Expression and Function of Hla‐dq8 (Dqa1*0301/Dqb1*0302) Genes in Transgenic Mice

Cheng, Shen; Baisch, Jeanine; Krco, Christopher J.; Savarirayan, Suresh; Hanson, Julie A.; Hodgson, Kelly; Smart, Michele; David, Chella S.

doi:10.1111/j.1744-313x.1996.tb00260.x

Cited by 54 publications

(30 citation statements)

References 9 publications

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“…The production and characterization of A␤ 0 DR2 (DRB1*1502), A␤ 0 DR3 (DRB1*0301), A␤ 0 DQ6 (DQA1*0103/DQB1*0601), and A␤ 0 DQ8 (DQA-1*0301/DQB1*0302) mice lacking endogenous class II molecules have been described previously (22)(23)(24)(25)(26)(27)(28). The HLA class II transgenic mice used in the present work were backcrossed to B10 mice for 10 generations, thus carry B10 genetic backgrounds.…”

Section: Micementioning

confidence: 99%

HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules

Paisansinsup

Deshmukh

Chowdhary

et al. 2002

The Journal of Immunology

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Abs to Ro/SSA Ags in the sera of patients with systemic lupus erythematosus and Sjögren’s syndrome are influenced by the HLA class II genes. To investigate the role of individual HLA class II genes in immune responses to human Ro60 (hRo60), mice lacking murine class II molecules and carrying either HLA genes DR2(DRB1*1502), DR3(DRB1*0301), DQ6(DQA1*0103/DQB1*0601), or DQ8(DQA1*0301/DQB1*0302), were immunized with rhRo60. The results show that hRo60 induces strong T and B cell responses in DR2, DR3, and DQ8 mice in comparison to weaker responses in DQ6 mice. In all mice, the majority of the dominant T cell epitopes were located in the amino portion (aa 61–185) and the carboxy portion (aa 381–525) of the hRo60 molecules. In contrast, the early dominant B cell epitopes were located in the middle and carboxy portion of the hRo60 molecule (aa 281–315 and 401–538). In DR2, DR3, and DQ8 mice, the B cell epitopes subsequently spread to the amino and carboxy portion of the hRo60 molecule but were limited to the middle and carboxy portion in DQ6 mice. The DR2 and DR3 mice produced the highest titers of immunoprecipitating Abs against hRo60 and native mouse Ro60. In addition, only DR2 mice exclusively produced immunoprecipitating Abs to native mouse Ro52 and Abs to mouse La by slot blot analysis, whereas in other strains of mice Abs to mouse La were cross-reactive with the immunogen. The results of the present study demonstrate the importance of HLA class II in controlling the immune responses to the Ro-ribonucleoprotein.

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Section: Micementioning

confidence: 99%

HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules

Paisansinsup

Deshmukh

Chowdhary

et al. 2002

The Journal of Immunology

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“…Tg mice expressing HLA-DQ8 (HLA-DQA1*0301 and HLA-DQB1*0302) and HLA-DQ6 (HLA-DQA1*0103 and HLA-DQB1*0601) were produced by our tg laboratory, as previously described (25,26). The HLA-DQ tg mice were mated to class II-deficient A␤ o (27), CD4 knockout (28), and hCD4 tg mice (29) to generate double-tg/double-knockout mice.…”

Section: Micementioning

confidence: 99%

Cockroach Allergen-Induced Eosinophilic Airway Inflammation in HLA-DQ/Human CD4+ Transgenic Mice

Papouchado¹,

Chapoval²,

Marietta³

et al. 2001

The Journal of Immunology

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Airway eosinophilic inflammation is a characteristic feature of allergic asthma. Exposure to allergens produced by the German cockroach (Blattella germanica) is a risk factor for allergic disease in genetically predisposed individuals, and has been linked to an increase in asthma morbidity among cockroach-sensitive inner city children. To determine the role and contribution of specific HLA class II in the pathogenesis of allergic airway inflammation in cockroach-induced asthma, we generated double-transgenic, double-knockout mice expressing human HLA-DQ8, HLA-DQ6, and CD4 molecules in the absence of mouse class II and mouse CD4. Mice were actively immunized and later challenged intranasally with cockroach allergen extract. These mice developed bronchoalveolar lavage fluid (BALF) eosinophilia and pulmonary eosinophilia. This was accompanied by an increase in total protein levels, IL-5, and IL-13 in BALF. There were also elevated levels of cockroach-specific serum IgG1 and total serum IgE. Histological analysis revealed peribronchial and perivascular eosinophilic inflammation in cockroach-treated mice. Other pathologic changes in the airways were epithelial cell hypertrophy and mucus production. Treatment with anti-DQ mAb significantly reduced pulmonary and BALF eosinophilia in cockroach allergen-sensitized mice. Aβ0 mice and transgenic mice expressing human CD4 molecule alone (without class II) or human HLA-DQ8 molecule (without CD4) treated in the same fashion showed no eosinophilia in bronchoalveolar fluid and no pulmonary parenchymal inflammation. Our results provide direct evidence that HLA-DQ molecules and CD4 T cells mediate cockroach-induced eosinophilic inflammation in the airways.

