The Immune Response:

transcript

• Introduction to Immunity

• Part I: Innate Immunity: Major Cells

• Part II: Innate Immunity: The Inflammatory Response

• Part III: Treatment of Inflammation

• Part IV: Adaptive Immunity

Introduction to Immunity

Functions of the Immune Response

The Immune Response

The Immune Response: A collective and coordinated response of cells of the immune system

1. Protects host from invasion of anything foreign • Ex. foreign pathogens, bacteria, parasites, viruses, the environment in general

2. Distinguishes “self” from non-self • Ex. cancer, autoimmune reactions• The immune system has a surveillance mechanism to identify itself

– When it recognizes something that is nonself, the immune system has mechanisms to kill the cell

– When the surveillance system breaks down or is over-challenged, disease occurs

3. Mediates healing • Modulate inflammatory process and wound repair• Immunity and inflammation are wrapped up together to make healing more

efficient

Results of Immune Dysfunction or Deficiency

• Immunodeficiency– Do not have the requisite amount of immunological ability

• Cannot keep up with what is going on

• Allergies/Hypersensitivities– The response to something is exaggerated

• Transplantation pathology

• Autoimmunity

Innate Immunity

• Natural resistance that a person is born with– Do not need anything else special

• Comprises physical, chemical, and cellular barriers that keep the self and the nonself apart

• First line of defense

• Ex. skin, mucosa– When radiator heat comes on, it dries out the mucosal

membranes and makes you more susceptible to microorganisms– A person in the healthcare system needs to take care of the skin

because dry skin makes a person more susceptible to invasion

Adaptive Immunity

• Acquired– When you are born and come into contact with antigens in the

environment, your body mounts a response• Are able to recognize the pathogen in the future

• Specific

• Amplified response with memory– Has a recognition system– There is a molecular memory in the body about what happened– Able to respond more quickly to the pathogen when interact with

it in the future

Components of the Adaptive Immune Response

• Divided into two major components:

1. Cell-mediated adaptive immunity- T cells

2. Antibody-mediated (humoral immunity)- Circulating antibodies- B cells produce the antibodies for humoral immunity

a. Antibody-mediated immunity is triggered by encounters with Antigens (Ags)

b. Antibodies are also known as Immunoglobulins (Igs)

Part I:

Innate Immunity

Primary Immune Cells of Innate Immunity

• Monocytes, macrophages, dendritic cells

• Neutrophils

• Eosinophils

• Basophils

• Mast cells

• Natural killer cells

Monocytes, Macrophages, and Dendritic cells

• Phagocytic cells that are located in different areas of the body• While macrophages are important cells of the innate immunity, they also

play key role in adaptive immunity

• Monocytes in blood Macrophages in tissues:

• Dendritic cells are phagocytic cells in the nervous system

• Include Kupffer, Langerhans, alveolar, peritoneal oligodendrocytes etc

• Phagocytize antigen present antigen (APC-antigen presenting cell)– Internalize and consume pathogens with lysosomes and peroxisomes– Process the antigen out of the substance that is foreign

• Takes the antigen, sticks it outside of itself, and presents it

• When activated, secrete cytokines (tumor necrosis factor, interleukin-1, and others), oxygen radicals, proteolytic enzymes, arachidonic acid metabolites, prostaglandins

– Release molecules that are very important in inflammation

• Macrophages are phagocytes17

Neutrophils

• AKA Polymorphonuclear leukocytes (PMN)

• Antigen binding and non-specific phagocytosis

• Inflammatory response: First-line defender against bacterial invasion, colonization, and infection

• Important in innate immunity– Responsible for antigen binding and phagocytosis

Eosinophils

• Inflammatory response

• Fight parasites (worms especially)

• May release chemicals in respiratory tract during allergic asthma– Release chemical mediators

Basophils

• Release potent mediators during allergic responses (e.g. histamine)

• Have binding sites for IgE antibodies (Type 1 Hypersensitivity)– The antibody will bind to antigen, and the basophil will release

the inflammatory substances

• Reside in blood

Mast Cells

• Also from bone marrow and share characteristics with basophils

• Located in tissues; not blood

• Releases histamine which is the hallmark of tissue inflammatory response.

Natural Killer Cells

Natural Killer CellsNatural Killer Cells: an effector cell important in innate

immunity.• Small % of lymphocytes

– Part of the lymphocyte population but are a small amount• Can bind with antibody coated target cell Antibody

dependent cell-mediated cytotoxicity (ADCC)– Can recognize the antibody and destroy the cell

• Can attack virus-infected cells or cancer cells without help or activation first– Important in immunosurveillance

• Can recognize antigen without MHC restrictions– Major histamine compatibility

• NO MEMORY– Lives by the minute by doing what it does

• Regulated by cytokines, prostaglandins and thromboxane

• Release NK perforins, enzymes, and toxic cytokines to destroy target cells

Outline of Immunity

Cytokines and the Immune Response

• Small, low molecular weight proteins (hormone-like) which are produced during all phases of the immune response.

– They are released form one area, move, and act on another area

– Short half-life

– Work in a parocrine system (acts locally) rather than an endocrine system

• This is characteristic of many of the immunological cytokines

• Primarily made by T cells and macrophages (lymphokines/ monokines) and act primarily on immune cells

– Lymphokines – a cytokine released from a lymphocyte (T cell)

– Monokines – a cytokine released from a macrophage

Processes that Cytokines are Involves in

• Innate immunity

• Adaptive immunity

• Hematopoiesis

Cytokines and Innate Immunity

• IL-1, IL-6, TNF (tumor necrosis factor) are important in the early inflammatory response.

• Derived mainly from macrophages,endothelial, and dendritic cells, and lymphocytes (T cells)

• Processes– Stimulate acute phase protein production by the liver– Stimulate the hypothalamus for a fever response– Increase adhesion molecules on the vascular

endothelium35

Acute Phase Protein Production by the Liver

• Overlaps with the ESR

• Increases cytokine release in the body-sensed by the liver-liver increases amount of acute-phase proteins (complement, clotting factors)– Increased cytokines due to inflammation

causes liver to produce more proteins, which increases ESR

Stimulate Hypothalamus for Fever Response

• Hypothalamus in the base of the brain thermoregulates the body

• One of the main reasons that you get a fever is because a cytokine burden increases enough to pass through the vasculature of the hypothalamus and resets the temperature of the body– Reason why anti-inflammatory decrease fever –

decrease the burden of the cytokine production, which decreases the reason that the hypothalamus causes fever

Increase in Adhesion Molecules

• Cytokines trigger the endothelium to put out adhesion molecules so that when a macrophage comes by it sticks to it and squeezes between the endothelium cells out into the tissue to fight infection

Cytokines and Adaptive Immunity

• Activate immune cells to proliferate and differentiate into effector and memory cells.

