Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies

Aaron Silva-Sanchez, Cun Ren Liu, Andre M. Vale, Mohamed Khass, Pratibha Kapoor, Ada Elgavish, Ivaylo I. Ivanov, Gregory C. Ippolito, Robert Schelonka, Trenton R. Schoeb, Peter D. Burrows, Harry W. Schroeder

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Variability in the developing antibody repertoire is focused on the third complementarity determining region of the H chain (CDR-H3), which lies at the center of the antigen binding site where it often plays a decisive role in antigen binding. The power of VDJ recombination and N nucleotide addition has led to the common conception that the sequence of CDR-H3 is unrestricted in its variability and random in its composition. Under this view, the immune response is solely controlled by somatic positive and negative clonal selection mechanisms that act on individual B cells to promote production of protective antibodies and prevent the production of self-reactive antibodies. This concept of a repertoire of random antigen binding sites is inconsistent with the observation that diversity (DH) gene segment sequence content by reading frame (RF) is evolutionarily conserved, creating biases in the prevalence and distribution of individual amino acids in CDR-H3. For example, arginine, which is often found in the CDR-H3 of dsDNA binding autoantibodies, is under-represented in the commonly used DH RFs rearranged by deletion, but is a frequent component of rarely used inverted RF1 (iRF1), which is rearranged by inversion. To determine the effect of altering this germline bias in DH gene segment sequence on autoantibody production, we generated mice that by genetic manipulation are forced to utilize an iRF1 sequence encoding two arginines. Over a one year period we collected serial serum samples from these unimmunized, specific pathogen-free mice and found that more than one-fifth of them contained elevated levels of dsDNA-binding IgG, but not IgM; whereas mice with a wild type DH sequence did not. Thus, germline bias against the use of arginine enriched DH sequence helps to reduce the likelihood of producing self-reactive antibodies.

Original languageEnglish (US)
Article numbere0118171
JournalPLoS One
Volume10
Issue number2
DOIs
StatePublished - Feb 23 2015

Fingerprint

Immunoglobulin Genes
Arginine
Immunoglobulins
Immunoglobulin G
Genes
arginine
Antigens
nucleotide sequences
Autoantibodies
antibodies
Antibodies
antigens
Binding Sites
V(D)J Recombination
Sequence Inversion
Complementarity Determining Regions
Specific Pathogen-Free Organisms
binding sites
germ cells
Reading Frames

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Silva-Sanchez, A., Liu, C. R., Vale, A. M., Khass, M., Kapoor, P., Elgavish, A., ... Schroeder, H. W. (2015). Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies. PLoS One, 10(2), [e0118171]. https://doi.org/10.1371/journal.pone.0118171

Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies. / Silva-Sanchez, Aaron; Liu, Cun Ren; Vale, Andre M.; Khass, Mohamed; Kapoor, Pratibha; Elgavish, Ada; Ivanov, Ivaylo I.; Ippolito, Gregory C.; Schelonka, Robert; Schoeb, Trenton R.; Burrows, Peter D.; Schroeder, Harry W.

In: PLoS One, Vol. 10, No. 2, e0118171, 23.02.2015.

Research output: Contribution to journalArticle

Silva-Sanchez, A, Liu, CR, Vale, AM, Khass, M, Kapoor, P, Elgavish, A, Ivanov, II, Ippolito, GC, Schelonka, R, Schoeb, TR, Burrows, PD & Schroeder, HW 2015, 'Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies', PLoS One, vol. 10, no. 2, e0118171. https://doi.org/10.1371/journal.pone.0118171
Silva-Sanchez, Aaron ; Liu, Cun Ren ; Vale, Andre M. ; Khass, Mohamed ; Kapoor, Pratibha ; Elgavish, Ada ; Ivanov, Ivaylo I. ; Ippolito, Gregory C. ; Schelonka, Robert ; Schoeb, Trenton R. ; Burrows, Peter D. ; Schroeder, Harry W. / Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies. In: PLoS One. 2015 ; Vol. 10, No. 2.
@article{c7178cc1722a4070b2c3af49b98ff1dc,
title = "Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies",
abstract = "Variability in the developing antibody repertoire is focused on the third complementarity determining region of the H chain (CDR-H3), which lies at the center of the antigen binding site where it often plays a decisive role in antigen binding. The power of VDJ recombination and N nucleotide addition has led to the common conception that the sequence of CDR-H3 is unrestricted in its variability and random in its composition. Under this view, the immune response is solely controlled by somatic positive and negative clonal selection mechanisms that act on individual B cells to promote production of protective antibodies and prevent the production of self-reactive antibodies. This concept of a repertoire of random antigen binding sites is inconsistent with the observation that diversity (DH) gene segment sequence content by reading frame (RF) is evolutionarily conserved, creating biases in the prevalence and distribution of individual amino acids in CDR-H3. For example, arginine, which is often found in the CDR-H3 of dsDNA binding autoantibodies, is under-represented in the commonly used DH RFs rearranged by deletion, but is a frequent component of rarely used inverted RF1 (iRF1), which is rearranged by inversion. To determine the effect of altering this germline bias in DH gene segment sequence on autoantibody production, we generated mice that by genetic manipulation are forced to utilize an iRF1 sequence encoding two arginines. Over a one year period we collected serial serum samples from these unimmunized, specific pathogen-free mice and found that more than one-fifth of them contained elevated levels of dsDNA-binding IgG, but not IgM; whereas mice with a wild type DH sequence did not. Thus, germline bias against the use of arginine enriched DH sequence helps to reduce the likelihood of producing self-reactive antibodies.",
author = "Aaron Silva-Sanchez and Liu, {Cun Ren} and Vale, {Andre M.} and Mohamed Khass and Pratibha Kapoor and Ada Elgavish and Ivanov, {Ivaylo I.} and Ippolito, {Gregory C.} and Robert Schelonka and Schoeb, {Trenton R.} and Burrows, {Peter D.} and Schroeder, {Harry W.}",
year = "2015",
month = "2",
day = "23",
doi = "10.1371/journal.pone.0118171",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies

