HLA-DR modulates autoantibody repertoire, but not mortality, in a humanized mouse model of systemic lupus erythematosus

T. Paisansinsup, A. N. Vallejo, H. Luthra, C. S. David

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

To evaluate the disease-modulating role of HLA-DR2 and DR3 molecules, which have been associated with systemic lupus erythematosus, a humanized mouse model was examined. HLA-DR2 (DRB1*1502)- and DR3 (DRB1*0301)-transgenic mice were backcrossed to the New Zealand Mixed 2410 (NZM 2410, H2z) strain. Seventh generation DR2 and DR3 transgene-positive animals along with their transgene-negative littermates and the parental strain NZM2410 were monitored for proteinuria, azotemia, autoantibody production, development of nephritis, and mortality. The results showed no significant differences in proteinuria, azotemia, or mortality between the backcrosses with and without HLA-DR2 or HLA-DR3. However, the genetic analysis of different backcrosses showed that heterozygosity at the endogenous H2-E locus (Ez/Eb) was strongly linked with acceleration of lupus nephritis in both HLA-DR2 and HLA-DR3 transgenics. More importantly, the presence of the HLA-DR2, but not the HLA-DR3, transgene significantly enhanced the production of anti-dsDNA, but not anti-ssDNA, anti-histone-dsDNA complex, or anti-histone, Abs. In contrast, neither HLA-DR2 nor HLA-DR3 influenced the development of glomerulonephritis or the degree of immune complex deposition. Moreover, nephritic kidneys from mice with and without HLA-DR2 or HLA-DR3 transgenes showed similar patterns of cytokine expression. Collectively, these findings provide molecular evidence that the association of HLA-DR2 or HLA-DR3 with lupus susceptibility is related to the type of autoantibody rather than to disease mortality. The use of a humanized mouse model provides a way of dissecting the roles of human MHC genes in systemic lupus erythematosus pathogenesis.

Original languageEnglish (US)
Pages (from-to)4083-4090
Number of pages8
JournalJournal of Immunology
Volume167
Issue number7
StatePublished - Oct 1 2001

Fingerprint

HLA-DR2 Antigen
HLA-DR3 Antigen
HLA-DR Antigens
Systemic Lupus Erythematosus
Autoantibodies
Mortality
Transgenes
Azotemia
Proteinuria
Histones
Kidney
HLA-DRB1 Chains
Lupus Nephritis
Nephritis
Glomerulonephritis
Antigen-Antibody Complex
New Zealand
Transgenic Mice
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

HLA-DR modulates autoantibody repertoire, but not mortality, in a humanized mouse model of systemic lupus erythematosus. / Paisansinsup, T.; Vallejo, A. N.; Luthra, H.; David, C. S.

In: Journal of Immunology, Vol. 167, No. 7, 01.10.2001, p. 4083-4090.

Research output: Contribution to journalArticle

Paisansinsup, T, Vallejo, AN, Luthra, H & David, CS 2001, 'HLA-DR modulates autoantibody repertoire, but not mortality, in a humanized mouse model of systemic lupus erythematosus', Journal of Immunology, vol. 167, no. 7, pp. 4083-4090.
Paisansinsup, T. ; Vallejo, A. N. ; Luthra, H. ; David, C. S. / HLA-DR modulates autoantibody repertoire, but not mortality, in a humanized mouse model of systemic lupus erythematosus. In: Journal of Immunology. 2001 ; Vol. 167, No. 7. pp. 4083-4090.
@article{162b9656dd184fb8999bb63c1cab8de8,
title = "HLA-DR modulates autoantibody repertoire, but not mortality, in a humanized mouse model of systemic lupus erythematosus",
abstract = "To evaluate the disease-modulating role of HLA-DR2 and DR3 molecules, which have been associated with systemic lupus erythematosus, a humanized mouse model was examined. HLA-DR2 (DRB1*1502)- and DR3 (DRB1*0301)-transgenic mice were backcrossed to the New Zealand Mixed 2410 (NZM 2410, H2z) strain. Seventh generation DR2 and DR3 transgene-positive animals along with their transgene-negative littermates and the parental strain NZM2410 were monitored for proteinuria, azotemia, autoantibody production, development of nephritis, and mortality. The results showed no significant differences in proteinuria, azotemia, or mortality between the backcrosses with and without HLA-DR2 or HLA-DR3. However, the genetic analysis of different backcrosses showed that heterozygosity at the endogenous H2-E locus (Ez/Eb) was strongly linked with acceleration of lupus nephritis in both HLA-DR2 and HLA-DR3 transgenics. More importantly, the presence of the HLA-DR2, but not the HLA-DR3, transgene significantly enhanced the production of anti-dsDNA, but not anti-ssDNA, anti-histone-dsDNA complex, or anti-histone, Abs. In contrast, neither HLA-DR2 nor HLA-DR3 influenced the development of glomerulonephritis or the degree of immune complex deposition. Moreover, nephritic kidneys from mice with and without HLA-DR2 or HLA-DR3 transgenes showed similar patterns of cytokine expression. Collectively, these findings provide molecular evidence that the association of HLA-DR2 or HLA-DR3 with lupus susceptibility is related to the type of autoantibody rather than to disease mortality. The use of a humanized mouse model provides a way of dissecting the roles of human MHC genes in systemic lupus erythematosus pathogenesis.",
author = "T. Paisansinsup and Vallejo, {A. N.} and H. Luthra and David, {C. S.}",
year = "2001",
month = "10",
day = "1",
language = "English (US)",
volume = "167",
pages = "4083--4090",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "7",