Cytokines and Hematopoiesis

• Cytokines that stimulate bone marrow pluripotent stem cells, progenitor cells and precursor cells to produce large numbers of platelets, erythrocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils and dendritic cells are termed Colony Stimulation Factors (CSFs)

PART II

Innate Immunity: THE INFLAMMATORY

RESPONSE

Inflammation

InflammationReaction of vascularized tissue to local injury (cellular)

manifesting as redness, swelling, heat, pain, loss of function

• Non-specific, chain of events similar regardless of injury type and extent– Stereotypic no matter the size of the injury

• Includes vascular and cellular changes

• Triggered when FIRST LINE OF Defense's integrity has been breached (skin, mucus membranes and damaged the endothelium or gotten to a vessel)– May be from the outside into the body or from the inside of the body

out (ex. vacularitis)

• Unpleasant and uncomfortable, but essential for survival• May lead to inflammatory diseases

Acute Inflammation

• 1. vascular phase

• 2. cellular phase

Acute InflammationVascular Phase

• After injury or insult, inflammation initiates a rapid vasoconstriction of small vessels in the local area

– The same thing as the rapid vasoconstriction that occurs in hemostasis

• This vasoconstriction is then followed by a rapid vasodilatation of arterioles and venules (vasoactive hyperemia) that supply the local area.

– Results in the erythema (redness) and warmth in the area due to the increased blood flow to the area

• Capillary permeability increases and fluid moves into the tissues (edema) causing swelling and pain.

– Due to cytokines that are released– The capillaries become more permeable – cells that make up the cell

wall become looser, allowing fluids and proteins to move out of the capillaries and into the tissue

Vascular PhasePossible Scenarios

1. Immediate transient response to minor injury• Ex. very small, sterile cut (ex. razor cut, paper cut)

• At first you do not notice the blood because of the rapid vasoconstriction but then after rapid vasoconstriction the vasodilation occurs

2. Immediate sustained response (several days; results in damaged vessels) • More of a traumatic event and possibly a less sterile field• Ex. step on a garden hose• The issue cannot resolve quickly and due to the hemostasis and clotting

necessary, the several day response results in extra damage to the skin and vessels

3. Delayed hemodynamic response (increase in capillary permeability 4-24 hours after injury ; e.g., radiation burns, sun burns)

• Have an insult but do not realize an effect until 4-24 hours after an injury• Ex. sunburn cooks the cells and damages them but they take a while to

build up the response and the damage so that the response takes a while to show

• Redness is the vasodilation, vascular permeability leads to the edema

Acute InflammationVascular Phase

Acute InflammationCellular Phase

• Ex. step on a garden rake and bacteria enters the site of injury

• Characterized by the movement of phagocytic cells into the site of injury

• Need to remove them by recycling them• Release of chemical mediators by sentinel cells in the

tissue (mast cells, basophils, macrophages) • Sentinel cells in the tissues release cytokines, the

endothelial cells recognize them, stick out adhesion molecules to allow phagocytic cells to stick to them

• Chemotaxis of the phagocytic cells from the vessels to the tissue because the cells of moving to the area of high signaling

• Increases capillary permeability and allows leukocytes to migrate to the local area.

• Water wants to leave the vasculature, making it easier for the cells to get out of the blood and into the tissue where they can fight infection

Acute InflammationCellular Phase

Inflammatory Mediators

• Histamine

• Plasma proteases

• Arachidonic acid metabolites

• Platelet aggregating factors

• Cytokines

Histamine

• One of the first mediators of inflammation causing dilatation and increased capillary permeability.

• Histamine high concentration in platelets, basophils, and mast cell– Allows there to be a cross talk between the

clotting cascade and platelet plug

• In mast cells histamine is released in response to binding of IgE Antibodies

Plasma Proteases

• Kinins, activated complement, clotting proteins

• Bradykinin causes increased capillary permeability and pain.– Byproduct of plasma proteases– Causes pain by binding to nociceptors

Arachidonic Acid Metabolites

• Metabolism of arachidonic acid into prostaglandins via the cyclooxygenase pathway

• Metabolism of arachidonic acid into leukotrienes via the lipoxygenase pathway

Metabolism of Arachidonic Acid into Prostaglandins via the Cyclooxygenase

Pathway

Metabolism of Arachidonic Acid into Prostaglandins via the Cyclooxygenase

Pathway

• Arachidonic metabolics are very, very important inflammatory mediators

• PGE1(prostaglandin E1) and PGE2, prostaglandin intermediates, are important in inducing inflammation

– Promoting the inflammatory pathways– Induces vasodilation and bronchoconstriction– Inhibits inflammatory cell function– Prostaglandins released during the pulsatile flow are important in

making blood not stick– Control of acid production in the stomach– Some are pro-inflammatory and some are pro-other things that are

important and beneficial to the body

• TXA2 (Thromboxane A2) promotes platelet aggregation and vasoconstriction

– Promotes branchoconstriction

• Non-steroidals (aspirin etc) inhibit the first enzyme in the cyclooxygenase pathway.

– Used pharmacologically to reduce inflammation

Metabolism of Arachidonic Acid into Leukotrienes via the Lipoxygenase

Pathway

Metabolism of Arachidonic Acid into Leukotrienes via the Lipoxygenase

Pathway• Leukotrienes are critically important

in the generalized response of anaphlaxis• C4, D4, E4: the slow releasing substances of

anaphylaxis (SRA’s). They cause slow sustained contraction of bronchiole smooth muscle. Are important in asthma and anaphylaxis.

