Genetic CD21 deficiency is associated with hypogammaglobulinemia.
BACKGROUND
Complement receptor 2 (CR2/CD21) is part of the B-cell coreceptor and expressed by mature B cells and follicular dendritic cells. CD21 is a receptor for C3d-opsonized immune complexes and enhances antigen-specific B-cell responses.


OBJECTIVE
Genetic inactivation of the murine CR2 locus results in impaired humoral immune responses. Here we report the first case of a genetic CD21 deficiency in human subjects.


METHODS
CD21 protein expression was analyzed by means of flow cytometry and Western blotting. CD21 transcripts were quantified by using real-time PCR. The CD21 gene was sequenced. Wild-type and mutant CD21 cDNA expression was studied after transfection of 293T cells. Binding of EBV-gp350 or C3d-containing immune complexes and induction of calcium flux in CD21-deficient B cells were analyzed by means of flow cytometry. Antibody responses to protein and polysaccharide vaccines were measured.


RESULTS
A 28-year-old man presented with recurrent infections, reduced class-switched memory B cells, and hypogammaglobulinemia. CD21 receptor expression was undetectable. Binding of C3d-containing immune complexes and EBV-gp350 to B cells was severely reduced. Sequence analysis revealed a compound heterozygous deleterious mutation in the CD21 gene. Functional studies with anti-immunoglobulin- and C3d-containing immune complexes showed a complete loss of costimulatory activity of C3d in enhancing suboptimal B-cell receptor stimulation. Vaccination responses to protein antigens were normal, but the response to pneumococcal polysaccharide vaccination was moderately impaired.


CONCLUSIONS
Genetic CD21 deficiency adds to the molecular defects observed in human subjects with hypogammaglobulinemia.
Department of Rheumatology and Clinical Immunology, University Hospital Freiburg, Freiburg, Germany. jens.thiel@uniklinik-freiburg.de
Jens
J
Thiel
Lucas
L
Kimmig
Ulrich
U
Salzer
Magdalena
M
Grudzien
Dirk
D
Lebrecht
Tina
T
Hagena
Ruth
R
Draeger
Nadine
N
Voelxen
Nadine
N
Völxen
Astrid
A
Bergbreiter
Stephanie
S
Jennings
Sylvia
S
Gutenberger
Annette
A
Aichem
Harald
H
Illges
Jonathan P
JP
Hannan
Anne-Kathrin
AK
Kienzler
Marta
M
Rizzi
Hermann
H
Eibel
Hans-Hartmut
HH
Peter
Klaus
K
Warnatz
Bodo
B
Grimbacher
Jörg-Andres
JA
Rump
Michael
M
Schlesier
D000328:Adult; D000361:Agammaglobulinemia / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling / Q000235:genetics; D015933:Complement C3d / Q000378:metabolism; D004252:DNA Mutational Analysis; D057809:HEK293 Cells; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D007239:Infections / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D008297:Male; D011485:Protein Binding / Q000235:genetics; D017464:Receptors, Complement 3d / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D014763:Viral Matrix Proteins / Q000378:metabolism
D000936:Antigen-Antibody Complex; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D017464:Receptors, Complement 3d; D014763:Viral Matrix Proteins; D015933:Complement C3d