Canonical Structure Repertoire of the Antigen-binding Site of Immunoglobulins Suggests Strong Geometrical Restrictions Associated to the Mechanism of Immune Recognition

Vargas-Madrazo, Enrique; Lara‐Ochoa, Francisco; Almagro, Juan C.

doi:10.1006/jmbi.1995.0633

Cited by 124 publications

(91 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For many 7183 V H gene elements, a single somatic mutation can yield the F33 and N57 motif found in MAb 13F1. The ability of the mouse genome to code for both protective and nonprotective specificities may underlie such perplexing observations as the fact that highly immunogenic polysaccharide-protein conjugate vaccines can elicit high-titer protective (13) annular IF pattern that is associated with Ab efficacy is consistent with the proposal that certain V H genes are required for carbohydrate binding (45) and the fact that class II Abs to GXM are all derived from the same Ab clan (25).…”

Section: Vol 69 2001mentioning

confidence: 56%

Molecular Basis for Immunoglobulin M Specificity to Epitopes inCryptococcus neoformansPolysaccharide That Elicit Protective and Nonprotective Antibodies

et al. 2001

View full text Add to dashboard Cite

The protective efficacy of antibodies (Abs) to Cryptococcus neoformans glucuronoxylomannan (GXM) is dependent on Ab fine specificity. Two clonally related immunoglobulin M monoclonal Abs (MAbs) (12A1 and 13F1) differ in fine specificity and protective efficacy, presumably due to variable (V)-region sequence differences resulting from somatic mutations. MAb 12A1 is protective and produces annular immunofluorescence (IF) on serotype D C. neoformans, while MAb 13F1 is not protective and produces punctate IF. To determine the Ab molecular determinants responsible for the IF pattern, site-directed mutagenesis of the MAb 12A1 heavy-chain V region (V H ) was followed by serological and functional studies of the various mutants. Changing two selected amino acids in the 12A1 V H binding cavity to the corresponding residues in the 13F1 V H altered the IF pattern from annular to punctate, reduced opsonic efficacy, and abolished recognition by an antiidiotypic Ab. Analysis of the binding of the various mutants to peptide mimetics revealed that different amino acids were responsible for GXM binding and peptide specificity. The results suggest that V-region motifs associated with annular binding and opsonic activity may be predictive of Ab efficacy against C. neoformans. This has important implications for immunotherapy and vaccine design that are reinforced by the finding that GXM and peptide reactivities are determined by different amino acid residues.The protective efficacy of antibodies (Abs) to the humanpathogenic fungus Cryptococcus neoformans depends on the Ab isotype and specificity (reviewed in references 3 and 46). The evidence that Ab specificity is critical for protective efficacy comes from studies of two clonally related immunoglobulin M (IgM) monoclonal Abs (MAbs) known as 12A1 and 13F1 (3, 31, 39, 46). Although these MAbs originated from the same B-cell precursor and use the same variable (V)-region genes, they differ in specificity as a result of V-region somatic mutations that translate into 12 amino acid differences (31, 39). The differences in specificity are manifested by differences in the indirect immunofluorescence (IF) binding pattern such that MAbs 12A1 and 13F1 produce annular and punctate patterns, respectively, after binding to serotype D C. neoformans cells (11,31,39). The annular binding pattern is correlated with opsonic efficacy, capsular reaction patterns, and complement activation kinetics (27) and Ab protection against serotype D organisms (31, 39). Since the MAb pair 12A1 and 13F1 have markedly different biological properties yet differ in sequence by only a few amino acids, they provide a unique opportunity for the study of Ab specificity.MAbs to C. neoformans capsular glucuronoxylomannan (GXM) have been grouped into five classes based on V-region usage and idiotype and serotype specificity (5). Class II MAbs include a large set of MAbs that bind to an immunodominant epitope found in all cryptococcal serotypes and are characterized by the use of V H 7183, J H 2, V 5.1, and J 1 gene eleme...

