Unit 2 Pathophysiology - Chapter 7 Innate Immunity

Question 1

First line of defense

Physical, Mechanical, and Biochemical Barriers and Normal Microbiome

Answer 1

Physical + mechanical barrier such as skin and mucous membrane

Question 2

Where are antibacterial peptides present?

Physical, Mechanical, and Biochemical Barriers and Normal Microbiome

Answer 2

Mucuos secretions, perspiration, saliva, tears, etc.

Question 3

Bacterial flora

Physical, Mechanical, and Biochemical Barriers and Normal Microbiome

Answer 3

They are normal and produce chemcials that prevent colonization by pathogens

Question 4

Inflammation

Second Line of Defense: Inflammation

Answer 4

Rapid, nonspecific protective response to cellular injury; vascularized tissue only

Question 5

Macroscopic and microscopic: Hallmarks of inflammation

Second Line of Defense: Inflammation

Answer 5

redness, swelling, heat, pain, loss of fx in inflamed tissues

accmulation of fluid and cells @ inflammatory site

Question 6

Complement system in general

Second Line of Defense: Inflammation

Answer 6

10% ciruclating serum proteins; produces several factors that destroy pathogens directly and can activate or collaborate w/ other components of innate and adaptive immune system.

Question 7

Prolonged tx w/ broad spectrum antibiotics allows for growth of?

Answer 7

Opportunistic pathogenic microorganisms, Candida albicans (yeast) or bacteria clostridium difficile

Question 8

Normal microbiome fx

Answer 8

Produce chemicals
* ammonia, phenols, indoles, and other toxic material
* toxic proteins: bacteriocins
help inhibit colonization

Question 9

Lactobacillus

Answer 9

Important in normal women vaginal microbiome

• produces hydrogen perxodie, lactic acid, bacteriocins
• antibiotics => risk for vaginosis (condition that happens when there is too much of certain bacteria in the vagina)

Question 10

Pseudomonas aeruginosa

Answer 10

normal microbiome of skin and protect against infections w/ stapylococcal and other bacteria

severe burns compromise integrity of skin

Question 11

Microcirculation for inflammation (4):

Answer 11

PRESTEP: arterioles constrict briefly
1. Vasodilation: cause slower blood + inc blood flow to injured site
2. Increased vascular permeability (contract of endothelial cells for larger pores, then exudation (oozing) or leakage, then edema or swelling) ==> plasma settles then blood comes in making it thicker and inc RBC => erythema or warmth
3. WBC adhere to inner wall of vessels and migrate through pores or enlarged junctions lining vessel (diapedesis)

Question 12

Benefits of inflammation

Answer 12

1. Prevent infection; dilute toxins produced by bacteria & dying cells; influx + activate plasma protein systems (complement, clotting) and incoming of other cells to eat debris
2. Limitation & control of inflammatory system via plasma protein systems, plasma enzymes, and cells prevent widespread
3. Interact with immune sys to elicit specific response w/ macrophage and lymphocytes
4. Prepping site for healing via removal of bacterial products, dead cells, other inflammation products thorugh epithelium or drainage => start healing and repair mechanism

Question 13

Classical pathway - complement system

Answer 13

activated by proteins of immune system (antibodies) bound to their specific targets (antigens)

c1 (maromolecular complex) => c1q must simultaneously bind to 2 antibody molecules (activate C4 and C2) => combo complex of c1, c4, c2 => produces C3a and C3b (c3 convertase + c3b to complex) [c3b is an opsonin can tag foreign material for phagocytic activity] => this complex changes substrate specificity to c5 => convert to c5a and c5b (MAC - membrane attack complex make pores in bacterial membrane)

Question 14

Lectin pathway - inflammation

Answer 14

antibody independent; activated by mannose- containing bacterial carbohydrates

mannose-binding lectin (MBL) binds to 2 mannose rich pathogen-associated molecular patterns on bacteria surface => activates complement MASP-1 & 2 => and the activate c4 and c2 => c3 convertase =>cleave C3 into C3a, a chemoattractant molecule, and C3b, which covalently binds to target surfaces and triggers phagocytosis

