Research
We investigate the molecular mechanisms linking autophagy and cytoskeleton dynamics with human immune responses, specifically in the context of monogenetic immunodeficiencies and immunodysregulation disorders, as well as in cancer. Our long-term goal is to identify new targets for the diagnosis and treatment of these diseases.
Autophagy - the major waste disposal and recycling system of the cells - ensures the proper functioning of several immune processes, including pathogen recognition, antigen processing and presentation, lymphocyte development and effector function, cell metabolism and inflammatory regulation. Dysfunctional autophagy has been implicated in numerous autoimmune diseases, including inflammatory bowel diseases.
Moreover, essential immune response processes such as cell migration, adhesion, division, vesicle trafficking, and cellular transduction rely on a finely tuned actin cytoskeleton dynamics, involving the assembly and disassembly of actin filaments. Human immune disorders caused by deleterious mutations in actin regulatory genes are known as actinopathies.
In particular, we study three disease models:
- LRBA deficiency, an immunodeficiency and immunodysregulation syndrome caused by abolishing biallelic mutations in LRBA. LRBA is linked to the trafficking of CTLA4-containing vesicles in regulatory T cells. Moreover, previous data from our group identified a novel role of LRBA in antigen processing and presentation via autophagy (Sindram E et al., BioRXIV).
- CTLA-4 insufficiency, caused by heterozygous germline mutations in CTLA-4. It is a complex immune dysregulation and immunodeficiency syndrome presenting with reduced penetrance and variable disease expressivity, suggesting the presence of additional disease modifiers that trigger the disease onset and severity.
- Colorectal cancer, is the fourth most common cancer in the world. Autophagy has been shown to inhibit the tumor development at early stages through multiple immune-related mechanisms.