show abstract

Section: Vol 69 2001mentioning

confidence: 56%

Molecular Basis for Immunoglobulin M Specificity to Epitopes inCryptococcus neoformansPolysaccharide That Elicit Protective and Nonprotective Antibodies

et al. 2001

View full text Add to dashboard Cite

show abstract

“…Validation of this hypothesis requires analysis of the molecular derivation of PUB1-and PS-reactive antibodies, which was beyond the scope of the present study. Nonetheless, the concept is supported by evidence that antibodies to carbohydrates and proteins use different variable region genes (49) and the proposal that discrete antigen specificities are conferred by separate immunoglobulin clans (23).…”

Section: Discussionmentioning

confidence: 75%

A Peptide Mimotope of Type 8 Pneumococcal Capsular Polysaccharide Induces a Protective Immune Response in Mice

Buchwald

Lees

Steinitz³

et al. 2005

Infect Immun

View full text Add to dashboard Cite

Increasing antibiotic resistance and a rising patient population at risk for infection due to impaired immunity underscore the importance of vaccination against pneumococci. However, available capsular polysaccharide vaccines are often poorly immunogenic in patients at risk for pneumococcal disease. The goal of this study was to explore the potential of peptide mimotopes to function as alternative vaccine antigens to elicit a type-specific antibody response to pneumococci. We used a human monoclonal immunoglobulin A (IgA) antibody (NAD) to type 8 Streptococcus pneumoniae capsular polysaccharide (type 8 PS) to screen a phage display library, and the phage PUB1 displaying the peptide FHLPYNHNWFAL was selected after three rounds of biopanning. Inhibition studies with phage-displayed peptide or the peptide PUB1 and type 8 PS showed that PUB1 is a mimetic of type 8 PS. PUB1 conjugated to tetanus toxoid (PUB1-TT) induced a type 8 PS-specific antibody response in BALB/c mice, further defining it as a mimotope of type 8 PS. The administration of immune sera obtained from PUB1-TT-immunized mice earlier (days 14 and 21) and later (days 87 and 100) after primary and reimmunization resulted in a highly significant prolongation of the survival of naive mice after pneumococcal challenge compared to controls. The survival of PUB1-TT-immunized mice was also prolonged after pneumococcal challenge nearly 4 months after primary immunization. The efficacy of PUB1-TT-induced immune sera provides proof of principle that a mimotope-induced antibody response can protect against pneumococci and suggests that peptide mimotopes selected by type-specific human antibodies could hold promise as immunogens for pneumococci.

show abstract

“…Antibodies with short loops in CDR-H2 and CDR-L1 appear to be preferentially specific for large antigens, whereas antibodies with long loops in CDR-H2 and CDR-L1 appear to be preferentially specific for small molecules, including haptens [40]. It is possible that the length, structure, and amino acid composition of CDR-H3 may also correlate with epitope structures that are likely to be found in either T-dependent or T-independent antigens and thus lead to differential selection of the CDR-H3 repertoire.…”

Section: Discussionmentioning

confidence: 96%

Categorical selection of the antibody repertoire in splenic B cells

et al. 2007

View full text Add to dashboard Cite

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.

show abstract

Canonical Structure Repertoire of the Antigen-binding Site of Immunoglobulins Suggests Strong Geometrical Restrictions Associated to the Mechanism of Immune Recognition

Cited by 124 publications

References 0 publications

Molecular Basis for Immunoglobulin M Specificity to Epitopes inCryptococcus neoformansPolysaccharide That Elicit Protective and Nonprotective Antibodies

Molecular Basis for Immunoglobulin M Specificity to Epitopes inCryptococcus neoformansPolysaccharide That Elicit Protective and Nonprotective Antibodies

A Peptide Mimotope of Type 8 Pneumococcal Capsular Polysaccharide Induces a Protective Immune Response in Mice

Categorical selection of the antibody repertoire in splenic B cells

Contact Info

Product

Resources

About