Question 15

Alternative pathway - inflammation

Answer 15

Activated by gram-negative bacterial and fungal cell wall polysaccharides

bacterial polysaccahrides bind and stablize c3b (breakdown from c3); complex binds with factor D, which activates factor B (enzyme), producing factor Bb; properdin (glycoprotein) stabilize complex => c3b/Bb/P complex that is a c5 convertase => activates c5

Question 16

Clotting system

Answer 16

Stops bleeding, localizes microorganisms, and provide meshwork for repair and healing

Question 17

Classical pathway can be activated by what other things, aside from antibodies?

Answer 17

heparin, DNA, RNA, C-reactive protein (increased during inflammation)

Question 18

What happens after c5 activation?

Answer 18

Cascade for inflammation continues through c6, c7, c8, and c9 to form MAC or membrane attack complex => cell lysis

Question 19

What are the fragments from C4, C2, C3, and C5

Answer 19

• c2b: causes vasodilation and increased permability (smooth muscle)
• c3a, c5a, and c4a (limited) are anaphylatoxins (complement peptides) => induce mast cell degranulation [c5a is stronger chemotactic factor than c3a; attracting leukocytes to site of infammation
• Carboxypeptidase => removes arginine from c3a and c5a => producing c3a desArg and C5a desArg, inactive as anaphylatoxins but retain chemotactic activity (prevents enlargement of inflammatory response to healthy tissues)

Question 20

Clotting system benefits (4)

Answer 20

1. prevent spread of infection
2. traps microorganisms and foreign bodies at inflammation site for removal
3. forms clot => stops bleeding
4. framework for future repair and healing (fibrin + platelets + other cells like erythrocytes, phagocytes, and microorganisms)

Question 21

How does clotting system activate? How about complement system

Answer 21

1. Substances released during injury + infection (collagen, proteinases (cleave internal peptide bonds), kallikrein (participation in the process of blood clotting and fibrinolysis and, through the release of bradykinin, in the regulation of vascular tone and inflammatory reactions), and plasma)
2. Extrinsic pathway activated by tissue factor (or tissue thrmboplastin) released by damaged endothelial cells in blood vessels react iwth factor VII
3. OR intrinsic (contact) pthway activated when vessel wall is damaged and Hageman factor (factor XII) in plasma contacts negatively charged subendothelial substances.
4. Pathways converage at factor X => this activation begins a common pathway l/t activation of fibrin that polymerizes to form a fibrin clot
5. For complement system, the activation of clotting system l/t protein fragments (fibrinopeptides A & B released from fibrinogen when fibrin is produced) that enhance inflammatory, response. Both of them are chemotactic for neutrophils and increase vascular permability of endothelial cells by enchancing bradykinin

Question 22

Kinin system

Answer 22

Augments inflammation; primary product bradykinin (dilation of blood veseels, acts w/ prostaglandins [created @ injury site helps control inflammation, blood flow, pain, formation of blood clots, induction of labor] to simulate nevre endings and inducec pain, cause smooth muscle cell contraction, increases vascular permeability, and may incease leukocyte chemotaxis.

Probably responsible for endothelial cell retraction and increased permeability in later phases of inflammation.

Question 23

Plasma kinin cascade

Answer 23

Plasma prekallikrein => kallikrein (incduced by prekallikrein activator same as factor XIIa (product of hageman factor factor XII of clotting cascade) => kininogen => bradykinin

Tissue kallikreins (saliva, sweat, tears, urine, feces => other inflammatory mediators) => serum kininogens => kallidin (lys-bradykinin) => bradykinin (w/ help of plasma aminopeptidase)

To limit extent, kininase enzyems degrade kinins rapidly in the plasma and tissues

Question 24

What different cells are involved in inflammatory process?

