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Surrogate light chain expressing human peripheral B cells produce self-reactive antibodies.

Meffre E, Schaefer A, Wardemann H, Wilson P, Davis E, Nussenzweig MC - J. Exp. Med. (2003)

Bottom Line: A majority of these autoantibodies are true antinuclear antibodies (ANA), and 50% of the ANAs are also reactive with a diverse group of antigens that include dsDNA, ssDNA, immunoglobulin, insulin, and bacterial lipopolysaccharide.Such antibodies are rarely encountered among conventional B cells.We conclude that V-preB+L+ B cells are a unique subset of normal circulating human B cells that escape central tolerance mechanisms and express self-reactive antibodies including potentially harmful ANAs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, The Rockefeller University, 1230 York Ave., New York, NY 10021, USA. meffree@hss.edu

ABSTRACT
Human B cells that coexpress surrogate and conventional light chains (V-preB+L+) show an unusual heavy and light chain antibody repertoire that display evidence of receptor editing. However, it is unclear whether V-preB+L+ B cells have been silenced by receptor editing or still express autoreactive antibodies. Here we report that 68% of the antibodies expressed by V-preB+L+ B cells are autoreactive. A majority of these autoantibodies are true antinuclear antibodies (ANA), and 50% of the ANAs are also reactive with a diverse group of antigens that include dsDNA, ssDNA, immunoglobulin, insulin, and bacterial lipopolysaccharide. Such antibodies are rarely encountered among conventional B cells. We conclude that V-preB+L+ B cells are a unique subset of normal circulating human B cells that escape central tolerance mechanisms and express self-reactive antibodies including potentially harmful ANAs.

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Polyreactive antibodies from V-preB+L+ B cells and M55 display similar IgH CDR3 features. Hydrophobic D reading frame and JH6 segments are in olive and brown boxes, respectively. Basic residues are in blue, and acidic amino acids are in red.
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fig5: Polyreactive antibodies from V-preB+L+ B cells and M55 display similar IgH CDR3 features. Hydrophobic D reading frame and JH6 segments are in olive and brown boxes, respectively. Basic residues are in blue, and acidic amino acids are in red.

Mentions: Autoantibodies reactive against DNA and Ig are prevalent in the serum of patients with systemic lupus erythematosus and rheumatoid arthritis, respectively. To determine whether V-preB+L+ antibodies recognize such antigens, we performed ELISAs for single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), IgM, insulin, and lipopolysaccharide (LPS) (Fig. 4) . As a positive control for polyreactivity, we used M55, a well-characterized polyreactive human antibody (22). 43% of antibodies expressed by V-preB+L+ cells (12 out of 28) recognized at least one of the above antigens and 32% (9 out of 28) bound to two or more antigens and were therefore polyreactive (Fig. 4). All of the polyreactive antibodies isolated from V-preB+L+ B cells showed long IgH CDR3s enriched in positively charged, hydrophobic, and aromatic amino acid residues encoded by unusual D reading frames and germline JH6 segments (Fig. 5) . Thus, the polyreactive antibodies showed the typical signature of V-preB+L+ Igs (5, 21). In contrast, only 4.8% (1 out of 21) of the antibodies expressed by conventional B cells were polyreactive, and these antibodies showed lower levels of reactivity than those from V-preB+L+ or M55 controls (Fig. 4). Similar low frequencies of polyreactivity were found in 93 antibodies cloned from naive human B cells (1). The one weakly polyreactive antibody isolated from conventional B cells differed from V-preB+L+ polyreactive antibodies in having a short IgH CDR3 without positively charged residues (KRV-18; Table S1). We conclude that antibodies expressed by V-preB+L+ B cells are frequently polyreactive.


Surrogate light chain expressing human peripheral B cells produce self-reactive antibodies.

Meffre E, Schaefer A, Wardemann H, Wilson P, Davis E, Nussenzweig MC - J. Exp. Med. (2003)

Polyreactive antibodies from V-preB+L+ B cells and M55 display similar IgH CDR3 features. Hydrophobic D reading frame and JH6 segments are in olive and brown boxes, respectively. Basic residues are in blue, and acidic amino acids are in red.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887722&req=5

fig5: Polyreactive antibodies from V-preB+L+ B cells and M55 display similar IgH CDR3 features. Hydrophobic D reading frame and JH6 segments are in olive and brown boxes, respectively. Basic residues are in blue, and acidic amino acids are in red.
Mentions: Autoantibodies reactive against DNA and Ig are prevalent in the serum of patients with systemic lupus erythematosus and rheumatoid arthritis, respectively. To determine whether V-preB+L+ antibodies recognize such antigens, we performed ELISAs for single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), IgM, insulin, and lipopolysaccharide (LPS) (Fig. 4) . As a positive control for polyreactivity, we used M55, a well-characterized polyreactive human antibody (22). 43% of antibodies expressed by V-preB+L+ cells (12 out of 28) recognized at least one of the above antigens and 32% (9 out of 28) bound to two or more antigens and were therefore polyreactive (Fig. 4). All of the polyreactive antibodies isolated from V-preB+L+ B cells showed long IgH CDR3s enriched in positively charged, hydrophobic, and aromatic amino acid residues encoded by unusual D reading frames and germline JH6 segments (Fig. 5) . Thus, the polyreactive antibodies showed the typical signature of V-preB+L+ Igs (5, 21). In contrast, only 4.8% (1 out of 21) of the antibodies expressed by conventional B cells were polyreactive, and these antibodies showed lower levels of reactivity than those from V-preB+L+ or M55 controls (Fig. 4). Similar low frequencies of polyreactivity were found in 93 antibodies cloned from naive human B cells (1). The one weakly polyreactive antibody isolated from conventional B cells differed from V-preB+L+ polyreactive antibodies in having a short IgH CDR3 without positively charged residues (KRV-18; Table S1). We conclude that antibodies expressed by V-preB+L+ B cells are frequently polyreactive.

Bottom Line: A majority of these autoantibodies are true antinuclear antibodies (ANA), and 50% of the ANAs are also reactive with a diverse group of antigens that include dsDNA, ssDNA, immunoglobulin, insulin, and bacterial lipopolysaccharide.Such antibodies are rarely encountered among conventional B cells.We conclude that V-preB+L+ B cells are a unique subset of normal circulating human B cells that escape central tolerance mechanisms and express self-reactive antibodies including potentially harmful ANAs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, The Rockefeller University, 1230 York Ave., New York, NY 10021, USA. meffree@hss.edu

ABSTRACT
Human B cells that coexpress surrogate and conventional light chains (V-preB+L+) show an unusual heavy and light chain antibody repertoire that display evidence of receptor editing. However, it is unclear whether V-preB+L+ B cells have been silenced by receptor editing or still express autoreactive antibodies. Here we report that 68% of the antibodies expressed by V-preB+L+ B cells are autoreactive. A majority of these autoantibodies are true antinuclear antibodies (ANA), and 50% of the ANAs are also reactive with a diverse group of antigens that include dsDNA, ssDNA, immunoglobulin, insulin, and bacterial lipopolysaccharide. Such antibodies are rarely encountered among conventional B cells. We conclude that V-preB+L+ B cells are a unique subset of normal circulating human B cells that escape central tolerance mechanisms and express self-reactive antibodies including potentially harmful ANAs.

Show MeSH