The Repertoire of Human Antibodies to the Carbohydrate Capsule of Streptococcus pneumoniae 6B

Park, M K; Sun, Yan; Olander, Jitka V.; Hoffmann, Jana; Nahm, Moon H.

doi:10.1093/infdis/174.1.75

Cited by 25 publications

(27 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, only one or two distinct Fab fragments of any single serotype specificity were isolated from an individual donor, and in some cases these appeared to be intraclonal variants. This result is consistent with previous studies showing that Ab responses to PPS Ags are markedly oligoclonal and can be dominated by the products of a single clone (31,34,46). Second, the MNC populations used for library construction were enriched for specific B cells using PPS-coated paramagnetic beads and were obtained 7 days after vaccination, a time when there is an increased frequency of PPS-specific B cells in the peripheral circulation (38).…”

Section: Discussionsupporting

confidence: 89%

“…Although this interest stems primarily from the need to evaluate vaccine immunogenicity and to establish reliable surrogates of protection, the Ab response to PPS antigens (Ags) represents an ideal opportunity to examine the inheritance and development of protective immunity in humans. Ab responses to PPS Ags are markedly oligoclonal within individuals (31,34,46), and consequently variable (V) region diversity is limited. This property leads to individual variation in PPS-specific Ab fine specificity (41), avidity, and protective efficacy (52,66).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Combinatorial Library Cloning of Human Antibodies toStreptococcus pneumoniaeCapsular Polysaccharides: Variable Region Primary Structures and Evidence for Somatic Mutation of Fab Fragments Specific for Capsular Serotypes 6B, 14, and 23F

Lucas¹,

Moulton²,

Tang³

et al. 2001

Infect Immun

View full text Add to dashboard Cite

Antibodies specific for capsular polysaccharides play a central role in immunity to encapsulated Streptococcus pneumoniae, but little is known about their genetics or the variable (V) region polymorphisms that affect their protective function. To begin to address these issues, we used combinatorial library cloning to isolate pneumococcal polysaccharide (PPS)-specific Fab fragments from two vaccinated adults. We determined complete V region primary structures and performed antigen binding analyses of seven Fab fragments specific for PPS serotype 6B, 14, or 23F. Fabs were of the immunoglobulin G2 or A isotype. Several V H III gene segments (HV 3-7, 3-15, 3-23, and 3-11) were identified. V L regions were encoded by several genes (KV 4-1, 3-15, 2-24, and 2D-29) and a gene (LV 1-51). Deviation of the V H and V L regions from their assigned germ line counterparts indicated that they were somatically mutated. Fabs of the same serotype specificity isolated from a single individual differed in affinity, and these differences could be accounted for either by the extent of mutation among clonal relatives or by usage of different V-region genes. Thus, functionally disparate anti-PPS antibodies can arise within individuals both by activation of independent clones and by intraclonal somatic mutation. For one pair of clonally related Fabs, the more extensively mutated V H was associated with lower affinity for PPS 14, a result suggesting that somatic mutation could lead to diminished protective efficacy. These findings indicate that the PPS repertoire in the adult derives from memory B-cell populations that have class switched and undergone extensive hypermutation.

show abstract

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Combinatorial Library Cloning of Human Antibodies toStreptococcus pneumoniaeCapsular Polysaccharides: Variable Region Primary Structures and Evidence for Somatic Mutation of Fab Fragments Specific for Capsular Serotypes 6B, 14, and 23F

Lucas¹,

Moulton²,

Tang³

et al. 2001

Infect Immun

View full text Add to dashboard Cite

show abstract

“…Overall, the isolated heavy chain genes were 87.3 to 100% identical to germ line sequences, with the majority of the mutations occurring in the CDRs. Previous studies demonstrated a similar range of mutations in response to polysaccharide antigens (3,20,27,37,39,49,50).…”

Section: Discussionmentioning

confidence: 63%

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

et al. 2005

View full text Add to dashboard Cite

Streptococcus pneumoniae is a leading cause of morbidity and mortality in both developed and developing countries. The current pneumococcal polysaccharide (PPS) vaccine is highly effective in young adults; however, vaccine efficacy is dramatically decreased in the elderly population. We hypothesized that the decreased vaccine efficacy in the elderly results from altered variable gene family usage. We have characterized the immunoglobulin G gene usage of the antibody response to PPS4 and PPS14 in 20 young and 20 elderly adults. The variable heavy (V H ) gene repertoire of human peripheral B cells was amplified by using PCR. A total of 364 heavy chain sequences with specificity for PPS4 and 305 heavy chain sequences for PPS14 were analyzed from young adults. In addition, a total of 325 sequences for PPS4 and 291 sequences for PPS14 were obtained from elderly adults. Complete sequence identity, somatic mutation frequencies, and V H gene usage was determined in response to PPS4 and PPS14. In all volunteers, the immune response to both polysaccharides consisted predominantly of heavy chains belonging to the V H 3 gene family. There were significant differences in the variable gene repertoire between young and elderly adults. Somatic mutation occurred more frequently in sequences derived from young compared to elderly derived sequences. With aging, a loss of oligoclonality was noted in response to PPS4 and PPS14 compared to young adults. The observed differences in V H repertoire, somatic mutation, and loss of oligoclonality may contribute to decreased vaccine efficacy in the elderly.

