A type of white blood cell that is found in connective tissues all through the body, especially under the skin, near blood vessels and lymph vessels, in nerves, and in the lungs and intestines. Mast cells play an important role in how the immune system responds to certain bacteria and parasites and they help control other types of immune responses. They contain chemicals such as histamine, heparin, cytokines, and growth factors. They release these chemicals during allergic reactions and certain immune responses. These chemicals have many effects, including the widening of blood vessels and angiogenesis. During an allergic response, they can cause flushing (a hot, red face) and itching. In large amounts, they can also cause abdominal cramps, muscle pain, nausea, vomiting, diarrhea, low blood pressure, and shock. Mast cells are part of the body’s immune system.

Many of the chemical mediators discussed in this section contribute in some way to inflammation and fever, which are nonspecific immune responses discussed in more detail in Inflammation and Fever. Cytokines stimulate the production of acute-phase proteinssuch as C-reactive protein and mannose-binding lectin in the liver. These acute-phase proteins act as opsonins, activating complement cascades through the lectin pathway.

Some cytokines also bind mast cells and basophils, inducing them to release histamine, a proinflammatory compound. Histamine receptors are found on a variety of cells and mediate proinflammatory events, such as bronchoconstriction (tightening of the airways) and smooth muscle contraction.

In addition to histamine, mast cells may release other chemical mediators, such as leukotrienes. Leukotrienes are lipid-based proinflammatory mediators that are produced from the metabolism of arachidonic acid in the cell membrane of leukocytes and tissue cells. Compared with the proinflammatory effects of histamine, those of leukotrienes are more potent and longer lasting. Together, these chemical mediators can induce coughing, vomiting, and diarrhea, which serve to expel pathogens from the body.

Certain cytokines also stimulate the production of prostaglandins, chemical mediators that promote the inflammatory effects of kinins and histamines. Prostaglandins can also help to set the body temperature higher, leading to fever, which promotes the activities of white blood cells and slightly inhibits the growth of pathogenic microbes.

Another inflammatory mediator, bradykinin, contributes to edema, which occurs when fluids and leukocytes leak out of the bloodstream and into tissues. It binds to receptors on cells in the capillary walls, causing the capillaries to dilate and become more permeable to fluids.

Hematopoiesis also gives rise to mast cells, which appear to be derived from the same common myeloid progenitor cell as neutrophils, eosinophils, and basophils. Functionally, mast cells are very similar to basophils, containing many of the same components in their granules (e.g., histamine) and playing a similar role in allergic responses and other inflammatory reactions. However, unlike basophils, mast cells leave the circulating blood and are most frequently found residing in tissues. They are often associated with blood vessels and nerves or found close to surfaces that interface with the external environment, such as the skin and mucous membranes in various regions of the body (Figure 17.15).

Mast cells

When an infection occurs, local immune cells react and emit signals or chemicals to recruit other immune cells. Among the first to respond are the mast cells that are found surrounding tissues and lymphatic vessels. When bacteria infect tissues, mast cells recognize parts of the bacterial cell wall and release cytokines that recruit neutrophils, eosinophils, basophils and T cells. As part of adaptive immunity, IgE antibodies mediate release of granules, a combination of chemicals that cause vasodilation (histamine, bradykinin), anti-coagulation (heparin), or cell lysis (lysozymes). In this way, mast cell orchestrate allergic responses.

Inflammation

When pathogens breach the epithelial barrier and enter a tissue, they encounter the resident mast cell, macrophages and dendritic cells. The macrophages and dendritic cells phagocytize the pathogen. The macrophage and mast cells release cytokines that attract neutrophils to the site of infection. This is the beginning of a complex innate immune response called inflammation. Inflammation results in the activation and accumulation of immune cells, the release of inflammatory chemicals and the activation of complement.

The four characteristic or cardinal signs and symptoms of inflammation are redness, heat, swelling and pain. Loss of function may also occur at the site depending on the extent of the injury. Inflammation is an attempt to restore tissue homeostasis by removing microbes, toxins or debris at the site of injury and to prepare the site for repair. Inflammation is a normal response to tissue damage and a vital part of tissue repair.

Whether the injury was due to abrasion, burns or viral infection, the inflammatory response has three basic stages:

1. Vasodilation and increased permeability of blood vessels. Vasodilation is an increase in blood vessel diameter that allows more blood to flow to the site of injury. Increased permeability permits proteins such as antibodies, clotting factors and complement to enter the injured area because they can leak out of the capillaries.
2. Emigration of phagocytes. Emigration is the movement of phagocytes from the blood into interstitial fluid. Phagocytes remove pathogens and dead tissue.
3. Tissue repair. In response to injury, mast cells in connective tissue and basophils in blood release histamine. Neutrophils and macrophages attracted to the site of injury also stimulate the release of histamine, which causes vasodilation and increased permeability of blood vessels. Leukotrienes (LTs) produced by basophils and mast cells increase permeability and are chemotactic agents that stimulate emigration. Other substances that contribute to vasodilation and increased permeability are blood kinins and complement components and prostaglandins released by damaged cells. Prostaglandins also intensify and prolong the pain associated with inflammation.

