Complement dysfunctions and non-canonical functions

Considering that some pathologies are associated with dysregulation or dysfunction of complement proteins, for example involving autoantibodies (SLE), our goal is to decipher the underlying molecular mechanisms, including the non-canonical functions of C1q and C1r and C1s proteases, i.e. other functions independent of complement, interconnected with other systems such as inflammation, coagulation, etc ... In the line of the study of the interaction of C1q with the LAIR-1 receptor, an inflammation modulator, we decipher new functions for the C1 complex subunits in various collaborative frameworks.

Pathological effects of C1r and C1s proteases - Christine GABORIAUD

We aim to understand the non-canonical pathological effects of C1s in two pathological contexts. Periodontal Ehlers-Danlos syndrome (pEDS) is associated with heterozygous mutations in the C1r and C1s protease genes. Through a collaborative project, we have clarified the molecular impact of these mutations, which involves constitutive activation of C1s. In the case of kidney cancer, we seek to understand how C1s allows tumor cells to escape immune surveillance, which leads to tumor progression.

Participants: Christine GABORIAUD, Véronique ROSSI, Jean-Baptiste REISER, Nicole THIELENS

• Johannes ZSCHOCK (Innsbruck medical university)
• Lubka ROUMENINA (CRC Paris)

Fundings: C1rsinEDS ANR-FWF (2016-2021); INCA PLBIO21-175 2021-2024

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement
Two different missense C1S mutations, associated to periodontal Ehlers-Danlos syndrome, lead to identical molecular outcomes
C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome
Complement C1s and C4d as prognostic biomarkers in renal cancer: emergence of non-canonical functions of C1s

Immune/inflammatory crosstalks of C1 components and HMGB1 – Christine GABORIAUD, Véronique ROSSI

The complement activator C1 complex and HMGB1 alarmin are two players in immune surveillance. Their regulatory processes and interconnection play an antagonistic role in the onset of the inflammatory response. The project aims to decipher the functional connections involved in the regulation of the inflammatory response and immune tolerance using a molecular dissection approach.

Participants: Christine GABORIAUD, Véronique ROSSI, Marie LORVELLEC, Jean Baptiste REISER, Nicole THIELENS

• Luca SIGNOR (Mass spectrometry Platform - IBS)

C1qEffero (ANR-16-CE-0019, 2018-2022), Labex EUR- UGA, PhD funding for Marie LORVELLEC (CBH-EUR-GS, ANR-17-EURE-003), ANR DYSALARM 2021-2025

Molecular basis of complement C1q collagen-like region interaction with the immunoglobulin-like receptor LAIR-1
Headless C1q: a new molecular tool to decipher its collagen-like functions
Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse
HMGB1 cleavage by complement C1s and its potent anti-inflammatory product

Autoantibodies detection and analysis in cohorts: potential pathological role? - Chantal DUMESTRE-PERARD

This approach has initiated in the pathological context of systemic lupus erythematosus (SLE), showing a correlation between the detection of some autoantibodies with certain clinical manifestations of the disease, particularly in the kidneys (active nephritis). This activity is continuing and could be extended to other clinical contexts

• Giovanna CLAVARINO (CHU Grenoble alpes, Immunology Laboratory)
• Pascal POIGNARD (AID team, IBS-CAID)

Funding: ANR DYSALARM 2021-2025

The immunopathology of complement proteins and innate immunity in autoimmune disease
Anti-ficolin-2 autoantibodies in SLE patients with active nephritis