Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize a few highly conserved structures present in many different microorganisms. The structures recognized are called pathogen-associated molecular patterns and include LPS from the gram-negative cell wall, peptidoglycan, lipotechoic acids from the gram-positive cell wall, the sugar mannose (common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial DNA, N-formylmethionine found in bacterial proteins, double-stranded RNA from viruses, and glucans from fungal cell walls. Most body defense cells have pattern-recognition receptors for these common pathogen-associated molecular pattern and 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 molecular patterns. All of this will be discussed in greater detail in upcoming pages.
The innate immune responses involve:
phagocytic cells (neutrophils, monocytes, and macrophages);
cells that release inflammatory mediators (basophils, mast cells, and eosinophils);
natural killer cells (NK cells); and
molecules such as complement proteins, acute phase proteins, and cytokines.
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. In the next several pages we will look at each of these in greater detail.
We will now take a closer look at the body defense cells located in the tissues.
Defense Cells in the Tissue: Macrophages, Dendritic Cells, and Mast Cells
When monocytes 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 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 and T-lymphocytes, are found supported by reticular fibers in lymph nodules, lymph nodes , 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 Activated macrophages develop a ruffled cytoplasmic membrane and produce increased numbers of lysosomes.
2. Processing antigens so they can be recognized by T-lymphocytes during the adaptive immune responses.
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 .
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 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 macrophage where they can be recogognized by complementary shaped T-cell receptors (TCR) and CD4 molecules on an effector T4-lymphocyte This interaction leads to the activation of that macrophage.
Like dendritic cells discussed below, macrophages are also capable of capturing and presenting protein antigens to naive T-lymphocytes although they are not as important in this function.
Macrophage-produced cytokines promote inflammation and induce fever, increase phagocytosis and energy output, promote sleep, activate resting T-lymphocytes, attract and activate neutrophils, and stimulate the replication of endothelial cells to form capillaries and fibroblasts to form connective scar tissue. Four important cytokines that macrophages produce are tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8).
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 where in their immature form they are attached by long cytoplasmic processes. Upon capturing antigens through pinocytosis and phagocytosis and becoming activated by proinflammatory cytokines, the dendritic cells detach from the epithelium, 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 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 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 where they can be recognized by complementary shaped T-cell receptors (TCR) and CD4 molecules on naive T4-lymphocyte
In addition, dendritic cells can bind peptide epitopes to MHC-I molecules 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
Dendritic cells also use toll-like receptors to recognize pathogen-associated molecular patterns. This interaction stimulates the production of co-stimulatory molecules that are also required for T-lymphocyte activation. Dendritic cells produce many of the same cytokines as macrophages, namely tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (ILl-6), and interleukin-8 (IL-8).
To view an electron micrograph of a dendritic cell presenting antigen to T-lymphocytes see the Web page for the University of Illinois College of Medicine.
C. Mast Cells
Mast cells, found throughout the connective tissue of the skin and mucous membranes, carry out the same functions as basophils. They release histamine, leukotriens, and prostaglandins, chemicals that promotes inflammation by causing vasodilation, increasing capillary permeability, and increasing mucous production. Mast cells are the cells that usually first initiate the inflammatory response.