Recruitment and selection of marginal zone B cells is independent of exogenous antigens,

Dammers, Peter M.; Kroese, Frans G. M.

doi:10.1002/eji.255590580

Cited by 12 publications

(15 citation statements)

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“…2 and 3). This suggests that MZ B cells, which have been thought not to undergo selection on BCR (8)(9)(10)(11), are actually subject to the same selective pressure that drives selection of FO cells, in fact to an even greater degree. We note that nonproductive rearrangements are imperfect proxies for pro-B cells; direct deep sequencing of rearrangements in pro-B cells, as has been recently performed (17), offers the possibility of comparing segment use in this population directly with that in pre-B, FO, and MZ cells as data on the frequency of specific gene segments are made available.…”

Section: Discussionmentioning

confidence: 99%

“…More recent sequencing studies have looked for differences in V H gene segment use between follicular (FO) B cells, which circulate through the spleen, and marginal zone (MZ) B cells, "innate-like" (7) cells in the spleen that are theorized not to undergo B-cell receptor (BCR)-based selection during maturation (8)(9)(10)(11). These studies also found no differences in V H use, although, again, the number of sequences studied was small.…”

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confidence: 99%

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Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

Kaplinsky

Sun

et al. 2014

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

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Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (V H )-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in V H gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use V H genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential V H gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.immunomics | principal component analysis | development T he mature antibody repertoire is shaped by selective forces that influence B-cell survival (1). Comparison of immature and mature B-cell subsets has shown that selection acts specifically on complementarity determining region 3 (CDR3) of the antibody heavy-chain molecule, an antigen-binding region that is a key determinant of antigen specificity (2). On average, mature B-cell subsets express antibodies that have shorter and more negatively charged CDR3s, which is the result of selection against autoreactive and polyreactive B cells (3,4).Each recombined antibody heavy-chain gene is composed of a variable (V H ), diversity (D), and joining (J H ) gene segment. Because the CDR3 region spans the V H -D-J H joint, investigators have asked whether selection might favor B cells whose antibodies use specific V H , D, or J H gene segments. Selection in favor of specific gene segments during B-cell maturation might help to explain the observed maturation-associated changes in CDR3 length and charge, and might suggest a preference for "hard-wired" antigen specificities. Evidence against selection would suggest that differences in CDR3 result exclusively from the nontemplated addition and deletion of nucleotides at the V H -D and D-J H junctions, and therefore that the death of B cells with counterselected CDR3s during maturation is simply the evolutionary cost (3) of maintaining this mechanism of generating antibody diversity.Nearly two decades ago, a low-throughput sequencing study in mice suggested that specific V H gene segments were used at different frequencies by pre-B cells (in which heavy-chain recombination has been completed) and mature B cells in the spleen (5). This observation was interpreted as selection for hard-wired specificities. However, the statistical robustness of this observation was limited by the small number of recombined genes that were sequenced, and although subsequent investigations have detected differences in V H use between pre-B and upstream pro-B cells, they have failed to confirm such differences between pre-B and...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

Kaplinsky

Sun

et al. 2014

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

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“…Studies from a number of investigators indicate that the marginal zone in both mice and rats, is often enriched for self-or poly-reactive B cells [12,[27][28][29]. Although without direct analysis of the binding characteristics of these marginal zone Ig these data must be viewed as circumstantial, there is evidence in the literature of an association between short, N regiondepleted CDR-H3 and self-and poly-reactivity, and between enrichment for charged CDR-H3 amino acids and pathogenic self-reactivity.…”

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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“…46 Furthermore, recruitment and selection of B cells in the splenic marginal zone in rodents are dependent on polyreactivity with autoantigens. 47 In rodents, polyreactive antibodies have antibacterial activity in the presence of complement, suggesting a role in the natural immunity against bacterial infection. 46 Whether human SMZL derives from natural antibody producing cells is uncertain.…”

Section: Discussionmentioning

confidence: 99%

Splenic marginal zone lymphoma with VH1-02 gene rearrangement expresses poly- and self-reactive antibodies with similar reactivity

Warsame

Aasheim

Nustad

et al. 2011

Blood

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One-third of all splenic marginal zone lymphomas (SMZL) use the IgH VH1-02 gene. These cases are usually not associated with hepatitis C virus infection. Of interest, the rearranged VH1-02 genes display similar complementarity determining regions 3, a finding confirmed by our study. The latter suggests that these SMZL may produce antibodies with similar reactivity. We produced recombinant antibodies from 5 SMZL cases with VH1-02 gene rearrangement to study the binding reactivity of these antibodies. Surprisingly, the recombinant antibodies demonstrated poly-and self-reactivity as demonstrated by their reactivity with nuclear, cytoplasmic, as well as membranous antigens expressed by human cells and by reactivity with human serum. This polyreactivity was specific as demonstrated by ELISA. The antibodies did not react with proteins on the cell surface that are IntroductionMarginal zone lymphomas are believed to arise from B lymphocytes residing in the marginal zone of the B-cell zone in secondary lymphoid tissue. The origin and function of human marginal zone B lymphocytes have not completely been elucidated, but marginal zone B cells likely have a function in the T-independent immune response. 1 Depending mainly on the organ in which marginal zone lymphoma arises, 3 distinct subtypes of marginal zone lymphoma are recognized: nodal, extra-nodal, and splenic marginal zone lymphomas (SMZL), arising from lymph nodes, mucosal sites, and the spleen, respectively. Together, those marginal zone lymphomas represent ϳ 8% of all lymphomas and are the third most-frequent lymphoma type. 2 SMZL as well as the extranodal marginal zone lymphomas are clinically low grade or indolent, whereas nodal marginal zone lymphomas have a more aggressive clinical course. 3 In contrast to nodal and extranodal marginal zone lymphomas, SMZLs are mostly systemic and are diagnosed with BM infiltration. A subset of extranodal marginal zone lymphomas occurring in the stomach and lung are characterized by the translocation t(11;18)(q21;q21) or variant translocation t(14;18)(q32;q21), resulting in overexpression of the MALT1 gene, and a minority of those lymphomas can show either a translocation t(3;14)(p14;q32), t(1;14)(p22;q32), or BCL10 mutation. Primary genetic alterations have not been demonstrated for nodal or SMZL. However, frequent deletion of the long arm of chromosome 7(del 7q31-32) as well as trisomy 3 have been documented in SMZL. 4 The importance of these genetic findings for the pathogenesis of SMZL is not clear. 5 Extranodal marginal zone lymphomas may occur secondary to chronic infection or chronic inflammation. 6 Extranodal marginal zone lymphoma arising in the stomach may occur secondarily to Helicobacter pylori-associated gastritis. 7 This led to the successful use of antibiotics for its treatment. 8 Similarly, marginal zone lymphoma arising in the thyroid gland and salivary gland can be secondary to chronic inflammation associated with autoimmune disease, such as Hashimoto thyroiditis or Sjö gren syndrome, respectively. 9,10 Othe...

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Recruitment and selection of marginal zone B cells is independent of exogenous antigens,

Cited by 12 publications

References 0 publications

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells

Categorical selection of the antibody repertoire in splenic B cells

Splenic marginal zone lymphoma with VH1-02 gene rearrangement expresses poly- and self-reactive antibodies with similar reactivity

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