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Previous Volume 354:1901-1912 May 4, 2006 Number 18 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Perspective by Rudd, C. E. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background The CD19 protein forms a complex with CD21, CD81, and CD225 in the membrane of mature B cells. Together with the B-cell antigen receptor, this complex signals the B cell to decrease its threshold for activation by the antigen.

Methods We evaluated four patients from two unrelated families who had increased susceptibility to infection, hypogammaglobulinemia, and normal numbers of mature B cells in blood. We found a mutation in the CD19 gene in all four patients. The CD19 gene in the patients and their first-degree relatives was sequenced, and flow-cytometric immunophenotyping of B cells, immunohistochemical staining of lymphoid tissues, and DNA and messenger RNA analysis were performed. B-cell responses on the triggering of the B-cell receptor were investigated by in vitro stimulation; the antibody response after vaccination with rabies vaccine was also studied.

Results All four patients had homozygous mutations in the CD19 gene. Levels of CD19 were undetectable in one patient and substantially decreased in the other three. Levels of CD21 were decreased, whereas levels of CD81 and CD225 were normal, in all four patients. The composition of the precursor B-cell compartment in bone marrow and the total numbers of B cells in blood were normal. However, the numbers of CD27+ memory B cells and CD5+ B cells were decreased. Secondary follicles in lymphoid tissues were small to normal in size and had a normal cellular composition. The few B cells that showed molecular signs of switching from one immunoglobulin class to another contained V_H-C and V_H-C transcripts with somatic mutations. The response of the patients' B cells to in vitro stimulation through the B-cell receptor was impaired, and in all four patients, the antibody response to rabies vaccination was poor.

Conclusions Mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective.

Source Information

From the Department of Immunology, Erasmus MC (M.C.Z., M.B., J.J.M.D.), and the Department of Pediatrics, Erasmus MC–Sophia (M.C.Z.), Rotterdam, the Netherlands; the Department of Pediatric Immunology and Allergy, Meram Medical Faculty, Selçuk University, Konya, Turkey (I.R.); the Group of Primary Immunodeficiencies, University of Antioquia, Medellín, Colombia (D.C., P.J.P., J.L.F.); the Department of Pathology, Academic Medical Center, Amsterdam (C.J.M.N.); the Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands (M.J.D.T.); and the Division of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany (C.W., B.G.).

Mr. van Zelm, Dr. Reisli, Dr. van der Burg, and Ms. Castaño contributed equally to the article.

Address reprint requests to Dr. van Dongen at the Department of Immunology, Molecular Immunology Unit, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands, or at j.j.m.vandongen{at}erasmusmc.nl.

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