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The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies.

ABSTRACT: Polyreactive antibodies bind to a variety of structurally unrelated antigens. The function of these antibodies, however, has remained an enigma, and because of their low binding affinity their biological relevance has been questioned. Using a panel of monoclonal polyreactive antibodies, we showed that these antibodies can bind to both Gram-negative and Gram-positive bacteria and acting through the classical complement pathway can inhibit bacterial growth by lysis, generate anaphylatoxin C5a, enhance phagocytosis, and neutralize the functional activity of endotoxin. Polyreactive antibody-enriched, but not polyreactive antibody-reduced, IgM prepared from normal human serum displays antibacterial activity similar to that of monoclonal polyreactive IgM. We conclude that polyreactive antibodies are a major contributor to the broad antibacterial activity of the natural antibody repertoire.

SUBMITTER: Zhou ZH

PROVIDER: S-EPMC2212603 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies.

Zhou Zhao-Hua ZH Zhang Yahong Y Hu Ya-Fang YF Wahl Larry M LM Cisar John O JO Notkins Abner Louis AL

Cell host & microbe 20070301 1

Polyreactive antibodies bind to a variety of structurally unrelated antigens. The function of these antibodies, however, has remained an enigma, and because of their low binding affinity their biological relevance has been questioned. Using a panel of monoclonal polyreactive antibodies, we showed that these antibodies can bind to both Gram-negative and Gram-positive bacteria and acting through the classical complement pathway can inhibit bacterial growth by lysis, generate anaphylatoxin C5a, enh ...[more]

PMID: 18005681

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Project description:To gain insight into the functional antibody repertoire of rabbits, the VH and VL repertoires of bone marrow (BM) and spleen (SP) of a naïve New Zealand White rabbit (NZW; Oryctolagus cuniculus) and that of lymphocytes collected from a NZW rabbit immunized (IM) with a 16-mer peptide were deep-sequenced. Two closely related genes, IGHV1S40 (VH1a3) and IGHV1S45 (VH4), were found to dominate (~90%) the VH repertoire of BM and SP, whereas, IGHV1S69 (VH1a1) contributed significantly (~40%) to IM. BM and SP antibodies recombined predominantly with IGHJ4. A significant proportion (~30%) of IM sequences recombined with IGHJ2. The VK repertoire was encoded by nine IGKV genes recombined with one IGKJ gene, IGKJ1. No significant bias in the VK repertoire of the BM, SP and IM samples was observed. The complementarity-determining region (CDR)-H3 and -L3 length distributions were similar in the three samples following a Gaussian curve with average length of 12.2 ± 2.4 and 11.1 ± 1.1 amino acids, respectively. The amino acid composition of the predominant CDR-H3 and -L3 loop lengths was similar to that of humans and mice, rich in Tyr, Gly, Ser and, in some specific positions, Asp. The average number of mutations along the IGHV/KV genes was similar in BM, SP and IM; close to 12 and 15 mutations for VH and VL, respectively. A monoclonal antibody specific for the peptide used as immunogen was obtained from the IM rabbit. The CDR-H3 sequence was found in 1,559 of 61,728 (2.5%) sequences, at position 10, in the rank order of the CDR-H3 frequencies. The CDR-L3 was found in 24 of 11,215 (0.2%) sequences, ranking 102. No match was found in the BM and SP samples, indicating positive selection for the hybridoma sequence. Altogether, these findings lay foundations for engineering of rabbit V regions to enhance their potential as therapeutics, i.e., design of strategies for selection of specific rabbit V regions from NGS data mining, humanization and design of libraries for affinity maturation campaigns.

Project description:B lymphocytes committed to the production of antibodies binding to antigens on pathogenic bacteria and viruses (natural antibodies) are common components of the normal human B cell repertoire. A major proportion of natural antibodies is capable of binding multiple antigens (polyreactive antibodies). Using B cells from three HIV-1 seronegative healthy subjects, and purified HIV-1 and beta-galactosidase from Escherichia coli as selecting antigen, we generated three natural IgM mAb to HIV-1 and a natural IgM mAb to beta-galactosidase. The three HIV-1-selected antibodies (mAb102, mAb103, and mAb104) were polyreactive. They bound with different affinities (Kd = 10(-6) to 10(-8) M) to the HIV-1 envelope gp160, the p24 core protein, and the p66 reverse transcriptase, but not to the 120 glycosylated env protein. They also bound to beta-galactosidase (Kd approximately 10(-7) M), tetanus toxoid, and various various self antigens. In contrast, the natural mAb selected for binding to beta-galactosidase (mAb207.F1) was monoreactive, in that it bound with a high affinity (Kd < 10(-8) M) to this antigen, but to none of the other antigens tested, including HIV-1. Structural analysis of the VH and VL segments revealed that the natural mAb utilized three segments of the VHIV gene family and one of the VHIII family, in conjunction with VL segments of the V lambda I, V lambda II, V lambda III, or V kappa IV subgroups. In addition, the natural mAb VH and VL segments were in unmutated or virtually unmutated (germline) configuration, including those of the monoreactive mAb207.F1 to beta-galactosidase, and were identical or closely related to those utilized by specific autoantibodies or specific antibodies to viral and/or bacterial pathogens. Thus, the present data show that both polyreactive and monoreactive natural antibodies to foreign antigen can be isolated from the normal human B cell repertoire. They also suggest that the VH and VL segments of not only polyreactive but also monoreactive natural antibodies can be encoded in unmutated or minimally mutated genes, and possibly provide the templates for the specific high affinity antibodies elicited by self or foreign antigens.

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The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies.

Publications

The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies.

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