Answer 24

Mast cells (release histamine [gastric acid, inflammation, vasodilation regulation, brnchoconstriction], endothelial cells, platelets, phagocytes (neutrophils, eosinophils, monocytes, and macrophages, dendritic cells), natural killer cells, and lymphocytes

Question 25

Plasma membrane pattern recognition receptors (PRRs)

Answer 25

Most cells express these receptors that recognize molecules produced by infectious microorganisms (pathogen-associated molecular patterns or PAMPs) or products of cellular damage (damange- associated molecular patterns or DAMPs)

includes toll-like receptors (TLRs) => recognize various PAMPs (located on microorganism’s cell wall or surface), host factors d/t stress or damaged cells, etc

Question 26

Cytokines

Answer 26

Cells of innate immune system secrete these biochemical mediators that help activate other cells (interleukins, chemokines, interferons, and other molecules)

• interleukin (regulate immune response as signalling, made by leukocytes)
• chemokines (chemo-attractant moleules to attract cells to sites of infection + inflammation
• interferon (antiviral factor block viral replication)

Question 27

interleukin-1 or IL-1

Answer 27

activates monocytes, other macrophages, and lymphocytes which improve innate and acquired immunity and acts as a growth factor for many cells => produced by macropages into two forms IL-1a and IL-1B // proliferation of neutrophils, chemotaxis (attract to inflammatory site), and cellular respiration + lysosomal enzyme activity (inc cellular killing), and endogenous pyrogen (activates hypothalamus to increase temperature body)

Question 28

Interleukin-6 (IL-6)

Answer 28

produced by macrophages, lymphocytes, fibroblasts, and other cells // induces hepatocytes (liver cells) to produce many proteins needed in inflammation; stimulate growth and differentiation of blood cells in the bone marrow and growth of fibroblasts (contributes to formation of connective tissue)

Question 29

Tumor necrosis factor-alpha (TNF-a)

Answer 29

secreted by macrophages and other cells (mast) in response to PAMPs (pathogen-associated molecular patterns) being recognized by TLRs (toll like receptor); TNF-a cleaved into soluble form d/t TNF-converting enzyme (TACE) => soluble TNF-a induce variety proinflammatory effects, such as improved endothelial cell adhesion molecule expression (mediate process of leukocyte adhesion to the endothelium and subsequent transmigration) and increased chemokine production by endothelial cells and macrophages

Systemic effects:
* induces fever as endogenous pyrogen
* increase synthesis of proinflammatory serum proteins by liver
* causes cachexia (muscle wasting) and intravascular thrombosis as consequence fo prolonged production in severe infection or cancer
* responsible for fatalities r/t shock by gram-neg bacterial infection

Question 30

Interferons

Answer 30

Produced by cells infected by viruses => one released from infected ones then interferons stimulate neighboring cells to produce substance that prevent infection

Question 31

Chemokines

Answer 31

Produced by different cells and induce leukocyte chemotaxis

Question 32

Mast cell

Answer 32

Initiates inflammation by releasing biochemical mediators (histamine, chemotactic factors) from preformed cytoplasmic granules and synthesizing other mediators (prostaglandins, leukotrienes) in response to stimulus (made from bone marrow; do not fully mature until recruited by tissue)

Activated by IgD (part of b cell receptor), which also activates basophils and mast cells [technically simulates release of IgM]

Question 33

Histamine

Answer 33

Released by mast cells; dilates capillaries and retracts endothelial cells lining capillaries, which increases vascular permeability.

Question 34

Endothelium?

