Laboratory of Virology and Immunology

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Identification of novel genes or proteins involved in the NF-kB alternative pathway induced by the lymphotoxin b receptor
       
       
  Director: J. Piette; contact: E.Dejardin@ulg.ac.be  
       
   
1) Characterization and identification of new genes and proteins that are involved in the alternative NF-kB pathway
 
   
 
   
The main goal of this project is to establish the biochemical characterization of known proteins such as NIK and IKK alpha, as well as, unknown proteins that are involved in the activation of the alternative NF-kB pathway Indeed, this pathway has been implicated in various biological settings like the control of the expression of chemokines and cytokines that are essential for secondary lymphoid organogenesis or B cell survival.
 
   
 
   
  We have recently discovered that two NF-kB signaling, that we have named the classical and the alternative pathway, emerged from the Lymphotoxin-Beta Receptor (LTβR). At least two kinases that are NIK and IKK are known to play a role in the activation of the alternative pathway but the way their kinase activity is induced is not well defined. We are also currently interested in deciphering the regions of the LTβR that mediate either the classical or/and the alternative pathway. To do so we are conducting diverse molecular genetic approaches to identify new LTβR-interacting proteins. Finally, our battery of fibroblasts deficient for proteins involved in LTβR pathways are suitable models for DNA arrays and chromatine immunoprecipitation (ChIP) studies for discovering new genes and their regulatory regions.
 
   
 
   
Altogether, our future results should prompt us to better understand how the LTβR mediates its multiple biological functions.  All the genomics and proteomics technologies needed for this project are available within our institution at the University of Liege (http://www.giga.ulg.ac.be).
 
   
 
   
 
   
2) Development of new therapeutics for the treatment of rheumatoid arthritis
 
   
 
   
Rheumatoid arthritis (RA) is a chronic disease that affects 1 percent of the world population. The disease progresses in three stages : first stage is the swelling of the synovial lining, causing pain, stiffness, redness and swelling around the joint ; second is the rapid division and growth of cells, or pannus, which causes the synovium to thicken ; and third stage, the inflamed cells release enzymes that may digest bone and cartilage. Early diagnosis and treatment of RA is critical if people want to continue living a productive lifestyle. However, studies have shown that current aggressive treatment of RA can solely relieve the pain, reduce the inflammation, stop or slow down the joint damage. Once the treatment is interrupted the symptoms reappear. So there is a real need for  treatments that would irreversibely erradicate the disease.
 
   
 
   
  Lymphoid neogenesis that gives rise to ectopic-lymphoid structures (or tertianery immune system) within the joints is certainly an important step in the development of the pathology. The organization of these ectopic-lymphoid structures relies on a proper segregation of different subsets of dendritic cells, B cells, T cells and on gradients of various cytokines and chemokines. Among these, a few, like BLC, SLC and ELC, are specifically controlled by the alternative NF-kB pathway. The main goal of this project is to design new chemical drugs that would interfere with the activation of the alternative NF-kB pathway in response to LTβR liation. We are currently building a robust biological assay for testing chemicals that would inhibit specifically the alternative NF-kB pathway. In collaboration with the Dr. B. Masereel (FUNDP, Belgium) we are working on the design of inhibitors directed against new intermediates of the alternative NF-kB patrhway.
 
   
 
   
 
   
 3) Molecular mechanisms controlling the expression and the anti-apoptotic activity of BAFF in B cell lymphomas
 
   
 
   
B cell activating factor of the TNF family (BAFF), also referred as B lymphocyte stimulator (BLyS), is a recently identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B cell development and homeostasis. Currently, three receptors have been identified that transmit signals upon BAFF binding and these include B cell maturation antigen (BCMA), B cell activating factor receptor (BAFFR), and transmembrane activator and CAML interactor (TACI). The striking effects of BAFF on normal B cell maintenance and survival and the largely B lineage-restricted pattern of receptor expression, raises the possibility that these TNF family ligands and receptors may be involved in the pathogenesis and maintenance of mature B lineage haematological malignancies.
 
   
 
   
    In contrast to normal B cells, malignant B cells show uncontrolled cell proliferation. BAFF levels are elevated in the serum of patients with B-lymphoid malignancies. Furthermore, among other cells BAFF is produced by malignant B cells and acts as an essential autocrine survival factor.
 
   
 
   
Our project is focused on two aspects : first to better understand how BAFF expression is elevated in B cell lymphomas ; second to elucidate the way BAFF transmits its anti-apoptotic activity through the BAFFR. To date little is known about inducers that modulate the rate of transcription of BAFF. Depending on the cell type, CD40, LTβR and IFNγ have demonstrated the capacity to induce BAFF production. However, the way these molecules mediate their signal is not well defined yet. We have some evidence that among others the transcription factor NF-kappaB is a key player.
 
   
 
   
The strong dependence of certain B cell lymphomas on BAFF might be a point of vulnerability, which offers exciting new therapeutic possibilities.
 
   
 
       
     
       
       
       
 
     
 
Last Update: April 2007