Complement and Inflammation Research

Our laboratory aims at understanding the unexpected roles of intracellularly active complement in the regulation of key basic processes of the cell in health and disease.

Complement is generally well appreciated as a serum-effective system and critical arm of innate immunity required for the detection and removal of invading pathogens. Work from Dr. Kemper's lab, however, has highlighted an equally profound impact of complement on adaptive immunity through direct regulation of CD4⁺ T cells: signals mediated by T cell-expressed anaphylatoxin receptor C3aR and the complement regulator CD46 (which binds the complement activation fragment C3b) are critical checkpoints in human T cell lineage commitment and control initiation and resolution of inflammatory Th1 responses. Further, they have discovered that activation of the key complement components C3 and C5 is not confined to the extracellular space but occurs intracellulary (the ‘Complosome’) and that intracellular C3 and C5 activation fundamentally dictates the magnitude of Th1-mediated inflammation, the production of granzyme B and IFN-g by cytotoxic CD8+ T cells and the secretion of highly proinflammatory IL-1b by monocytes and macrophages. Consequently, perturbations in complosome activity in immune cells contributes majorly to a range of human disease states, including recurrent infections, autoimmunity (arthritis, SLE, CAPS, and scleroderma), chronic organ rejection, cancer, and cardiovascular disease.

Likely the most exciting recent development in their work is the observation that intracellular C3 and C5 are unexpected critical orchestrators of basic cellular processes, including the control of cell metabolism (induction of nutrient flux, glycolysis and oxidative phosphorylation), mitochondrial activity (directionality of the electron transport chain (ETC), impact on TCA cycle and ROS production) and gene transcription. Thus, CIRS has created a novel research area and propose that understanding the unexpected functions of the complosome will deliver critical new knowledge about cell biology in health and disease.

The central goal of Dr. Kemper's research programme is therefore to define the functional roles and regulative mechanisms of intracellular/autocrine complement and assess their biological relevance with an eye on delivering druggable targets in these pathways to therapeutically intervene in diseases (recently, the lab has broadened its interest heavily towards the role of the complosome in meningeal immunity and neurodegenerative disorders (such as MS)). To achieve this overarching goal, Dr. Kemper's lab are currently focusing on three key questions:

1. What is the composition of the Complosome in different cells?
2. What are the functions of the Complosome?
3. How is the Complosome regulated?

They utilize immune/tissue cells from healthy donors, from patients with complement deficiencies, from patients with immune cell-driven infectious, autoimmune disease or cancer and from patients with deviations in novel ‘complosome’-regulated pathways for gene and scRNA arrays, epigenetic landscape evaluation, and (spatial) proteomic and metabolomic assessments. This unbiased approach driven by human genetics and robust experimental in vitro systems will be combined with appropriate small animal (mouse) in vivo models to define biological significance of proteins/pathways discovered and to develop preclinical animal models for future pharmacological targeting. To achieve the latter, the Kemper lab is collaborating via a CRADA with Apellis Pharmaceuticals, Inc.