Answer 34

Help leukocytes leave vessel and allow more fluid to pass into tissue

Question 35

Platelets

Answer 35

interact w/ coagulation cascade => stop bleed and release mediators that control inflammation

Question 36

polymorphonuclear neutrophil (PMN)

Answer 36

predominant phagocytic cell in EARLY inflammtory repsonse; exits circulation via diapedesis (squeeze through endothelial cells) and moves to site via chemotaxis

Question 37

Eosinophils

Answer 37

releases product important in inflammatory response control and main cell that kills parasitic organisms

Question 38

Macrophage

Answer 38

predominant phagocytic cell in late inflammatory response (highly phagocytic) responsive to cytokines and promotes wound healing

Question 39

Dendritic cells

Answer 39

collect antigens at site of inflammation and transporting them to site (such as lymph nodes) where immunocompetent B and T cells reside

Question 40

Phagocytosis steps

Answer 40

1. recognition and attachemnt
2. engulfment
3. formation of phagosome and phaglysosome (engulf microorganisms => then form these phagocytic vacuoles => toxic products (o2 metabolities) and lysosomal enzymes kill and digest cell)
4. destrurction of pathogen

Question 41

Oposonins

Answer 41

antibody and c3b complement, coat microorganism and make them prone to phagocytosis by binding them more tightly to phagocyte

Question 42

Vascular changes and sx of inflammation

Answer 42

Redness, heat, swelling, and pain

Question 43

Leukocytosis

Answer 43

increase in levels of circulating leukocytes

Question 44

Chronic inflammation

Answer 44

continuation of acute inflammation that lasts 2 weeks or longer; dense infiltration of lymphocytes and macrophages; body may wall off and isolate infection via formation of a granuloma

Question 45

Resolution (regeneration)

Answer 45

tissue returns to nearly normal fx and structure; repair is healing by scar tissue formation

Question 46

Primary intention

Answer 46

damaged tissue with little tissue lost or injured can regenerate

Question 47

Secondary intention

Answer 47

Tissue that suffer extensive damange or incapable of regeneration then process of repair or scar formation is next best step.

Question 48

Dysfucntional wound healing can be caused by?

Answer 48

ischemia, excessive bleed, excessive fibrin deposition, prediposed (diabetes), wound infection, lack of nutrients, drugs, altered collagen synthesis

Question 49

Dehiscence

Answer 49

when wound pulls apart at suture line

Question 50

Contracture

Answer 50

deformity caused by excessive shortening of collagen in scar tissue

Question 51

Neonate - inflammatory

Answer 51

transiently depressed inflammatory function (in terms of neutrophil chemotaxis and alternative complement pathway activity)

Question 52

Aging and inflammation

Answer 52

altered innate and adaptive immune systems

Question 53

granulocytes

Answer 53

neutrophils, eosinophils, basophils, or mast cells

Question 54

Types of phagocytic cells

Answer 54

monocytes, macrophages, neutrophils, tissue dendritic cells, and mast cells.

Question 55

type III hypersenstivity

Answer 55

• Type III hypersensitivity - mediated by immune complexes => antibody (immunoglobulins are produced by plasma cells [B-cells])
• systemic (compared to type II, which are organ or tissue specific) since immune complexes can precipitate in various tissues such as skin, joints, vessels, or glomeruli and trigger the classical complement pathway.
• B-cells intially make IgM (seceted or bound to plasma cell surface of b-cell surface) => first crosslinking of two IgM receptors w/ an antigen causes absorption into cell => B-cell presents a piece of antigen to t-helper cell via T-cell receptor + MHC II molecule [on b-cell] + co-stimuling molecule CD4 => additionally, the b-cell’s CD40 binds with T-cell’s CD40L [separately from membrane] => cause t-cell to release cytokines => activates b-cell plus “class switching” causing a change in what antibodies are made in b-cell => typically, in this hypersensitive rxn, IgM becomes IgG (able to cross placenta, main blood antibody for secondary responses, binds to phagocytes)
• Antigens** (soluble or free flowing or bound to cell surfaces) => antibodies binding to antigen already bounded to cell surfaces aren’t considered immune complexes (type II hypersensitivity)**
• Soluble (free floating) + IgG = immune complexes
• marked for macrophages or other phagocytes
• e.g lupus => DNA + nucleoproteins (released from damaged cell) become targets as autoantigens (usually only non-self reactive b & t cells are allowed to mature, but system isn’t perfect] since some of these cells escape that process
• continued e.g - this results in many IgG-DNA autoantigen => these antibodies will bind with each other for form a small antigen-antibdo complex => less immunogenic [less attracttive to macrophages and don’t get removed from bloodstream as fast]
• they make there way to basement membrane layer of various blood vessels and attach or deposited
• this activates the complement system (c1-c9 => enzymatic cascade to clear infections
  a) c1 binds to antibody-antigen complex that sets off a chain reaction that activates c2-c9 (this activaed complemet protein is cleaved by another enzyme)
  b) results in fragments c3a, c4a, c5a => anaphylatoxins causing increased vascular permeability +** [type II uses complements in less amounts another distinction vs type III where large amounts of complment are consumed (c3+c4)]** // act as to chemokines that can recruit other cells (like neutrophils) to the basement membrane site