Inflammation

Granulocytes include basophils, eosinophils, and neutrophils. Basophils and eosinophils are important for host defense against parasites. They also are involved in allergic reactions. Neutrophils, the most numerous innate immune cell, patrol for problems by circulating in the bloodstream. They can phagocytose, or ingest, bacteria, degrading them inside special compartments called vesicles.

Mast cells also are important for defense against parasites. Mast cells are found in tissues and can mediate allergic reactions by releasing inflammatory chemicals like histamine.

Monocytes, which develop into macrophages, also patrol and respond to problems. They are found in the bloodstream and in tissues. Macrophages, "big eater" in Greek, are named for their ability to ingest and degrade bacteria. Upon activation, monocytes and macrophages coordinate an immune response by notifying other immune cells of the problem. Macrophages also have important non-immune functions, such as recycling dead cells, like red blood cells, and clearing away cellular debris. These "housekeeping" functions occur without activation of an immune response.

Dendritic cells (DC) are an important antigen-presenting cell (APC), and they also can develop from monocytes. Antigens are molecules from pathogens, host cells, and allergens that may be recognized by adaptive immune cells. APCs like DCs are responsible for processing large molecules into "readable" fragments (antigens) recognized by adaptive B or T cells. However, antigens alone cannot activate T cells. They must be presented with the appropriate major histocompatiblity complex (MHC) expressed on the APC. MHC provides a checkpoint and helps immune cells distinguish between host and foreign cells.

Natural killer (NK) cells have features of both innate and adaptive immunity. They are important for recognizing and killing virus-infected cells or tumor cells. They contain intracellular compartments called granules, which are filled with proteins that can form holes in the target cell and also cause apoptosis, the process for programmed cell death. It is important to distinguish between apoptosis and other forms of cell death like necrosis. Apoptosis, unlike necrosis, does not release danger signals that can lead to greater immune activation and inflammation. Through apoptosis, immune cells can discreetly remove infected cells and limit bystander damage. Recently, researchers have shown in mouse models that NK cells, like adaptive cells, can be retained as memory cells and respond to subsequent infections by the same pathogen.

Adaptive Cells

B cells have two major functions: They present antigens to T cells, and more importantly, they produce antibodies to neutralize infectious microbes. Antibodies coat the surface of a pathogen and serve three major roles: neutralization, opsonization, and complement activation.

Neutralization occurs when the pathogen, because it is covered in antibodies, is unable to bind and infect host cells. In opsonization, an antibody-bound pathogen serves as a red flag to alert immune cells like neutrophils and macrophages, to engulf and digest the pathogen. Complement is a process for directly destroying, or lysing, bacteria.

Antibodies are expressed in two ways. The B-cell receptor (BCR), which sits on the surface of a B cell, is actually an antibody. B cells also secrete antibodies to diffuse and bind to pathogens. This dual expression is important because the initial problem, for instance a bacterium, is recognized by a unique BCR and activates the B cell. The activated B cell responds by secreting antibodies, essentially the BCR but in soluble form. This ensures that the response is specific against the bacterium that started the whole process.

Every antibody is unique, but they fall under general categories: IgM, IgD, IgG, IgA, and IgE. (Ig is short for immunoglobulin, which is another word for antibody.) While they have overlapping roles, IgM generally is important for complement activation; IgD is involved in activating basophils; IgG is important for neutralization, opsonization, and complement activation; IgA is essential for neutralization in the gastrointestinal tract; and IgE is necessary for activating mast cells in parasitic and allergic responses.

T cells have a variety of roles and are classified by subsets. T cells are divided into two broad categories: CD8+ T cells or CD4+ T cells, based on which protein is present on the cell's surface. T cells carry out multiple functions, including killing infected cells and activating or recruiting other immune cells.

CD8+ T cells also are called cytotoxic T cells or cytotoxic lymphocytes (CTLs). They are crucial for recognizing and removing virus-infected cells and cancer cells. CTLs have specialized compartments, or granules, containing cytotoxins that cause apoptosis, i.e., programmed cell death. Because of its potency, the release of granules is tightly regulated by the immune system.