}

TY - JOUR

T1 - HLA-DR modulates autoantibody repertoire, but not mortality, in a humanized mouse model of systemic lupus erythematosus

AU - Paisansinsup, T.

AU - Vallejo, A. N.

AU - Luthra, H.

AU - David, C. S.

PY - 2001/10/1

Y1 - 2001/10/1

N2 - To evaluate the disease-modulating role of HLA-DR2 and DR3 molecules, which have been associated with systemic lupus erythematosus, a humanized mouse model was examined. HLA-DR2 (DRB1*1502)- and DR3 (DRB1*0301)-transgenic mice were backcrossed to the New Zealand Mixed 2410 (NZM 2410, H2z) strain. Seventh generation DR2 and DR3 transgene-positive animals along with their transgene-negative littermates and the parental strain NZM2410 were monitored for proteinuria, azotemia, autoantibody production, development of nephritis, and mortality. The results showed no significant differences in proteinuria, azotemia, or mortality between the backcrosses with and without HLA-DR2 or HLA-DR3. However, the genetic analysis of different backcrosses showed that heterozygosity at the endogenous H2-E locus (Ez/Eb) was strongly linked with acceleration of lupus nephritis in both HLA-DR2 and HLA-DR3 transgenics. More importantly, the presence of the HLA-DR2, but not the HLA-DR3, transgene significantly enhanced the production of anti-dsDNA, but not anti-ssDNA, anti-histone-dsDNA complex, or anti-histone, Abs. In contrast, neither HLA-DR2 nor HLA-DR3 influenced the development of glomerulonephritis or the degree of immune complex deposition. Moreover, nephritic kidneys from mice with and without HLA-DR2 or HLA-DR3 transgenes showed similar patterns of cytokine expression. Collectively, these findings provide molecular evidence that the association of HLA-DR2 or HLA-DR3 with lupus susceptibility is related to the type of autoantibody rather than to disease mortality. The use of a humanized mouse model provides a way of dissecting the roles of human MHC genes in systemic lupus erythematosus pathogenesis.

AB - To evaluate the disease-modulating role of HLA-DR2 and DR3 molecules, which have been associated with systemic lupus erythematosus, a humanized mouse model was examined. HLA-DR2 (DRB1*1502)- and DR3 (DRB1*0301)-transgenic mice were backcrossed to the New Zealand Mixed 2410 (NZM 2410, H2z) strain. Seventh generation DR2 and DR3 transgene-positive animals along with their transgene-negative littermates and the parental strain NZM2410 were monitored for proteinuria, azotemia, autoantibody production, development of nephritis, and mortality. The results showed no significant differences in proteinuria, azotemia, or mortality between the backcrosses with and without HLA-DR2 or HLA-DR3. However, the genetic analysis of different backcrosses showed that heterozygosity at the endogenous H2-E locus (Ez/Eb) was strongly linked with acceleration of lupus nephritis in both HLA-DR2 and HLA-DR3 transgenics. More importantly, the presence of the HLA-DR2, but not the HLA-DR3, transgene significantly enhanced the production of anti-dsDNA, but not anti-ssDNA, anti-histone-dsDNA complex, or anti-histone, Abs. In contrast, neither HLA-DR2 nor HLA-DR3 influenced the development of glomerulonephritis or the degree of immune complex deposition. Moreover, nephritic kidneys from mice with and without HLA-DR2 or HLA-DR3 transgenes showed similar patterns of cytokine expression. Collectively, these findings provide molecular evidence that the association of HLA-DR2 or HLA-DR3 with lupus susceptibility is related to the type of autoantibody rather than to disease mortality. The use of a humanized mouse model provides a way of dissecting the roles of human MHC genes in systemic lupus erythematosus pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=0035478001&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035478001&partnerID=8YFLogxK

M3 - Article

C2 - 11564830

AN - SCOPUS:0035478001

VL - 167

SP - 4083

EP - 4090

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 7

ER -