Cutting Edge: Selection of B Lymphocyte Subsets Is Regulated by Natural IgM

Baker, Nicole; Ehrenstein, Michael R.

doi:10.4049/jimmunol.169.12.6686

Cited by 62 publications

(49 citation statements)

References 23 publications

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“…It has been proposed that the suppressed generation and diversification of B cells may lead to the expansion of long-lived B cell, including B-1 and MZ B cells, which contribute to maintain the production of natural Abs in a homeostatic manner (2,5,6). In addition, mice lacking serum IgM have been reported to show a MZ expansion, which was reversed by the administration of polyclonal IgM, but not of a mAb (51). However, although the B cell diversity in the spleen and LN of QM mice is contracted to two major populations (Fig.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Marginal Zone B Cell Development in the Mouse with Limited B Cell Diversity: Role of the Antigen Receptor Signals in the Recruitment of B Cells to the Marginal Zone

Kanayama

Cascalho

Ohmori

2005

The Journal of Immunology

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The quasimonoclonal (QM) mouse provides an intelligible model to analyze the B cell selection as the competition between two major 4-hydroxy-3-nitrophenylacetyl-specific B cell populations whose BCR are comprised of the knockin VH17.2.25 (VHT)-encoded H chain and the λ1 or λ2 L chain. In this study, we show the QM system is useful to examine how BCR signals guide a subset of B cells to the marginal zone (MZ). Compared with the control C57BL/6 mice, the QM mice had ∼2.7-fold increased number of B cells exhibiting the MZ B cell phenotype and a larger MZ area in the spleen. Interestingly, VHT/λ2 B cells significantly predominated over VHT/λ1 B cells in MZ-(VHT/λ1:VHT/λ2 ≈ 3:7) and transitional 2-B cell subsets, while these two populations were comparable in immature, transitional 1, and mature counterparts. Thus, the biased use of λ2 in the MZ B cells may be the result of selection in the periphery. The enlargement of MZ B cell compartment and the preferred recruitment of the VHT/λ2 B cells were further augmented by doubling the VHT gene, but dampened by the dysfunction of Bruton’s tyrosine kinase, suggesting a positive role of BCR signaling in this selection. Comparison of Ag specificity between VHT/λ1 and VHT/λ2 IgM mAbs revealed a polyreactive nature of the VHT/λ2 BCR, including the reactivity with ssDNA. Taken together, it is suggested that polyreactivity (including self-reactivity) of BCR is crucial in driving B cells to differentiate into the MZ phenotype.

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Section: Discussionmentioning

confidence: 99%

Analysis of Marginal Zone B Cell Development in the Mouse with Limited B Cell Diversity: Role of the Antigen Receptor Signals in the Recruitment of B Cells to the Marginal Zone

Kanayama

Cascalho

Ohmori

2005

The Journal of Immunology

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“…For example, the role of IgM might be linked to its binding to a putative Fc receptor (47)(48)(49) or perhaps attributable to simple aggregation of the Ag, thereby making it more immunogenic. Moreover, mice lacking secretory IgM have developmental defects in their B-cell compartment secondary to the lack of secretory IgM, and it is conceivable that this explains their impaired Ab responses (37,50).…”

Section: Discussionmentioning

confidence: 99%

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Rutemark

Alicot

Bergman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen–Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cμ13, with a point mutation in the gene encoding the third constant domain of the μ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cμ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.

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“…IgM antibodies are involved in numerous immunological functions including protection against infection, 1-3 prevention of autoimmunity, 4,5 B-cell homeostasis [6][7][8] and immunosurveillance against tumors. 9,10 IgM biological roles also include opsonization of apoptotic cells, resulting in accelerated clearance by phagocytic cells.…”

Section: Introductionmentioning

confidence: 99%

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

et al. 2008

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Natural IgM are involved in numerous immunological functions but the genetic factors that control the homeostasis of its secretion and upholding remain unknown. Prompted by the finding that C57BL/6 mice had significantly lower serum levels of IgM when compared with BALB/c mice, we performed a genome-wide screen and found that the level of serum IgM was controlled by a QTL on chromosome 13 reaching the highest level of association at marker D13Mit266 (LOD score¼3.54). This locus was named IgMSC1 and covered a region encompassing the interferon-regulatory factor 4 gene (Irf4). The number of splenic mature B cells in C57BL/6 did not differ from BALB/c mice but we found that low serum levels of IgM in C57BL/6 mice correlated with lower frequency of IgM-secreting cells in the spleen and in the peritoneal cavity. These results suggested that C57BL/6 mice have lower efficiency in late B-cell maturation, a process that is highly impaired in Irf4 knockout mice. In fact, we also found reduced Irf4 gene expression in B cells of C57BL/6 mice. Thus, we propose Irf4 as a candidate for the IgMSC1 locus, which controls IgM homeostatic levels at the level of B-cell terminal differentiation

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Cutting Edge: Selection of B Lymphocyte Subsets Is Regulated by Natural IgM

Cited by 62 publications

References 23 publications

Analysis of Marginal Zone B Cell Development in the Mouse with Limited B Cell Diversity: Role of the Antigen Receptor Signals in the Recruitment of B Cells to the Marginal Zone

Analysis of Marginal Zone B Cell Development in the Mouse with Limited B Cell Diversity: Role of the Antigen Receptor Signals in the Recruitment of B Cells to the Marginal Zone

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

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