first line of defense
keratinized skin and mucosa
produce variety of chemicals
acidity of skin secretions (pH 3 to 5) inhibits bacterial growth
lipids in sebum & dermcidin in eccrine sweat are toxic to bacteria
vaginal secretions are also very acidic
stomach mucosa secretes concentrated HCl acid solution and protein-digesting enzymes to kill microorgs.; sticky mucus in digestive/respiratory passageways; mucus coated nose hairs and cilia in resp tract
If the skin/mucosa are penetrated, this second line of defense kicks in
internal; antimicrobial proteins, phagocytes, other cells
hallmark of 2nd line of defense: inflammation
Macrophages are derived from?
Monocytes (WBCs): Monocytes leave the bloodstream, enter the tissues, and develop into macrophages
Wander throughout the tissue spaces in search of cellular debris and foreign invaders; like alveoli in lungs
like Kupffer cells in liver & microglia of brain, are permanent residents of particular organs
-most abundant WBC type
-become phagocytic on encountering infectious material in tissues
1) phagocyte adheres to pathogens/debris
2) phagocyte forms pseudopods that eventually engulf the particles forming a PHAGOSOME
3)lysosome fuses with the phagocytic vesicle, forming a PHAGOLYSOSOME
4) lysosomal enzymes digest the particles, leaving a residual body
5) Exocytosis of the vesicle removes indigestible & residual material
In order for a phagocyte to accomplish ingestion, what must occur?
Adherence; cling to the pathogen, which is made possible by recognizing the pathogen's Carbohydrate signature;
Adherence is more probable/efficient when complement proteins or antibodies coat foreign particles, called opsonization, the coating provides handles that the phagocyte receptors can bind to
the process of coating foreign particles with complement proteins or antibodies, that form handles for phagocyte receptors to bind to
liberate a deluge of free radicals, including nitric oxide and super oxide, that have potent killing abilities.
killing of pathogens
-more killing is caused by oxidizing chemicals, which increase osmolarity and pH in the phagolysosome which then activates other protein-digesting enzymes that digest invaders
-neutrophils also produce antimicrobial chemicals, called DEFENSINS, that pierce the pathogen's membrane
Natural Killer (NK) cells
- "police" the body in blood & lymph
-defensive cells can lyse & kill cancer cells and virus-infected body cells before the adaptive immune system is activated.
-part of a group of large granular lymphocytes
-called the "pit bulls" of the defense system
- Not phagocytic, they kill by inducing the target cell to undergo apoptosis, uses same killing mechanism as cytotoxic T cells
-secrete potent chemicals that enhance inflammatory response
the inflammatory response & cardinal signs
-triggered when there's body tissue injuries from trauma, intense heat, irritating chemicals or infection by viruses, fungi, or bacteria
-cardinal signs: redness, heat, swelling, pain
*some consider, functional impairment to be a 5th
Beneficial effects of the inflammatory response
1) prevents the spread of damaging agents to nearby tissues
2) disposes of cell debris & pathogens
3) sets the stage for repair
Toll- like Receptors (TLRs)
-Surface membrane receptors on macrophages and certain cells of boundary tissues; role in triggering immune responses
-Triggers release of chemicals called Cytokines
Sources of inflammatory mediators
injured tissue cells, phagocytes, lymphocytes, basophils, and blood proteins
inflammatory chemicals released other than the main histamine
prostaglandins, kinins, leukotrienes, and complement which all cause the arterioles to dilate
As more blood flows into the area, local hyperemia occurs
-Congestion with blood which accounts for redness and heat of inflamed region
which is causes by exudate is local swelling that presses adjacent nerve endings, contributing to a sense of pain
-an increase in WBCs that is characteristic of inflammation
- neutrophils enter blood from red bone marrow in response to chemicals called leukocytosis-inducing factors released by injured cells. within a few hours, the number of neutrophils in blood increases four to fivefold.