The four major CD4+ T-cell subsets are TH1, TH2, TH17, and Treg, with "TH" referring to "T helper cell." TH1 cells are critical for coordinating immune responses against intracellular microbes, especially bacteria. They produce and secrete molecules that alert and activate other immune cells, like bacteria-ingesting macrophages. TH2 cells are important for coordinating immune responses against extracellular pathogens, like helminths (parasitic worms), by alerting B cells, granulocytes, and mast cells. TH17 cells are named for their ability to produce interleukin 17 (IL-17), a signaling molecule that activates immune and non-immune cells. TH17 cells are important for recruiting neutrophils.

Regulatory T cells (Tregs), as the name suggests, monitor and inhibit the activity of other T cells. They prevent adverse immune activation and maintain tolerance, or the prevention of immune responses against the body's own cells and antigens.

Communication

Immune cells communicate in a number of ways, either by cell-to-cell contact or through secreted signaling molecules. Receptors and ligands are fundamental for cellular communication. Receptors are protein structures that may be expressed on the surface of a cell or in intracellular compartments. The molecules that activate receptors are called ligands, which may be free-floating or membrane-bound.

Ligand-receptor interaction leads to a series of events inside the cell involving networks of intracellular molecules that relay the message. By altering the expression and density of various receptors and ligands, immune cells can dispatch specific instructions tailored to the situation at hand.

Cytokines are small proteins with diverse functions. In immunity, there are several categories of cytokines important for immune cell growth, activation, and function.

• Colony-stimulating factors are essential for cell development and differentiation.
• Interferons are necessary for immune-cell activation. Type I interferons mediate antiviral immune responses, and type II interferon is important for antibacterial responses.
• Interleukins, which come in over 30 varieties, provide context-specific instructions, with activating or inhibitory responses.
• Chemokines are made in specific locations of the body or at a site of infection to attract immune cells. Different chemokines will recruit different immune cells to the site needed.
• The tumor necrosis factor (TNF) family of cytokines stimulates immune-cell proliferation and activation. They are critical for activating inflammatory responses, and as such, TNF blockers are used to treat a variety of disorders, including some autoimmune diseases.

Toll-like receptors (TLRs) are expressed on innate immune cells, like macrophages and dendritic cells. They are located on the cell surface or in intracellular compartments because microbes may be found in the body or inside infected cells. TLRs recognize general microbial patterns, and they are essential for innate immune-cell activation and inflammatory responses.

B-cell receptors (BCRs) and T-cell receptors (TCRs) are expressed on adaptive immune cells. They are both found on the cell surface, but BCRs also are secreted as antibodies to neutralize pathogens. The genes for BCRs and TCRs are randomly rearranged at specific cell-maturation stages, resulting in unique receptors that may potentially recognize anything. Random generation of receptors allows the immune system to respond to unforeseen problems. They also explain why memory B or T cells are highly specific and, upon re-encountering their specific pathogen, can immediately induce a neutralizing immune response.

Major histocompatibility complex (MHC), or human leukocyte antigen (HLA), proteins serve two general roles.

MHC proteins function as carriers to present antigens on cell surfaces. MHC class I proteins are essential for presenting viral antigens and are expressed by nearly all cell types, except red blood cells. Any cell infected by a virus has the ability to signal the problem through MHC class I proteins. In response, CD8+ T cells (also called CTLs) will recognize and kill infected cells. MHC class II proteins are generally only expressed by antigen-presenting cells like dendritic cells and macrophages. MHC class II proteins are important for presenting antigens to CD4+ T cells. MHC class II antigens are varied and include both pathogen- and host-derived molecules.

MHC proteins also signal whether a cell is a host cell or a foreign cell. They are very diverse, and every person has a unique set of MHC proteins inherited from his or her parents. As such, there are similarities in MHC proteins between family members. Immune cells use MHC to determine whether or not a cell is friendly. In organ transplantation, the MHC or HLA proteins of donors and recipients are matched to lower the risk of transplant rejection, which occurs when the recipient's immune system attacks the donor tissue or organ. In stem cell or bone marrow transplantation, improper MHC or HLA matching can result in graft-versus-host disease, which occurs when the donor cells attack the recipient’s body.

Complement refers to a unique process that clears away pathogens or dying cells and also activates immune cells. Complement consists of a series of proteins found in the blood that form a membrane-attack complex. Complement proteins are only activated by enzymes when a problem, like an infection, occurs. Activated complement proteins stick to a pathogen, recruiting and activating additional complement proteins, which assemble in a specific order to form a round pore or hole. Complement literally punches small holes into the pathogen, creating leaks that lead to cell death. Complement proteins also serve as signaling molecules that alert immune cells and recruit them to the problem area.