• Target of the newer anti-asthma drugs, e.g., montelukast (Singulair), which act as leukotriene inhibitors

Arachidonic Acid Diagram

Platelet Aggregating Factor

• Induced platelet aggregation– Pathways that are important for hemostasis are also

important in the immune and inflammatory pathways

• Neutrophil activation

• Eosinophil chemotaxis

Complement System

Complement System• Functionally analogous to the clotting

cascade in hemostasis

• Primary mediator of the innate and adaptive humoral immune response. Produce inflammatory response, lyse foreign cells, increase phagocytosis

• About 20 plasma proteins. Circulate in inactive form much like clotting factors (C1, C4, C2, C3, C5C9). Proteins must be activated in the proper sequence in order to have their end effect (as with the clotting factors)

• Non-specific and no memory76

Complement Pathways for Activation

• Classical pathway depends on: 1. Binding of IgG or IgM to invading organisms

- antibodies bind to invading organisms 2. Binding of complement to circulating antigen-antibody

complex (complement fixation)

- undergoes molecular change that promotes the activation complement

- complement sees this and there is a molecular recognition

• Alternate pathway is triggered by interactions between complement and polysaccharides on microbes

• Lectin pathway is activated by binding proteins interacting with cell surface proteins in bacteria and yeast– Lectin can be recognized by complement and activates it– Lection is located inside cells and is seen when cells lyse

Results of Complement

Results of Complement• MAC (membrane attack complex) insertion into target

cell membrane holes in cell membrane (lysis)– Form a pore that sticks into a cell and causes the cell to die

through membrane depolarization

• Opsonization - C3b coats Ag-Ab complexes– Helps out neutrophils and macrophages with phagocytosis– Opsonization is when an antibody binds to bacteria

• Complement binds to the antigen-antibody complex and opsonizes it so that the phagocytes want to phagocytize the complex even more

• Chemotaxis - C3a stimulates mast cells and basophils to release histamine and attract neutrophils and others

• C3a and C5a produce anaphylatoxin inducing histamine release in mast cells and basophils:

• Leads to contraction of smooth muscle, vascular permeability, edema• Complement, if activated, will bind to these cells and cause them to

release histamine

Complement PathwaysDiagram

Chronic InflammationPersistent Irritants

• Ex. talc, silica, asbestos that are breathed deeply into the respiratory tract, surgical sutures– The chronic inflammation causes persistent problems that

results in disease

• Some bacteria (tuberculosis, syphilis)– Can be in the body for a long time, escape surveillance, and

cause inflammation

• Injured tissue surrounding healing fracture– Keep stressing the healing fracture, leading to inflammation

• Inflammatory process lasts a prolonged amount of time– Sustained types of response

Chronic InflammationPatterns

• Non-specific diffuse accumulation of macrophages and lymphocytes leading to fibroblast proliferation and scar tissue formation– Relsease cytokines and mediators that lead to the fibroblast

proliferation and scar tissue formation– Ex. in the respiratory tract of smokers the epithelium begins dying

and as the body goes to replace it, it says that the epithelium is difficult to replace so it replaces it with less ciliated, good cells, and then a scar tissue and fibroblasts

• Granulomatous lesion epitheloid cells form granuloma:– Lesions are very discrete

• Ex. splinters, foreign bodies• After a couple of days, a granulomatous lesion forms and

encapsulates the splinter• Eventually fibroblasts form around it and the nodule stays there

for a long time– Ex. Tuberculosis tubercle

• Waiting for the immune system to decrease so that the tuberculosis can come back

Chronic InflammationCauses and Characteristics

Due to:• Recurrent or progressive acute inflammation

(smoking), OR• Low-grade responses that fail to evoke acute

responses (talc, silica, asbestos, tb)

Characteristics:• Infiltration by mononuclear cells (Macs and

Lymphs); not Neutrophils like in acute inflammation.

• Proliferation of fibroblasts ( scarring) ; not exudates

Manifestations of InflammationExudation

• Local manifestation of inflammation

• Extra vascular influx of fluid with high concentration of proteins, salts, cells (WBC) and cell debris– The fluid from the vessel leaves the vessel and enters into

the tissues

• Fluid dilutes injurious chemicals

• Fluid brings in complement, Abs, and other chemotactic substances to injured areas in the tissues due to osmotic gradient

• The extra vascular proteins also act to pull water out of plasma blood viscosity clotting because water is taken out and cells are left behind (increase hemotocrit); containment of pathogens cellular phase begins

Manifestations of InflammationTypes of Exudate

• Serous watery; low in protein– Early exudate

• Fibrinous large amounts of fibrinogen in the exudate• Membranous necrotic debris in fibrinous matrix on

mucus membrane surfaces– Forms a muscosy sheen on certain membranous surfaces

• Purulent degraded white cells, protein, tissue debris– Ex. white looking acne blemish

• Hemorrhagic severe leakage of red cells from capillaries– Blood leaves the vasculature and enters the tissue– Ex. petechiae, purpura

Systemic Manifestations of Inflammation

• Most all of the inflammatory mediators have very short half lives so autocrine and paracrine signaling predominates.– Mechanisms whereby cells secrete substances and they act very, very

locally• Compared to endocrine systems

• If the site of inflammation is large enough or robust enough of if the inflammation is in the circulation, systemic manifestations can be evident in addition to the local manifestations

• Acute phase response

• Lymphadenitis

Acute Phase Responses

Acute Phase ResponsesAcute-Phase Response (hours-days after onset)

• Increase in plasma proteins (e.g., C-reactive protein)– Increased erythrocyte sedimentation rate (ESR)

• Fever (IL-1, IL-6 and TNF effects on hypothalamus)– Drive the hypothalamus to increase body temeprature

• Leukocytosis (presence of immature neutrophils; “band cells”)– Are consuming leukocytes to significant amounts and are trying to

replace them – Similar to the reticulocytes in red blood cells– Band cells are indicative are immature neutrophils

• Skeletal muscle catabolism (mobilize amino acids for protein synthesis)– When there is active inflammation, individuals do not feel well, lose the

drive to eat, do not take in enough nutrition, ask the liver to make a bunch of proteins

• Break down the skeletal muscle to increase amino acid pool and make more proteins

– Negative nitrogen balance– Skeletal muscle is wasting

Lymphadenitis

• Regional swelling of lymph nodes, painful upon palpation

• A swollen lymph node is indicative of an inflammatory event in a local area or regional area– The regional swelling is an indication of systemic

inflammation

Part III:

Treatment of Inflammation

Types of Treatment of Inflammation

• Focus: Prevent the synthesis and release of pro-inflammatory mediators, such as prostaglandins

• NSAIDs

• Steroids

Treatment of InflammationDiagram

Treatment of InflammationNSAIDs

• NSAIDS: nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins and thromboxane (e.g., aspirin, et al.) through the cyclooxygenase pathway• Inhibit the enzymatic conversion

Treatment of InflammationSteroids

• Steroids: given systemically or topically

• Have a multiplicity of actions, many of which impair immune cell proliferation or cytokine release.

