Human HLA-DRS gene hypervariable region homology in the biobreeding BB rat

Selection of the diabetic-resistant subline as a rheumatoid arthritis research tool to characterize the immunopathologic response to human type II collagen

W. C. Watson, J. P. Thompson, K. Terato, M. A. Cremer, Andrew Kang

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Abstract

Collagen arthritis (CA), an autoimmune model of rheumatoid arthritis (RA), has been studied in various animals. However, it has not been studied in an animal with a genetic background relevant to RA. We selected rats from a diabetic-resistant (DR) subline of the diabetic BB rat because they have an autoimmune disease-prone background, but not the immunodeficiencies of the diabetic BB rat, and the third hypervariable region (HVRIII) of the BB RT1γ gene appeared to encode a nucleotide sequence of the human HLA DRγ gene, which has been reported to be associated with susceptibility to RA. We synthesized oligonucleotide primers flanking the RTLDO HVRIII, cloned polymerase chain reaction-amplified DNA into M13mp18, and confirmed the presence of the susceptibility sequence (SS) (RRRAA) by the dideoxy sequencing method in a colony ofDR BB/Wor-UTM rats. When immunized with human type II collagen (CII) in incomplete Freunds adjuvant (IFA), arthritis developed rapidly by day 10 with 100% incidence. Light and electron microscopy revealed an unusually severe and aggressive, bidirectional pattern of cartilage resorption by synovial and subchondral mononuclear and multinucleated inflammatory cells. These findings coincided with a predominant humoral response to the cyanogen bromide (CB) 11 fragment of the human CII molecule by the pathogenic IgG2a isotype. This study provides further support to the role of CA as a relevant RA model, the specific roles of the CB11 fragment as a major site of arthritogenic epitopes, and of antibody mechanisms in the pathogenesis of CA. Furthermore, the identification of an RA SS in an immune response gene of the DR BB rat presents a novel opportunity to determine with an animal model the role of other antigens as well as this SS in RA.

Original languageEnglish (US)
Pages (from-to)1331-1339
Number of pages9
JournalJournal of Experimental Medicine
Volume172
Issue number5
DOIs
StatePublished - Nov 1 1990

Fingerprint

Inbred BB Rats
Collagen Type II
Rheumatoid Arthritis
Experimental Arthritis
Research
Genes
Cyanogen Bromide
DNA Primers
Autoimmune Diseases
Cartilage
Epitopes
Electron Microscopy
Animal Models
Light
Antigens
Polymerase Chain Reaction
Antibodies
DNA
Incidence

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

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title = "Human HLA-DRS gene hypervariable region homology in the biobreeding BB rat: Selection of the diabetic-resistant subline as a rheumatoid arthritis research tool to characterize the immunopathologic response to human type II collagen",
abstract = "Collagen arthritis (CA), an autoimmune model of rheumatoid arthritis (RA), has been studied in various animals. However, it has not been studied in an animal with a genetic background relevant to RA. We selected rats from a diabetic-resistant (DR) subline of the diabetic BB rat because they have an autoimmune disease-prone background, but not the immunodeficiencies of the diabetic BB rat, and the third hypervariable region (HVRIII) of the BB RT1γ gene appeared to encode a nucleotide sequence of the human HLA DRγ gene, which has been reported to be associated with susceptibility to RA. We synthesized oligonucleotide primers flanking the RTLDO HVRIII, cloned polymerase chain reaction-amplified DNA into M13mp18, and confirmed the presence of the susceptibility sequence (SS) (RRRAA) by the dideoxy sequencing method in a colony ofDR BB/Wor-UTM rats. When immunized with human type II collagen (CII) in incomplete Freunds adjuvant (IFA), arthritis developed rapidly by day 10 with 100{\%} incidence. Light and electron microscopy revealed an unusually severe and aggressive, bidirectional pattern of cartilage resorption by synovial and subchondral mononuclear and multinucleated inflammatory cells. These findings coincided with a predominant humoral response to the cyanogen bromide (CB) 11 fragment of the human CII molecule by the pathogenic IgG2a isotype. This study provides further support to the role of CA as a relevant RA model, the specific roles of the CB11 fragment as a major site of arthritogenic epitopes, and of antibody mechanisms in the pathogenesis of CA. Furthermore, the identification of an RA SS in an immune response gene of the DR BB rat presents a novel opportunity to determine with an animal model the role of other antigens as well as this SS in RA.",
author = "Watson, {W. C.} and Thompson, {J. P.} and K. Terato and Cremer, {M. A.} and Andrew Kang",
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AU - Watson, W. C.

AU - Thompson, J. P.

AU - Terato, K.

AU - Cremer, M. A.

AU - Kang, Andrew

PY - 1990/11/1

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AB - Collagen arthritis (CA), an autoimmune model of rheumatoid arthritis (RA), has been studied in various animals. However, it has not been studied in an animal with a genetic background relevant to RA. We selected rats from a diabetic-resistant (DR) subline of the diabetic BB rat because they have an autoimmune disease-prone background, but not the immunodeficiencies of the diabetic BB rat, and the third hypervariable region (HVRIII) of the BB RT1γ gene appeared to encode a nucleotide sequence of the human HLA DRγ gene, which has been reported to be associated with susceptibility to RA. We synthesized oligonucleotide primers flanking the RTLDO HVRIII, cloned polymerase chain reaction-amplified DNA into M13mp18, and confirmed the presence of the susceptibility sequence (SS) (RRRAA) by the dideoxy sequencing method in a colony ofDR BB/Wor-UTM rats. When immunized with human type II collagen (CII) in incomplete Freunds adjuvant (IFA), arthritis developed rapidly by day 10 with 100% incidence. Light and electron microscopy revealed an unusually severe and aggressive, bidirectional pattern of cartilage resorption by synovial and subchondral mononuclear and multinucleated inflammatory cells. These findings coincided with a predominant humoral response to the cyanogen bromide (CB) 11 fragment of the human CII molecule by the pathogenic IgG2a isotype. This study provides further support to the role of CA as a relevant RA model, the specific roles of the CB11 fragment as a major site of arthritogenic epitopes, and of antibody mechanisms in the pathogenesis of CA. Furthermore, the identification of an RA SS in an immune response gene of the DR BB rat presents a novel opportunity to determine with an animal model the role of other antigens as well as this SS in RA.

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