Immunoglobulin V
            <sub>H</sub>
            3 Gene Products: Natural Ligands for HIV gp120

Berberian, Linda; Goodglick, Lee; Kipps, Thomas J.; Braun, Jonathan

doi:10.1126/science.7690497

Cited by 265 publications

(176 citation statements)

References 42 publications

(14 reference statements)

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“…Although there is no direct evidence for a superantigen that stimulates rabbit B cell proliferation, certain features of rabbit B cells are consistent with the existence of such a molecule (38). For example, all rabbit V H gene segments belong to the V H III family (1), which is the major source of V H gene segments shown, in other species, to bind B cell superantigens such as Staphylococcal protein A (39) and HIV gp120 (40). Furthermore, Pospisil et al (38) observed preferential expansion of a subpopulation of rabbit appendix B cells that express particular IgH allotypic framework region specificities.…”

Section: Discussionmentioning

confidence: 90%

Intestinal Microflora and Diversification of the Rabbit Antibody Repertoire

Lanning

Sethupathi

Rhee

et al. 2000

The Journal of Immunology

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The rabbit establishes its primary Ab repertoire by somatically diversifying an initial repertoire that is limited by restricted V H gene segment usage during VDJ gene rearrangement. Somatic diversification occurs in gut-associated lymphoid tissue (GALT), and by about 1-2 mo of age nearly all Ig VDJ genes are somatically diversified. In other species that are known to establish their primary Ab repertoire by somatic diversification, such as chicken, sheep, and cattle, diversification appears to be developmentally regulated: it begins before birth and occurs independent of exogenous factors. Because somatic diversification in rabbit occurs well after birth in GALT, the diversification process may not be developmentally regulated, but may require interaction with exogenous factors derived from the gut. To test this hypothesis, we examined Ab repertoire diversification in rabbits in which the appendix was ligated shortly after birth to prevent microbial colonization and all other organized GALT was surgically removed. We found that by 12 wk of age nearly 90% of the Ig VDJ genes in PBL were undiversified, indicating that intestinal microflora are required for somatically diversifying the Ab repertoire. We also examined repertoire diversification in sterilely derived remote colony rabbits that were hand raised away from contact with conventional rabbits and thereby acquired a different gut microflora. In these remote colony rabbits, GALT was underdeveloped, and 70% of the Ig VDJ genes in PBL were undiversified. We conclude that specific, currently unidentified intestinal microflora are required for Ab repertoire diversification. The Journal of Immunology, 2000, 165: 2012-2019.T he rabbit is one of a few vertebrate species known to make limited use of combinatorial joining of multiple V H, D H , and J H gene segments during Ig heavy chain gene rearrangement. Although there are more than 100 V H gene segments available within the rabbit Ig heavy chain locus, many of which appear to be potentially functional (1), the 3Ј-most V H gene segment, V H 1, is utilized in 80 -90% of VDJ gene rearrangements (2). Most of the remaining 10 -20% of VDJ gene rearrangements utilize only two other V H gene segments, V H x and V H y (3). Rabbit B cells diversify their VDJ genes in gut-associated lymphoid tissue (GALT) 4 at 1-2 mo of age through two targeted mutational processes: a somatic gene conversion-like mechanism that transfers tracts of nucleotide sequence from upstream V H gene segment donors into the rearranged V H gene segment (4), and somatic hypermutation that distributes point mutations throughout the entire VDJ gene (5-7). At that time, the B cell population is also expanded through proliferation in GALT. B cell proliferation and Ig VDJ gene diversification in GALT results in a large population of B cells that express a wide range of Ab specificities.Several studies have established the importance of GALT in B cell proliferation and VDJ gene diversification. Weinstein et al. (7), for example, determined VDJ gene nucleotide...

