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Lamprey VLRB response to influenza virus supports universal rules of immunogenicity and antigenicity.

Altman MO, Bennink JR, Yewdell JW, Herrin BR - Elife (2015)

Bottom Line: Jawless vertebrates evolved a parallel system of humoral immunity, which recognizes antigens not with Ig, but with a structurally unrelated receptor called the variable lymphocyte receptor B (VLRB).We exploited the convergent evolution of Ig and VLRB antibodies (Abs) to investigate if intrinsic chemical features of foreign proteins determine their antigenicity and immunogenicity.Each focuses ~80% of the response on hemagglutinin (HA), mainly through recognition of the major antigenic sites in the HA globular head domain.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, United States.

ABSTRACT
Immunoglobulins (Igs) are a crown jewel of jawed vertebrate evolution. Through recombination and mutation of small numbers of genes, Igs can specifically recognize a vast variety of natural and man-made organic molecules. Jawless vertebrates evolved a parallel system of humoral immunity, which recognizes antigens not with Ig, but with a structurally unrelated receptor called the variable lymphocyte receptor B (VLRB). We exploited the convergent evolution of Ig and VLRB antibodies (Abs) to investigate if intrinsic chemical features of foreign proteins determine their antigenicity and immunogenicity. Surprisingly, we find lamprey VLRB and mouse Ig responses to influenza A virus are extremely similar. Each focuses ~80% of the response on hemagglutinin (HA), mainly through recognition of the major antigenic sites in the HA globular head domain. Our findings predict basic conservation of Ab responses to protein antigens, strongly supporting the use of animal models for understanding human Ab responses to viruses and protein immunogens.

No MeSH data available.


Related in: MedlinePlus

Paratope signature of VLRBs.(A) Contact residues determined by the crystal structures of VLRBs in complex with their antigens are highlighted in orange. RBC36 against H trisaccharide (3E6J); aGPA.23 against TF disaccharide (4K79); VLR4 against BclA (3TWI); and VLRB.2D against HEL (3G39). (B) Enrichment or shortfall of each amino acid in the contact residues relative to the total amino acids found in the full VLRB was determined from the ratio of frequency of each amino acid in contact residues vs the frequency in the total VLRB sequence. Leucine was excluded from the analysis as it is the major structural amino acid of VLRBs. No M, K, or P were found among the contact residues. Shortfall was determined by estimating, based on total VLRB frequency, how many amino acids would be there if the amino acid distribution was even throughout the VLRB.DOI:http://dx.doi.org/10.7554/eLife.07467.018
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fig5: Paratope signature of VLRBs.(A) Contact residues determined by the crystal structures of VLRBs in complex with their antigens are highlighted in orange. RBC36 against H trisaccharide (3E6J); aGPA.23 against TF disaccharide (4K79); VLR4 against BclA (3TWI); and VLRB.2D against HEL (3G39). (B) Enrichment or shortfall of each amino acid in the contact residues relative to the total amino acids found in the full VLRB was determined from the ratio of frequency of each amino acid in contact residues vs the frequency in the total VLRB sequence. Leucine was excluded from the analysis as it is the major structural amino acid of VLRBs. No M, K, or P were found among the contact residues. Shortfall was determined by estimating, based on total VLRB frequency, how many amino acids would be there if the amino acid distribution was even throughout the VLRB.DOI:http://dx.doi.org/10.7554/eLife.07467.018

Mentions: Analysis of hundreds of VLRB sequences has previously revealed a bias towards aromatic amino acids at the variable positions on the concave surface (Velikovsky et al., 2009). In these analyses, less than half of the variable position residues contact antigen. When only the antigen contacting residue frequency is quantified, the amino acids are biased towards Tyr, Trp, Asn, and Asp residues (Figure 5). A similar bias towards these residues in antigen-contacting positions of Ig has also been observed (Mian et al., 1991; Davies and Cohen, 1996; Ramaraj et al., 2012; Robin et al., 2014). These similarities may account for the recognition of similar epitopes. If so, this may also represent the optimal general solution for producing a single family of receptors capable of recognizing what is essentially an infinite array of antigens with high specificity and affinity.10.7554/eLife.07467.018Figure 5.Paratope signature of VLRBs.


