Diversity of Immunoglobulin Light Chain Usage in the Human Immune Response to Haemophilus influenzae Type b Capsular Polysaccharide

Adderson, Elisabeth E.; Shackelford, Penelope G.; Quinn, Anthony; Wilson, Patricia M.; Carroll, William L.

doi:10.1203/00006450-199303000-00022

Cited by 62 publications

(87 citation statements)

References 4 publications

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“…The majority of V H genes fall into the VH3 gene family (22 members, or 43%), with VH1, VH3, and VH4 gene families collectively comprising 86% of all V H gene sequences. Restricted patterns of heavy and light chain gene usage have been described for a number of autoimmune and naturally occurring immune responses, including idiopathic thrombocytopenic purpura, systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, and Haemophilus influenzae type b infection, among others (35)(36)(37)(38)(39). However, nonstochastic utilization of V H gene segments has been reported to occur in the normal human antibody repertoire as well, with overrepresentation of VH3-23 and VH4-34, possibly due to mechanisms of both preferential rearrangement of V H gene loci and receptor-dependent selection (40,41).…”

Section: Discussionmentioning

confidence: 99%

Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display

Payne¹,

Ishii²,

Kacir³

et al. 2005

J. Clin. Invest.

133

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Pemphigus is a life-threatening blistering disorder of the skin and mucous membranes caused by pathogenic autoantibodies to desmosomal adhesion proteins desmoglein 3 (Dsg3) and Dsg1. Mechanisms of antibody pathogenicity are difficult to characterize using polyclonal patient sera. Using antibody phage display, we have isolated repertoires of human anti-Dsg mAbs as single-chain variable-region fragments (scFvs) from a patient with active mucocutaneous pemphigus vulgaris. ScFv mAbs demonstrated binding to Dsg3 or Dsg1 alone, or both Dsg3 and Dsg1. Inhibition ELISA showed that the epitopes defined by these scFvs are blocked by autoantibodies from multiple pemphigus patients. Injection of scFvs into neonatal mice identified 2 pathogenic scFvs that caused blisters histologically similar to those observed in pemphigus patients. Similarly, these 2 scFvs, but not others, induced cell sheet dissociation of cultured human keratinocytes, indicating that both pathogenic and nonpathogenic antibodies were isolated. Genetic analysis of these mAbs showed restricted patterns of heavy and light chain gene usage, which were distinct for scFvs with different desmoglein-binding specificities. Detailed characterization of these pemphigus mAbs should lead to a better understanding of the immunopathogenesis of disease and to more specifically targeted therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display

Payne¹,

Ishii²,

Kacir³

et al. 2005

J. Clin. Invest.

133

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show abstract

“…The mechanism(s) responsible for this phenomenon is not known, but presumably the coupling of protein caniers to the PS brings carrier-specific T cells into play that promote the activation and differentiation of Hib PS-specific B cells. Pauciclonality is a striking feature of the antibody response to Hib PS, as evidenced by limited clonotypic diversity (7,8), common use of an unmutated subgroup I1 VK region derived from the A2 gene (9), and predominance of VHIII chains (10)(11)(12). A crossreactive idiotype, designated HibId-1, is a marker for anti-Hib PS antibodies having the V K I I A~ region (1 3).…”

mentioning

confidence: 99%

Vaccine-Induced Human Antibody Responses to the Haemophilus influenzae b Polysaccharide in Severe Combined Immunodeficient Mice Engrafted with Human Leukocytes

et al. 1992

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ABSTRACT. We examined the ability of severe combined immunodeficient (=ID) mice-human peripheral blood leukocyte (PBL) chimeras to respond to immunization with Haemophilus influenza b polysaccharide (Hib PS) vaccines. Two to 3 wk after PBL engraftment, human-PBL-SCID mice, prepared with PBL from one of five adult donors, were immunized with free or protein-conjugated Hib PS. Antibody to Hib PS was quantitated in preimmunization and postimmunization sera. Before immunization, anti-Hib PS antibody was detectable (>lo ng/mL) in three of 40 mice. Of the 37 human-PBL-SCID mice not having detectable serum antibody before immunization, 31 produced 220 ng/mL (22-fold increase) anti-Hib PS antibody 2 to 3 wk after immunization. Both free and proteinconjugated forms of Hib PS were immunogenic. Geometric mean anti-Hib PS antibody levels ranged from 50 to 139 ng/mL. Vaccine-induced anti-Hib PS antibodies frequently expressed HibId-1, a cross-reactive idiotype that predominates the in vivo human antibody response to Hib PS. However, among mice engrafted with PBL from a single donor, the HibId-1 distribution was highly skewed, suggesting that clonally distinct B cells were being stimulated in individual mice. These findings indicate that human PBL transplanted into SCID mice are functionally responsive to Hib PS antigenic challenge. This system may serve as a useful model for studying the regulation and cellular requirements for human polysaccharide immunity. (Pediatr Res 32: 132-135,1992)

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“…All anti-script). VJ joints of the majority of anti-Hib polysaccharide Hib polysaccharide VH genes sequenced to date are members of antibody light chain variable region genes, including all X antithe VH3 gene family (7). However, serologic analysis indicates bodies and the predominant V,II A2-encoded K antibodies, are that some individuals also express a small portion of antibodies notable for the presence of an arginine residue.…”

Section: Developmentally Restricted Ig Gene Diversificationmentioning

confidence: 99%

“…Approximately 60% of serum gens at 12 mo of age or older (86). Additionally, each individual antibody of older children and adults is encoded by a single V,II appears to generate anticarbohydrate antibodies from a limited gene, A2, and at least a portion of these antibodies are encoded number of B cell clones and, in contrast to antibody directed in an unmutated form, irrespective of antigen presentation as against protein antigens, these antibodies are not characterized plain polysaccharide or polysaccharide-protein conjugate form by extensive somatic hypermutation (7,8,87). Programmed (8,89,96).…”

Section: Developmentally Restricted Ig Gene Diversificationmentioning

confidence: 99%

“…clonal human antibodies specific for this antigen. The polymer-CDR-3 regions of both heavy and light chain variable region ase chain reaction was used to clone variable region genes from genes, created by VDJ and VJ joints, respectively, also appear to these cell lines (7,8) (Table 2). The most striking feature of this be relatively restricted.…”

Section: Developmentally Restricted Ig Gene Diversificationmentioning

confidence: 99%

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Development of the Human Antibody Repertoire

et al. 1992

Pediatr Res

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Diversity of Immunoglobulin Light Chain Usage in the Human Immune Response to Haemophilus influenzae Type b Capsular Polysaccharide

Cited by 62 publications

References 4 publications

Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display

Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display

Vaccine-Induced Human Antibody Responses to the Haemophilus influenzae b Polysaccharide in Severe Combined Immunodeficient Mice Engrafted with Human Leukocytes

Development of the Human Antibody Repertoire

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