Role of B cells tuberculosis immunity and inflammation – B-TB

On the one side, the in vitro analysis of the biological response of B cells stimulated with mycobacteria or mycobacterial compounds will be analyzed. In parallel, the characteristics (effector molecules produced, genes being used) by B cells purified form the lungs of infected mice will be determined.

We have already identified molecular effectors utilized by B cells upon infection. These include cellular receptors expressed by B cells and capable of recognizing mycobacteria as well as csoluble molecules released by B cells upon infection. Our results are promising to conclude that B cells do play a role in anti-tuberculous immune responses as well as during lung inflammation.

At this stage, we plan to establish animal models allowing us to understand the mechanisms whereby B cells react to mycobacterial infection in this new host-pathogen dialog.

We have already published a review describing the current knowledge and our anticipations on the role played by B cells in the generation and maintenance of multi-cellular structure typically found in tuberculosis, termed granuloma.

Front Immunol. 2012;3:405. doi: 10.3389/fimmu.2012.00405. Epub 2013 Jan 7. Emerging trends in the formation and function of tuberculosis granulomas.
Lugo-Villarino G, Hudrisier D, Benard A, Neyrolles O.

Tuberculosis (TB) remains one of the deadliest infectious diseases, with nearly 9.5 million new cases and 1.7 million deaths reported in 2010. Increased knowledge of TB immunity may help design novel intervention strategies, including improved diagnostic methods, novel immunotherapeutic agents and a vaccine better than Bacillus Calmette-Guérin (BCG) against Mycobacterium tuberculosis (Mtb). Furthermore, TB reactivation is one of the major side effects of interventions based on the administration of therapeutic antibodies. This is well illustrated by treatments targeting tumor necrosis factor-alpha (TNFa) in patients with rheumathoid arthritis, and this issue has also been raised in the case of more recently introduced B-cell depleting agents such as anti-CD20 antibodies.
Fundamental advances made in the last 20 years in the fields of basic immunology and TB immunity have considerably improved our understanding of the protective immune response against Mtb by recognizing the importance of interferon-gamma (IFN?)- and TNFa-producing CD4+ T cells, and of other cells and cytokines playing complementary and important functions. In this context, the role of B cells in TB immunity did not escape reconsideration, but it has been investigated only superficially in animal models of global B cell deficiency. As highlighted in several recent reports, such models do not allow understanding the contribution of B-cell specific pathways in immunity to pathogens.
Based on a strong body of preliminary data obtained in our laboratory in the past 18 months and delivered for the first time in this proposal, we are convinced that several antibody-independent B cell-specific signaling mechanisms playing a part in TB immunity are yet to be discovered and fully understood. In the current project we propose to investigate the role of B cells in its multiple facets using global gene expression profiling in murine models of TB, including animals in which genes of interest are inactivated in B cells only. The B-TB project will generate new knowledge regarding the innate functions of B cells elicited by Mtb or Mtb components in anti-mycobacterial immunity in vitro and in vivo. This new knowledge may then be exploited in the context of the natural or vaccine-induced immunity to TB. In particular, better understanding the contribution of B cells in TB will undoubtedly help i) to access new markers based on B cell biology in order to evaluate immunity to TB in patients and in future clinical trials, ii) to propose new vaccinal approaches taking into account the role(s) of B cells in TB immunity and iii) to keep under control the safety of B cell-targeting immunotherapeutics in the context of mycobacterial infections.
Our project is based on a concurring collaboration between two laboratories (Partners 1 & 2), which have a 3 year-lasting experience of efficient sharing of expertises to ensure a synergistic use of local resources and knowledge. The project is also conducted in collaboration (outside the ANR funding framework, should the proposal be selected) with specialists of B cells (Dr Simon Fillatreau, DRFZ, Berlin, Germany) and of immune signatures of TB infection (Dr Anne O’Garra, MRC, London, UK) of international repute.