Age‐related alterations of somatic hypermutation and CDR3 lengths in human Vκ4‐expressing B lymphocytes

Troutaud, Danielle; Drouet,; Decourt,; Morvan, Le; Cogné, Michel

doi:10.1046/j.1365-2567.1999.00779.x

Cited by 21 publications

(14 citation statements)

References 26 publications

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“…Intrinsic defects of isolated B-cell lineage have already been observed during aging (22)(23)(24)(25). While the proliferative response of purified mouse B-lymphocytes was maintained through aging, their apoptotic susceptibility and capacity for activation were modified.…”

Section: Discussionmentioning

confidence: 99%

Aged mice exhibit distinct peripheral B‐cell phenotypes differing in apoptotic susceptibility: An ex vivo analysis

Verdier¹,

Malissein²,

E³

et al. 2006

Cytometry Pt A

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Background: Age-related changes in the antibody response have been classically associated with alterations in T-cell help, but increasing evidence shows that intrinsic B-cell defects exist. This article analyzes the apoptotic susceptibility of peripheral B-cells in aged and young control mice. Materials and Methods: Freshly isolated lymphocytes from spleen and Peyer's patches (PPs) were labeled for Bcell lineage (B220 1 cells) and germinal center B subset (GCs, B2201 /PNA 1 cells). Alternatively, splenic B-cells purified by MACS were used. Apoptosis was monitored by the Annexin V binding, incorporation of 3,3 0 -dihexyloxacarbocyanine iodide (DiOC 6 (3)), propidium iodide (PI) staining, and morphological changes. Moreover, intracellular Bcl-2 expression and Bad phosphorylation status were also analyzed in B-cells. Results: We showed in aging mice an enhanced Annexin V

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Section: Discussionmentioning

confidence: 99%

Aged mice exhibit distinct peripheral B‐cell phenotypes differing in apoptotic susceptibility: An ex vivo analysis

Verdier¹,

Malissein²,

E³

et al. 2006

Cytometry Pt A

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“…To our knowledge, research regarding the circulating V L repertoire in aging humans is limited to analysis of the V4 gene family (24). Troutaud et al (24) analyzed V4-J rearrangements and V4 mutational frequencies in the peripheral blood mononuclear cells isolated from young and elderly (mean age ϭ 83 years) individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Troutaud et al (24) analyzed V4-J rearrangements and V4 mutational frequencies in the peripheral blood mononuclear cells isolated from young and elderly (mean age ϭ 83 years) individuals. These authors demonstrated significantly lower levels of somatic mutation, specifically replacement mutations, with aging.…”

Section: Discussionmentioning

confidence: 99%

Immune Response to Pneumococcal Polysaccharides 4 and 14 in Elderly and Young Adults: Analysis of the Variable Light Chain Repertoire

et al. 2005

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Streptococcus pneumoniae is a human bacterial pathogen responsible for serious infections including pneumonia. The currently licensed polysaccharide vaccine provides 60 to 80% protection in young adults, but in the elderly the vaccine efficacy is drastically reduced despite normal antibody levels. We hypothesized that the reduced vaccine efficacy in the elderly results from altered variable gene family usage. We have analyzed the light chain gene usage in 20 young (20 to 30 years of age) and 20 elderly (65 to 86 years of age) adults in response to pneumococcal polysaccharide 4 (PPS4) and PPS14. We generated a variable light chain library using B cells specific for PPS4 and PPS14 from each vaccinated individual. We determined complete sequences and somatic mutation frequencies in all isolated variable light chain fragments. Six gene families, 1, 2, 3, 4, 1, and 3, were identified in response to PPS4 and PPS14 in both age groups. Comparison of young and elderly adults demonstrated significant differences in 4, 1, and 3 gene usage in response to PPS4 and PPS14. With aging, there was a significant increase in 4 gene usage and a significant decrease in 1 and 3 gene usage in response to both PPS4 and PPS14. Although both V1 and V3 gene products demonstrated extensive mutations, there was no age-related difference in mutational frequency per gene family. These findings suggest an age-related change in light chain gene usage in response to PPS4 and PPS14.The incidence of pneumococcal pneumonia is significantly increased in individuals Ͼ65 years of age (13). Several studies (8,18) have demonstrated a significant impairment in the immune response to pneumococcal polysaccharides in the elderly, particularly those Ͼ77 years of age, associated with a markedly decreased efficacy of the pneumococcal vaccine (6, 23).The molecular mechanisms responsible for the decreased immune response in the elderly remain poorly understood. Nicoletti et al. (15) studied the immune response to phosphorylcholine (PC) in aged mice vaccinated with Streptococcus pneumoniae. These studies demonstrated a significant functional impairment in the immune response to PC despite normal antibody concentrations. Molecular analysis of the anti-PC-specific antibody repertoire in aged mice revealed a significantly altered V gene usage compared to young immunized mice (14).To date, studies examining the structure-function relationship of antipneumococcal antibodies have been performed using human monoclonal antibodies (1, 22, 26), combinatorial libraries (12,17,27,28), and monoclonal antibodies derived from a transgenic mouse strain with human immunoglobulin loci (2, 19). All studies, with the exception of those using the transgenic mouse, have analyzed the V repertoire using peripheral blood mononuclear cells obtained from young high responders. Although these studies have enriched our knowledge concerning the human immune response to pneumococcal polysaccharide (PPS), they were not designed to represent the in vivo antibody repertoire response to PPS in the...

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“…[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.…”

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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Age‐related alterations of somatic hypermutation and CDR3 lengths in human Vκ4‐expressing B lymphocytes

Cited by 21 publications

References 26 publications

Aged mice exhibit distinct peripheral B‐cell phenotypes differing in apoptotic susceptibility: An ex vivo analysis

Aged mice exhibit distinct peripheral B‐cell phenotypes differing in apoptotic susceptibility: An ex vivo analysis

Immune Response to Pneumococcal Polysaccharides 4 and 14 in Elderly and Young Adults: Analysis of the Variable Light Chain Repertoire

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

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