The Immune System is a powerful defense network of cells and molecular mediators that is present within the blood and also integrated within every tissue and organ of our body. However the immune system can have a dark side.

 

In addition to defending us against infections and cancerous cells, our immune system also has important “peace-keeping” roles to keep us healthy and in balance with the microbial world all around us. Unfortunately, many debilitating chronic diseases such as rheumatoid arthritis, lupus, inflammatory bowel disease or multiple sclerosis can result when the immune system fails to maintain this balance and continually goes on the attack, causing damage to our own body.  Immune responses to some infections are so powerful and out of control that they can give rise to a “cytokine storm” that is lethal.  The cells of the immune system can also go out of control in different ways to give rise to many types of cancers, including leukemias and lymphomas.

The Marshall lab focuses on a type of immune cell called B lymphocytes, which are unique in their ability to produce powerful immune defence proteins called antibodies. 

 

B cells are targeted by many vaccines to provide long lasting protection from infections. However, B cells and the antibodies they produce also have other important regulatory roles in maintaining health throughout the body including the intestinal tract and other mucosal surfaces.  Besides producing antibodies, these cells interact with other cells of the immune system to control their activities and secrete cytokines that act as “immunological hormones”.  When not appropriately regulated, activated B cells can trigger damaging immune responses and can produce antibodies that attack the body in chronic autoimmune diseases such as systemic lupus erythematosus. In addition, defective regulation of B cell activation processes can lead to continual cell division, causing B cell leukemia or lymphoma. Like all cells of the immune system, B cells are controlled by receptor proteins on their cell surface. These receptors allow them to sense the presence of microbial molecules and tissue damage, as well as sensing how other immune cells are responding.

Signals from cell surface receptors determine whether B cells divide to produce more copies of themselves or differentiate to become either immune activators (amplifying the immune response), immune regulators (to dampen down the immune response) or antibody-secreting factories. This critical cellular “decision-making” occurs through a process known as Signal Transduction. 

 

Cell surface receptors deliver their signals to the interior of the cell through a network of signal transduction proteins that are collectively responsible for re-programming the activities of the cell, including their cell division, migration within tissues of the body, their metabolic energy-producing pathways, their epigenetic programming and gene expression patterns and ultimately whether they function in a beneficial or harmful way during an immune response. The Marshall Lab is characterizing a signal transduction pathway consisting of interacting proteins and enzymes that modify plasma membrane lipids and orchestrate functional re-programming of B cells and other immune cells.  The specific focus of the lab is on the phosphoinositide 3-kinase pathway (PI3K), including studies on p110 delta and gamma isoforms, PI phosphatases SHIP, INPP4 and PTEN and PI-binding proteins Bam32/DAPP1, TAPP1/2, Lamellipodin, Btk and Akt.