Early Restriction of the Human Antibody Repertoire

Schroeder, Harry W.; Hillson, Jan; Perlmutter, Roger M.

doi:10.1126/science.3118465

Cited by 525 publications

(384 citation statements)

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“…The VH1-69 immunoglobulin segment is expressed in the restricted repertoire of fetal liver B lymphocytes and is thought to be involved in natural immunity. 40,41 A productive VH1-69 rearrangement is present in ϳ1.6% of normal B lymphocytes in adults. 42 VH1-69 is rearranged in ϳ10 to 20% of B-cell chronic lymphocytic leukemia 30,43 and a VH1-69 monoclonal rearrangement is present in the majority of patients with type II mixed cryoglobulinemia, a typical HCV-related disorder.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin Gene Mutations and Frequent Use of VH1-69 and VH4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma

Marasca

Vaccari

Luppi

et al. 2001

The American Journal of Pathology

137

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Section: Discussionmentioning

confidence: 99%

Immunoglobulin Gene Mutations and Frequent Use of VH1-69 and VH4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma

Marasca

Vaccari

Luppi

et al. 2001

The American Journal of Pathology

137

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“…Human germline Ig V H -gene CDRs, particularly CDR1, are highly prone to R mutations We applied the computer algorithm to the analysis of the inherent Rf and R:S mutation ratio values of the CDRs and FRs of 24 selected human germline V H genes [21][22][23][24][25][26][27][28][29][30][31][32][33][34] , including H11 (Table 1). These V H genes are among those most-frequently expressed in the early and adult B-cell repertoires and encode natural antibodies and antibodies to foreign antigens, as well as autoantibodies in autoimmune patients.…”

Section: Hhs Public Accessmentioning

confidence: 99%

The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement

1994

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The variable (V) genes of antigen-selected antibodies are known to exhibit a higher frequency of amino acid replacement mutations in the sequences encoding the antigen-contacting complementarity-determining regions (CDRs) than in those encoding the 'structural' framework regions (FRs). Here, Bernard Chang and Paolo Casali analyse the impact of regional differences in the codon composition of human germline Ig V H and V L genes on regional differences in the frequency of replacement mutations in the gene products (i.e. the antigen-binding sites of antibody molecules). This analysis reveals that CDR and FR sequences can differ significantly in their inherent susceptibility to amino acid replacement given any single nucleotide change. Thus, the CDR sequences of all the Ig V H genes analysed comprise a higher frequency of codons susceptible to replacement mutations than would be expected for a random sequence. Conversely, the FR sequences comprise codons less susceptible to replacement mutations than expected. Random accumulation of nucleotide changes throughout the coding sequence of an Ig V-gene segment containing CDRs inherently more prone to replacement mutations than the respective FRs would inevitably yield a higher rate of amino acid replacements in the CDRs than in the FRs. This would provide a fertile structural substrate of hypervariability for antigen selection while still maintaining the structural integrity of the FRs.The production of antibodies with progressively higher affinity for antigen is an important feature of B-cell clonotypes recruited by repeated antigenic challenge, and is referred to as affinity maturation 1 . The molecular basis of this process was first unveiled by the analysis of the binding affinity and primary structure of monoclonal antibodies (mAbs) generated at successive stages of murine immune responses to different conjugated haptens and antigens [2][3][4][5][6][7][8][9][10] . The first exposure to antigen results in recruitment of B-cell clonotypes that bind antigen by virtue of the combinatorial and junctional specificity of their unmutated surface receptors (Ig V segments). Subsequent exposures to antigen lead to accumulation of somatic point mutations in the antibody V segments and antigen selection of the highaffinity mutated B-cell clonotypes. Sequential rounds of mutation and selection eventually result in restriction of the response to those B cells with the best 'fit' for antigen 11,12 . Somatic point mutations in Ig V-gene segmentsIn the absence of negative or positive selective pressure on the gene product, a random mutational process would entail an even distribution of nucleotide changes yielding amino HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript acid replacements (R mutations) and nucleotide changes not yielding amino acid replacements (S, or silent, mutations) throughout the coding sequence. However, antigenselected antibodies have been shown to include a higher frequency of R mutations in the Ig V-gene complemen...

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“…[4][5][6] In general the fetal repertoire is more restricted than the adult repertoire. [7][8][9] Several studies have shown that there are significant differences between the fetal, cord blood, and adult immunoglobulin repertoires in mice and humans. 8,[10][11][12][13][14][15][16][17][18][19][20][21] In humans, the VH4 family is represented throughout life but continues to increase as a function of age (particularly the VH4-34 and VH4-59 gene segments).…”

Section: Introductionmentioning

confidence: 99%

Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire

Kolar

Yokota

Rossi

et al. 2004

Blood

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Several characteristics of the immunoglobulin (Ig) repertoire in fetuses and adults set them apart from each other. Functionally, this translates into differences in the affinity and effectiveness of the humoral immune response between adults and the very young. At least 2 possibilities could explain these differences: (1) fetal and adult lymphocyte progenitors differ significantly in their potential to form a diverse repertoire, and (2) factors extrinsic to the immunoglobulin locus are more influential to the character of the repertoire. To address this we used nonobese diabetic-severe combined immunodeficient-␤ 2 microglobulin knockout (NOD/SCID/␤ 2 m ؊/؊ ) mice reconstituted with human B-cell progenitors to compare the immunoglobulin repertoire potential of human fetal, cord blood, and adult sources. We found nearly identical VH and JH gene segment use and only modest differences in the third complementarity determining region of the immunoglobulin heavy chain (HCDR3). We conclude that the repertoire potential is remarkably similar regardless of the age of the individual from which progenitors are derived. Age-related differences in the immunoglobulin repertoire and variance of B-cell responses to immunization appear to arise from selection rather than from changes in recombination of the immunoglobulin locus itself. IntroductionAge-related changes in the human humoral immune system have long been known to occur and involve the nature of the antibodies that form the primary effectors of B-cell-mediated immunity. Both fetuses and older adults exhibit properties in their immunoglobulin (Ig) repertoire that differ from that seen in young adults.Neonates are vulnerable to certain pathogens and respond poorly to immunization, even though they (and fetuses) display some degree of immunologic competence. [1][2][3] This could reflect the immaturity of lymphocytes and antigen-presenting cells, or could be a result of persisting immunosuppressive aspects of the fetal environment. [4][5][6] In general the fetal repertoire is more restricted than the adult repertoire. [7][8][9] Several studies have shown that there are significant differences between the fetal, cord blood, and adult immunoglobulin repertoires in mice and humans. 8,[10][11][12][13][14][15][16][17][18][19][20][21] In humans, the VH4 family is represented throughout life but continues to increase as a function of age (particularly the VH4-34 and VH4-59 gene segments). 16 Developmental age-related changes in the third complementarity determining region of the immunoglobulin heavy chain (HCDR3) are even more dramatic, as length, for example, increases with age. The DHQ52 gene segment is commonly used in fetal sequences but is rarely found in adults. HCDR3 length is markedly reduced in fetal compared with adult sequences. 7,14,20,22 D and J gene segment preferences, as well as N nucleotide additions and exonuclease activity, account for this difference. These findings suggest that the antigen receptors on fetal B lymphocytes have a much more restricted range ...

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Early Restriction of the Human Antibody Repertoire

Cited by 525 publications

References 35 publications

Immunoglobulin Gene Mutations and Frequent Use of VH1-69 and VH4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma

Immunoglobulin Gene Mutations and Frequent Use of VH1-69 and VH4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma

The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement

Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire

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