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Severe attenuation of the B cell immune response in Msh2-deficient mice.

Vora KA, Tumas-Brundage KM, Lentz VM, Cranston A, Fishel R, Manser T - J. Exp. Med. (1999)

Bottom Line: Recently, results obtained from mice with targeted inactivations of postreplication DNA mismatch repair (MMR) genes have been interpreted to demonstrate a direct role for MMR in antibody variable (V) gene hypermutation.These include lack of progression of the germinal center (GC) reaction associated with increased intra-GC apoptosis, severely diminished antigen-specific immunoglobulin G responses, and near absence of anamnestic responses.Interpretation of the impact of an MMR deficiency on the mechanism of V gene somatic hypermutation could be easily confounded by these perturbations.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology and The Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.

ABSTRACT
Recently, results obtained from mice with targeted inactivations of postreplication DNA mismatch repair (MMR) genes have been interpreted to demonstrate a direct role for MMR in antibody variable (V) gene hypermutation. Here we show that mice that do not express the MMR factor Msh2 have wide-ranging defects in antigen-driven B cell responses. These include lack of progression of the germinal center (GC) reaction associated with increased intra-GC apoptosis, severely diminished antigen-specific immunoglobulin G responses, and near absence of anamnestic responses. Mice heterozygous for the Msh2 deficiency display an "intermediate" phenotype in these regards, suggesting that normal levels of Msh2 expression are critical for the B cell response. Interpretation of the impact of an MMR deficiency on the mechanism of V gene somatic hypermutation could be easily confounded by these perturbations.

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In vitro proliferative responses of Msh2-deficient T cells. Total lymph node cells were stimulated with either 4 μg/ml Con A or irradiated  spleen cells from BALB.K mice (allo-MHC) for 48 h, as described in Materials and Methods, and pulsed with [3H]thymidine to measure proliferation.  Plate-bound anti-CD3 stimulation was also performed in this fashion (see Materials and Methods), but using splenic T cells enriched as described. The  cells used for each experiment were derived from at least two mice of each genotype.
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Figure 5: In vitro proliferative responses of Msh2-deficient T cells. Total lymph node cells were stimulated with either 4 μg/ml Con A or irradiated spleen cells from BALB.K mice (allo-MHC) for 48 h, as described in Materials and Methods, and pulsed with [3H]thymidine to measure proliferation. Plate-bound anti-CD3 stimulation was also performed in this fashion (see Materials and Methods), but using splenic T cells enriched as described. The cells used for each experiment were derived from at least two mice of each genotype.

Mentions: To assess generic T cell activation and proliferation function, in vitro stimulations of lymph node and splenic T cells were performed. No significant differences in anti-CD3–, Con A–, or alloantigen-induced proliferative responses were observed among Msh2 +/+, +/−, or −/− T cells (Fig. 5). In addition, KLH-primed lymph node T cells obtained from Msh2-deficient mice proliferated in response to restimulation with KLH in vitro to an extent that did not differ reproducibly from wild-type cells (data not shown).


Severe attenuation of the B cell immune response in Msh2-deficient mice.

Vora KA, Tumas-Brundage KM, Lentz VM, Cranston A, Fishel R, Manser T - J. Exp. Med. (1999)

In vitro proliferative responses of Msh2-deficient T cells. Total lymph node cells were stimulated with either 4 μg/ml Con A or irradiated  spleen cells from BALB.K mice (allo-MHC) for 48 h, as described in Materials and Methods, and pulsed with [3H]thymidine to measure proliferation.  Plate-bound anti-CD3 stimulation was also performed in this fashion (see Materials and Methods), but using splenic T cells enriched as described. The  cells used for each experiment were derived from at least two mice of each genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2192912&req=5

Figure 5: In vitro proliferative responses of Msh2-deficient T cells. Total lymph node cells were stimulated with either 4 μg/ml Con A or irradiated spleen cells from BALB.K mice (allo-MHC) for 48 h, as described in Materials and Methods, and pulsed with [3H]thymidine to measure proliferation. Plate-bound anti-CD3 stimulation was also performed in this fashion (see Materials and Methods), but using splenic T cells enriched as described. The cells used for each experiment were derived from at least two mice of each genotype.
Mentions: To assess generic T cell activation and proliferation function, in vitro stimulations of lymph node and splenic T cells were performed. No significant differences in anti-CD3–, Con A–, or alloantigen-induced proliferative responses were observed among Msh2 +/+, +/−, or −/− T cells (Fig. 5). In addition, KLH-primed lymph node T cells obtained from Msh2-deficient mice proliferated in response to restimulation with KLH in vitro to an extent that did not differ reproducibly from wild-type cells (data not shown).

Bottom Line: Recently, results obtained from mice with targeted inactivations of postreplication DNA mismatch repair (MMR) genes have been interpreted to demonstrate a direct role for MMR in antibody variable (V) gene hypermutation.These include lack of progression of the germinal center (GC) reaction associated with increased intra-GC apoptosis, severely diminished antigen-specific immunoglobulin G responses, and near absence of anamnestic responses.Interpretation of the impact of an MMR deficiency on the mechanism of V gene somatic hypermutation could be easily confounded by these perturbations.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology and The Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.

ABSTRACT
Recently, results obtained from mice with targeted inactivations of postreplication DNA mismatch repair (MMR) genes have been interpreted to demonstrate a direct role for MMR in antibody variable (V) gene hypermutation. Here we show that mice that do not express the MMR factor Msh2 have wide-ranging defects in antigen-driven B cell responses. These include lack of progression of the germinal center (GC) reaction associated with increased intra-GC apoptosis, severely diminished antigen-specific immunoglobulin G responses, and near absence of anamnestic responses. Mice heterozygous for the Msh2 deficiency display an "intermediate" phenotype in these regards, suggesting that normal levels of Msh2 expression are critical for the B cell response. Interpretation of the impact of an MMR deficiency on the mechanism of V gene somatic hypermutation could be easily confounded by these perturbations.

Show MeSH
Related in: MedlinePlus