MHC association in autoimmune arthritis

MHC 与自身免疫性关节炎的关系

基本信息

  • 批准号:
    8093106
  • 负责人:
  • 金额:
    $ 4.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-06-28 至 2011-02-28
  • 项目状态:
    已结题

项目摘要

Susceptibility to and severity of many autoimmune diseases, including arthritis, are known to be closely linked with particular class II MHC alleles, but the mechanism of these associations remains unknown. We have found that class II alleles that form unusually low-stability complexes with class II-associated invariant chain peptides (CLIP) are disproportionately represented among alleles that confer susceptibility to autoimmunity. Our recent work indicates that variations in class II/CLIP affinity affect the stability, longevity, and abundance of class II molecules in model antigen presenting cells (APC) and can modulate antigen presentation. Mechanisms by which variations in class II/CLIP affinity could influence susceptibility to autoimmunity include alterations in central selection events or peripheral tolerance or activation events, all of which are controlled by antigen presentation. Here, we propose to study whether varying class II/CLIP affinity can influence autoimmune disease pathogenesis in a whole animal. We will: 1) Establish 2 short-term mouse models in which the affinity of CLIP for class II has been modulated, using two arthritis-prone haplotypes. This will be achieved by re-constituting irradiated mice with HSC expressing invariant chains with wild type CLIP (with low affinity for MHC II) or mutated CLIP (with high affinity for MHC II); 2) Measure the effects of class II/CLIP affinity on class II stability, longevity, and abundance in primary APC types from these mice, including in the context of inflammatory stimuli; 3) Determine whether modulation of class II/CLIP affinity in BM-derived APC modulates disease in the KRN model and key immunologic features in this model. The results of these experiments will shape future studies, in which we will extend this work to the second mouse model of arthritis, as well as develop a long-term model to investigate arthritis pathogenesis using mice that stably express high-affinity CLIP/Ii. If expression of high affinity CLIP in hematopoietic cells is sufficient for disease protection, it may provide new therapeutic options for individuals at risk for arthritis. Although it has been known for a number of years that certain proteins, the HLA proteins, are a critical genetic risk factor for arthritis and other debilitating autoimmune diseases, the explanation for this genetic link has remained unknown. We will perform experiments in a mouse model of arthritis to test a novel hypothesis for the mechanism of this association. If successful, our experiments will shed new light on the mechanism(s) of disease initiation and pathogenesis in arthritis, and may suggest new treatment approaches for people who are at high risk for arthritis.
对许多自身免疫性疾病的易感性和严重程度,包括关节炎,是

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Reduced locomotor activity correlates with increased severity of arthritis in a mouse model of antibody-induced arthritis.
在抗体诱导的关节炎小鼠模型中,运动活动的减少与关节炎严重程度的增加相关。
Transgene expression in various organs post BM-HSC transplantation.
  • DOI:
    10.1016/j.scr.2013.10.010
  • 发表时间:
    2014-01
  • 期刊:
  • 影响因子:
    1.2
  • 作者:
    Wang, Nan;Rajasekaran, Narendiran;Hou, Tieying;Mellins, Elizabeth D.
  • 通讯作者:
    Mellins, Elizabeth D.
Comparison of transduction efficiency among various lentiviruses containing GFP reporter in bone marrow hematopoietic stem cell transplantation.
不同含GFP报告基因的慢病毒在骨髓造血干细胞移植中的转导效率比较。
  • DOI:
    10.1016/j.exphem.2013.07.002
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    2.6
  • 作者:
    Wang,Nan;Rajasekaran,Narendiran;Hou,Tieying;Lisowski,Leszek;Mellins,ElizabethD
  • 通讯作者:
    Mellins,ElizabethD
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Elizabeth D Mellins其他文献