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Section: Discussionmentioning

confidence: 90%

Intestinal Microflora and Diversification of the Rabbit Antibody Repertoire

Lanning

Sethupathi

Rhee

et al. 2000

The Journal of Immunology

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“…4 As illustrated for the anti-VIP IgG in Table II, large gains in catalytic competence occur due to enhanced antigen binding affinity (reduced K m ). Certain polypeptides are recognized by IgM Abs present in the preimmune repertoire with high affinity, for example, the superantigens staphylococcal protein A and HIV gp120 5 are recognized by IgM Abs containing VH3 family domains with K d in the nanomolar range (46,47). Moreover, specific IgM Abs with improved affinity for individual antigens emerge by adaptive V domain maturation processes (16,48).…”

Section: Discussionmentioning

confidence: 99%

Ontogeny of Proteolytic Immunity

Planque

Bangale

Song

et al. 2004

Journal of Biological Chemistry

104

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Antigen-specific IgG Abs 1 in autoimmune and alloimmune disease are described to catalyze chemical reactions (1-3). Examples of catalytic Abs raised by routine experimental immunization with ordinary antigens have also been published (4 -7). However, no consensus has developed whether naturally occurring catalytic Abs represent rare accidents arising from adaptive sequence diversification processes or genuine enzymes with important functional roles. The major reason is that the turnover (k cat ) of antigen-specific IgG Abs is low. Some catalytic Abs express catalytic efficiencies (k cat /K m ) comparable to conventional enzymes, but this is due to high affinity recognition of the antigen ground state (reviewed in Ref. 8).Certain enzymes cleave peptide bonds by a mechanism involving the formation of a transient covalent intermediate of the substrate and a nucleophilic residue present in the active site. The nucleophiles are generated by intramolecular activation mechanisms, e.g. the activation of Ser/Thr side chain hydroxyl groups by hydrogen bonding to His residues, and can be detected by covalent binding to electrophilic phosphonate diesters (9, 10). Using these compounds as covalently reactive analogs of antigens (CRAs), we observed that IgG Abs express nucleophilic reactivities comparable to trypsin (11). Despite their nucleophilic competence, IgG Abs display low efficiency proteolysis, presumably due to deficiencies in steps occurring after formation of the acyl-Ab intermediate, viz., water attack on the intermediate and product release. Occupancy of the B cell receptor (BCR, surface Ig complexed to ␣ and ␤ subunits along with other signal transducing proteins) by the antigen drives B cell clonal selection. Proteolysis by the BCR is compatible with clonal selection, therefore, only to the extent that the release of antigen fragments is slower than the rate of antigeninduced transmembrane signaling necessary for induction of cell division. Immunization with haptens mimicking the charge characteristics of the transition state (12) has been suggested as a way to surmount the barrier to adaptive improvement of catalytic rate constants. Catalysis by designer IgG Abs obtained by these means, however, also proceeds only slowly.In mice and humans, the initial Ab repertoire consists of ϳ100 heritable VL and VH genes. Adaptive maturational processes expand the repertoire by several orders of magnitude. The initial BCR complex on the pre-B cell surface contains V-(D)-J rearranged Ig chains as a complex with surrogate L chains (reviewed in Ref. 13). Precise assignment of the B cell differentiation stage at which cell division becomes antigen-dependent is somewhat ambiguous, but it is generally believed that non-covalent antigen binding to the pre-BCR is not required for initial cell growth. / chains replace the surrogate L chain at the later stages of antigen-driven B cell differentiation, which is accompanied by diversification via somatic hypermutation processes and continued gene rearrangements (14,15). V-(D)-J gene ...

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“…Recently, the superantigen residues of the gp120 engaged in binding to Ig V H 3 have been identified (Goodglick et al, 1995;Karray and Zouali, 1997). It has been reported that the repertoire of Ig V H genes binding to gp120 is restricted to a limited number of Ig V H 3 genes (VH26,[3][4][5][6][7][8][9][10][11][12][13][14][15] with high homology (96% to 100%) to germline configuration and that gp120 binding is sensitive to somatic mutation (Berberian et al, 1993;Karray and Zouali, 1997). In Ig V H 3 underexpressed HIV-related LIP, we did not detect any clones belonging to those limited Ig V H 3 genes (VH26,[3][4][5][6][7][8][9][10][11][12][13][14][15].…”

Section: Discussionmentioning

confidence: 99%