=================

anaphylatxoins
* smooth muscle cells contraction, for example bronchospasms
* increase in the permeability of blood capillaries
* C5a indirectly mediates chemotaxis—receptor-mediated movement of leukocytes in the direction of the increasing concentration of anaphylatoxins

examples -
* C5a has the highest specific biological activity and is able to act directly on neutrophils and monocytes to speed up the phagocytosis of pathogens.
* C3a works with C5a to activate mast cells, recruit antibody, complement and phagocytic cells and increase fluid in the tissue, all of which contribute to the initiation of the adaptive immune response.
* C4a is the least active anaphylatoxin.

=============
c) e.g neutrophils try to phagocytize immune complex but usually can’t causing them to degranulate meaning they dump lysosomal enzymes and reactive oxygen specis => l/t inflammation and tissue necrosis => vasculitis (infammation of blood vessels
f) causing FURTHER cellular destruction, more autoantigen release, repeating entire cycle
* common examples: kidneys (glomerulonephritis) since blood filtered // joints - blood plasma is being filtered to produce synovial fluid [inflammation of the joints or arthritis]
* another major distinction between type II hypersenstitivity (correspond to tissue w/ presenting antigen where antibodies attach to and destroy cells) vs type III (immune complexes deposited into tissue, rather then where they are made)

common type III hypersensitivity rxns
* henoch-schonlein purpura (a disorder that causes the small blood vessels in your skin, joints, intestines and kidneys to become inflamed and bleed. The most striking feature of this form of vasculitis is a purplish rash, typically on the lower legs and buttocks.)
* hypersensitivity vasculitis (leukocytoclastic vasculitis?) - an extreme reaction to a drug, infection, or foreign substance that leads to inflammation and damage to blood vessels of the skin. Signs and symptoms may include purple-colored spots and patches on the skin; skin lesions on the legs, buttocks, or trunk; blisters on the skin; hives (urticaria); and/or open sores with dead tissue (necrotic ulcers).
* reactive arthritis - joint pain and swelling triggered by an infection in another part of the body — most often the intestines, genitals or urinary tract. This condition usually targets the knees, ankles and feet.
* farmer’s lungs - allergy to moldy crop dust that makes breathing difficult. Untreated, it can cause permanent lung damage and death.
* post-streptococcal glomeurlonephritis

