The proposal's overall objective is to test mechanisms by which maternal microchimerism may contribute to chronic inflammation in systemic lupus erythematosus nephritis (SLE-N). Elevated levels of fetal and maternal microchimerism (MMc) have been found within blood and tissues of patients with systemic sclerosis, SLE, and dermatomyositis. However, microchimerism is also common in healthy individuals. Moreover, previous studies were not able to control for disease activity or immunosuppression, which may affect tolerance to chimeric cells. The PI has found maternal cells in infant organs differentiated into hematopoietic cells, cardiac myocytes, hepatocytes, and renal tubular epithelial cells. Long-term persistence to MMc implies immune tolerance, and loss of tolerance to MMc may lead to chronic inflammation within target organs harboring maternal cells. The Pi's preliminary data suggests that peripheral T lymphocytes from pediatric SLE patients are hyper-reactive to maternal cells. Moreover, SLE patients showed a trend toward decreased MMc in the blood. Thus, host lymphocytes reactive to maternal antigens within tissues may also clear maternal cells from the blood. This study will be the first to directly test the correlation of MMc in blood with SLE disease activity and immunosuppression. In addition, we will test a mechanistic model for how maternal cells bearing alloantigens may stimulate the host immune system to contribute to chronic inflammatory disease.
Specific Aim #1 will test the hypothesis that levels of MMc in blood correlate with disease activity and immunosuppression in pediatric patients with SLE-N.
Specific Aim #2 will investigate direct T lymphocyte alloreactivity to maternal antigens in SLE-N patients compared to controls. Tolerance to maternal antigen presenting cells will be tested for correlations with disease activity, immunosuppression, and presence or absence of MMc.
Specific Aim #3 will investigate indirect T lymphocyte alloreactivity to maternal antigens presented by host APC in SLE-N patients compared with controls using apoptotic or necrotic maternal cells as sources of maternal antigens.
Specific Aim #4 will test the role of T regulatory cells in tolerance to maternal antigens. The finding that maternal cells are targets forT lymphocytes in SLE patients would lead to future investigations to determine which antigens are targeted. Peptides blocking host- maternal cell interactions in vitro could potentially be used in vivo as specific treatments for SLE nephritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051545-05
Application #
8120758
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
2007-09-13
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$360,380
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2016) Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Ann Rheum Dis 75:2007-2013
Zhao, Jian; Giles, Brendan M; Taylor, Rhonda L et al. (2016) Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. Ann Rheum Dis 75:242-52
Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9
Zhao, Jian; Wu, Hui; Langefeld, Carl D et al. (2015) Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus. Clin Immunol 161:157-62
Martins, M; Williams, A H; Comeau, M et al. (2015) Genetic association of CD247 (CD3?) with SLE in a large-scale multiethnic study. Genes Immun 16:142-50
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2013) MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet 9:e1003336
Sakurai, Daisuke; Zhao, Jian; Deng, Yun et al. (2013) Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression. PLoS Genet 9:e1003870
Kaufman, Kenneth M; Zhao, Jian; Kelly, Jennifer A et al. (2013) Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. Ann Rheum Dis 72:437-44
Manku, Harinder; Langefeld, Carl D; Guerra, Sandra G et al. (2013) Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4. PLoS Genet 9:e1003554
Lessard, Christopher J; Adrianto, Indra; Ice, John A et al. (2012) Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am J Hum Genet 90:648-60

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