Gene organization of DC and DX subregions of the human major histocompatibility complex.

Okada, Kiyotaka; Boss, Jeremy M.; Prentice, Holly; Spies, Thomas A.; Mengler, Rosemarie; Auffray, Charles; Lillie, James W.; Grossberger, Dario; Strominger, Jack L.

doi:10.1073/pnas.82.10.3410

Cited by 146 publications

(70 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Transgenic mice were generated by the microinjection of a 33-kb genomic fragment containing the genes encoding HLA-DQ8 (DQA1*0301/DQB1*0302), along with their endogenous promoters and flanking sequences (21), into embryos of MHC class II-…”

Section: Resultsmentioning

confidence: 99%

A Spontaneous Model for Autoimmune Myocarditis Using the Human MHC Molecule HLA-DQ8

Taylor

Havari

McInerney

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

Genome-wide analyses have shown that the MHC class II region is the principal locus that confers susceptibility to a number of human autoimmune diseases. Due to the high degree of linkage disequilibrium across the MHC, it has been difficult to dissect the contribution of individual genes to disease susceptibility. As a result, intensive efforts have been made to generate mice transgenic for human class II molecules as models of autoimmune disease. However, in every case, additional manipulations—such as immunization with Ag in adjuvant, expression of immunostimulants on target tissues, or coexpression of TCR transgenes—have been required to induce disease. In this study, we show that expression of the human HLA-DQ8 (DQA1*0301/DQB1*0302) molecule alone in three lines of transgenic nonobese diabetic murine class II-deficient (mII−/−) mice results in the spontaneous development of autoimmune myocarditis. The disease shares key features of human myocarditis and was characterized by lymphocytic infiltrates in the myocardium and cardiac myocyte destruction, circulating IgG autoantibodies against cardiac myosin heavy chain, and premature death due to heart failure. We demonstrate that myocarditis could be transferred into healthy HLA-DQ8+RAG-1−/−mII−/− nonobese diabetic recipients with lymphocytes, but not sera. It has been widely thought that autoimmune myocarditis is of infectious etiology, with the immune responses arising secondary to cardiac damage from pathogens. These studies provide direct experimental evidence that spontaneous autoimmune myocarditis can occur in the absence of infection and that expression of HLA-DQ8 confers susceptibility to this organ-specific autoimmune disease.

show abstract

Section: Resultsmentioning

confidence: 99%

A Spontaneous Model for Autoimmune Myocarditis Using the Human MHC Molecule HLA-DQ8

Taylor

Havari

McInerney

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The DQA1*0301 and DQB1*0302 genes were not microinjected as two separate genomic fragments (i.e., from cosmids H11A and X10A; Ref. 17), but rather the entire DQ8 gene (containing both ␣ and ␤ segments plus upstream regulatory elements) was injected as a single large DNA fragment, having been isolated from the cosmid pDC␤2 (17). This DQ8 transgenic NOD line has been assigned the formal designation NOD.Tg(CD2-CD4,HLA-DQA1*0301,HLA-DQB1*0302)1Ell.…”

Section: Methodsmentioning

confidence: 99%

CD4 T Cells Play Major Effector Role and CD8 T Cells Initiating Role in Spontaneous Autoimmune Myocarditis of HLA-DQ8 Transgenic IAb Knockout Nonobese Diabetic Mice