• Stop the metabolism of arachidonic acid from cell membrane phospholipids

COX-1 and COX-2

• Both produce prostaglandins and thromboxane (TXA) and convert arachidonic acid into prostaglandins

• Found in many different tissues

• Inhibition of COX-1 is responsible for the adverse effects of NSAID’s because the drug works on all COX-1 tissue types• COX-1 inhibition impairs the gastrointestinal mucosal barrier and

gastric erosion and ulceration may result

• COX-1 inhibition impairs renal function so that sodium and water retention can result• Leads to edema and hypertension

• COX-1 inhibition decreases the creation of thromboxane, which prevents platelet aggregation, which may produce bleeding. • Such inhibition may also prevent myocardial infarction or ischemic (thrombotic)

stroke in patients with overactive coagulation pathways.111

• COX-2 is predominantly in immune cells.

• Inhibiting COX-2 results in the therapeutically desirable effects of NSAID’s:• If you are targeting inflammation, you should really be targeting COX-2

because it is more specific

• Suppression of inflammation

• Decreasing systemic side effects• Alleviation of pain

• Reduction of fever

• However, many of the non-steroidals inhibit both COX-1 and COX-2113

Contraindications

• NSAIDs

• Hypersensitivity syndrome

NSAIDs

• NSAIDs should be avoided in mid to late pregnancy since:

• They may cause premature closure of the ductus arteriosus.

• A shunt in the heart in the developing fetus that allows proper blood flow• Important in maternal-fetal circulation and oxygenation of the fetus

• They might also cause prolonged bleeding following delivery because of their effects on platelets.

Hypersensitivity Syndrome

• Hypersensitivity syndrome caused by COX inhibition:

• This is not an allergic response because there are no antibodies to the NSAID; in susceptible individuals, any NSAID can trigger the reaction.

• Certain people are more sensitive to NSAIDs just because

• Symptoms are similar to those of anaphylaxis.

• Susceptible individuals should avoid all NSAIDS

Aspirin

• An irreversible inhibitor of both COX-1 and COX-2 (it is nonselective).

• Metabolized (with a half-life of ~20 minutes) to salicylic acid, which inhibits both COXs reversibly and has a longer half-life than aspirin

• The anti-inflammatory activity is due to both the irreversible inhibition of both COXs by aspirin and reversible inhibition by salicylic acid.

Uses of Aspirin

• Anti-inflammatory• Anti-pyretic (suppression of fever)• Analgesic

• Dysmenorrhea

• Menstrual cramps are due to the production of prostaglandins

• Aspirin decreases smooth muscle cramping

• Suppression of platelet aggregation

Uses of AspirinSuppression of Platelet

Aggregation

Uses of AspirinSuppression of Platelet Aggregation

• This use is usually accomplished by administration of an 81-mg enteric-coated tablet each morning.

– Allows the drug to pass through the stomach and be absorbed in the intestine

– Do not want aspirin to dissolve in the stomach because it affects gastric pH

• The aspirin irreversibly inhibits COX-1 in platelets it encounters in the portal circulation, but in its 81 mg form it is completely metabolized on first pass and has no systemic effects.

– When aspirin is taken, any platelets in circulation are irreversibly inhibited but on the second time, the aspirin is converted to salicyclic acid and reversibly inhibit platelets

• Taking the small dose allows it to be that only the platelets in the circulation are irreversibly affected (because of the short life of the platelets)

• Over time, a substantial portion of platelets are affected by the low dose aspirin without undue systemic side effects.

Adverse EffectsCommon to all Aspirin Formulations

• Salicylism: tinnitus, headache and dizziness caused by high doses such as the doses that are used in rheumatoid arthritis. Respiratory alkalosis may also result.

• Reye’s syndrome: a fatal syndrome of liver failure in children suffering from chickenpox or influenza who use aspirin. For this reason, it is recommended that children be only given acetaminophen or ibuprofen for febrile illness. With this recommendation, the incidence of Reye’s syndrome has plummeted.

• Poisoning: before childproof caps were mandated by law, aspirin poisoning was a common cause of illness and death in children. This is no longer such a problem

• The toxicity of aspirin in children is what prompted the mandation of childproof safety caps

Aspirin Formulation

Aspirin Formulation• Plain aspirin tablets.

• Buffered aspirin: includes sodium bicarbonate to neutralize stomach acid and prevent gastric irritation.

• The sodium bicarbonate acts as the buffer

• Inhibit the prostaglandins, allowing the gastric mucosa to temporarily go down but you are also buffering the aspirin so you are helping it out

• Enteric coated aspirin: remains intact in the stomach and dissolves in the duodenum; prevents gastric irritation.

• Timed released: makes no sense for an irreversible drug that is completely metabolized on first pass

• Rectal suppositories: Not recommended due to inconsistent absorption and rectal ulceration.

Aspirin Dosage

• Is commonly available in: • regular strength (327 mg)• extra-strength (500 mg) • low-dose (81 mg) tablets

• Used by adults for the inhibition of platelets• There is no evidence that taking more than 81 mg leads to further

platelet aggregation

• Adults: 650-1000 mg in one dose can be repeated every 4 hours.

• Children: aspirin is not recommended unless specifically requested by the child’s physician.

• Inhibition of platelets: 81 mg per day.131

Other Non-Selective NSAIDs

• Non-specific COX-1 and COX-2 inhibitors

• Specific COX-2 inhibitors

Non-specific COX-1 and COX-2 Inhibitors

• Nonspecific COX-1 and -2 inhibitors (aspirin, Ibuprofen, naproxen, etc.):

• All have interactions with warfarin (Coumadin); they may potentiate bleeding tendencies produced by warfarin

• Coagulation studies should be obtained frequently and warfarin dosage adjusted in patients who take both an NSAID and warfarin

Specific COX-2 Inhibitors

Specific COX-2 Inhibitors• Have recently been associated with increased risk of heart attacks.

• A result of clinical trials but many of the reasons are not known• Could inhibit prostacycline, which is a positive mediator

• Purported to produce fewer adverse effects in some individuals, such as GI irritation, bleeding, and sodium/water retention. However, data in the general population to support this contention is shaky.

