Although rare in prevalence, humans with a complete deficiency in one of the early components for the classical pathway of the complement system almost always lead to an onset of systemic lupus erythematosus (SLE), regardless of race, sex and HLA backgrounds. Intriguingly, between 33 and 50% of White SLE patients have low gene copy number of complement C4, specifically C4A. Most SLE patients also have acquired phenotypic deficiencies of complement due to immune complex-driven activation and consumption. The association of genetic deficiencies with SLE suggests that complement protects against SLE. Yet, the association of acquired deficiencies, due to complement activation, with SLE and LN, suggests that complement is also an important driver of SLE disease activity. To fully understand the role of complement in SLE pathogenesis and progression, it is imperative to decipher the exact details of genetic and phenotypic diversities in the complement system. Investigators of this proposal have a long history of research on complement genes and proteins in SLE. Leveraging on recent technological advances, we propose to investigate comprehensively the roles of the complement system on genetic predisposition and modulation of disease profiles and complications in human SLE and LN.
The Specific Aims are: (1) To investigate the genetic diversities of complement C4 in SLE and healthy controls of European, African and East-Asian ancestries. The frequencies and effect sizes of SLE risk factors vary substantially among races. We will determine the gene copy number variations of total C4, C4A and C4B, long C4 and short C4 and examine their roles on genetic susceptibility to SLE in the context of linkage disequilibrium with HLA-DRB1 variants in three different racial groups, in adult onset and childhood onset patients; (2) To investigate how genotypic diversities of complement modulate complement phenotypic profiles and SLE disease features. We will investigate the correlations between complement genetic variants and their serum protein levels, relationships of processed activation products with hematologic and cardiovascular diseases, plus their interactions with type I interferon stimulated gene expression. A group of SLE patients will be selected for in-depth analyses for all complement genes through exome sequencing; and (3) To characterize changing complement phenotypes during periods leading from LN disease quiescence to disease flare, and to disease remission. Longitudinal phenotype measurements will include complement proteins (activators, regulators, receptors), activation fragments, and complement autoantibodies in the circulation and in the urine. The temporal relationship between changing complement phenotypes and LN flare onset/remission will be analyzed, and the influences of genetic variation in complement on these relationships will be established. This proposal will yield important knowledge on how variants of the complement system contribute to genetic predisposition and disease progression of SLE and LN. It will facilitate precision diagnosis and effective therapies of this female dominant chronic disease.

Public Health Relevance

The complement system is an important effector arm of the immune response. This proposal seeks to study thoroughly the genes and proteins of the complement system on the cause and modifications of disease profiles and outcomes in human lupus and lupus nephritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR073311-01
Application #
9500213
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Wang, Yan Z
Project Start
2018-07-08
Project End
2023-05-31
Budget Start
2018-07-08
Budget End
2019-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205