Systemic juvenile idiopathic arthritis is associated with HLA-DRB1 in Europeans and Americans of European descent
  • DOI:
    10.1186/1546-0096-10-s1-a6
  • 发表时间:
    2012-07-13
  • 期刊:
  • 影响因子:
    2.300
  • 作者:
    Michael Ombrello;Elaine F Remmers;Alexei A Grom;Wendy Thomson;Alberto Martini;Marco Gattorno;Seza Ozen;Ahmet Gul;John F Bohnsack;Andrew S Zeft;Elizabeth D Mellins;Jane L Park;Claudio Len;Colleen Satorius;Ricardo AG Russo;Terri H Finkel;Rae SM Yeung;Rayfel Schneider;Sampath Prahalad;David N Glass;Roger C Allen;Nico Wulffraat;Pierre Quartier;Maria Odete E Hilario;Kevin Murray;Sheila Oliveira;Jordi Anton;Anne Hinks;Eleftheria Zeggini;Carl Langefeld;Susan Thompson;Jeffrey Chaitow;Justine Ellis;Davinder Singh;Andre Cavalvanti;Blanca Bica;Flavio Sztajnbok;Hakon Hakonarson;Katherine A Siminovitch;Kirsten Minden;Peter Haas;Tobias Schwarz;Daniel L Kastner;Patricia Woo
  • 通讯作者:
    Patricia Woo
Demographic, clinical and treatment characteristics of the carra registry systemic JIA cohort
  • DOI:
    10.1186/1546-0096-12-s1-p64
  • 发表时间:
    2014-09-17
  • 期刊:
  • 影响因子:
    2.300
  • 作者:
    Ginger Janow;Laura Schanberg;Soko Setoguchi;Elizabeth D Mellins;Rayfel Schneider;Yukiko Kimura
  • 通讯作者:
    Yukiko Kimura

Elizabeth D Mellins的其他文献

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{{ truncateString('Elizabeth D Mellins', 18)}}的其他基金

Inflammasome function and SJIA
炎症小体功能和 SJIA
  • 批准号:
    8513260
  • 财政年份:
    2012
  • 资助金额:
    $ 4.82万
  • 项目类别:
Inflammasome function and SJIA
炎症小体功能和 SJIA
  • 批准号:
    8285388
  • 财政年份:
    2012
  • 资助金额:
    $ 4.82万
  • 项目类别:
Immunoglobulin as a novel ligand for HLA-DM
免疫球蛋白作为 HLA-DM 的新型配体
  • 批准号:
    8177239
  • 财政年份:
    2011
  • 资助金额:
    $ 4.82万
  • 项目类别:
Immunoglobulin as a novel ligand for HLA-DM
免疫球蛋白作为 HLA-DM 的新型配体
  • 批准号:
    8264930
  • 财政年份:
    2011
  • 资助金额:
    $ 4.82万
  • 项目类别:
A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study
IL-1 在 SJIA 单核细胞表型中的作用:一项 RAPPORT 辅助研究
  • 批准号:
    8325175
  • 财政年份:
    2010
  • 资助金额:
    $ 4.82万
  • 项目类别:
A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study
IL-1 在 SJIA 单核细胞表型中的作用:一项 RAPPORT 辅助研究
  • 批准号:
    8146977
  • 财政年份:
    2010
  • 资助金额:
    $ 4.82万
  • 项目类别:
A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study
IL-1 在 SJIA 单核细胞表型中的作用:一项 RAPPORT 辅助研究
  • 批准号:
    8530018
  • 财政年份:
    2010
  • 资助金额:
    $ 4.82万
  • 项目类别:
A role for IL-1 in SJIA monocyte phenotypes: A RAPPORT ancillary study
IL-1 在 SJIA 单核细胞表型中的作用:一项 RAPPORT 辅助研究
  • 批准号:
    8088935
  • 财政年份:
    2010
  • 资助金额:
    $ 4.82万
  • 项目类别:
Protective Mechanisms Against Pandemic Respiratory Virus (Resource D)
针对流行性呼吸道病毒的保护机制(资源 D)
  • 批准号:
    7657181
  • 财政年份:
    2008
  • 资助金额:
    $ 4.82万
  • 项目类别:
Mechanism of MHC Association with Type 1 Diabetes
MHC与1型糖尿病的关联机制
  • 批准号:
    7479078
  • 财政年份:
    2008
  • 资助金额:
    $ 4.82万
  • 项目类别:

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