Regulation of Anti–double-stranded DNA B Cells in Nonautoimmune Mice: Localization to the T–B Interface of the Splenic Follicle

Mandik-Nayak, Laura; Bui, Anh; Noorchashm, Hooman; Eaton, Ashlyn; Erikson, Jan

doi:10.1084/jem.186.8.1257

Cited by 167 publications

(208 citation statements)

References 63 publications

(94 reference statements)

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“…For example, short, N-less CDR-H3 are a marker of the neonatal CDR-H3 repertoire in both mouse and human, which is itself enriched for self-and poly-reactivity [30,31] An excess of charged amino acids in CDR-H3 has been associated with pathogenic self-reactivity, especially to DNA [16,[32][33][34]. In this light, it should be noted that B cells expressing anti-dsDNA reactivity have been shown to be excluded from the follicles [35]. It is possible that use of short, polar CDR-H3 sequences facilitates self-and polyreactivity, which in turn contributes to the pre-activation that marks the MZ subset.…”

Section: Discussionmentioning

confidence: 99%

Categorical selection of the antibody repertoire in splenic B cells

et al. 2007

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In the bone marrow, the passage of developing B cells through critical checkpoints of differentiation is associated with a reduction of specific categories of CDR3 of the Ig heavy chain (CDR-H3), particularly those with excessive hydrophobic or charged amino acids and those with a length of eight or fewer residues. To gain insight into the role of CDR-H3 content in the development of B cells in the spleen, we compared the sequences of V H 7183DJCl transcripts from sorted transitional T1, marginal zone, and follicular B cell subsets to those expressed by immature IgM + IgD -and mature IgM lo IgD hi B cells in the bone marrow. Although differences in V H utilization were noted, the T1 CDR-H3 repertoire showed extensive similarity to that of immature bone marrow B cells, and the follicular CDR-H3 repertoire most resembled that of mature bone marrow B cells. Unlike the splenic follicular and bone marrow mature B cell CDR-H3 repertoires, the marginal zone B cell CDR-H3 repertoire retained both short and highly charged amino acid motifs, including those with two arginines. Our findings suggest that antigen binding sites containing specific categories of CDR-H3 sequence content may inhibit, permit, or even facilitate passage of the host B cell through critical checkpoints in peripheral as well as central development.

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Section: Discussionmentioning

confidence: 99%

Categorical selection of the antibody repertoire in splenic B cells

et al. 2007

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“…Anergic B cells fail to secrete Ab in response to LPS or Ag immunization due to receptor unresponsiveness (17,18,20). Some anergic B cells exhibit reduced surface IgM levels (21,22), decreased lifespan (20,23), and exclusion from the lymphoid follicle (23,24). In the case of B cells specific for the lupus-associated Ag, Smith (Sm), a partially anergic phenotype is evident.…”

mentioning

confidence: 99%

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

Gilbert¹,

Carnathan²,

Cogswell

et al. 2007

The Journal of Immunology

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Autoimmunity results from a breakdown in tolerance mechanisms that regulate autoreactive lymphocytes. We recently showed that during innate immune responses, secretion of IL-6 by dendritic cells (DCs) maintained autoreactive B cells in an unresponsive state. In this study, we describe that TLR4-activated DCs from lupus-prone mice are defective in repressing autoantibody secretion, coincident with diminished IL-6 secretion. Reduced secretion of IL-6 by MRL/lpr DCs reflected diminished synthesis and failure to sustain IL-6 mRNA production. This occurred coincident with lack of NF-κB and AP-1 DNA binding and failure to sustain IκBα phosphorylation. Analysis of individual mice showed that some animals partially repressed Ig secretion despite reduced levels of IL-6. This suggests that in addition to IL-6, DCs secrete other soluble factor(s) that regulate autoreactive B cells. Collectively, the data show that MRL/lpr mice are defective in DC/IL-6-mediated tolerance, but that some individuals maintain the ability to repress autoantibody secretion by an alternative mechanism.

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“…Unlike transgenics expressing higher affinity receptors for soluble IgG (29) or reacting to membrane-bound hen egg lysozyme (HEL) (3) or H-2 Ags (4), SMI B cells are not deleted and are found in peripheral lymphoid compartments. Additionally, they are not rendered anergic as a consequence of maturational arrest or exclusion from the B cell follicles of the spleen, as are those of other mice such as those specific for dsDNA (40,41) or sHEL (2,6,42).…”

Section: Discussionmentioning

confidence: 99%

Transgenic Expression of a Human Polyreactive Ig Expressed in Chronic Lymphocytic Leukemia Generates Memory-Type B Cells That Respond to Nonspecific Immune Activation

Widhopf

Brinson

Kipps

et al. 2004

The Journal of Immunology

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We generated transgenic mice, designated SMI, expressing unmutated H and L chain Ig genes encoding a low-affinity, polyreactive human (h)IgM/κ rheumatoid factor. These animals were compared with control AB29 transgenic mice expressing a hIgM/κ rheumatoid factor specific for human IgG, with no detectable reactivity with mouse proteins. SMI B cells expressed significantly lower levels of surface hIgM/κ than did the B cells of AB29 mice, but still could be induced to proliferate by surface Ig cross-linking in vitro and could be deleted with anti-Id mAb in vivo. Transgene-expressing B cells of AB29 mice had a B-2 phenotype and were located in the primary follicle. In contrast, a relatively high proportion of hIgM-expressing B cells of SMI mice had the phenotype of B-1 B cells in the peritoneum or marginal zone B cells in the spleen, where they were located in the periarteriolar sheath, marginal zone, and interfollicular areas that typically are populated by memory-type B cells. Although the relative proportions of transgene-expressing B cells in both types of transgenic mice declined with aging, SMI mice experienced progressive increases in the serum levels of IgM transgene protein over time. Finally, SMI transgene-expressing B cells, but not AB29 transgene-expressing B cells, were induced to secrete Ab when cultured with alloreactive T cells. These results indicate that expression of polyreactive autoantibodies can allow for development of B cells that are neither deleted nor rendered anergic, but instead have a phenotype of memory-type or Ag-experienced B cells that respond to nonspecific immune activation.

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Regulation of Anti–double-stranded DNA B Cells in Nonautoimmune Mice: Localization to the T–B Interface of the Splenic Follicle

Cited by 167 publications

References 63 publications

Categorical selection of the antibody repertoire in splenic B cells

Categorical selection of the antibody repertoire in splenic B cells

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

Transgenic Expression of a Human Polyreactive Ig Expressed in Chronic Lymphocytic Leukemia Generates Memory-Type B Cells That Respond to Nonspecific Immune Activation

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