Overview of the Immune-Inflammatory Systems

1. Overview of the Immune-Inflammatory Systems •Ancient Greek concepts of disease centered upon the imbalances between the four humors that made up the body: --blood; --phlegm;   --black bile; --yellow bile. •This concept led to the widespread use of phlebotomy and purgation in an attempt to restore the proper balance and to cure.

2. Overview of the Immune-Inflammatory Systems (cont’d) •Although now considered naïve these concepts have left their mark on our language: --An excess of bile (produced by the spleen) was associated with depression of mood. The word "melancholy" (literally "black bile") describes such a state. --A term for enraged people "venting their spleen", refers to release of excess black bile stored there. --Excessively calm people can be described as "phlegmatic". --Treatment for excessive passion or "hot-bloodedness" was administration of cucumber seed, which gave rise to the cliché "cool as a cucumber".

3. Acute Inflammation-Historical •Ancient name of inflammation was similar to "internal fire" •Consistent with the nature of local injury. •Especially the vascular reaction, which can be spectacular: --patch of red skin or mucosa can swell up and become red, hot and painful. •Concept of inflammation has a colorful history due to the reason that it is closely linked to the history of infection

4. Acute Inflammation-Historical (cont’d) •Remember, infection is not the same as inflammation! •Infection means that bacteria, viruses or fungi have invaded the tissues -- this usually causes inflammation.

5. Acute Inflammation-Historical (cont’d) •In Greek times, inflammation was an infected wound, for obvious reasons, most wounds became infected, and healed only after a period of suppuration (or pus formation). •Misled our ancient physicians to believe that pus formation is a necessary step to healing, they concluded: --pus was a kind of 'badness' coming out of the wound, pus formation was encouraged, the more-the better; --pus was thought to arise somehow through a decay in blood, the best way to stop this decay was to remove as much blood as possible, the more-the better. 

6. Acute Inflammation-Historical (cont’d) •You can imagine the consequences of 'bleeding' these patients. •The ancient Romans added very little to the story, except in the 1st century A.D., Cornelius Celsus, provided a clinical definition of inflammation so precise we have not improved it!

7. Acute Inflammation-Signs •The major signs of inflammation, says Celsus are four: "Rubor et Tumor cum Calore et Dolore", •"Redness and swelling with heat and pain"

8. Acute Inflammation-Signs (cont’d) •We call these symptoms the "Cardinal signs" of inflammation: Redness- caused by the dilation of the blood vessels Heat- due to the increase of blood in the inflamed area Swelling- due to the enlargement of the blood vessels Pain- caused by the pressure on nerve endings by the swollen tissue, and by the action of kinins on the nerve ending.

9. Overview of the Immune-Inflammatory Systems (cont’d) •Immune-inflammatory system is the mechanism used by the body to protect us against harmful foreign substances. •2 broad headings are consistent with this system: (1) Innate Immunity --mechanisms present at birth, usually non-specific.

10. Overview of the Immune-Inflammatory Systems (cont’d)   (2) Acquired Immunity --mechanisms specific to the foreign agent; --requires prior exposure to that agent for full expression; --act later in the immune response; --supplement the protection afforded by innate mechanisms;

11. Innate Immunity •Mechanisms of innate immunity are concerned with: --prevention of entry of microorganisms and other noxious substances into the body, --first line of defense following entry to the tissues. •Protected from entry of microorganisms into various tissues: --physical barriers to infection- Intact skin and mucous membranes together form an effective barrier. --chemical agents- Body secretions exert a wide range of antimicrobial effects (low pH to hydrolytic enzymes).

12. Innate Immunity (cont’d) --physical actions- Respiratory and GI tracts are coated with sticky mucus that traps many microorganisms: infected mucus is excreted by action of ciliated cells; urethra colonization is reduced by washing action of urination; gut is similarly protected by the action of defecation.

13. Phagocytosis •If the above mechanisms fail to prevent the establishment of pathogenic microorganisms in the tissues: --Complement Pathway activation and Phagocytosis. •Phagocytic cells are the first-line of defense against invading microorganisms once the epithelial/mucosal barrieris breached.

14. 3 important phagocytic cells: --neutrophils (acute inflammation) microbial invasion, short-lived cells --monocytes (chronic inflammation and immune system) long-lived cells, removal of certain m'organisms, and in processing/presentation of antigen to T-cells. --macrophages (chronic inflammation and inmune system) reticuloendothelial system clears foreign particulate matter and destroys senescent/abnormal blood cells.