Question 56

Type I hypersensitivity

Answer 56

• rely on IgE antibody [type I] or IgE mediated or IMMEDIATE hypersenstivity
• most allergic reactions (IgE mediated) // also protect aganist parasitic worms // bind to mast cells + basophils
• molecules from outside your body (foods, mold, dander, bee stings, pollen, drugs/meds) // skin (latex, lotions, soaps)
• they are called “antigens” as well => allergens in this case
  Two steps
  a. First exposure “sensitization”
  b, Subsequent exposure “more serious rxn”
• genetic predisposition (t-helper cells more hypersensitive to certain allergens)
• Pollen inhaled => body has specific T-cells that work against that pollen => allergen => picked up by immune cells in the membrane in airway in this case => migrate to lymph nodes (process happens despite being allergic or not)
• this antigen-presenting cell (dendritic + macrophages are some examples) present to naive t-helper cell (never seen antigen before) in lymph node + present a co-stimulatory molecule to ACTIVATE effective immune response
• When binded, naive t-helper changes into a primed t-helper cell => differentiates into a type 2 t helper cell (TH2 cell) d/t presence of various small proteins or interleukins (that can sway the change of cell to TH2)
• these are interlukin 4, 5, 10 (ALL cytokines) // the activated TH2 cells also release their own interleukin 4 => they activate b- cells to undergo antibody class switching => b-cells switch from making IgM to IgE (specifc to antigen or allergen)
• Including release of interleukin 4, the TH2 also release IL 5 => stimulate production and activation of eosinophils (granulocyte that can degranulate “release toxic substrates that damage invading cells and nearby host cells)
• continuation… these allergen-specific (e.g pollen){ IgE antibodies have HIGH affinity for Fc episilon receptors on Mast cells (another type of granulocyte) => attach to surface of mast cells (these FCe receptors), which give them the name of “cytotropic antibodies” since they can bind to cell surface
• mast cell in a sense ready for combat or activated => this l/t completetion of sensitization phase

=============================
* in second exposure (reexposure of previous antigen after some time)
* those mast cells coated w/ those antibodies (IgE) binds to thes same antigen (two or more of them to crosslink the IgE antibodies) => signal mast cell to degranulate => RELEASING proinflammatory molecules called mediators => allergic rxn
“early phase reactions
a. Histamine (one of the major mediators) => bind to H1 receptors => cause smooth muscle around bronchi to contract => airway gets smaller l/t difficult breathing /// also caused blood vessel dilation => l/t increased permeability of walls => l/t increased blood flow to affected area + fluid can easily leak out into interstitium causing edema (swelling) + urticaria (hives - rash of round, red welts on skin that itch w/ possible swelling)
b. other mediators => activate eosinophils and proteases (chop up large proteins into small peptides)
* ALL these happen within minutes of 2nd exposure
late phase reactions (8-12 hrs after exposure)
a. More immune cells - TH2 (type 2 t helper cells), eosinophils, and basophils (another type of granulocyte) are recruited to site where allergen is located d/t cytokines and pro-inflammatory molecules produced in earlier phase
b. Same interleukins 4, 5, 10, but also leukotrienes (smaller molecules made out of fatty acids and facilitate communication between a local group of cells)
c. Specifically leukotriene (LTB4 and LTC4) can cause:
i) smooth muscle contraction (similar to histamine) => which can damage epithelium as well
ii) attract immune cells - neutrophils, mast cells, eosinophils (even after allergens are long gone!)

========
mild sx
* hives (urticaria)
* eczema
* allergic rhinitis (inflammation of the nose)
* asthma

Large load?
* bee stings
* seafood
* peanuts

severe sx’s include!
* INCREASED vascular permeability
* constriction of airway => body cannot supply vital organs with enough o2 rich blood => anaphylactic shock

tx -
* antihistamines (reduce vascular permeability, and bronchoconstriction)
* corticosteroids - reduce inflammaotyr response
* epinephrine - IM or IV (constrict blood vessels)

