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 patterns 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 blood.
Defense Cells in the Blood:The Leukocytes
All leukocytes are critical to body defense. There are normally between 5,000-10,000 leukocytes per cubic millimeter (mm3) of blood and these can be divided into five major types: neutrophils, basophils, eosinophils, monocytes, and lymphocytes. The production of colonies of the different types of leukocytes is called leukopoiesis and is induced by various cytokines known as colony stimulating factors or CSFs .
A complete blood count (CBC) is a laboratory test which, among other things, detemines the total number of both leukocytes and erythrocytes per ml of blood. In general, an elevated WBC count (leukocytosis ) is seen in infection, inflammation, leukemia, and parasitic infestations. A decreased WBC count (leukopenia ) is generally seen in bone marrow depression, severe infection, viral infections, autoimmune diseases, malignancies, and malnutrition. For example, infections may increase the total leukocyte count two to three times the normal level by dramatically increasing the number of neutrophils.
A differential white blood cell count (leukocyte differential count) determines the number of each type of leukocyte calculated as a percentage of the total number of leukocytes. This information can be useful diagnostically because different diseases or disorders can cause an increase or a decrease in the various types of WBCs. For example, when doing a differential WBC count, neutrophils are usually divided into segs (a mature neutrophile having a segmented nucleus) and bands (an immature neutrophil with an incompletely segmented or banded nucleus). During an active infection, people are generally producing large numbers of new neutrophils and therefore will have a higher percentage of the immature band forms. (An increase in band forms is sometimes referred to as a “shift to the left” because on laboratory slips used for differential WBC counts, the heading for bands is to the left of the heading for mature neutrophils or segs.)
The five types of leukocytes fall into one of two groups, the polymorphonuclear leuckocytes and the mononuclear leukocytes.
A. Polymorphonuclear leukocytes (granulocytes) have irregular shaped nuclei with several lobes and their cytoplasm is filled with granules containing enzymes and antimicrobial chemicals. They include the following:
Neutrophils are the most abundant of the leukocytes, normally accounting for 54-75% of the WBCs. An adult typically has 3,000-7,500 neutrophils/mm3 of blood but the number may increase two- to three-fold during active infections. They are called neutrophils because their granules stain poorly – they have a neutral color – with the mixture of dyes used in staining leukocytes. The nucleus of a neutrophil has multiple lobes.
a. Neutrophils are important phagocytes.
b. Their granules contain various agents for killing microbes. These include lysozyme , lactoferrin , acid hydrolase , and myeloperoxidase . These agents kill microbes intracellularly during phagocytosis but are also often released extracellularly where they kill not only microbes but also surrounding cells and tissue, as will be discussed later under phagocytosis.
c. They release the enzyme kallikrein which catalyzes the generation of bradykinins . Bradykinins promote inflammation by causing vasodilation , increasing vascular permeability, and increasing mucous production. They are also chemotactic for leukocytes and stimulate pain.
d. They release enzymes which catalyze the synthesis of prostaglandins from arachidonic acid in cell membranes. Certain prostaglandins promote inflammation by causing vasodilation and increasing capillary permeability. They also cause constriction of smooth muscles, enhance pain, and induce fever.
e. They are short-lived, having a life span of a few hours to a few days, and do not multiply. However, the bone marrow makes about 80,000,000 new neutrophils per minute.
Eosinophils normally comprise 1-4% of the WBCs (50-400/mm3 of blood). They are called eosinophils because their granules stain red with the acidic dye eosin, one of the mixture of dyes used when staining leukocytes. The nucleus of an eosinophil typically appears lobed.
b. They are capable of phagocytosis but primarily they release their contents into the surrounding environment to kill microbes extracellularly.
c. The substances they release defend primarily against fungi, protozoa, and parasitic worms, pathogens that are too big to be consumed by phagocytosis.
e. Their life span is 8-12 days.
Basophils normally make up 0-1% of the WBCs (25-100/mm3 of blood). They are called basophils because their granules stain a dark purplish blue with the basic dye methylene blue, one of the mixture of dyes that is used when staining leukocytes. Basophils have a lobed nucleus.
a. Basophils release histamine , leukotrienes , and prostaglandins , chemicals that promotes inflammation by causing vasodilation , increasing capillary permeability, and increasing mucous production. Basophils also heparin and PAF .
b. Their life span is probably a few hours to a few days.
Monocytes normally make up 2-8% of the WBCs (100-500/mm3 of blood).
a. Monocytes are important phagocytes.
B. Monocytes differentiate into macrophages when they leave the blood and enter the tissue. Macrophages and dendritic cells are very important in phagocytosis and serve as antigen-presenting cells in the adaptive immune responses (see below). They produce a variety of cytokines that play numerous roles in body defense.
c. They are long-lived (life span of months) and can multiply.
Lymphocytes normally represent 25-40% of the WBCs (1,500-4,500/mm3 of blood).
a. Lymphocytes mediate the adaptive immune responses.
b. Only a small proportion of the body’s lymphocytes are found in the blood. The majority are found in lymphoid tissue. In fact the collective mass of all the lymphocytes in the human body is about the same as the mass of the brain!
c. Lymphocytes circulate back and forth between the blood and the lymphoid system of the body.
d. They have a life span of days to years.
e. There are 3 major populations of lymphocytes:
1. B-lymphocytes (B-cells) mediate humoral immunity (antibody production) and have B-cell receptors (sIg) on their surface for antigen recognition. Generally 10-20% of the lymphocyte are B-lymphocytes. They differentiate into antibody-secreting plasma cells.
2. T-lymphocytes (T-cells) mediate cellular immunity (the production of cytotoxic T-lymphocytes and cytokines) and regulate the adaptive immune responses. Generally 60-80% of the lymphocytes are T-lymphocytes. Based on biochemical markers on their surface, there are two major classes of T-lymphocytes:
a. T4-lymphocytes (CD4+ T-lymphocytes) have CD4 molecules and T-cell receptors (TCRs) on their surface for antigen recognition. They function to regulate the adaptive immune responses through cytokine production.
b. T8-lymphocytes (CD8+ T-lymphocytes) have CD8 molecules and T-cell receptors (TCRs) on their surface for antigen recognition. They differentiate into T8-suppressor cells and cytotoxic T-lymphocytes (CTLs).
3. NK cells (natural killer cells) are lymphocytes that lack B-cell receptors and T-cell receptors. They kill cells bound by antibody or lacking MHC-I molecules on their surface.