Take home points: July 2015

Mast cell interactions with B and T cells
• Mast cells communicate with other cells by:
o Releasing chemicals to tell another cell to do something
o Other cells releasing chemicals to tell mast cells to do something
o Moving right up against other cells, which allows the cells to “talk”
• B cells are white blood cells that make antibodies and protect against infections.
o Mast cells can tell B cells to make IgE, an allergy antibody.
o When mast cells touch B cells, the mast cells can release IL-6 which tells B cells to live longer.
o Mast cells can tell B cells to make IgA, an antibody.
• T cells are white blood cells that have many functions.
o T cells and mast cells are found close together in many inflammatory conditions, like ulcerative colitis.
o Activated T cells can activate mast cells.
o Mast cells can tell T cells to proliferate and produce inflammatory molecules.
o A kind of T cell called Treg (T reg, like in regulatory) cells can make mast cells harder to activate and interfere with degranulation.

Mast cells in kidney disease
• Kidney disease is often not identified until 60-70% of functional kidney cells have been damaged beyond repair.
• Mast cells are rare in healthy kidneys.
o Damaged kidneys can have up to 60x the normal amount of mast cells.
o Mast cell count is not related to disease severity.
• Atopic disease, like atopic dermatitis and allergic asthma, is linked to idiopathic nephrotic disease, kidney disease of unknown origin.
o The nephrotic disease and atopic disease could be manifestations of the same overarching condition.
o In patients with both, IgE levels are high.
• Tryptase is elevated in some patients with kidney damage.
• Mast cells are responsible for bringing other inflammatory cells to the damaged kidney.
• Mast cells can cause fibrosis in kidneys.
• In some roles, mast cells can protect kidneys from damage.

Regulation of mast cells by IgE and stem cell factor (SCF)
• Mast cells are mostly regulated in two ways
• IgE binds to the IgE receptor (FceRI) on mast cells and activates them
o Activation by IgE results in degranulation and secretion of mediators
o IgE induces mediator release by affecting the amount of calcium inside mast cells
• Stem cell factor (SCF) binds to the CKIT receptor on mast cells and tells them to stay alive
o SCF also increases degranulation and production of cytokines
o SCF helps mast cells to adhere to other cells

Mast cells in vascular disease: Part 3
• Mast cells are involved in the formation and growth of aneurysms
• Activated mast cell populations are increased in vessels that rupture
• Chymase, a mast cell mediator, can degrade vessels and increase risk of rupture
• Leukotrienes contribute to aneurysm formation

Mast cell interactions with B and T cells

Mast cells communicate with many other cells of various types in the body. The type of communication we have discussed here most often is via mediator release – mast cells release mediators and they trigger an action in another cell by binding to a receptor, or the other cells release mediators that act on mast cell receptors. Another method of interaction is for cells to physically contact with each other. Mast cells use these techniques to impact the behavior of other cells.

B cells are lymphocytes, a kind of white blood cell. They form part of the adaptive immune system, the arm of immunity that is learned over the course of your life. They make antibodies when exposed to allergens or antigens from infectious agents. They help amplify the immune response during infection, can release cytokines and some become memory B cells, which allow for rapid response to a previously encountered organism.

Mast cells produce and release IL-4, IL-5, IL-6 and IL-13, all of which regulate the development of B cells and which role they develop toward. Mast cells can induce IgE production by B cells via binding of OX40 on the B cell to the OX40 receptor on the mast cell. In the absence of an activating signal, mast cells are able to cause unactivated B cells to proliferate and become IgM producing cells.

Resting and activated mast cells inhibit B cell death and promote proliferation of undifferentiated B cells. When the B cells are activated, this effect is exaggerated. These changes occur when mast cells and B cells are in contact and mast cells have released IL-6. Activated mast cells can drive B cells toward becoming CD138+ plasma cells or producing IgA.

T cells are also lymphocytes. There are several types of T cells and all perform very specialized functions. Mast cells and T cells are often found in close physical proximity in inflamed spaces. Conditions in which this commonly occurs include sarcoidosis, irritable bowel disease, rheumatoid arthritis and prolonged allergic processes.

Contact between mast cells and T cells initiates gene expression in mast cells. When the T cells are activated, it also induces mast degranulation, production/release of TNFa, release of MMP-9, inhibition of MMP-1, and release of IL-4 and IL-6. This occurs due to binding between the surface molecules LFA-1 and ICAM-1. Another receptor on mast cell surfaces, LTβR, can be bound by T cells. This initiates release of IL-4, IL-6, TNFa, CXCL2 and CCL5 by mast cells. In the presence of TNFa, binding to OX40 on activated CD4+ T cells by mast cells causes T cell proliferation and cytokine production.

Mast cells can express proteins on their surfaces called major histocompatibility complex I and II. These proteins literally show pieces of a phagocytosed, or “eaten”, pathogen. Showing these pieces to other cells allows them to fight infection in a specialized way. When mast cells express MHC II, they can steer T cells toward developing into specific types, including Treg cells. When mast cells express MHC I, they increase CD8+ T cell populations and ability to kill infectious agents. CD8+ T cells can cause MHC I expression by mast cells.

Mast cells and Treg cells are found in close proximity in secondary lymphoid and mucosal tissues. Activated Treg cells reduce the amount of IgE receptors on mast cells when they come into contact. They also cause release of TGF-b and IL-10. Treg cells interfere with degranulation via the OX40 receptor on mast cells.

References:

Gri, Giorgia, et al. Mast cell: an emerging partner in immune interaction. Front. Immunol., 25 May 2012.

Brill, A., Baram, D., Sela, U., Salamon, P., Mekori, Y. A., and Hershkoviz, R. Induction of mast cell interactions with blood vessel wall components by direct contact with intact T cells or T cell membranes in vitro. Clin. Exp. Allergy 2004; 34, 1725–1731.