Ankylosing spondylitis (AS) is a painful, incurable autoimmune disease that affects millions of people worldwide. Although it is clear that both environmental and genetic factors are involved in the disease, the cause and pathogenesis of AS remain unclear. A strong link with the MHC class I allele HLA-B27 has implicated antigen processing as an underlying factor, and this hypothesis was strengthened by the recent demonstration that polymorphisms in ERAP1 (an aminopeptidase that we and others have shown is associated with antigen processing) affect the risk of developing AS. We hypothesize that ERAP1 polymorphisms either directly or indirectly affect substrate selection and trimming, so that different ERAP1 alleles alter the levels of arthritogenic or protective peptides presented on HLA-B27. We will test this hypothesis using biochemical assays for substrate specificity, cultured cells to measure effects on antigen processing, and transgenic mice to test effects on disease in vivo. We will also test the effects of ERAP1 polymorphisms on other pathways that have been proposed to affect AS pathogenesis, including the assembly and stability of HLA- B27 and shedding of cytokine receptors.
The Aims of this project are to determine the functional effects of ERAP1 polymorphisms and to understand the molecular pathogenesis of AS. The long-term goals of this project are to predict the risk of AS in individuals, and to develop methods to prevent and treat AS. We will also apply the understanding of AS pathogenesis to other autoimmune diseases that are linked to MHC class I alleles.

Public Health Relevance

Ankylosing spondylitis is a painful, chronic, incurable autoimmune disease that affects millions of people worldwide. Although it is clear that both genetic and environmental factors are involved, the underlying causes and mechanisms of the disease are not known. In this project I will take advantage of a recently-described association with the gene ERAP1 to identify mechanisms that cause ankylosing spondylitis, with the ultimate goal of developing new techniques to predict the risk of ankylosing spondylitis, and to prevent and treat the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056981-03
Application #
8284209
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mao, Su-Yau
Project Start
2010-07-15
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$295,488
Indirect Cost
$101,088
Name
Michigan State University
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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Aldhamen, Yasser A; Seregin, Sergey S; Aylsworth, Charles F et al. (2014) Manipulation of EAT-2 expression promotes induction of multiple beneficial regulatory and effector functions of the human innate immune system as a novel immunomodulatory strategy. Int Immunol 26:291-303
Seregin, Sergey S; Rastall, David P W; Evnouchidou, Irini et al. (2013) Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens. Autoimmunity 46:497-508
Aldhamen, Yasser A; Seregin, Sergey S; Rastall, David P W et al. (2013) Endoplasmic reticulum aminopeptidase-1 functions regulate key aspects of the innate immune response. PLoS One 8:e69539
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