Role of mast cells in autoimmune diseases

There is a lot of overlap between autoimmune and allergic diseases.  They are both manifested by “hypersensitive” immune responses. When we were first learning about these illnesses, autoimmune diseases were originally called “experimental allergic” diseases.  This persisted until the late 1960’s.  There is a lot we still don’t know about autoimmune diseases.  What we do know is that we need all the parts of the immune system to work together in order for the disease process to occur. 

There are two ways autoimmunity can start.  One is for a T cell to become activated and start making many copies of itself.  T cells naturally go to inflamed sites and have many ways of calling local cells, like mast cells, to come help with the inflammatory response, including by mast cell degranulation.  When it does this to one of your own cells, and not something dangerous, like an infecting organism, it damages your body.  Another way for autoimmunity to start is for a B cell to have a self-reactive receptor.  B cells have special receptor “locks” that bind to the “key” on things our body finds dangerous, like bacteria.  But sometimes B cells accidentally have receptor “locks” that bind to the “keys” on our own cells.  Usually, our body kills these B cells in the bone marrow, but sometimes some escape into the body.  T cells and B cells need help to continue an autoimmunity response.  Your body has many barriers in place to make sure this doesn’t happen. 

It is widely thought that mast cells are important in autoimmune disease.  Multiple sclerosis, rheumatoid arthritis, and bullous pemphigoid are all autoimmune diseases in which high numbers of mast cell mediators are frequently seen at sites of inflammation.  Research in animal models has shown that stabilizing mast cells and treating degranulation can show reduction in damage and symptoms. 

In RA, the body targets the joints.  Mast cells normally live in the joints.  In RA patients, they are present in 6-25X times the normal quantity.  Tryptase is believed to initiate an inflammatory response by complexing with heparin to cause the release of signals like TNF and IL-1b to call neutrophils to the site. Tryptase fits into the locks of other nearby cells and tells them to release a molecule called IL-17.  IL-17 tells mast cells to increase degranulation and secretion.  This specific action allows mast cells to secrete molecules that degrade bone and cartilage.  In some lab studies, high numbers of mast cells in joints and severity of symptoms can be reduced by use of mast cell stabilizing drugs.

Bullous pemphigoid is a skin disease that causes skin blisters.  Large scale degranulation happens very early in the disease process.  Degranulated mast cells are found in skin lesions where histamine, tryptase and other mast-cell molecules are found in the blister fluid.  This phenomenon has been observed since the late 70’s.

MS is a CD4+ T cell mediated disease in which the body destroys the myelin sheath that protects nerves.  (Think of the myelin sheath as a sleeve, and the nerve as an arm – it fits right over it.)  Mast cells are found in brain plaques in post-mortem brain examination, as well as precursors for tryptase and histamine.  These two chemicals are also found in the cerebral spinal fluid of some patients. 

And then of course, there's the fact that the overwhelming majority of people I know with mast cell disease, including myself, have at least one autoimmune disease, sometimes more.  However, despite this obvious circumstantial evidence, it is still not completely obvious what mast cells are doing to sustain autoimmune disease.

One of the ways researchers think mast cells contribute is by the use of TLRs (toll-like receptors.)  These receptor "locks” recognize the “keys” on infectious organisms, like bacteria.  When the “key” binds to a TLR, the cell having the receptor becomes activated and causes the cell to make lots of inflammatory molecules that damage tissues.  The damaged tissues are then recognized by T or B cells, which become activated themselves.  Autoimmunity follows. 

More and more, we are realizing that TLRs are very important in autoimmune activity.  Several types of TLRs are found on the surfaces of mast cells, and they have been shown to be functional.  Activating a mast cell via TLR2 causes it to produce IL-17 (interleukin), IFN-gamma (interferon), TNF (tumor necrosis factor), and IL-1B (an interleukin.) 

Self-reactive IgG and IgE antibodies are often found in autoimmune and allergic diseases, including atopic dermatitis, RA, lupus, Hashimoto’s thyroiditis, Graves’ disease, bullous pemphigoid and MS.  Many of the self-antigens that react with IgE are homologous to environmental antigens.  This is the heart of the matter.  The part of your cell that the IgE molecule sticks to, causing other cells to think that particular cell is dangerous, looks like something else the IgE usually sticks to in its normal function.  Your IgE thinks your cell is something else. 

Mast cells also have several IgG receptors, which can also activation and degranulation.  IgG antibodies are found in BP, RA, lupus and MS.  It is thought that these IgG receptors on mast cells are activated in these diseases, and causes the release of mast cell molecule IL-1b (interleukin.) 

Mast cells are thought to trigger other inflammatory cells arriving at a site.  Mast cells then directly interact with some cells, including neutrophils and T cells.  TNF, released by mast cells, contributes to T cells activating and making many copies of themselves. 

There is also a newer idea that T cells can change the function of mast cells.  In lab experiments, activated T cells can make mast cells release molecule IL-8 to signal other cells to come.  There is also a molecule on the outside of T cells that can “stick” to a molecule on the outside of mast cells that can make mast cells degranulate.

Despite a significant amount of evidence pointing toward a role for mast cells in autoimmune disease, some remain skeptical.  This is likely because lab experiment using animal models have often not been able to prove the relationship effectively.  This may be because there is another factor involved in these various cell interactions that we don’t yet know about.  However, many doctors feel that the current evidence for mast cell involvement is sufficient to agree that mast cells are involved in these processes.  Whatever the reason, the topic of mast cell involvement in autoimmune disease is still hotly debated in the medical community.