I. THE INNATE IMMUNE SYSTEM

C. CELLS INVOLVED IN BODY DEFENSE

2. Defense Cells in the Tissue: Dendritic Cells, Macrophages, and Mast Cells

The overall purpose of this Learning Object is:
1) to learn the names of defense cells such as macrophages, dendritic cells, and mast cells that are located in body tissues; and
2) to learn the various roles each one plays in innate and adoptive immune defenses.

LEARNING OBJECTIVES FOR THIS SECTION

Innate immunity refers to antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to an antigen (def). This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection.

Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPS and include LPS from the gram-negative cell wall, peptidoglycan and lipotechoic acids from the gram-positive cell wall, the sugar mannose (a terminal sugar common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial and viral unmethylated CpG DNA, bacterial flagellin, the amino acid N-formylmethionine found in bacterial proteins, double-stranded and single-stranded RNA from viruses, and glucans from fungal cell walls. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also act as PAMPS. (Because all microbes, not just pathogenic microbes, possess PAMPs, pathogen-associated molecular patterns are sometimes referred to as microbe-associated molecular patterns or MAMPs.)

Most body defense cells have pattern-recognition receptors for these common PAMPSand so there is an immediate response against the invading microorganism. Pathogen-associated molecular patterns can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathways. In all, the innate immune system is thought to recognize approximately 103 of these microbial molecular patterns.

The innate immune responses do not improve with repeated exposure to a given infection and involve the following:

Examples of innate immunity include anatomical barriers, mechanical removal, bacterial antagonism, pattern-recognition receptors, antigen-nonspecific defense chemicals, the complement pathways, phagocytosis, inflammation, and fever.

We will now take a closer look at the body defense cells located in the tissues.

2. Defense Cells in the Tissue: Dendritic Cells, Macrophages, and Mast Cells

a. Dendritic Cells (def)

Most dendritic cells are derived from monocytes and are referred to as myeloid dendritic cells. They are located throughout the epithelium of the skin, the respiratory tract, and the gastrointestinal tract, as well as lymphoid tissues and organ parenchyma (def). In these locations, in their immature form, they are attached by long cytoplasmic processes. Upon capturing antigens through pinocytosis and phagocytosis and becoming activated by inflammatory cytokines, the dendritic cells detach from their initial site, enter lymph vessels, and are carried to regional lymph nodes. By the time they enter the lymph nodes, they have matured and are now able to present antigen to the everchanging populations of naive T-lymphocytes (def) located in the cortex of the lymph nodes.

The primary function of dendritic cells is to capture and present protein antigens to naive T-lymphocytes . (Naive lymphocytes are those that have not yet encountered an antigen.) Dendritic cells engulf microorganisms and other materials and degrade them with their lysosomes. Peptides from microbial proteins are then bound to a groove of unique molecules called MHC-II molecules (def) produced by macrophages, dendritic cells, and B-lymphocytes. The peptide epitopes bound to the MHC-II molecules are then put on the surface of the dendritic cell (see Fig. 2) where they can be recognized by complementary shaped T-cell receptors (TCR) and CD4 molecules (def) on naive T4-lymphocyte (def) (see Fig. 3).

 

In addition, dendritic cells can bind peptide epitopes to MHC-I molecules (def) and present them to naiveT8-lymphocytes. The MHC-I molecules with bound peptide on the dendritic cell are recogognized by complementary shaped T-cell receptors (TCR) and CD8 molecules on naive T8-lymphocyte (def) (see Fig. 4).

These interactions enable the T4-lymphocytes or T8-lymphocytes to become activated, proliferate, and differentiate into effector cells (def). This will be discussed in detail in Unit 5.

Myeloid dendritic cells also use toll-like receptors (TLRs) to recognize pathogen-associated molecular patterns or PAMPs (see Fig. 5). The interaction of the PAMP with its TLR stimulates the production of co-stimulatory molecules that are also required for T-lymphocyte activation. Dendritic cells produce many of the same inflammatory cytokines as macrophages, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8). They also can produce interleukin-12 (IL-12), a cytokine that can activate natural killer T-lymphocytes (NKT cells).

Another type of dendritic cell, the plasmacytoid dendritic cell, uses its TLRs to recognize viral PAMPs. This interaction results in the production and secretion of type I interferons (def).

