The studies in this proposal test the hypothesis that HLA alleles, HLA self-peptides and microbial mimicry, in concert, contribute to the pathogenesis of systemic sclerosis (SSc). Observations leading to the hypothesis point to a central role for the HLA-DRP I molecule and are at least fourfold. The first is the finding that a woman's risk of SSc is significantly increased by prior birth of a child who was HLA-compatible for DRbeta1. Second, particular HLA alleles increase risk of SSc, and include an amino acid sequence of the DR11 DRbeta1 chain (aa67-71, """"""""FLEDR"""""""") that is shared with DRbeta5. Third, human cytomegalovirus (HCMV) is known to negatively impact conditions of chimerism that arise from transplantation and spontaneously occurring microchimerism has recently been implicated in SSc, as has HCMV. Finally, HCMV has sequence identity with a conserved sequence of HLA-DRbeta1 (aa 53-57), that extends further (aa 53-58, """"""""LGRPDE"""""""") for DRB1 alleles that encode for DR11, which is associated with SSc. The proposed experiments will provide the initial test of the concept that HLA peptides derived from DRbeta1 function in cellular communications among host cells and between host and non-host cells. The first Specific Aim will design candidate peptides that encompass the identified sequences of the DRbeta1 molecule and will test them in binding and functional T cell assays. The second and third Specific Aims will identify, enumerate and characterize peptide specific T cells using artificial antigen presenting cells (aAPC) complexed with the HLA self-peptides and peptides derived from the homologous HCMV sequence. The aAPC is a very recently developed technique that offers an advantage over tetramers in capturing low affinity interactions due to permissive movement within a liposorne membrane. The aAPC will be used in a T cell capture assay to isolate peptide specific T cells which will then be phenotypically and functionally characterized in SSc patients and in controls. Analysis will be conducted for cytokine production and differential gene expression from sorted cells of SSc patients and controls. Finally, in the fourth Specific Aim, Real-Time PCR will be used to quantitatively assess microchimerism in peripheral blood mononuclear cell subsets from the same patients and controls. The results of the proposed experiments will permit the initial test of a model of pathogenesis that incorporates a concert of contributory factors including specific HLA alleles, HLA-relationships among host and non-host cells, and microbial mimicry in disease pathogenesis. Studies are designed so as to maximize the potential to advance understanding of disease pathogenesis in a way that could potentially lead to the development of new therapeutic modalities for this difficult disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048084-03
Application #
6607038
Study Section
Special Emphasis Panel (ZAR1-RJB-A (M3))
Program Officer
Gretz, Elizabeth
Project Start
2001-09-30
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$319,914
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Adams, K M; Yan, Z; Stevens, A M et al. (2007) The changing maternal ""self"" hypothesis: a mechanism for maternal tolerance of the fetus. Placenta 28:378-82
Albani, Salvatore; Prakken, Berent (2006) T cell epitope-specific immune therapy for rheumatic diseases. Arthritis Rheum 54:19-25
Loubiere, L S; Lambert, N C; Madeleine, M M et al. (2005) HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women. Rheumatology (Oxford) 44:318-22
Lambert, N C; Pang, J M; Yan, Z et al. (2005) Male microchimerism in women with systemic sclerosis and healthy women who have never given birth to a son. Ann Rheum Dis 64:845-8
Giannoni, Francesca; Barnett, Joellen; Bi, Kun et al. (2005) Clustering of T cell ligands on artificial APC membranes influences T cell activation and protein kinase C theta translocation to the T cell plasma membrane. J Immunol 174:3204-11
Prakken, Berent J; Samodal, Rodrigo; Le, Tho D et al. (2004) Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci U S A 101:4228-33
de Kleer, Isme M; Wedderburn, Lucy R; Taams, Leonie S et al. (2004) CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 172:6435-43
Lambert, Nathalie C; Erickson, Timothy D; Yan, Zhen et al. (2004) Quantification of maternal microchimerism by HLA-specific real-time polymerase chain reaction: studies of healthy women and women with scleroderma. Arthritis Rheum 50:906-14
Adams, Kristina M; Nelson, J Lee (2004) Microchimerism: an investigative frontier in autoimmunity and transplantation. JAMA 291:1127-31
Lambert, Nathalie; Nelson, J Lee (2003) Microchimerism in autoimmune disease: more questions than answers? Autoimmun Rev 2:133-9

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