Polysaccharide vaccines as probes of antibody repertoires in man

Lucas, Alexander H.; Reason, Donald C.

doi:10.1111/j.1600-065x.1999.tb01343.x

Cited by 51 publications

(44 citation statements)

References 76 publications

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“…These results do not necessarily follow from oligoclonality itself and, given the combinatorial diversity available to the immune system, it is quite remarkable that such a limited diversity is seen between individuals. A similar recurrence in gene usage is seen in the response to Hib PS, where most individuals utilize an A2 L chain paired with a VH3-23 H chain to form Hib PS-specific Fabs (16). It has been suggested that the high-molecular-weight capsular polysaccharides, which are polymers of smaller repeating subunits, lack epitope diversity and that this results in the observed oligoclonality of the response.…”

Section: Discussionmentioning

confidence: 70%

Recurrent Variable Region Gene Usage and Somatic Mutation in the Human Antibody Response to the Capsular Polysaccharide ofStreptococcus pneumoniaeType 23F

Zhou¹,

et al. 2002

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Combinatorial cloning and expression library analysis were used to isolate human antibody Fab fragments specific for the capsular polysaccharide of Streptococcus pneumoniae serotype 23F. Thirty 23F-specific Fabs were isolated from seven vaccinated donors, and the sequences of the heavy (H)-and light (L)-chain variable regions were determined. All individuals utilized either the V A23 L chain, the V L6 L chain, or both chains in forming the 23F-specific combining site. V A23 L chains paired primarily with VH3-23 H chains. V L6 L chains were more promiscuous in heavy-chain usage between individuals. Both H and L chains were mutated, primarily in the complementarity-determining regions, compared to their closest germ line counterpart, suggesting a recall response that has undergone affinity maturation. H-chain isotypes were reflective of those found in the serum. Shared somatic modifications demonstrated that immunoglobulin G2 (IgG2) and IgA antibodies arose from the same somatically matured B cell. Our results indicate that the response to the serotype 23F pneumococcal capsular polysaccharide is oligoclonal within the individual, with one or two paratope families accounting for the majority of expressed antibody. We also determined that, in spite of the combinatorial diversity available to the immune system, the 23F-specific response is highly restricted at the population level, with the same two L-chain-determined paratope families recurring in all individuals. Lastly, analysis of the isolated Fabs indicate all have undergone extensive somatic mutation, as well as class switch, maturational events that presumably require the participation of T cells.Streptococcus pneumoniae is a significant human pathogen causing pneumonia, bacteremia, meningitis, and otitis media. The pathogenic pneumococci are surrounded by a complex capsule composed of polymeric sugars, C polysaccharide, peptidoglycan, and surface proteins. The pneumococcal capsular polysaccharides (PPS), are heterogeneous in structure, with at least 90 different serotypes occurring within the species S. pneumoniae. PPS epitopes are immunogenic in adults and elicit antibodies that protect against infection. A vaccine containing capsular polysaccharides from 23 pneumococcal serotypes (23-valent) is available and is currently recommended for persons over 65 years of age and for other adults considered to be at increased risk of developing pneumococcal disease. Purified capsular polysaccharides do not, however, induce a protective antibody response in infants, who comprise one of the primary populations at risk. Consequently, a 7-valent polysaccharide-protein conjugate vaccine has been developed and shown to be efficacious in infants and has recently been licensed for use in this age group. Capsular polysaccharides are defined as TI-2 (T-cell-independent) antigens based on their repetitive structure and lack of immunogenicity in xid mice and human infants. The serum response to these polysaccharides in adults is oligoclonal and restricted in isotype, with immunog...

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Section: Discussionmentioning

confidence: 70%

Recurrent Variable Region Gene Usage and Somatic Mutation in the Human Antibody Response to the Capsular Polysaccharide ofStreptococcus pneumoniaeType 23F

Zhou¹,

et al. 2002

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“…The Fab pair 14-3-14-4 and Fab 23F-1 used HV 3-23, but their CDR-3s were distinctive, and they paired with different L chains. This promiscuity of HV 3-23 is perhaps not too surprising in light of the fact that this gene segment is commonly expressed in the peripheral repertoire (61), is used by a plethora of Abs having reactivities with either self or foreign Ags (47), and is a prominent member of the Hib PS repertoire, where it pairs with the KV 2D-29 V region to form the canonical combining site (37,48). Table 3 summarizes our Fab results and the results of previous studies of V region gene segment usage by PPSspecific monoclonal Abs (MAbs).…”

Section: Discussionmentioning

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

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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.

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“…26 Children under the age of 2 y are unable to make an efficient immune response to T-independent antigens such as plain polysaccharide vaccines. This phenomenon is not well understood but present models suggest (1) an immaturity of most B cells, e.g., lack of CD21/complement receptor 2 on neonatal B cells, [27][28][29] (2) differences in activation requirements between primary and secondary B cells with young children having primary B cells that require both BCR signaling and T cell help for activation, 30 (3) low frequency of marginal zone B cells, 31,32 (4) lower levels of complement C3, and (5) immaturity of marginal zone dendritic cells and the marginal zone in young children. 33 Although there are no data in infants, B MEM responses to plain polysaccharide and glycoconjugate vaccines have been compared when given to adolescents and adults.…”

Section: -Valent Pneumococcal Polysaccharide Vaccine (Ppv-23)mentioning

confidence: 99%