Completed Infection & Immunity Lungs & Breathing

Complement, SLE and modulation of the adaptive immune response.

Funder Wellcome Charity-funded
Recipient organisation Imperial College London
Funding £1.3M
Period Oct 2009 — Sept 2014

In plain English

AI plain-English summary

A fault in a single immune system protein—complement receptor 3—can tip the body into attacking its own tissues, causing the autoimmune disease lupus. This matters because lupus is a chronic, debilitating condition with no cure, and the underlying mechanisms remain poorly understood. The researchers are building on clinical observations that people with certain genetic variations in complement proteins are far more likely to develop lupus. They want to find out exactly how these variations disrupt the immune system’s ability to distinguish self from non-self—specifically, how they affect the way dendritic cells present antigens from dying cells to B cells, and how that might break tolerance. If successful, this work will reveal the molecular steps that lead from a genetic variant to full-blown autoimmunity. That knowledge could eventually point to new drug targets for lupus and other autoimmune diseases. The project is fundamental science, driven by curiosity about how the complement system controls adaptive immunity. Past discoveries in this area have already linked complement deficiencies to lupus; this research aims to explain why.

View original technical description
The aim of our work is to understand how complement contributes to controlling the immune system, particularly in relation to autoimmunity. Our research follows clinical observations of powerful links between complement deficiencies and development of systemic lupus erythematosus (SLE). Recently genetic variations within the alpha chain of complement receptor 3 (ITGAM - CD11b) have been identified as one of the major susceptibility factors for SLE but the functional effects of these variants are still unknown. These associations suggest that the complement system mediates critical cellular interaction(s) modulating the adaptive immune response. In this proposal we seek to explore why, in the presence of genetic complement aberrations/variants, there is dysregulation of the mechanisms underlying tolerance to self-antigens and development of autoimmunity. The specific aims are: 1) to determine how complement modulates the tolerance to antigens associated to apoptotic cells 2) to investigate whether complement deficient dendritic cells (DCs) directly alter B cell effector functions 3) to explore how polymorphisms of the alpha chain of the complement receptor 3 lead to the development of SLE The results will enhance our knowledge of the causes of SLE and have a broader applicability to the role of complement in other conditions.

View the original record at the funder ↗

Researchers

Marina Botto (EPMC Awardee)

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Original classification

Programme Grant

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