Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056981-02
Application #
8110051
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
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$295,488
Indirect Cost

  Institution

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

  Publications

Pepelyayeva, Yuliya; Rastall, David P W; Aldhamen, Yasser A et al. (2018) ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis. Sci Rep 8:12464
Rastall, David P W; Alyaquob, Fadel S; O'Connell, Patrick et al. (2017) Mice expressing human ERAP1 variants associated with ankylosing spondylitis have altered T-cell repertoires and NK cell functions, as well as increased in utero and perinatal mortality. Int Immunol 29:277-289
Aldhamen, Yasser A; Pepelyayeva, Yuliya; Rastall, David P W et al. (2015) Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells. J Innate Immun 7:275-89
Rastall, David P W; Aldhamen, Yasser A; Seregin, Sergey S et al. (2014) ERAP1 functions override the intrinsic selection of specific antigens as immunodominant peptides, thereby altering the potency of antigen-specific cytolytic and effector memory T-cell responses. Int Immunol 26:685-95
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
Koestler, Benjamin J; Seregin, Sergey S; Rastall, David P W et al. (2014) Stimulation of innate immunity by in vivo cyclic di-GMP synthesis using adenovirus. Clin Vaccine Immunol 21:1550-9
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
Zervoudi, Efthalia; Saridakis, Emmanuel; Birtley, James R et al. (2013) Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses. Proc Natl Acad Sci U S A 110:19890-5
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
Evnouchidou, Irini; Birtley, James; Seregin, Sergey et al. (2012) A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing. J Immunol 189:2383-92

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