• Much more expensive than nonselective NSAIDS• A nonselective NSAID is equally effective as a COX-2 inhibitor

• Include:– Rofecoxib (withdrawn from the market) – Valdecoxib (withdrawn from the market)– Celecoxib (Celebrex) is still available

Acetaminophen

Acetaminophen• Does not inhibit COX in the periphery; MOA is unclear

• Is not a COX inhibitor

• Has no anti-inflammatory activity.

• Does not decrease inflammatory mediators

• No side effects of gastric ulceration, sodium and water retention.

• No effect on platelets or coagulation.

• Uses

– Antipyretic

– Analgesic 139

AcetaminophenAdverse Effects

• Adverse effects: Hepatoxicity

• Usually occurs because of overdose

• Decreases liver function and may increase toxicity

• Greatly exacerbated by concurrent alcohol use; so, hepatoxicity may occur at therapeutic doses in heavy drinkers.

• Hepatotoxicity from acetaminophen has resulted in deaths from liver failure.

AcetaminophenDrug Interactions

• May affect warfarin metabolism because it is metabolized by the liver to increase levels of warfarin and increase its anticoagulant effects.

AcetaminophenDosages

• Available in 327 mg and 500 mg tablets.

• Adult dose is 650 mg to 1000 mg every 4-6 hours with a daily limit of 3 g (3000 mg).

• Dosage is reduced depending on the age of the child

Formulations of NSAIDs and Acetaminophen

NSAIDS and acetaminophen are found in many formulations

Be careful !

Part IV:

Adaptive Immunity

Active Adaptive Immunity

• Active passive immunity - Through immunizations

• Active natural immunity - Through having the disease

• Present for a life-time

Passive Adaptive Immunity

• Transferred from another source (in utero, breast milk, antibodies)

• Short-term– It is only around as long as we are given the

substances

Characteristics of the Adaptive Immune Response

• Self tolerance: Discrimination of self and non-self

• Self-regulation: the immune system can initiate, maintain, and down-regulate without help of the nervous system (NS) or other systems– This is one of the only body systems that can do this

• Specificity: Targets very specific antigens• Diversity: Can invoke specific immune response

to an indefinite number of different antigens• Memory: Makes memory cells (only IS and CNS

have memory)

Major Functional Cells of the Adaptive Immune Response

B-Cell Lymphocytes including:

• Plasma B Cells

• Memory B Cells

T-Cell Lymphocytes including:

• T-Helper Cells

• Cytotoxic T Cells

Antigens

Antigens: Initiators of Immune response and Adaptive Immunity

Antigens (aka immunogens) are:• Substances foreign to the host which stimulate an immune response• Antigens are ligands that are recognized by receptors on immune

cells and by antibodies (immunoglobulin's; Igs)• Often proteins or polysaccharides and less often lipids or nucleic

acids.– Your DNA can actually act as an antigen in some instances, but it is not as

common

Locations of Antigens

Antigens are found on:• Bacteria, fungi, protozoa, parasites or non-

microbial agents such as pollens, plant resin, insect venom, transplanted organ.

AntigensDiagram

Immunity Antigens

Immunity Antigens• Many antigens are large molecules.

– The antigen may be recognized by multiple antibodies at a number of locations

• Small fragments, often single sites, can be immunologically active. These sites are called epitopes.

• Antigens or epitopes are what is recognized by a specific Ig receptor

• Often a single antigen can have several antigenic sites. A distinct lymphocyte clonal population will recognize each distinct site

• Certain small molecules are unable to stimulate an immune response (Haptens) .– Too small to stimulate a response– These molecules can become immunologically active when bound to a carrier

protein (e.g., penicillin hypersensitivity) • The body is now able to recognize the body as foreign and can

recognize the antigen as foreign

Major Histocompatibility Complex

• Cell surface molecules which provide a mechanism to differentiate “self” from “non-self”

– The portion of your DNA that encodes for your MHC molecules is what makes you unique

• This becomes important when we want to transplant organs because one person’s MHC may not match the other person’s MHC

• Region of genetic information that makes each individual of one and the same species different:

• aka Human Leukocyte Antigens (HLA) since these were first identified on white blood cells.

• Cytotoxic T cells and helper T cells both recognize MHC complexed with antigen

• Because these molecules (MHC) play a big role in transplant rejection, they are also termed antigens in this instance.

MHC-II Complex

MHC-II Molecules• Found primarily on antigen-presenting cells (APC’s) such as

macrophages, dendritic cells, and B lymphocytes.

• MHC-II molecule contains a groove in them that contains a recognition site which binds a peptide fragment of an antigen from pathogens engulfed/digested during phagocytosis.

• The APC comes into contact with a virus, recognizes an antigen on the virus, activates complement, opsonizes the virus, which increases the phagocytic action, the phagocytic cell ingests the virus, takes the foreign antigen and then presents it on itself– Holds the antigens out to a T helper cell and the T cell agrees that it is

foreign – The T cell then calls in other players to become immune to it and calls

cytokines to destroy the cell

• Helper T cells (Th) recognize these complexes on APC’s and they become activated.

MHC-II Molecules

MHC-I Molecules

MHC-I Molecules• Found on cell surface glycoproteins on most nucleated cells of body. • They Interact with antigen receptor and CD8 molecule on cytotoxic T

lymphocytes (Tc)– Tc cells are responsible for direct cell killing

• The virus enters a cell and the cell presents the virus on the outside– Indicates that the cell has been infected with the virus

• Cytotoxic T-cells (Tc) become activated only when they are presented with an antigen associated with a Class I MHC.

• MHC has the ability to present antigens on our body cells– Distinguishes self from non-self

• Antigen peptides associate with MHC-I in cells that are infected with intracellular pathogen

– E.g., as virus multiplies, small degraded peptides associate with MHC-I and are transported to the membrane.

– This antigen-MHC complex communicates with the Tc cell and the host cell is destroyed.