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“…Expression of HLA class II molecules in H-2Aβ 0 mice induces the selection of CD4 + Vβ TCR + cells and restores CD4 + T-cell population in the periphery to a substantial level (5.0-9.3%) (37). There is no surface expression of H-2Aα b , H-2Eβ b , or H-2Aα/HLA-DQβ hybrid molecules on peripheral blood lymphocyte in HLA-DQ transgenic mice (36)(37)(38). The DQ-negative, Aβ 0 full sibs were used as controls.…”

Section: Methodsmentioning

confidence: 92%

“…The production and characterization of transgenic mice expressing human DQ6 (HLA-DQA1*0103 and HLA-DQB1*0601) and DQ8 (HLA-DQA1*0301 and HLA-DQB1*0302) genes in mice deficient in endogenous class II molecules (H-2Aβ 0 ) have been described previously (36)(37)(38). Expression of HLA class II molecules in H-2Aβ 0 mice induces the selection of CD4 + Vβ TCR + cells and restores CD4 + T-cell population in the periphery to a substantial level (5.0-9.3%) (37).…”

Section: Methodsmentioning

confidence: 99%

“…However, in all of these animal models, MHC class II molecules are mouse derived. We have generated transgenic mice expressing human DQ6 (HLA-DQA1*0103 and HLA-DQB1*0601) and DQ8 (HLA-DQA1*0301 and HLA-DQB1*0302) genes (36)(37)(38). These mice lack endogenous class II molecules, and the only functional class II molecules on antigen-presenting cells (APCs) are human DQ6 or DQ8.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Short ragweed allergen induces eosinophilic lung disease in HLA-DQ transgenic mice

Chapoval¹,

Nabozny²,

Marietta³

et al. 1999

J. Clin. Invest.

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The familial incidences of allergy and asthma suggest a genetic basis for these diseases. Recently, genome-wide searches and candidate gene approaches have been used to examine the possible involvement of a number of genes in the development of atopy and asthma. The regions of potential linkage to markers were detected with one or more asthma phenotypes on chromosomes 5q, 6p, 11q, 12q, 13q, and 14q, respectively (1-3).Human leukocyte antigen (HLA) molecules are encoded by highly polymorphic gene families located on chromosome 6p. They play a pivotal role in regulating the T-cell immune response and have been implicated in susceptibility to a wide range of diseases with an immunologic basis. The association of HLA haplotypes and ragweed allergy was the first human Ir (immune response) gene to be recognized (4), and HLA-DR2 and HLA-DQ6 restriction of IgE reactions to antigen 5 is well documented (5-7). Recently, strong relationships between the immune response to several highly purified allergens and specific HLA-DR and DQ haplotypes have been published (reviewed in ref. 8). In addition, specific HLA-DR and DQ molecules have been shown to be implicated in house dust mite asthma (9, 10), aspirin-induced asthma (11), soybean epidemic asthma (12), and occupational asthma and atopy involving isocyanates (13) or acid anhydrides (14). However, the role and contribution of specific HLA class II molecules in the development of allergic asthma are unknown and are difficult to assess in humans because of their genetic heterogeneity.Eosinophils play an important role in the pathogenesis of allergic airway inflammation. The infiltration of the airway wall with a large number of activated eosinophils and release of their toxic granule proteins and lipid metabolites cause damage to bronchial epithelial cells (15)(16)(17)(18)(19). It is believed that an airway hyperresponsiveness, the hallmark of asthma, occurs as a result of this eosinophil-mediated damage. In the majority of clinical studies, pulmonary eosinophilia has been shown to correlate with disease severity (15,17), and the resolution of airway eosinophilia correlates with the remission of asthma symptoms (16).Recently, a number of murine models of antigeninduced pulmonary eosinophilia and airway hyperreactivity (AHR) have been developed to study the role of B cells (20,21), T cells (20,(22)(23)(24), mast cells (25), NK cells (20), dendritic cells (26), IgE and its receptor (27, 28), cytokines (29-32), leukotrienes (33), and costimulatory molecules (34,35) in the mechanisms of immune responses in asthma. However, in all of these animal models, MHC class II molecules are mouse derived. We have generated transgenic mice expressing human DQ6 (HLA-DQA1*0103 and HLA-DQB1*0601) and DQ8 (HLA-DQA1*0301 and HLA-DQB1*0302) genes (36-38). These mice lack endogenous class II molecules, and the only functional class II molecules on antigen-presenting cells (APCs) are human DQ6 or DQ8. The human leukocyte antigen (HLA) restriction of the IgE response to different allergens in humans ...

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Expression and Function of Hla‐dq8 (Dqa10301/Dqb10302) Genes in Transgenic Mice

Cited by 54 publications

References 9 publications

HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules

HLA Class II Influences the Immune Response and Antibody Diversification to Ro60/Sjögren’s Syndrome-A: Heightened Antibody Responses and Epitope Spreading in Mice Expressing HLA-DR molecules

Cockroach Allergen-Induced Eosinophilic Airway Inflammation in HLA-DQ/Human CD4+ Transgenic Mice

Short ragweed allergen induces eosinophilic lung disease in HLA-DQ transgenic mice

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