*clinging of phagocytes to the inner walls of the capillaries and postcapillary venules
-inflamed endothelial cells sprout cell adhesion molecules (CAMs) that signal "this is the place!" As neutrophils encounter these CAMs, they slow and roll along the surface, achieving an initial foothold. When activated by inflammatory chemicals, CAMs on neutrophils bind tightly to endothelial cells
Continued chemical signaling prompts the neutrophils to flatten and squeeze through the capillary walls which is called diapedesis
inflammatory chemicals act as homing devices or more precisely chemotactic agent. neutrophils and other WBCs migrate up the gradient of chemotactic agents to the cite of injury (positive chemotaxis). within an hour after the inflam response has been, neutrophils have collected at the site and are devouring any foreign materials
Mixture of dead or dying neutrophils, broken-down tissue cells and living and dead pathogens can accumulate in the wound. An abscess, sac of pus that may be walled off by collagen fibers, can form if the inflammatory response fails to clear the area of debris.
resistant to digestion by the macrophages that engulf them. Being in the macrophages, protects them from prescription antibiotics and infectious granulomas form (tumor-like growth)
enhance the innate defenses by attacking microorganisms directly or by hindering their ability to reproduce.
- most important of these are interferons and complement proteins
-small proteins secreted by virus infected cells to alert and protect nearby cells that have not been infected yet
-they diffuse to nearby cells, where they stimulate synthesis of proteins that "interfere" with viral replication in the still- healthy cells by blocking protein synthesis and degrading viral RNA
-not virus specific
-also activate macrophages and mobilize NK cells, which act directly against malignant cells
IFN-beta and IFN- alpha have what effect and what is each one used to treat?
Both reduce inflammation, and keep it in control
- IFN- beta is used to treat patients with multiple sclerosis, a devastating demyelinating disease
-IFN- alpha is used to treat genital warts and hepatitis-C
Complement System (or simply complement) is what?
- a nonspecific defensive mechanism that "complements" or enhances the effectiveness of BOTH innate and adaptive defenses
- it provides a major mechanism for destroying foreign substances in the body; it unleashes chemical mediators that amplify all aspects of the inflammatory process;
Complement System includes ?
- a group of at least 20 plasma proteins that normally circulate in the blood in an inactive state
-C1 through C9, factors B, D, P and several regulatory proteins
- activated by two pathways
classical pathway of complement
- depends on the binding of antibodies to the invading organisms and the subsequent binding of C1 to the microorganism-antibody complexes, step called complement fixation
-antibodies coating the surface of a pathogen activate complement proteins C1, C4, and C2, which in turn activates C3
alternative pathway of complement
- C3 spontaneously activates and attaches to pathogen membranes.
-Factors B, D, and P stabilize spontaneously activate C3.
The two pathways of complement converge at C3 , then what?
It splits C3 into two pieces, C3a and C3b.
-C3a promotes inflammation (with the help of C5a)
-C3b enhances phagocytosis by acting as an opsonin. In certain target cells (mostly bacteria), C3b also activates other complement proteins that can form a membrane attack complex (MAC)
Membrane Attack Complex (MAC)
- MACs form from activated complement components (C5b to C6 to C9) that insert into the target cell membrane, creating funnel-shaped pores that can lyse the target cell. This ensures lysis of the target cell by inducing massive influx of water
C3b molecules provide handles that receptors on macrophages and neutrophils can adhere to, so engulfing can occur more rapidly
C3a & other cleavage products form during complement fixation amplify the inflammatory response how?
- by stimulating mast cells and basophils to release histamine and by attracting neutrophils and other inflam cells to the area
is an abnormally high body temperature (normal is 98.6ºF or 37ºC); it's a systemic response to invading microorganisms
-body temp is regulated by the cluster of neurons in the hypothalamus, "thermostat"
-the thermostat is reset upward in response to chemicals called PYROGENS secreted by leukocytes and macrophages exposed to foreign substances in the body.
Mild to moderate fevers vs high fevers
-high fevers are dangerous because they denature enzymes
-mild/moderate fevers seem to benefit the body; fever increases metabolic rate of tissue cells in general, to speed up the repair process