Defenses of the Body - Innate Defenses
The defenses of the body are traditionally divided into two arms:
1.) Innate / Nonspecific Defenses - Many of these are the physical and biochemical barriers which prevent microbes from entering and establishing themselves.
2.) Adaptive / Specific Defenses - these defenses are based on T-cell and B-cell reponses. A key characteristic of these responses is that there is memory of the encounter. A second encounter will cause a forceful response that is tailor-made for the organism.
A. Mechanical, Physical and Chemical Barriers
Skin - See pages 313 and 314 (fig. 23.1 and 23.2), and pages 91 - 92 for a discussion of skin structure and protective mechanismsTough, no bacteria can penetrate unaided.
Dry (most skin infections take place in the wetter areas).
Acid ( approximately pH 5), Low temperature, Skin cells are constantly shedding, high salt content.
Lysozyme in the pores.
Skin Associated Lymphoid Tissue - SALT - underlies the skin
Importance of all this is emphasized in burn patients where these defenses are destroyed. Severe infections by Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pyogenes. See pages 394 - 396.
Mucous Epithelia -
mucus - contains polysaccharides and proteins which trap organisms. Ciliated cells and parastalsis and cough reflex moves trapped organisms out. (ie.: Muco-ciliary escalator in the lungs.)
Lots of lysozyme and lactoferrin. Lactoperoxidase produces O2-. There is alot of IgA.
Mucosa Associated Lymphatic Tissue- MALT (and the Gut Associated Lymphatic Tissue - GALT) contain alot of macrophages and lymphocytes. Also there are specialized M- cells which pass bacteria down into the MALT.
Attributes of Selected areas
Mouth - rich resident microflora.
Lungs - sterile if not compromised Otherwise this is a vulnerable area. If organisms get down into the alveolar area they have easy access to the blood.
Stomach - Low pH is an important barrier
Small Intestine - Paneth cells in the crypts produce lysozyme and defensins.
Urethra - flow of urine important.
Female Genitalia - microflora very important. Mucus plug in the cervix important in preventing movement of microbes into the uterus. Can sperm carry bacteria?
B. Complex Biological Responses of Innate Immunity
Complex biological responses include:
- Complement Activation
- Inflammation and Fever
These cells trigger inflammation and allergies. They have Fc-IgE receptors
Macrophages can be resting or angry and they have several activation states in between. They are phagocytic cells and they are very important in antigen presentation.
These cells have a receptor for antigen - called the T cell receptor (TcR).
These cells make antibody. Their antigen receptor is the antibody on their surface. If a B-cell is actively secreting antibody, it is called a plasma cell.
These cells kill virus infected cells and tumor cells. They have an antigen receptor but it is still not well understood. Fig 4.27 shows an NK cell killing a tumor cell. Fig 4.28 shows how the "kiss of death" is performed.
The lymphoid system is composed of
(1) the primary lymphoid organs -- the thymus and the bone marrow --where B-cells and T-cells are produced and
(2) the secondary lymphoid organs -- a collection of lymph nodes dispersed throughout the body. The SALT and MALT (GALT, peyer's patches, appendix, tonsils) discussed above are secondary lymphoid organs as are all the lymph nodes and the spleen. The secondary lymphoid organs are connected by both lymphatic vessels and blood vessels. Interstitial fluid which percolates thru the tissues is collected by the lymphatic vessels and filtered through the lymph nodes before being shunted back into the bloodstream. Lymphatic fluid (lymph) is pumped through the vessels by skeletal muscle contraction.
Fig. 4.8 shows a dissection of a mouse that had been recently injected IV with a carbon suspension. Note where the carbon has localized. The liver and the spleen are very dark and the lungs and intestines are noticeably grayer. These areas are loaded with macrophages which have apparently cleared all of the carbon from the blood stream within the 5 minute time span of the experiment.
a.) chemotaxis -- phagocytic cells are attracted by
(1) microbial products,
(2) complement fragments generated when complement is activated,
(3) compounds liberated when mast cells and platelets become activated
(4) compounds and debris generated when tissues are damaged. (2 , 3 and 4 are commonly seen during inflammation.)
b.) adherence -- phagocytic cells "stick" to their targets by
(1) non-specific receptors -- see fig 4.11,
(2) C3b receptors if the target cell is coated with C3b -- see fig 4.15,
(3) Fc receptors if the target cell is coated with antibody -- see fig 5.7.
Coating target cells with either C3b or antibody so that phagocytes can adhere to them is called opsonization and the C3b or the antibody is called opsonin.
c.) endocytosis, killing and digestion (see fig. 4.11 and 4.13) --
the phagosome and then the phagolysosome (the digestive vacuole) is formed. A variety of enzymes and reactive compounds go to work on the ingested microbes: damaging cell walls and cell membranes, capturing any free iron and digesting the microbes.
d.) antigen presentation (see fig. 5.12 and 5.11) --
pieces of the digested microbe are displayed on the surface of the phagocytic cell for T-cells to see. The pieces are placed onto the major histocompatibilty complex proteins (MHC proteins or MHC antigens - see fig 5.9) which stud the surface of the phagocyte. This function is very important in macrophages and so they are often called antigen presenting cells or APC's.
Complement consists of a number of serum proteins which exist in the serum in an inactive form. These proteins can be activated in a cascade-like fashion by
(1) microbial cells in the alternative pathway or
(2) antigen-antibody complexes in the classical pathway. Once activated, complement can:(1) destroy all cells (even host cells) in the activation area,
(2) cause inflammation (complement is an anaphylatoxin),
(3) opsonize microbial cells (complement is an opsonin) and
(4) attract leukocytes to the area (complement is a chemotaxin).
(See fig 5.3 and 5.4 on pg. 65; fig. 4.22 on pg. 57; fig. 4.14 on pg. 53).
will cause an acute inflammatory response (acute inflammation). The purpose of inflammation is to limit damage, thwart and destroy invading organisms, and then promote tissue repair.
In inflammation, the vasoactive amines, anaphylatoxins, chemotactic factors, prostaglandins and leukotrienes lead to the classic signs and symptoms of inflammation:
These signs are due to:
Although the predominate cell type in acute inflammation is the polymorphonuclear leukocyte, macrophages may become involved. If macrophages do become involved (see fig. 4.20), they will release Interleukin-1 (Il-1) and Tumor Necrosis Factor (TNF). These two cytokines have many functions including the ability to reset the body's thermostat and cause fever.
Cytokines released by macrophages will also stimulates the liver to synthesize and release a variety of acute phase proteins (see fig. 4.24). C-reactive protein is one of these which damages bacterial cell walls and fixes complement.
In a successful inflammatory reponse, fibroblasts responding to a variety of cytokines, lay down collagen and scar tissue. Repair cytokines promote the regeneration of damaged tissues
If the acute inflammatory response does not resolve the problem, a chronic inflammatory response may be generated. In chronic inflammation, macrophages and T-cells become the predominate cell types. Granuloma and delayed hypersensitivity refer to particular types of chronic inflammation.
Cells that are infected by virus can synthesize and secrete either alpha-interferon and/or beta-interferon (a-IFN, b-IFN). These interferons bind to other, still uninfected, cells and stimulate the uninfected cells to synthesize anti-viral proteins which interfer with and abort virus infections in those cells (see fig. 4.25 and fig 9.10).