MHC-I MoleculesDiagram

Virus particles

Comparison of MHC-II and MHC-I

Humoral vs. Cell-Mediated Immunity

• Lymphocyte stem cells are located in the bone marrow

1. Lymphocytes which migrate through lymphoid tissue B cells (make antibodies)

2. Lymphocytes which migrate through the thymus T lymphocytes (cell-mediators)

Development of B Lymphocytes and T

Lymphocytes

Development of B Lymphocytes and T Lymphocytes

• If the bone marrow lymph cell matures in the thymus, it is called a T cell– T cells can become memory, cytotoxic, or helper T cells– Cell mediated immune response

• If the cell leaves the bone marrow and goes to the bursal equivalent tissue (lymphoid tissue), it becomes a B cell– Can become a memory cell or antibodies (plasma cell)– Produce cells that make antibodies

• A part of the humoral immune system

Development of B Lymphocytes and T

LymphocytesDiagram

B Lymphocytes

Responsible for antibody production (humoral immunity)

Function• Identified by the presence of surface immunoglobulin (antibody)

bound to them permanently that functions as an antigen receptor, particular CD proteins and complement receptors

• Plasma cells are antibody factories

• Manufactures specific antibodies that target bacteria, neutralize bacterial toxins, prevent viral infection, and produce immediate allergic response

• Formed from bone marrow stem cells --Pre-maturation in the bone marrow to immature precursor cells --Genetic rearrangement results in a unique receptor and type of effector

antibody (IgM or IgD)- shown an antigen by a presenting cell

- the plasma cell recognizes the cell with the antigen and inside the cell itself, a genetic rearrangement is made so that the antibody will only ever recognize the specific antigen

Differentiation of B Lymphocytes

•Mature B Lymphocytes leave the bone marrow, enter the blood and travel to peripheral tissues

• B lymphocytes bind antigens with help of Th and then

differentiate into

1.Plasma cells (large # of cells: which are responsible for antibody secretion) 2.Memory cells (small # of cells: pre-programmed to become plasma cells from that clonal line)

B LymphocytesDiagram

B LymphocytesDescription

• Helper T cell can present cell to B cell and the B cell can recognize the antigen from then on– Later, if the B cell recognizes the antigen it can do

something about it

• A mature B cell produces a memory B cell and a plasma cell

• A memory just remembers what antigen it should recognize and then goes dormant

• Plasma cells are not dormant like memory cells– Produce antibodies– Look for the foreign antigen 188

Activation of B Lymphocytes

AntibodiesPrimary Immune Response

• Sensitization – Antigen is first introduced into the body

– Antigen is processed by Antigen Presenting Cells (APCs)

• Activation– MHC complexed Antigen is recognized by Th cells

• Differentiation– Activated Th cells release cytokines and trigger B

lymphocytes to proliferate into a clonal line of plasma cells and memory cells

– Plasma cells release antibody

• This time course has a significant lag time.

AntibodiesSecondary Immune Response

• Once re-challenged with antigen at a later time, the memory cells recognize antigen and respond quickly to the antigen.

• Immunization boosters (e.g., tetanus) take advantage of this response.

Primary and Secondary B Lymphocyte Immune Response

Diagram

Description

Description• A B cell that has never been exposed to an antigen but is

mature is naïve– A naïve B cell does not know what it wants to be yet

• The first time that a B cell sees the antigen, the antigen has to be injected, complement binds to it, presented to helper T cells, B cell is sensitizes and becomes a memory B cell or a plasma cell– Takes about two weeks– Creates a bunch of memory B cells that remember the antigen

and can mount a quicker response

• The second exposure is very quick because the memory B cell is present– Secondary immune response

Antibody Types (Immunoglobulins)

• IgA

• IgM

• IgD

• IgE

• IgG

IgA Antibodies

•Secretory (saliva, colostrum, bronchial, pancreatic, GI,prostatic, vaginal).

•Prevents viral and bacterial binding to epithelial tissues.

•IgA is first line of defense in mucosal tissues

–Secretions can bind the pathogen so that it does not enter the vasculature

IgM Antibodies

•Large macromolecular Ig complex.

•First Ig made in response to an antigen.

•First antibody type made by a newborn–During fetal development, the fetus is receiving Igs passively

IgD Antibodies

• Found primarily on cell membranes of B Lymphocytes.

• Acts as antigen receptor.

IgE Antibodies

• Involved in inflammation, allergic responses and combating parasitic infections.

• Antigen binding to IgE on mast cells or basophils causes histamine release

• Important in inflammation and allergies.

IgG Antibodies

• Most abundant circulating antibody in blood

• Only Ab that can cross the placenta.

• Ig in fetus/newborn is passed from mother until new Ig’s are formed by newborn.

• Targets bacteria, virus and toxins.

• Can activate complement.210

Maternal vs. Fetal/newborn IgG Contributions

T Lymphocytes

T Lymphocytes Responsible for cell mediated immunity

• Formed from bone marrow stem cells which migrate to the thymus (T) for maturation. Mature T-cells then migrate to peripheral lymphoid organs

• Genetic modification to form a unique T-cell antigen receptor (clonal selection)

• Produce a specific receptor (T cell receptor) which recognizes the antigen

• TCR: two polypeptide grooves that recognize processed antigen-peptide MHC complexes.

• -TCR is associated with CD3 cell surface molecules, which is a protein

• The TCR is bound to the CD3 protein

• Subpopulations of CD proteins offer further cell specificity:

• 1. CD4+: T-helper cells (have CD3 and CD4)• 2. CD8+: T-cytotoxic (have CD3 and CD8)

Types of T Lymphocytes

• CD4 cells: T helper cells

• CD8 cells: Cytotoxic T cells

Helper T Cell

• Helper T cell (Th or CD4+ cell): Regulatory cells

Master switch of immune system• Do not do direct cell killing• Recognizes Ag-MHC-II complex• Once activated by APC, they release cytokines that

affect most other cells of immune system– Orchestrate the immune response by telling the B cells

what to become and by secreting cytokines• Activated Th cell can differentiate into distinct sub-populations based on cytokines secreted

by the APC.

Cytotoxic T Cell

Cytotoxic T cell (Tc or CD8+ cell): Effector • Get activated by Th cells• Recognize Ag-MHC-I complex on infected cells• Destroy infected cells by releasing cytolytic enzymes,

toxic cytokines, Perforins• Important in controlling intracellular pathogens (bacteria

and viruses) • Do a lot of self vs. nonself checking• Natural killer cells do not check the MHC, like the

cytotoxic cells do– Tc cells are much more selective

Types of T LymphocytesDiagram

Cell-mediated Immunity

• Provide protection from viruses, bacteria, cancer cells

• T lymphocytes and macrophages predominate

• APC cells present MHCII-Ag to Th cells

– Th cells become activated by antigen recognition and by interleukin-2.

– Th cells then produce IL-2 and IL-4 to drive clonal expansion of Th cells and Interferon-gamma which activate Tc cells (cytotoxic T cells).

