# Complement in Human Lupus: Deficiencies, Profiles and Complications

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2022 · $411,151

## Abstract

Project Summary/Abstract
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 comple...

## Key facts

- **NIH application ID:** 10414786
- **Project number:** 5R01AR073311-05
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** DANIEL J BIRMINGHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $411,151
- **Award type:** 5
- **Project period:** 2018-07-08 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10414786

## Citation

> US National Institutes of Health, RePORTER application 10414786, Complement in Human Lupus: Deficiencies, Profiles and Complications (5R01AR073311-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10414786. Licensed CC0.

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