Developmental Regulation of the Human Antibody Repertoire<sup>a</sup>

Schroeder, Harry W.; Mortari, Frank; Shiokawa, Satoshi; Kirkham, Perry M.; Elgavish, Rotem A.; Bertrand, F. E.

doi:10.1111/j.1749-6632.1995.tb55834.x

Cited by 94 publications

(45 citation statements)

References 55 publications

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“…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. 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].…”

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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“…We did, however, identify these atypical rearrangements at a frequency of 3% in 9969 DJ H rearrangements, which was similar to the frequency found in the 1043 NP V H DJ H rearrangements. In neonates and adults, P V H DJ H rearrangements have generally shorter CDR3s compared with NP V H DJ H rearrangements (28,35). In V H DJ H rearrangements with two D genes, the median CDR3 was 66 nt for P rearrangements and 81 for NP rearrangements.…”

Section: Discussionmentioning

confidence: 99%

Sterile DJH Rearrangements Reveal that Distance Between Gene Segments on the Human Ig H Chain Locus Influences Their Ability To Rearrange

Hansen

Lange

Barington

2015

The Journal of Immunology

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Rearrangement of the Ig locus occurs in two steps. First, a JH gene is rearranged to a D gene followed by a VH gene rearranging to the DJH rearrangement. By next generation sequencing, we analyzed 9969 unique DJH rearrangements and 5919 unique VHDJH rearrangements obtained from peripheral blood B cells from 110 healthy adult donors. We found that DJH rearrangements and nonproductive VHDJH rearrangements share many features but differ significantly in their use of D genes and propensity for somatic hypermutation. In D to JH gene rearrangements, the D genes proximal to the JH locus are used more frequently than JH locus distal D genes, whereas VH locus proximal D genes were observed more frequently in nonproductive VHDJH rearrangements. We further demonstrate that the distance between VH, D, and JH gene segments influence their ability to rearrange within the human Ig locus.

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“…Thus class switch to IgG did not favor more "mature" V H regions, but instead class-switched sequences were randomly chosen from the immature primary IgM repertoire as for length and D H gene use. These immature structural characteristics might contribute to the well-known polyreactivity, low affinity, and increased autoreactivity of neonatal IgG (16).…”

Section: Discussionmentioning

confidence: 99%

“…We speculate that these limitations in the neonatal Ig H chain repertoire may in part be responsible for the characteristically low affinity and increased polyreactivity and autoreactivity of the neonatal IgG repertoire as compared with the adult one (16).…”

mentioning

confidence: 99%

The Postnatal Maturation of the Immunoglobulin Heavy Chain IgG Repertoire in Human Preterm Neonates Is Slower than in Term Neonates

Zemlin

Hoersch

Zemlin

et al. 2007

The Journal of Immunology

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During the perinatal period the development of the IgH chain CDR3 (CDR-H3) repertoire of IgM transcripts is maturity-dependent and not influenced by premature exposure to Ag. To study whether maturity-dependent restrictions also predominate in the perinatal IgG repertoire we compared 1000 IgG transcripts from cord blood and venous blood of extremely preterm neonates (24–28 wk of gestation) and of term neonates from birth until early infancy with those of adults. We found the following. First, premature contact with the extrauterine environment induced the premature development of an IgG repertoire. However after preterm birth the diversification of the IgG repertoire was slower than that after term birth. Second, the IgG repertoire of preterm neonates retained immature characteristics such as short CDR-H3 regions and overrepresentation of DH7–27. Third, despite premature exposure to the extrauterine environment, somatic mutation frequency in IgG transcripts of preterm infants remained low until they reached a postconceptional age corresponding to the end of term gestation. Thereafter, somatic mutations accumulated with age at similar rates in preterm and term neonates and reached 30% of the adult level after 6 mo. In conclusion, class switch was inducible already at the beginning of the third trimester of gestation, but the developing IgG repertoire was characterized by similar restrictions as those of the developing IgM repertoire. Those B cells expressing more “mature” H chain sequences were not preferentially selected into the IgG repertoire. Therefore, the postnatal IgG repertoire of preterm infants until the expected date of delivery differs from the postnatal repertoire of term neonates.

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Developmental Regulation of the Human Antibody Repertoire^a

Cited by 94 publications

References 55 publications

Categorical selection of the antibody repertoire in splenic B cells

Categorical selection of the antibody repertoire in splenic B cells

Sterile DJH Rearrangements Reveal that Distance Between Gene Segments on the Human Ig H Chain Locus Influences Their Ability To Rearrange

The Postnatal Maturation of the Immunoglobulin Heavy Chain IgG Repertoire in Human Preterm Neonates Is Slower than in Term Neonates

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Developmental Regulation of the Human Antibody Repertoirea

Cited by 94 publications

References 55 publications

Categorical selection of the antibody repertoire in splenic B cells

Categorical selection of the antibody repertoire in splenic B cells

Sterile DJH Rearrangements Reveal that Distance Between Gene Segments on the Human Ig H Chain Locus Influences Their Ability To Rearrange

The Postnatal Maturation of the Immunoglobulin Heavy Chain IgG Repertoire in Human Preterm Neonates Is Slower than in Term Neonates

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Developmental Regulation of the Human Antibody Repertoire^a