The B cell SH2/PH domain-containing adaptor Bam32/DAPP1 is required for T cell-independent II antigen responses.
BACKGROUND
Bam32/DAPP1 is a B cell adaptor composed of both a PH and an SH2 domain. Previous studies in cell culture and chicken DT40 cells have indicated that Bam32 is critical for normal signaling downstream of the B cell receptor (BCR).


RESULTS
We now study the function of Bam32 in mice in which Bam32 has been disrupted by a viral gene trap approach. Although B and T cell development is normal in Bam32(-/-) mice, B cell proliferation is reduced by about 50% after BCR crosslinking when compared with Bam32(+/+) mice. Differences in the activation of Erk, Jnk and p38 Map kinases, PLCgamma, and Ca(2+) flux do not account for the defect in proliferation as activation was similar in Bam32(+/+) and Bam32(-/-) B cells. Interestingly, whereas antibody response to T-dependent (TD) and T-independent (TI)-I antigens was similar between Bam32(+/+) and Bam32(-/-) mice, TI-II responses were defective in Bam32(-/-) mice; Bam32(-/-) mice failed to undergo isotype class switch recombination (CSR) to produce IgG3 antibodies due to a cell-autonomous defect in generation of IgG3 germline transcripts. The defect in TI-II antigen response led to an impaired antibody response to immunization with type 3 Streptococcus pneumoniae capsular polyschaccharide (PS), resulting in a markedly increased susceptibility to infection by Streptococcus pneumoniae.


CONCLUSIONS
These findings indicate that Bam32 specifically couples an upstream signal to the IgG3 isotype heavy chain CSR and suggest that defects in Bam32 may account for the increased susceptibility to encapusulated organisms in a subset of immunodeficient patients.
Department of Pharmacology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York 10016, USA.
Emanuel
E
Fournier
Steven J
SJ
Isakoff
Kyung
K
Ko
Christopher J
CJ
Cardinale
Giorgio G
GG
Inghirami
Zhai
Z
Li
Maria A
MA
Curotto de Lafaille
Edward Y
EY
Skolnik
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000917:Antibody Formation; D000955:Antigens, T-Independent / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D008074:Lipoproteins / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D015336:Molecular Probe Techniques; D011233:Precipitin Tests; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018909:src Homology Domains / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000955:Antigens, T-Independent; D002352:Carrier Proteins; C403524:Dapp1 protein, mouse; D007074:Immunoglobulin G; D008074:Lipoproteins; D008565:Membrane Proteins; D011947:Receptors, Antigen, B-Cell