Question 57

Type II hypersenstivity

Answer 57

• hypersensitivity => damages the body..
• cytotoxic hypersensitivity d/t a lot of d/o’s invovle antibody mediated destruction of healthy cells
• furthermore, these disorders tend to be tissue specific (meaning antibodies are specific to one type of tissue or organ)
• Central tolerance => developing immune cells that are self-reactive (destory own cells) get destroyed or inactivated whereas immune cells aren’t are allowed to survive [occurs in primary lymphoid organs => thymus (t-cells) and bone marrow (b-cells)] // however some self reactive t and b cells escape
• they can attack own tissue (causing autoimmune disease)
• e.g => self-reactive b cells create IgM or w/ help of CD4 positive T helper cells causes creation of IgG antibodies
• both these antibodies bound to antigens on host cells => there are two types of antigens involved with type II hypersensitivity
  a. intrinsic - an antigen the host cell normally makes
  b. extrinsic - an antigen from an infection or even some medications (e.g penicillin gets attached to host cell)
• penicillin attached to RBC => becomes an extrinsic antigen => an IgG (binds to phagocytes) or rarely IgM antibody that is “penicillin specific” might bind it creating an antigen-antibody complex (normally this happens to a normal infection), expect this is host tissue
• 1st cytotoxic mechanism of type II hypersensitivity => complement system (small proteins, enzymatic cascade, fights infection)
• which will kill the RBC (w/ complement proteins) attached with complexes
• c1 binds to fc portion (fc fragment on antibody recognized by and fc receptors are on lymphocytes, neut, NK, and mast cells) of antibody => engaging c2-c9 (some are activated by being cleaved) => c3a, c4a, and c5a (cleaved fragments) act as chemotactic factors (attract certain cells, or neutrophils to be exact)
• neutrophils arrive to site and degranulate or dump a bunch of enzymes like peroxidase ( catalyze the oxidation of a substrate by hydrogen peroxide or an organic peroxide), myeloperoxidase (catalyzing the formation of powerful reactive oxygen intermediates, which are potent antimicrobial tools against phagocytosed pathogens), and proteinase 3 (broad proteolytic activity and degrades a variety of extracellular matrix proteins) => all generate oxygen radicals that are highly cytotoxic to cells and can cause tissue damage
• in this example => can cause hemolytic anemia (or autoimmune hemolytic anemia) including thrombocytopenia or neutropenia
• ANOTHER example [goodpasture’s syndrome] where antibodies bind to intrinsic antigens on collagen of the basement membrane in their glomeruli in kidney or alveoli in the lungs
• 2nd cytotoxic mechanism ===> c5b and c6-c8 + multiple c9 together form a membrane attack complex (MAC) => MAC attacks the cell by inserting itslef into the cell membrane, creating a channel that allows fluid and molecules to flow in/out of cell, d/t osmotic differences => fluid rushes into cell causing swelling and eventualy bursts (cell lysis) and dying [essentially cytotoxic]

=======
tests to check (e.g autoimune hemolytic anemia)
1) direct coomb’s test, person’s RBCs are separated from plasma and mixed with coomb’s reagents (antihuman globulin or an antibody against human antibodies) => if RBC agglutiante or clump up that means there is a possiblility that those RBCs have antibodies on the surface
2) indirect coomb’s test - blood group incompatiblity => pt’s serum is mixed with lab RBCs w/ known antigens on surface then once again mixed with coomb’s reagent => iof agglutination occurs that indicates presence of antibodies
* this indirect test is performed to figure out if you have antibodies before being exposed to an antigen (e.g mismatched blood transfusion, second pregnancy with mismatched Rh factor between mother + child)

=========
* third cytotoxic mechanism ===> IgG antibodies coat a blood cell and are bound by c3b (complement protein fragment) => cell is opsonized, meaning it is targeted for phagocytosis (macrophages, neutrophils for e.g)
* antigen-antibody complex and the cell it’s attached to encounter a phagocyte in the spleen (body’s blood filtration organ)
* phagocyte binds to fc tail of antibody or c3b bound to the IgG then engulfs and destroys the cell
* fourth cytotoxic mechanism ==> antibody-depedent cell-mediated cytotoxicity (ADCC) => bound antigen-antibody complex gets recognized by immune cells called natural killer cells => NK cells recognize Fc tail of antibody causing them to release toxic granules (perforins => similar to MAC => form pores in the cell, except pores this time allow enzyme entry that are like silent asassins called granzymes + granulysin that work together to cause cell death in an apoptotic or “quiet’ method w/ no surrounding inflammation
* non-cytotoxic mechanism – antibody mediated cellular dysfunction => antibody blocks other things when it binds to the antigen => changing cell fx
* e.g Mysathenia gravis => antibodies bind to acetylcholine receptor in muscles blocking the binding of Ach => muscles do not get stimulated causing progressive weakness
* e.g Also grave’s disease - antibodies target receptors that stimulate thyroid hormone production - by getting in the way and activate the receptors => overproduction of thyroid hormone (hyperthyroidism)

overall
* antibody-mediated
* generally cytotoxic (tissue specific)