show abstract

“…Whereas the latter had been shown only for protein antigens, this report is the first to demonstrate that the XenoMouse repertoire is sufficient to generate an antipolysaccharide response. More work is needed to establish how closely the anti-PPS response of XenoMouse mice resembles that of humans, since the repertoire of XenoMouse mice does not contain a human locus and the light chain contributes to the human antibody response to PPS (27,32). However, our finding that like antibodies to PPS from humans (3,25,27,40), XenoMouse-derived MAbs to PPS 3 use V H 3 genes suggests that the anti-PPS response in these animals is restricted to V H 3 as it is in humans.…”

Section: Discussionmentioning

confidence: 99%

Production of Protective Human Antipneumococcal Antibodies by Transgenic Mice with Human Immunoglobulin Loci

Russell¹,

Corvalan²,

Gallo³

et al. 2000

Infect Immun

View full text Add to dashboard Cite

Infections with Streptococcus pneumoniae remain a significant cause of morbidity and mortality. To gain insight into structure-function relationships for human antibodies to pneumococcal capsular polysaccharide (PPS), we studied the response of transgenic mice reconstituted with human immunoglobulin loci, XenoMouse, to PPS antigens in a pneumococcal vaccine. Enzyme-linked immunosorbent assays of sera from mice vaccinated with a 23-valent pneumococcal vaccine revealed that they produced serotype-specific human antibodies, with the greatest response being to the PPS of serotype 3 (PPS 3). Molecular sequence analysis of three monoclonal antibodies (MAbs) to PPS 3 generated from lymphoid cells from mice vaccinated with a 23-valent pneumococcal vaccine or a PPS 3-bovine serum albumin conjugate revealed that they all used heavy-chain immunoglobulin genes from the V H 3 family, two expressed light chain genes from the human V1 family, and one expressed a mouse light chain. The protective efficacy of the two MAbs was examined in mice. A 10-g dose of both, and a 1-g dose of one, significantly prolonged survival from a lethal serotype 3 infection in CBA/N mice. Our data show that XenoMouse mice produced protective, serotype-specific human antibodies to PPS 3, and they lend support to the proposal that these animals represent a useful model to study the human antibody response to PPS antigens.Available pneumococcal vaccines consist of the purified capsular polysaccharides (PPS) of the most common serotypes of Streptococcus pneumoniae that cause disease in adults and children. Though immunogenic in normal individuals, PPS-based vaccines are poorly immunogenic in adult patients who are at increased risk for pneumococcal infections (reviewed in reference 33). Our group and others have shown that human antibodies to PPS are derived from restricted B-cell subsets which express V H 3 gene family segments (3,27,40). However, these studies were based largely on studies of polyclonal serum antibodies. Characterization of the molecular genetic structure of antibodies to the capsular polysaccharide of Haemophilus influenzae type b (4, 28) has provided insight into possible mechanisms of disease susceptibility and vaccine failure in patients with decreased expression of the genetic elements used in the response (16). This is relevant to S. pneumoniae, because overall (8) and serotype-specific V H 3 expression is decreased in human immunodeficiency virus-infected individuals (3), a group with reduced responses to pneumococcal vaccines (reviewed in reference 33) and increased susceptibility to pneumococcal infection (23).To date, the genetic makeup of a limited number of human monoclonal antibodies (MAbs) to a limited number of PPS serotypes generated by Epstein-Barr virus transformation of lymphocytes from vaccinated recipients has been described, namely, two MAbs to PPS 3 derived from different individuals (39), one to PPS 8 (46) and one to PPS 6B (40). Epstein-Barr virus transformation is difficult and unpredictable. In addition, all...

show abstract

The Repertoire of Human Antibodies to the Carbohydrate Capsule of Streptococcus pneumoniae 6B

Cited by 25 publications

References 42 publications

Combinatorial Library Cloning of Human Antibodies toStreptococcus pneumoniaeCapsular Polysaccharides: Variable Region Primary Structures and Evidence for Somatic Mutation of Fab Fragments Specific for Capsular Serotypes 6B, 14, and 23F

Combinatorial Library Cloning of Human Antibodies toStreptococcus pneumoniaeCapsular Polysaccharides: Variable Region Primary Structures and Evidence for Somatic Mutation of Fab Fragments Specific for Capsular Serotypes 6B, 14, and 23F

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

Production of Protective Human Antipneumococcal Antibodies by Transgenic Mice with Human Immunoglobulin Loci

Contact Info

Product

Resources

About