Severe Attenuation of the B Cell Immune Response in Msh2-deficient Mice

Vora, Kalpit A.; Tumas-Brundage, Kathleen M.; Lentz, Vicky M.; Cranston, Aaron; Fishel, Richard; Manser, Tim

doi:10.1084/jem.189.3.471

Cited by 80 publications

(71 citation statements)

References 56 publications

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“…Mismatch-repair proteins have been implicated in Ig hypermutation [49][50][51], but the potential for indirect effects, such as genomic instability and reduced proliferative potential from mismatch repair deficiency [52,53], has obscured their importance in Ig hypermutation. The fact that mismatch-repair-deficient mice display a significant alteration in the Ig mutational pattern (namely a bias for targeting of GC nucleotides) suggests a direct role in Ig hypermutation, because it is difficult to explain how a defect in proliferation would yield an alteration in the pattern of hypermutation.…”

Section: Discussionmentioning

confidence: 99%

Somatic immunoglobulin hypermutation

Diaz

Casali

2002

Current Opinion in Immunology

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Immunoglobulin hypermutation provides the structural correlate for the affinity maturation of the antibody response. Characteristic modalities of this mechanism include a preponderance of pointmutations with prevalence of transitions over transversions, and the mutational hotspot RGYW sequence. Recent evidence suggests a mechanism whereby DNA-breaks induce error-prone DNA synthesis in immunoglobulin V(D)J regions by error-prone DNA polymerases. The nature of the targeting mechanism and the trans-factors effecting such breaks and their repair remain to be determined.

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Section: Discussionmentioning

confidence: 99%

Somatic immunoglobulin hypermutation

Diaz

Casali

2002

Current Opinion in Immunology

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“…with NP 15 -CGG precipitated in alum and boosted at day 30 postimmunization as previously described (24). Blood samples were collected at day 21 (preimmune), day 11 postimmunization (primary response), and day 37 (secondary response).…”

Section: Immunizationsmentioning

confidence: 99%

“…UNG and MSH2/ MSH6 are partially redundant for SHM and CSR, but they are not completely equivalent. In vitro CSR to IgG1 and IgG3 (i.e., measured in purified, cytokine-stimulated naive B cells from mice) is reduced by .10-fold in Ung 2/2 B cells, but only by ∼3-fold in MSH2/MSH6-deficient B cells (9)(10)(11)(12)(13)(14)(15). However, Msh2 2/2 mice produce up to 10-fold less anti-NP IgG1 titers than wild-type (wt) mice after immunization (15,16).…”

mentioning

confidence: 99%

“…In vitro CSR to IgG1 and IgG3 (i.e., measured in purified, cytokine-stimulated naive B cells from mice) is reduced by .10-fold in Ung 2/2 B cells, but only by ∼3-fold in MSH2/MSH6-deficient B cells (9)(10)(11)(12)(13)(14)(15). However, Msh2 2/2 mice produce up to 10-fold less anti-NP IgG1 titers than wild-type (wt) mice after immunization (15,16). Furthermore, Msh2 2/2 and Msh6 2/2 mice show not only severe skewing of the SHM spectrum because of reduced SHM at A:T pairs, but also a change in the distribution of mutations and significant reduction in overall SHM accumulation (11,13,16,17).…”

mentioning

confidence: 99%

“…The defects on Ab diversification displayed by Msh2 2/2 mice are therefore more severe than what could be predicted from the defects measured by in vitro assays. This seems to be related to imbalances in B cell populations (15,16) and impaired germinal center B cell proliferation in vivo (12,15,17), which may be linked to the MSH2/MSH6 functions in cell-cycle regulation (18). Although the analysis of Msh2 2/2 mice highlights the limitations of deducing in vivo phenotypes from in vitro data, the fact that UNG deficiency in vitro has a much greater effect on CSR than MSH2/MSH6 deficiency (9,10) would predict isotype switching to be severely compromised by UNG ablation in vivo.…”

mentioning

confidence: 99%

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Separation of Function between Isotype Switching and Affinity Maturation In Vivo during Acute Immune Responses and Circulating Autoantibodies in UNG-Deficient Mice

Zahn

Daugan

Safavi

et al. 2013

The Journal of Immunology

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Activation-induced deaminase converts deoxycytidine to deoxyuridine at the Ig loci. Complementary pathways, initiated by the uracil-DNA glycosylase (UNG) or the mismatch repair factor MSH2/MSH6, must process the deoxyuridine to initiate class-switch recombination (CSR) and somatic hypermutation. UNG deficiency most severely reduces CSR efficiency and only modestly affects the somatic hypermutation spectrum in vitro. This would predict isotype-switching deficiency but normal affinity maturation in Ung−/− mice in vivo, but this has not been tested. Moreover, puzzling differences in the amount of circulating Ig between UNG-deficient humans and mice make it unclear to what extent MSH2/MSH6 can complement for UNG in vivo. We find that Ab affinity maturation is indeed unaffected in Ung−/− mice, even allowing IgM responses with higher than normal affinity. Ung−/− mice display normal to only moderately reduced basal levels of most circulating Ig subclasses and gut-associated IgA, which are elicited in response to chronically available environmental Ag. In contrast, their ability to produce switched Ig in response to immunization or vesicular stomatitis virus infection is strongly impaired. Our results uncover a specific need for UNG in CSR for timely and efficient acute Ab responses in vivo. Furthermore, Ung−/− mice provide a novel model for separating isotype switching and affinity maturation during acute (but not chronic) Ab responses, which could be useful for dissecting their relative contribution to some infections. Interestingly, Ung−/− mice present with circulating autoantibodies, suggesting that UNG may impinge on tolerance.

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A new murine model of humoral immuno‐deficiency specifically affects class switching to T‐independent antigens

et al. 2004

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Immunoglobulin (Ig) isotype deficiencies are among the most common and least characterized humoral immunodeficiencies. A thorough understanding of their immunological and genetic features has been hampered by their extreme heterogeneity and the paucity of suitable animal models. Here, we report the initial characterization of a new mouse model with selective Ig deficiency. SENCARA mice display low serum IgG3 levels as well as severely deficient IgG3 responses to T cell-independent (TI) type 1 and 2 antigens. However, despite the significant block in class switching, expression of activation-induced deaminase and + 3 germ-line transcription after TI antigen immunization are normal. IgG3 production in response to in vitro LPS stimulation was also normal, ruling out a specific defect in the C + 3 switch machinery. A decrease in the number of peritoneal B1a cells and enlarged splenic marginal zones were observed. The immunodeficiency is inherited as an autosomal, semidominant, essentially monogenic trait in SENCARA × C57BL/6 crosses. The SENCARA humoral immunodeficiency constitutes a novel immune phenotype, resembling human conditions such as IgG2 deficiency. This new mouse model will be of interest for the understanding of mechanisms involved in TI immune responses and may provide new insights into the molecular basis of human Ig deficiencies.

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Severe Attenuation of the B Cell Immune Response in Msh2-deficient Mice

Cited by 80 publications

References 56 publications

Somatic immunoglobulin hypermutation

Somatic immunoglobulin hypermutation

Separation of Function between Isotype Switching and Affinity Maturation In Vivo during Acute Immune Responses and Circulating Autoantibodies in UNG-Deficient Mice

A new murine model of humoral immuno‐deficiency specifically affects class switching to T‐independent antigens

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