15. Classification of White Blood Cells (Leukocytes) 1. Based on the shape of the nucleus: Mononuclear Polymorphonuclear ¯ ¯ single, non-segmented nucleus nuclei of varying shapes, inter-connected segments ¯ ¯ ¯ Monocytes Lymphocytes Granulocytes (neutrophils, basophils, eosinophils)

16. Classification of White Blood Cells (Leukocytes) cont’d 2. Based on the presence or absence of specific staining granules: Granulocytes Agranulocytes ¯ ¯ neutrophils, basophils, monocytes, eosinophils lymphocyte this group contains specific- this group has relatively staining granules few staining granules

17. Classification of White Blood Cells (Leukocytes) cont’d 3. Based on the site of origin: Myeloid Lymphoid ¯ ¯ remember, all blood cells lymphocytes ultimately are are made in bone marrow derived from the lymphoid besides lymphocytes stemcell in BM, but the cells are made in the thymus, spleen and lymph nodes

18. Classification of White Blood Cells (Leukocytes) cont’d 4. Based on their function: Phagocytes Immunocytes ¯ ¯ Neutrophils Monocytes major role in immune system ¯ ¯ Microphages Macrophages ¯¯¯ other WBC's that have a minorLymphocytes, Monocytes, Macrophages phagocytic role are eosinophils¯ B- and T-cells

19. Smaller cell, nucleus is “oval”, specific granules appear, cytoplasm is no longer “basophilic” (blue), and is now “acidophilic” (pink), Wright’s stain Polymorphonuclear leukocyte (PMN), smallest of the series, segmented nucleus Large nucleus, few cytoplasmic bodies GM-CFU Numerous azurophilic granules, still a blast b/c mitotic activity remaining Nucleus is “sausage” shaped, this cell enters the bloodstream, 2-6% of neutrophils in blood No longer a blast, mitosis has stopped, nucleus is now “kidney shaped”

21. Compartment Activity Life-time Bone Marrow Proliferating ~5 days Storage Bloodstream Circulating ®t1/2 ~7 hrs Marginating ® adhering and migrating through endothelium Tissues Moving freely ~3 days Site of infection- Fixed  Birth ® Release ® Migration ® Death = ~9-10 days { { { Movement and Control of Neutrophils

22. Compartment Activity Life-time Bone Marrow Proliferating ~5 days Storage Bloodstream Circulating ®t1/2 ~7 hrs Marginating ® adhering and migrating through endothelium Tissues Moving freely ~3 days Site of infection- Fixed  Birth ® Release ® Migration ® Death = ~9-10 days { { { Movement and Control of Neutrophils

23. Compartment Activity Life-time Bone Marrow Proliferating ~5 days Storage Bloodstream Circulating ®t1/2 ~7 hrs Marginating ® adhering and migrating through endothelium Tissues Moving freely ~3 days Site of infection- Fixed  Birth ® Release ® Migration ® Death = ~9-10 days { { { Movement and Control of Neutrophils

24. Compartment Activity Life-time Bone Marrow Proliferating ~5 days Storage Bloodstream Circulating ®t1/2 ~7 hrs Marginating ® adhering and migrating through endothelium Tissues Moving freely ~3 days Site of infection- Fixed  Birth ® Release ® Migration ® Death = ~9-10 days { { { Movement and Control of Neutrophils

25. Cellular Events--PMN Exudation •accumulation of leukocytes, principally neutrophils, is the most important feature of the acute inflammatory reaction. •Sequence of events by the leukocytes: 1. margination; 2. adhesion; 3. emigration toward a chemotactic stimulus; 4. phagocytosis and intracellular degradation; 5. extracellular release of leukocyte products.

26. Respiratory Burst 1) Generation of "superoxide" (O2-), a highly reactive species: NADPH Oxidase 2O2 + NADPH ------------------> 2O2- + NADP+ + H+ •superoxide is extremely unstables and undergoes a change, called "dismutation" to form hydrogen peroxide (H2O2) 2) Generation of hydrogen peroxide (H2O2): superoxide dismutase 2O2- + 2H+ ------------------> H2O2+ O2

27. Respiratory Burst 1) Generation of "superoxide" (O2-), a highly reactive species: NADPH Oxidase 2O2 + NADPH ------------------> 2O2- + NADP+ + H+ •superoxide is extremely unstables and undergoes a change, called "dismutation" to form hydrogen peroxide (H2O2) 2) Generation of hydrogen peroxide (H2O2): superoxide dismutase 2O2- + 2H+ ------------------> H2O2+ O2

28. Respiratory Burst (cont’d) •primary reactive species that are actually responsible for killing ingested m’organisms are generated from superoxide and hydrogen peroxide, in a complex series of secondary reactions: 3) Hydroxyl radical (OH•) is known to attack DNA H2O2 + O2 ------------------> OH• + OH- + O2 4) Hypochlorous acid (HOCl) exerts a number of toxic effects. myeloperoxidase H2O2 + Cl- ---------------------> HOCl + H2O

29. Respiratory Burst (cont’d) •primary reactive species that are actually responsible for killing ingested m’organisms are generated from superoxide and hydrogen peroxide, in a complex series of secondary reactions: 3) Hydroxyl radical (OH•) is known to attack DNA H2O2 + O2 ------------------> OH• + OH- + O2 4) Hypochlorous acid (HOCl) exerts a number of toxic effects. myeloperoxidase H2O2 + Cl- ---------------------> HOCl + H2O

30. Respiratory Burst (cont’d) •primary reactive species that are actually responsible for killing ingested m’organisms are generated from superoxide and hydrogen peroxide, in a complex series of secondary reactions: 3) Hydroxyl radical (OH•) is known to attack DNA H2O2 + O2 ------------------> OH• + OH- + O2 4) Hypochlorous acid (HOCl) exerts a number of toxic effects. myeloperoxidase H2O2 + Cl- ---------------------> HOCl + H2O