 

Antigen-presenting cells (def) or APCs will be discussed in greater detail in Unit 5.

 

b. Macrophages (def)

When monocytes (def) leave the blood and enter the tissue, they become activated and differentiate into macrophages. Those that have recently left the blood during inflammation and move to the site of infection through positive chemotaxis (def) are sometimes referred to as wandering macrophages.

In addition, the body has macrophages already stationed throughout the tissues and organs of the body. These are sometimes referred to as fixed macrophages. Many fixed macrophages are part of the mononuclear phagocytic (reticuloendothelial) system. They, along with B-lymphocytes (def) and T-lymphocytes (def), are found supported by reticular fibers in lymph nodules, lymph nodes (see Fig. 1), and the spleen where they filter out and phagocytose foreign matter such as microbes. Similar cells derived from stem cells, monocytes, or macrophages are also found in the liver (Kupffer cells), the kidneys (mesangial cells), the brain (microglia), the bones (osteoclasts), the lungs (alveolar macrophages), and the gastrointestinal tract (peritoneal macrophages).

Macrophages actually have a number of very important functions in body defense including:

1. killing of microbes, infected cells, and tumor cells by phagocytosis.

Macrophages that have engulfed microorganisms become activated by a subset of T-helper lymphocytes called Th1 cells (see Fig. 6). Activated macrophages develop a ruffled cytoplasmic membrane and produce increased numbers of lysosomes.

2. processing antigens so they can be recognized by T-lymphocytes (def) during the adaptive immune responses (def).

Macrophages, as well as the dendritic cells mentioned below, process antigens through phagocytosis and present them to T-lymphocytes. Because of this function, they are often referred to as antigen-presenting cells or APCs (def) .

Macrophages primarily capture and present protein antigens to effector T-lymphocytes. (Effector lymphocytes are lymphocytes that have encountered an antigen, proliferated, and matured into a form capable of actively carrying out immune defenses.) Macrophages engulf the microorganism and degrade it with their lysosomes. Peptides from microbial proteins are then bound to a groove of unique molecules called MHC-II molecules (def) produced by macrophages, dendritic cells (def), and B-lymphocytes (def). The peptide epitopes bound to the MHC-II molecules are then put on the surface of the macrophage (see Fig. 2) where they can be recogognized by complementary shaped T-cell receptors (TCR) and CD4 molecules on an effector T4-lymphocyte (def) (see Fig. 3). This interaction leads to the activation of that macrophage. This will be discussed in detail in Unit 5.

Like dendritic cells discussed above, macrophages are also capable of capturing and presenting protein antigens to naive T-lymphocytes although they are not as important in this function.

 

3. secreting proteins called cytokines (def) that play a variety of roles in non-specific body defense.

Macrophage-produced cytokines promote inflammation and induce fever, increase phagocytosis and energy output, promote sleep, activate resting T-lymphocytes (def), attract and activate neutrophils (def), and stimulate the replication of endothelial cells (def) to form capillaries and fibroblasts (def) to form connective scar tissue. Four important cytokines that macrophages produce (as mentioned in Unit 1 under endotoxin) are tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8). Cytokines will be discussed in more detail in Unit 4 and Unit 5.

 

 

c. Mast Cells (def)

Mast cells are typically the immunological first responders to infection and carry out many of the same inflammatory-mediating functions as basophils. There are two types of mast cells in the body: mast cells found in the connective tissue (def) and mast cells found throughout the mucous membranes.

The granules of mast cells contain such mediators as histamine (def), eosinophil chemotactic factor, neutrophil chemotactic factor, platelet activating factor (def), and cytokines (def) such as IL-3, IL-4, IL-5, IL-6, and TNF. They also possess pathways for synthesizing leukotriens (def) and prostaglandins (def), chemicals that promote inflammation (def) by causing vasodilation (def), increasing capillary permeability, and increasing mucous production.

Mast cells have pattern-recognition receptors or PRRs (def) on their surface that interact with pathogen-associated molecular patterns or PAMPs (def) of microbes. After the PAMPs bind to their respective PRRs, they release the contents of their granules. These chemical mediators promote inflammation and attract neutrophils to the infected site.

 

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