• Tc cells and macrophages form the basis of the cell- mediated cell destruction in the immune response, while Th cells modulate the process.

Cell-mediated and Humoral ImmunityDiagram

Cell-mediated and Humoral Immunity

Description

Cell-mediated and Humoral ImmunityDescription

• T helper cell recognizes the antigen that becomes activated, releases cytokines, sensitizes B cell, helper T cell recruits Tc cell, Tc cell can kill cells that recognize the MHC-1 antigen

• When B cells are sensitized, they either make memory cells or plasma cells

• T helper cells orchestrate virtually the entire process

• Both the memory cells and the other cells all have specific genetic memory for the certain antigen

Natural Killer Cells

Natural Killer CellsNatural Killer Cells: an effector cell important in innate

immunity.• Small % of lymphocytes• Can bind with antibody coated target cell Antibody

dependent cell-mediated cytotoxicity (ADCC)• Can attack virus-infected cells or cancer cells without

help or activation first• Can recognize antigen without MHC restrictions

– Difference between NK and T cells• NO MEMORY• Activity is regulated by cytokines, prostaglandins and

thromboxane locally• Release NK perforins, enzymes, and toxic cytokines to

destroy target cells – They do not phagocytize

Cytotoxic C vs. Natural Killer Cells

Cytotoxic T Cells

• T lymphocyte• Do phagocytize• Do have memory• Do require MHC-1

restrictions

Natural Killer Cells• Small percentage of

lymphocytes• Do not phagocytize

– Release NK perforins, enzymes, and toxic cytokines to destroy target cells

• Do not have memory• Do not require MHC

restrictions• Activity is regulated by

cytokines, prostaglandins and thromboxane locally

Secondary Lymphoid Organs

• Connected by blood and lymphatic vessels

• The secondary lymphoid organs provide an environment for lymphocytes to circulate, meet and fight antigens, spread antigens, encounter information

• Lymphocytes circulate constantly between blood tissuelymphatic ducts lymph nodes thoracic duct –bloodstream– This is a good place for immunosurveillance

Lymph Nodes

• Localize and prevent the spread of infection

• Contain both B and T cells

• Discrete locations of concentration of the lymphatic system

• Good place to aggregate and look for antigens

Spleen

• Filters and processes antigens from blood

• Contains both B and T cells• Functions as a reservoir for blood (red

pulp)• RBC “graveyard” Hb released• Macrophages and other phagocytic cells

in white pulp• Some parts innervated by sympathetic

MALT (Mucosa –Associated Lymphoid Tissue):

• Major portion of secondary lymphoid tissues• Non-encapsulates areas of lymphoid tissue• Around mucosal membranes of respiratory,

digestive, and urogenital tract. – Located at the interface of the environment and

your body

• Contains T and B lymphocytes. • E.g. tonsils, Peyer’s Patches (intestine),

appendix

Secondary Lymphoid OrgansDiagram

Immunodeficiency

• Abnormality in one or more branches of the Immune System (IS)

1. Antibody-mediated (aka Humoral) 2. Cell mediated 3. Complement 4. Phagocytosis

– Increased vulnerability to opportunistic disease (infections and malignancies)

– Diseases may cross or more of these branches

Normal Immunity in Infancy

• After 6 months, maternal Igs

• Between 1-2 years adult levels of all Igs are reached

• First Ig to be produced by maturing plasma cells is IgM

• IgM can transform into other Igs after antigenic stimulus

Primary Immunodeficiency

• Transient hypogammaglobulinemia

• Defective congenital or inherited genes are rare and include– X linked agammaglobulinemia – Bruton’s= – DiGeorge Syndrome – lack of thymus development

– Severe combined immunodeficiency syndrome (SCID)

Transient Hypogammaglobulinemia

Transient Hypogammaglobulinemia of Infancy (B cell) involves:• The transient lack of antibodies in infancy• Delay in maturation process of B cells • Prolonged deficiency in IgG levels • Fewer B cells = fewer Antibodies

• More prone to opportunistic infections – Increased amount of upper respiratory and middle ear

infections

• Resolves at ± 2-4 yrs old• Many children are not specifically tested for this

because it resolves250

X-Linked Agammaglobulinemia Bruton’s

• Impaired ability of B lymphocytes to produce antibodies

• More common in males

• Have much less or no humoral immunity

DiGeorge Syndrome

• Affects T cells – Problems with the development of the thymus

• Impaired ability of T-helper lymphocytes (Th cells) to orchestrate an immune response or Cytotoxic T- lymphocytes (Tc cells) to mount a cytotoxic response

Severe Combined Immunodeficiency Syndrome

(SCID)

Severe Combined Immunodeficiency Syndrome (SCID)

• No T or B cells !!!

• Tends to be in the stem cell lineage of these cells

• Need a bone marrow transplant

Secondary Immunodeficiency

Acquired later in life due to:• Selective loss of Igs through GI and/or GU tracts - e.g. Nephrotic Syndrome

- the kidney is not able to obtain protein, so it passes into the urine- loss of the protein leads to a loss of antibodies

• Chronic or recurrent infections with:– AIDS– Viruses, Fungi, Intracellular bacteria (TB)– Burden the immune system

• Neoplasia (e.g. Lymphoma)– Lead to an inability to produce cells in the bone marrow

• Iatrogenic causes (e.g. immunosuppressive therapy with cyclosporine)

– You are treating one issue by suppressing the immune system but are creating another problem

• Stress and aging• Drug abuse and maternal alcoholism

– Due to alterations in the nervous system and the liver’s ability to produce proteins

Hypersensitivity Disorders

•Exaggerated immune responses to allergens (Ags)–Ex. pollen

•Leads to inflammation and tissue injury caused by inhalation (depends on the amount of antigen and how we come into contact with the antigen), ingestion, skin contact, or injection

•Sensitization depends on:–Allergen–Exposure–Person’s genetic make-up

Types of Hypersensitivity Disorders

Hypersensitivity Disorders• Four Types

Type I: IgE-mediated hypersensitivity

Type II: Antibody-mediated hypersensitivity

Type III: Immune Complex Allergic Disease

Type IV: T-cell mediated Hypersensitivity

Type I HypersensitivityIgE Mediated

• Appears within few minutes; fades within few hours

• Minor symptoms : localized, pruritic (itchy), skin wheal

• Severe symptoms: vasodilation and bronchoconstriction (=anaphylactic shock)

