed data; and M.R. and K.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE17269).
This article contains supporting information online at www.pnas.org/cgi/content/full/0901984106/DCSupplemental.