Complement in physiology and pathology

The complement system is a potent innate immune surveillance system present in the blood and various tissues. Its proteins can even act intracellularly. Its primary function is to protect the host from pathogens. However, an overactivation of the complement system can lead to host tissue damage and chronic inflammation. Recently, it has become evident that many diseases are associated with abnormal function of the complement proteins.

Our research objective is to gain a comprehensive understanding of the functions and mechanisms of action of complement proteins in both physiological and pathological contexts. Additionally, we aim to explore the potential utility of these proteins as biomarkers or therapeutic targets. To achieve this, we have devised an integrated approach called “Complementomics”. It includes an exploration of the gene expression, genetic variants, in situ protein localization, presence in plasma of the complement proteins, their activation fragments and autoantibodies targeting complement proteins, as well as their relation to different cell types and their activation status in tissues and in biological fluids. Through this holistic approach, we aim to gain a comprehensive understanding of complement functions in various locations within the body. By uncovering novel biological functions, we hope to contribute to the development of potential therapeutic strategies and biomarkers for complement-related diseases.

Main projects developed in this theme

  • To discover the intracellular mechanism of action of complement proteins and their implication in the pathological process of cancer, autoimmunity and kidney injury. 
  • To identify the binding sites and functional consequences of anti-complement proteins autoantibodies and monoclonal immunoglobulins and their relevance for the disease process of kidney diseases.
  • To understand how complement participates to the organ injury in systemic autoimmune diseases.
  • To explore the mechanism of complement activation in diseases with heme overload and its contribution to organ injury.
  • To define complement biomarkers in plasma and in tissues, allowing to predict prognosis of diseases for which complement contributes to the pathophysiology and response to complement therapeutics.

Intracellular complement proteins in physiology and pathology

We explore: 1) What is the biological relevance and mechanism of action of the intracellular complement proteins; 2) How intracellular complement drives glomerular, vascular and tubular injury. 3) How intracellular complement promotes tumor progression. Understanding the basic mechanisms of intracellular action of the complement proteins will lead to a better understanding of the pathophysiology and will open up the gateway for intracellular complement therapeutic targeting. (PI: Lubka Roumenina)

Complement and cancer:

We study complement as a modulator of the tumor cell fate and tumor microenvironment and its actions within the complement cascade as well as its non-canonical functions. Gained fundamental knowledge will allow us to search for novel prognostic markers in patients’ cohorts with renal and lung cancers. (PI: Lubka Roumenina/ Marie-Agnes Dragon-Durey, in collaboration with Fridman’s group and Cremer’s group)

Complement and kidney diseases

  • Complement in C3 glomerulopathies and atypical hemolytic uremic syndrome:

Thanks to our cohorts, among the largest cohorts in the world, we study the molecular mechanisms of complement overactivation and tissue injury in these prototypical complement-mediated kidney diseases. We discovered the mechanisms of action of novel auto-antibodies and genetic abnormalities in these diseases. Our work has a major societal impact, thanks to transfer to diagnostics and patients’ management, through the Complement diagnostics laboratory of Dr. Fremeaux-Bacchi in HEGP hospital and the collaborating clinicians. (PI: Veronique Fremaux-Bacchi/ Sophie Chauvet)

These clinical and fundamental reserach projects belong to those of the National reference Center from rare diseases MARHEA « Maladie rénale rare héréditaire de l’enfant et de l’adulte » and FAI2R « Filière de Santé des Maladies auto-immunes et auto –inflammatoires » head by the department of Néphrologie from European hospital Georges Pompidou (PI: Sophie Chauvet).

  • Complement in monoclonal gammopathies and kidney diseases:

We discovered that the monoclonal immunoglobulin from patients with this condition is able to enhance complement alternative pathway overactivation independently of its antigenic specificity. We study how the biochemical properties of either polyclonal or monoclonal immunoglobulin in these patients modulate the balance of C3/C5 convertase activity; how it influences the intra renal immune cell infiltration and blood immune response and how this correlates with renal prognosis. (PI: Sophie Chauvet/ Véronique Frémeaux-Bacchi).

  • Complement and renal complications during pregnancy

We aim to better understand the contribution of complement to obstetrical pathologies, notably preeclampsia and its kidney complications, and to find out whether it is a suitable therapeutic target. We have particular interest to the kidney complications during pregnancy of patients with sickle cell disease. (PI: Anne Grunenwald)

Complement and systemic autoimmune diseases:

  • Complement in Antiphospholipid syndrome (APS)

We are seeking to characterize the complement-dependent mechanisms involved in APS in order to define one or more targets of the complement cascade that could be modulated by one of the many complement-targeting molecules available to date, and to envisage prospects for innovative treatments. The research is being conducted in close collaboration with the Immunology Laboratory at the Georges Pompidou European Hospital.  (PI: Marie Agnes Dragon-Durey).

  • Complement in vasculitis 

Several systemic auto-immune diseases implying complement activation have kidney involvent (ANCA vasculitis, connectivite, IgA vasculitis, Goujerot Sjogren syndrome..). The aim of our project is to establish the exact contribution of complement in disease phenotype, response to the standard of care treatment and to determine the place of new complement inhibtors in the therapeutic stratgey These clinical and fundamental reserach projects belong to those of the National reference Center from rare diseases  FAI2R « Filière de Santé des Maladies auto-immunes et auto –inflammatoires » head by the department of Néphrologie from European Hospital Georges Pompidou (PI: Sophie Chauvet/ Jean Paul Duong in collaboration with A. Karras, HEGP).

  • Complement in systemic lupus erythematosus

Complement plays a paradoxal role in systemic lupus erythematosis. Its overactivation is a hallmark of the disease, but also deficiencies of classical pathway proteins are strong, albeit very rare, genetic predisposing factors for its development. We explore the functional consequences of genetic complement deficiency and anti-complement proteins autoantibodies in systemic lupus and lupus nephritis. (PI: Lubka Roumenina/Marie Agnes Dragon-Durey).

  • Complement in diseases with heme overload:

We explore the pathological role of heme-mediated complement activation in the disease process of sickle cell disease and rhabdomyolysis-induced acute kidney injury. We are testing heme scavengers and complement inhibitors as therapeutic strategies for these diseases. (PI: Lubka Roumenina/ Anne Grunenwald).

Members

Researchers

  • Prof. Lubka T. Roumenina, DR INSERM
  • Prof. Jean-Paul Duong-Van-Huy, PU-PH, Université Paris Cité, pathologist, Hôpital Necker-Enfants Malades
  • Dr. Sophie Chauvet, MCU-PH Université Paris Cité, nephrologist, Hôpital européen Georges-Pompidou
  • Dr. Marie-Agnès Dragon-Durey, MCU-PH Université Paris Cité biologist, Hôpital européen Georges-Pompidou
  • Dr. Véronique Fremeaux-Bacchi, PH, biologist, Hôpital européen Georges-Pompidou
  • Dr Anne Grunenwald, PH, nephrologist, Centre hospitalier intercommunal de Poissy-Saint-Germain-en-Laye

Post docs

  • Carine El Sissy
  • Nicolas S Merle
  • Sara Soares

PHD students

  • Anna Duval
  • Marie-Sophie Meuleman
  • Mikel Rezola Artero
  • Marina De Castro Deus
  • Idris Boudhabhay

Engineers

  • Emma Fleury (IE)
  • Celine Mayinga (IE)
  • Julie Peliconi (IE)