Hayward¹,

Bautista-Lopez²,

Suzuki³

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

In humans, spontaneous autoimmune attack against cardiomyocytes often leads to idiopathic dilated cardiomyopathy (IDCM) and life-threatening heart failure. HLA-DQ8 transgenic IAb knockout NOD mice (NOD.DQ8/Ab0; DQA1*0301, DQB1*0302) develop spontaneous anticardiomyocyte autoimmunity with pathology very similar to human IDCM, but why the heart is targeted is unknown. In the present study, we first investigated whether NOD/Ab0 mice transgenic for a different DQ allele, DQ6, (DQA1*0102, DQB1*0602) would also develop myocarditis. NOD.DQ6/Ab0 animals showed no cardiac pathology, implying that DQ8 is specifically required for the myocarditis phenotype. To further characterize the cellular immune mechanisms, we established crosses of our NOD.DQ8/Ab0 animals with Rag1 knockout (Rag10), Ig H chain knockout (IgH0), and β2-microglobulin knockout (β2m0) lines. Adoptive transfer of purified CD4 T cells from NOD.DQ8/Ab0 mice with complete heart block (an indication of advanced myocarditis) into younger NOD.DQ8/Ab0 Rag10 animals induced cardiac pathology in all recipients, whereas adoptive transfer of purified CD8 T cells or B lymphocytes had no effect. Despite the absence of B lymphocytes, NOD.DQ8/Ab0IgH0 animals still developed complete heart block, whereas NOD.DQ8/Ab0β2m0 mice (which lack CD8 T cells) failed to develop any cardiac pathology. CD8 T cells (and possibly NK cells) seem to be necessary to initiate disease, whereas once initiated, CD4 T cells alone can orchestrate the cardiac pathology, likely through their capacity to recruit and activate macrophages. Understanding the cellular immune mechanisms causing spontaneous myocarditis/IDCM in this relevant animal model will facilitate the development and testing of new therapies for this devastating disease.

show abstract

“…Mice expressing HLA-DQ6 and HLA-DQ8 (42) transgenes were produced by our transgenic laboratory as previously described (43). In brief, cosmid H11A, containing DQA1*0301 and DQB1*0302 genes (44), and cosmid X10A, containing DQB1*0302, were microinjected into (CBA/J ϫ B10.M)F 2 embryos, resulting in B10.M-DQ8 transgenic mice. Similarly, a 40-kb construct containing DQB1*0601, derived from a cosmid isolate from the AKIBA cell line, was microinjected into (CBA/J ϫ B10.M)F 2 embryos, producing B10.M-DQ6 ␤ transgenic mice (45), and a construct containing the DQA1*0103 gene, also derived from the AKIBA cell line, was microinjected into (CBA/J ϫ B10.M)F 2 embryos, resulting in B10.M-DQ6 ␣ transgenic mice.…”

Section: Methodsmentioning

confidence: 99%

HLA-DQB1 polymorphism determines incidence, onset, and severity of collagen-induced arthritis in transgenic mice. Implications in human rheumatoid arthritis.

Bradley¹,

Nabozny²,

Cheng³

et al. 1997

J. Clin. Invest.

View full text Add to dashboard Cite

Certain HLA-DR alleles have been associated with predisposition to human rheumatoid arthritis (RA). There is also evidence that certain HLA-DQ alleles may also be important in determining susceptibility to RA. We have previously demonstrated that mice transgenic for HLA-DQ8, a DQ allele associated with susceptibility to RA, develop severe arthritis after type II collagen immunization. To investigate the influence of polymorphic difference at the DQ loci on susceptibility to arthritis, we generated mice transgenic for HLA-DQ6, an allele associated with a nonsusceptible haplotype. The DQ6 mice were found to be resistant to collagen-induced arthritis. We also assessed the combined effect of an RA-susceptible and an RA nonassociated DQ allele by producing double-transgenic mice expressing DQ6 and DQ8 molecules, representing the more prevalent condition found in humans where heterozygosity at the DQ allele is common. The double-transgenic mice developed moderate CIA when immunized with CII when compared with the severe arthritis observed in DQ8 transgenic mice, much like RA patients bearing both susceptible and nonsusceptible HLA haplotypes. These studies support a role for HLA-DQ polymorphism in human RA. (

show abstract

Gene organization of DC and DX subregions of the human major histocompatibility complex.

Abstract: The DC and DX subregions of the human major histocompatibility complex (MHC) have been cloned from a cosmid library made from a human B-cell line, Priess.

Cited by 146 publications

References 35 publications

A Spontaneous Model for Autoimmune Myocarditis Using the Human MHC Molecule HLA-DQ8

A Spontaneous Model for Autoimmune Myocarditis Using the Human MHC Molecule HLA-DQ8

CD4 T Cells Play Major Effector Role and CD8 T Cells Initiating Role in Spontaneous Autoimmune Myocarditis of HLA-DQ8 Transgenic IAb Knockout Nonobese Diabetic Mice

HLA-DQB1 polymorphism determines incidence, onset, and severity of collagen-induced arthritis in transgenic mice. Implications in human rheumatoid arthritis.

Contact Info

Product

Resources

About