Lamprey VLRB response to influenza virus supports universal rules of immunogenicity and antigenicity.

Altman MO, Bennink JR, Yewdell JW, Herrin BR - Elife (2015)

Paratope signature of VLRBs.(A) Contact residues determined by the crystal structures of VLRBs in complex with their antigens are highlighted in orange. RBC36 against H trisaccharide (3E6J); aGPA.23 against TF disaccharide (4K79); VLR4 against BclA (3TWI); and VLRB.2D against HEL (3G39). (B) Enrichment or shortfall of each amino acid in the contact residues relative to the total amino acids found in the full VLRB was determined from the ratio of frequency of each amino acid in contact residues vs the frequency in the total VLRB sequence. Leucine was excluded from the analysis as it is the major structural amino acid of VLRBs. No M, K, or P were found among the contact residues. Shortfall was determined by estimating, based on total VLRB frequency, how many amino acids would be there if the amino acid distribution was even throughout the VLRB.DOI:http://dx.doi.org/10.7554/eLife.07467.018
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4552221&req=5

fig5: Paratope signature of VLRBs.(A) Contact residues determined by the crystal structures of VLRBs in complex with their antigens are highlighted in orange. RBC36 against H trisaccharide (3E6J); aGPA.23 against TF disaccharide (4K79); VLR4 against BclA (3TWI); and VLRB.2D against HEL (3G39). (B) Enrichment or shortfall of each amino acid in the contact residues relative to the total amino acids found in the full VLRB was determined from the ratio of frequency of each amino acid in contact residues vs the frequency in the total VLRB sequence. Leucine was excluded from the analysis as it is the major structural amino acid of VLRBs. No M, K, or P were found among the contact residues. Shortfall was determined by estimating, based on total VLRB frequency, how many amino acids would be there if the amino acid distribution was even throughout the VLRB.DOI:http://dx.doi.org/10.7554/eLife.07467.018
Mentions: Analysis of hundreds of VLRB sequences has previously revealed a bias towards aromatic amino acids at the variable positions on the concave surface (Velikovsky et al., 2009). In these analyses, less than half of the variable position residues contact antigen. When only the antigen contacting residue frequency is quantified, the amino acids are biased towards Tyr, Trp, Asn, and Asp residues (Figure 5). A similar bias towards these residues in antigen-contacting positions of Ig has also been observed (Mian et al., 1991; Davies and Cohen, 1996; Ramaraj et al., 2012; Robin et al., 2014). These similarities may account for the recognition of similar epitopes. If so, this may also represent the optimal general solution for producing a single family of receptors capable of recognizing what is essentially an infinite array of antigens with high specificity and affinity.10.7554/eLife.07467.018Figure 5.Paratope signature of VLRBs.

Bottom Line: Jawless vertebrates evolved a parallel system of humoral immunity, which recognizes antigens not with Ig, but with a structurally unrelated receptor called the variable lymphocyte receptor B (VLRB).We exploited the convergent evolution of Ig and VLRB antibodies (Abs) to investigate if intrinsic chemical features of foreign proteins determine their antigenicity and immunogenicity.Each focuses ~80% of the response on hemagglutinin (HA), mainly through recognition of the major antigenic sites in the HA globular head domain.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, United States.

ABSTRACT
Immunoglobulins (Igs) are a crown jewel of jawed vertebrate evolution. Through recombination and mutation of small numbers of genes, Igs can specifically recognize a vast variety of natural and man-made organic molecules. Jawless vertebrates evolved a parallel system of humoral immunity, which recognizes antigens not with Ig, but with a structurally unrelated receptor called the variable lymphocyte receptor B (VLRB). We exploited the convergent evolution of Ig and VLRB antibodies (Abs) to investigate if intrinsic chemical features of foreign proteins determine their antigenicity and immunogenicity. Surprisingly, we find lamprey VLRB and mouse Ig responses to influenza A virus are extremely similar. Each focuses ~80% of the response on hemagglutinin (HA), mainly through recognition of the major antigenic sites in the HA globular head domain. Our findings predict basic conservation of Ab responses to protein antigens, strongly supporting the use of animal models for understanding human Ab responses to viruses and protein immunogens.

No MeSH data available.


Related in: MedlinePlus