AU - Silva-Sanchez, Aaron

AU - Liu, Cun Ren

AU - Vale, Andre M.

AU - Khass, Mohamed

AU - Kapoor, Pratibha

AU - Elgavish, Ada

AU - Ivanov, Ivaylo I.

AU - Ippolito, Gregory C.

AU - Schelonka, Robert

AU - Schoeb, Trenton R.

AU - Burrows, Peter D.

AU - Schroeder, Harry W.

PY - 2015/2/23

Y1 - 2015/2/23

N2 - Variability in the developing antibody repertoire is focused on the third complementarity determining region of the H chain (CDR-H3), which lies at the center of the antigen binding site where it often plays a decisive role in antigen binding. The power of VDJ recombination and N nucleotide addition has led to the common conception that the sequence of CDR-H3 is unrestricted in its variability and random in its composition. Under this view, the immune response is solely controlled by somatic positive and negative clonal selection mechanisms that act on individual B cells to promote production of protective antibodies and prevent the production of self-reactive antibodies. This concept of a repertoire of random antigen binding sites is inconsistent with the observation that diversity (DH) gene segment sequence content by reading frame (RF) is evolutionarily conserved, creating biases in the prevalence and distribution of individual amino acids in CDR-H3. For example, arginine, which is often found in the CDR-H3 of dsDNA binding autoantibodies, is under-represented in the commonly used DH RFs rearranged by deletion, but is a frequent component of rarely used inverted RF1 (iRF1), which is rearranged by inversion. To determine the effect of altering this germline bias in DH gene segment sequence on autoantibody production, we generated mice that by genetic manipulation are forced to utilize an iRF1 sequence encoding two arginines. Over a one year period we collected serial serum samples from these unimmunized, specific pathogen-free mice and found that more than one-fifth of them contained elevated levels of dsDNA-binding IgG, but not IgM; whereas mice with a wild type DH sequence did not. Thus, germline bias against the use of arginine enriched DH sequence helps to reduce the likelihood of producing self-reactive antibodies.

AB - Variability in the developing antibody repertoire is focused on the third complementarity determining region of the H chain (CDR-H3), which lies at the center of the antigen binding site where it often plays a decisive role in antigen binding. The power of VDJ recombination and N nucleotide addition has led to the common conception that the sequence of CDR-H3 is unrestricted in its variability and random in its composition. Under this view, the immune response is solely controlled by somatic positive and negative clonal selection mechanisms that act on individual B cells to promote production of protective antibodies and prevent the production of self-reactive antibodies. This concept of a repertoire of random antigen binding sites is inconsistent with the observation that diversity (DH) gene segment sequence content by reading frame (RF) is evolutionarily conserved, creating biases in the prevalence and distribution of individual amino acids in CDR-H3. For example, arginine, which is often found in the CDR-H3 of dsDNA binding autoantibodies, is under-represented in the commonly used DH RFs rearranged by deletion, but is a frequent component of rarely used inverted RF1 (iRF1), which is rearranged by inversion. To determine the effect of altering this germline bias in DH gene segment sequence on autoantibody production, we generated mice that by genetic manipulation are forced to utilize an iRF1 sequence encoding two arginines. Over a one year period we collected serial serum samples from these unimmunized, specific pathogen-free mice and found that more than one-fifth of them contained elevated levels of dsDNA-binding IgG, but not IgM; whereas mice with a wild type DH sequence did not. Thus, germline bias against the use of arginine enriched DH sequence helps to reduce the likelihood of producing self-reactive antibodies.

UR - http://www.scopus.com/inward/record.url?scp=84923382900&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923382900&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0118171

DO - 10.1371/journal.pone.0118171

M3 - Article

C2 - 25706374

AN - SCOPUS:84923382900

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e0118171

ER -