Molecular basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases

Tsaiwei Olee, Pei Ming Yang, Katherine A. Siminovitch, Nancy J. Olsen, Jan Hillson, Jennifer Wu, Franklin Kozin, Dennis A. Carson, Pojen P. Chen

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Recently, combined serological and molecular studies of autoantibodies have revealed that these antibodies play an important role in the normal function of the immune system and in the development of the B cell repertoire. Accordingly, we hypothesized that a homozygous deletion of a critical autoantibody-associated Ig variable (V) gene may alter the immune system and thus predispose the host to autoimmune disorders. Initial experiments revealed several restriction fragment length polymorphisms (RFLP) of the Humhv3005 gene, that is likely to encode heavy chains of rheumatoid factors, and the closely related 1.9III gene. By probing EcoR1-digested DNA with the Humhv3005/P1 probe, we found that one of the four major hybridizing bands was missing in ∼ 20% of patients with either rheumatoid arthritis or systemic lupus erythematosus, but only 2% of normal subjects. To delineate the genetic basis of this polymorphism, we have now employed the PCR to amplify and analyze hv3005, 1.9III, and homologous genes in individuals with characteristic RFLP genotypes. Our results indicate that the human Vh gene repertoire contains several hv3005- and 1.9III-like genes, and that a complete deletion of the hv3005-like genes is relatively restricted to a subset of autoimmune patients. These findings provide initial evidence for deletion of developmentally regulated autoreactive V genes in autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)193-203
Number of pages11
JournalJournal of Clinical Investigation
Volume88
Issue number1
DOIs
StatePublished - Jan 1 1991

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Restriction Fragment Length Polymorphisms
Autoantibodies
Autoimmune Diseases
Genes
Immune System
Rheumatoid Factor
Systemic Lupus Erythematosus
Rheumatoid Arthritis
B-Lymphocytes
Genotype
Polymerase Chain Reaction
Antibodies
DNA

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Olee, Tsaiwei ; Yang, Pei Ming ; Siminovitch, Katherine A. ; Olsen, Nancy J. ; Hillson, Jan ; Wu, Jennifer ; Kozin, Franklin ; Carson, Dennis A. ; Chen, Pojen P. / Molecular basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases. In: Journal of Clinical Investigation. 1991 ; Vol. 88, No. 1. pp. 193-203.
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Molecular basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases. / Olee, Tsaiwei; Yang, Pei Ming; Siminovitch, Katherine A.; Olsen, Nancy J.; Hillson, Jan; Wu, Jennifer; Kozin, Franklin; Carson, Dennis A.; Chen, Pojen P.

In: Journal of Clinical Investigation, Vol. 88, No. 1, 01.01.1991, p. 193-203.

Research output: Contribution to journalArticle

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AU - Olee, Tsaiwei

AU - Yang, Pei Ming

AU - Siminovitch, Katherine A.

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AU - Carson, Dennis A.

AU - Chen, Pojen P.

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AB - Recently, combined serological and molecular studies of autoantibodies have revealed that these antibodies play an important role in the normal function of the immune system and in the development of the B cell repertoire. Accordingly, we hypothesized that a homozygous deletion of a critical autoantibody-associated Ig variable (V) gene may alter the immune system and thus predispose the host to autoimmune disorders. Initial experiments revealed several restriction fragment length polymorphisms (RFLP) of the Humhv3005 gene, that is likely to encode heavy chains of rheumatoid factors, and the closely related 1.9III gene. By probing EcoR1-digested DNA with the Humhv3005/P1 probe, we found that one of the four major hybridizing bands was missing in ∼ 20% of patients with either rheumatoid arthritis or systemic lupus erythematosus, but only 2% of normal subjects. To delineate the genetic basis of this polymorphism, we have now employed the PCR to amplify and analyze hv3005, 1.9III, and homologous genes in individuals with characteristic RFLP genotypes. Our results indicate that the human Vh gene repertoire contains several hv3005- and 1.9III-like genes, and that a complete deletion of the hv3005-like genes is relatively restricted to a subset of autoimmune patients. These findings provide initial evidence for deletion of developmentally regulated autoreactive V genes in autoimmune diseases.

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