CD20 deficiency in humans results in impaired T cell–independent antibody responses
Taco W. Kuijpers, … , Eric Eldering, René A.W. van Lier
Taco W. Kuijpers, … , Eric Eldering, René A.W. van Lier
Published December 21, 2009
Citation Information: J Clin Invest. 2010;120(1):214-222. https://doi.org/10.1172/JCI40231.
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Research Article Immunology

CD20 deficiency in humans results in impaired T cell–independent antibody responses

Abstract

CD20 was the first B cell differentiation antigen identified, and CD20-specific mAbs are commonly used for the treatment of B cell malignancies and autoantibody-mediated autoimmune diseases. Despite this the role of CD20 in human B cell physiology has remained elusive. We describe here a juvenile patient with CD20 deficiency due to a homozygous mutation in a splice junction of the CD20 gene (also known as MS4A1) that results in “cryptic” splicing and nonfunctional mRNA species. Analysis of this patient has led us to conclude that CD20 has a central role in the generation of T cell–independent (TI) antibody responses. Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient. Consistent with this, TI antipolysaccharide B cell responses were severely impeded in CD20-deficient mice. Our study therefore identifies what we believe to be a novel type of humoral immunodeficiency caused by CD20 deficiency and characterized by normal development of antigen-independent B cells, along with a reduced capacity to mount proper antibody responses.

Authors

Taco W. Kuijpers, Richard J. Bende, Paul A. Baars, Annette Grummels, Ingrid A.M. Derks, Koert M. Dolman, Tim Beaumont, Thomas F. Tedder, Carel J.M. van Noesel, Eric Eldering, René A.W. van Lier

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Figure 2

Analysis of CD20 expression and gene sequences of the patient, parents, and sibling.

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Analysis of CD20 expression and gene sequences of the patient, parents, ...
(A) FACS analysis of CD20 and CD19 expression in indicated PBMC samples of normal controls and family members. MFI of CD20 staining is indicated above the plots. In a cohort of healthy children (age, 3 months to 10 years; n = 30), mean CD20 expression ranged between 874 and 1,230. (B) Agarose gel analysis of CD20 cDNA fragments of the patient, family members, and a control, revealing aberrant mRNA species in the patient and her parents. Cloning and sequencing of the cDNA fragments showed that the smallest fragment contains a complete deletion of exon 5 (not shown). The 3 fragments with increased MW contained variable parts of intron 5 sequence (see below in C). (C) CD20 gene sequences surrounding the exon 5/intron 5 boundary, as determined from cDNA and genomic fragments. The 11–base pair insertion at the noncanonical splice site is underlined in the mutated genomic sequence. The CD20 intron/exon structure is indicated on top, and the normal and aberrant sequences found in the patient cDNA clones are depicted below. The noncanonical GC splice donor site at intron 5 and the cryptic splice sites used as a result of the mutation are boxed. (D) Family pedigree indicating consanguinity of the parents. Normal and aberrant CD20 alleles are indicated by white and black, respectively.