Abstract
B-cell chronic lymphocytic leukemia (B-CLL) patients expressing unmutated immunoglobulin heavy variable regions (IGHVs) use the IGHV1-69 B cell receptor (BCR) in 25% of cases. Since HIV-1 envelope gp41 antibodies also frequently use IGHV1-69 gene segments, we hypothesized that IGHV1-69 B-CLL precursors may contribute to the gp41 B cell response during HIV-1 infection. To test this hypothesis, we rescued 5 IGHV1-69 unmutated antibodies as heterohybridoma IgM paraproteins and as recombinant IgG1 antibodies from B-CLL patients, determined their antigenic specificities and analyzed BCR sequences. IGHV1-69 B-CLL antibodies were enriched for reactivity with HIV-1 envelope gp41, influenza, hepatitis C virus E2 protein and intestinal commensal bacteria. These IGHV1-69 B-CLL antibodies preferentially used IGHD3 and IGHJ6 gene segments and had long heavy chain complementary determining region 3s (HCDR3s) (≥21 aa). IGHV1-69 B-CLL BCRs exhibited a phenylalanine at position 54 (F54) of the HCDR2 as do rare HIV-1 gp41 and influenza hemagglutinin stem neutralizing antibodies, while IGHV1-69 gp41 antibodies induced by HIV-1 infection predominantly used leucine (L54) allelic variants. These results demonstrate that the B-CLL cell population is an expansion of members of the innate polyreactive B cell repertoire with reactivity to a number of infectious agent antigens including intestinal commensal bacteria. The B-CLL IGHV1-69 B cell usage of F54 allelic variants strongly suggests that IGHV1-69 B-CLL gp41 antibodies derive from a restricted B cell pool that also produces rare HIV-1 gp41 and influenza hemagglutinin stem antibodies.
Original language | English |
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Article number | e90725 |
Number of pages | 9 |
Journal | PLoS ONE |
Volume | 9 |
Issue number | 3 |
DOIs | |
Publication status | Published - 10 Mar 2014 |
Keywords
- Alleles
- Amino Acid Sequence
- Antibodies, Monoclonal
- Antibodies, Neoplasm
- Bacteria
- Cell Line, Tumor
- Cross Reactions
- HIV Antigens
- HIV Infections
- HIV-1
- Hepacivirus
- Hepatitis C Antigens
- Humans
- Hybridomas
- Immunoglobulin Heavy Chains
- Immunoglobulin Variable Region
- Intestines
- Leukemia, Lymphocytic, Chronic, B-Cell
- Molecular Sequence Data
- Paraproteins
- Protein Binding
- Receptors, Antigen, B-Cell
- Recombinant Proteins
- Sequence Alignment
- Symbiosis
- Treatment Outcome