Question 58

IV hypersensitivity complex

Answer 58

• Type I-III => involve antibodies => humoral mediated responses [immediate]
• IV => T-cell mediated resposne => “T helper cells” (CD4+ t cells) and cytotoxic T cells ( Tc cells) [DELAYED process]
• Delayed type hypersensitivity

e.g Poison Ivy => contains urushiol => reacts w/ proteins in the skin (epithelial) => altering those proteins [CD4+ t cells]
1) immune system now recognizes them as foreign!
2) antigen-presenting cell processes them and present them to naive T helper cell (by presenting portion of protein w/ MHC class 2 receptor which T helper cells are able to recognize and bind to)
3) This binding causes APC to release cytokines (IL-12) causing native t-helper cell to differentiate => type 1 t helper cell known as th1 cell
4) This Th1 cell releases cytokines, such as IFN-gamma, which activate macrophages
5) Macrophages release TNF-alpha and IL-1 => causing expression of receptors on endothelial cells to recruit more leukocytes to area [these macrophages also perform phagocytosis and release reactive O2 species + toxic lysosomal enzymes]
6) l/t damage of tissue that manifests after exposure to poison ivy
7) constant antigen presentation => causes more macrophages and leukocytes to differentiate into macrophages, which release IL-12 and activating Th1 - cells => macrophages become epitheloid cells that form multi-nucleate giant cells (langhans giant cell + foreign body giant cell) => these are already surrounded by lymphocytes + fibrosis + other epitheloid cells => creating a granuloma
7) APC part 2 => another cytokine called IL-6 / IL-1 + other cytokines => causing naive t helper cells to differentiate into subtype of t helper cells called th17
8) th17 will release IL-17 activating neutrophils (causing similar inflammatory actions caused by macrophages)

• Takes times this process => in terms of activation, recruitment needed for response
• in this case, vesicular dermatitis after 27-72 hrs after exposure to poison ivy

Another example => Tuberculosis (TB) skin test => infection with mycobacterium tuberuculosis?
* if previously exposed, the immune will attack the protein components => raised, indurate (hard) lesion [hours to days]
* Another e.g => contact dermatitis d/t metal allergies [nickel jewelry, latex as well]

PART B [CD8+ t cells]
type 4 hypersensitivity can also involve cytotoxic t cells which attack **target cells directly **
* examples include type 1 diabetes where cytotoxic t cells target insulin-secreting beta cells of pancreas
* Rheumatoid arthritis => tc cells target joint tissue
* hashimoto’s disease => tc cells attack thyroid hormone producing folluclar cells
* graft rejection => tc cells target graft cells
* virus
* when recognition occurs => cytotoxic t cells release vesicles containing a perforin and granzyme complex
* perforins (create pores in target cells) then allow granzymes to be released from complex (create pore?) => these released proteases that induce apoptosis or programmed cell death
* ALSO a cytotoxic t cell can bind to a fast receptor expressed on a target cell using a fast ligand => this also activates apoptotic death of the target cell
* bind via MHC I receptor on target cell + t cell receptor
* IMPORTANT in autoimmune diseases

Question 59

IgM

Answer 59

attach to surface of b-cell or secreted into blood; responsible for early stages of immunity

• fixes complement, immune system memory
• main antibody for primary responses

Question 60

IgA

Answer 60

• secreted into mucous, saliva, tears, colostrum
• tags pathogens for destruction