• Triggered by the binding of an antigen (allergen) to mast cell or basophil with attached IgE, leading to degranulation:– The antigen-antibody complex binds to a mast cell or basophil

and that cell degranulates• Release a lot of histamine

• Ex. pollen allergy in the spring264

Type I HypersensitivityPrimary Response

Primary Phase: Fast-acting or primary mediators:•Histamine•Complement•Acetylcholine causes

bronchoconstriction and vasodilation of small vessels

•Eosinophil chemotactic factor (ECF) causes chemotaxis

•Kinins: Prepared from inactive form•Can result in a significant, localized

event266

Type I HypersensitivitySecondary Response

Secondary Phase: Slow-reacting or secondary substances of anaphylaxis:•Leukotrienes: lipid based; cause

vasodilation, chemotaxis, bronchioconstriction

•Cytokines: ( Interleukins and Tumor Necrosis Factor)

•Platelet activating factor (PAF)•Prostaglandins (PGs) : lipid based

Type I HypersensitivityDiagram

Types of IgE-mediated Hypersensitivity Disorders

• Atopic

• Non-atopic

Atopic Disorders

Atopic Disorders•Atopic = Local Anaphylaxis: •Local reaction to common allergens

– Ex. allergic rhinnitus– Organ specific– High IgE serum levels and high basophil

and mast cell numbers– Allergic rhinitis, allergic asthma, atopic

dermatitis (eczema), certain food allergies, certain aspects of latex allergy

– Diagnosis needs careful history, identification of nasal eosinophilia and skin testing.

Non-atopic Disorders

•Non-atopic = Systemic Anaphylaxis:

–Not organ specific –Can be lethal (anaphylactic shock) –Common allergens are : Nuts, shellfish,

penicillin, insect stings, etc.–Urticaria (hives) , pruritis (itching) ,

bronchospasm (asthma), angioedema, contraction of GI and uterine muscles, laryngeal edema asphyxiation and erythema

Antihistamines (H1 blockers)

• Two types of histamine receptors – H1 and H2– H1 receptor blockers block the effects of

histamine that are responsible for allergy symptoms (Type 1 hypersensitivity)

– H2 blockers block the secretion of stomach acid (to be covered in a later lecture)

H1 Blockers

• See Table 66-1 in Lehne

• Most first generation H1 blockers also block muscarinic receptors and have sedating properties

• Second generation H1 blockers (non-sedating antihistamines) do not cross the BBB very well.– Also do not block muscarinic receptors very well.

• More tolerated with fewer side effects

H1 Blockers Block Histamine Receptors

• Block symptoms of allergies that are due to histamine– Remember, histamine is only one of the

mediators of Type 1 hypersensitivity

• Symptoms of a cold are caused by viral infection, not Type 1 hypersensitivity– H1 blockers are probably not useful for cold

symptoms.– However, in many combination cold pills, you will

find an antihistamine.282

Type II HypersensitivityAntibody-Mediated

• Have preformed reactions to an antigen and then when you come into contact with the antigen, you have a reaction

Types of Type II Antibody-mediated Disorders:• ABO antigens in blood transfusion reactions• Rh Antigens of fetus (erythroblastosis fetalis)• Drug Reactions (e.g., penicillin)

– Binds to a carrier in the body and then is recognized

• Autoimmune hemolytic anemia: Antibodies against own RBCs

• Graft rejections, parasites (lysis without phagocytosis)– Mount a hypersensitivity reaction to the

antigens in the graft

Type II HypersensitivityAntibody Cytotoxicity

• IgG and IgM antibodies interact with antigens on cell surfaces. This activates complement and/or Antibody-dependent cell-mediated cytotoxicity: e.g., the activation of Natural Killer Cells (NK)– Involves antigens on RBCs, neutrophils,

platelets, basement membranes – Involves stimulation or inhibition of cellular

function

Type II HypersensitivityInjuries

• Complement fixation inflammation, opsonization with phagocytosis, or cell lysis– Antibody-dependent cell-mediated

cytotoxicity: Null or NK cells recognize antibodies and release toxins causing cell lysis

Type III HypersensitivityComplex Allergic Disease

Triggers and Injuries

Type III HypersensitivityComplex Allergic Disease

Triggers and InjuriesTriggered by: • Formation of insoluble Antigen-antibody

complexes in blood circulation or extravascular sites, leading to:

- Precipitate formation - Complement activation

• Injuries due to:– Change in blood flow– Vascular permeability– Inflammatory response

Type III HypersensitivityAntigen-Antibody Complexes

• Antigen-Antibody complexes are formed and– Get deposited in the blood vessels, which activates

complement, which in turn causes vasculitis (inflammation of the vessels), and leads to vessel wall damage.

• Antigens bound to antibodies bind with one another and become insoluble complexes, settle down toward the endothelium, activate complement, the MAC complex goes into the endothelium and kills the endothelium– Leads to a vasculitis secondary to lack of blood flow

Type III HypersensitivityDiagram

Immune Complex DisordersLocalized

• At site of injection, localized tissue necrosis due to blockage by Ag-Ab complexes that precipitate

• Onset within 4-10 hrs

Results of Immune Complex Disorders

Vasculitis: - If Blood vessel bursts hemorrhage into surrounding

tissue - If Blood vessel becomes occluded ischemia necrosis

Immune complex pneumonitis (Allergic Pneumonitis):

- Probably involves Type IV hypersensitivity as well- E.g., Miner’s, farmer’s, pigeon breeder’s, mushroom

lung - Individuals inhale the antigen that results in vasculitis

in the respiratory tract- Cough, malaise, fever, dyspnea, radiographic densities

Immune Complex DisordersSystemic

• Systemic response• Urticaria (hives), edema, rash, fever• Antigen-antibody complexes precipitate in

blood vessels, joints, heart, kidneys. This leads to pain and edema in these areas (rheumatoid arthritis)

• Usually temporary; symptoms go away when the antigen is taken away

• Penicillin, foods, drugs, insect venoms can initiate the response.

• Need preformed antibodies to drive this response

Type IV HypersensitivityT-cell Mediated

• Delayed: 24-72 hours after exposure• Triggered by specifically sensitized T lymphocytes

(CD4 memory cells) and Not antibodies• The T cell system is presensitized to the antigen

– When the antigen is present, there is an exaggerated response

• T cell and Antigen combine and release lymphokines which attracts macrophages. Macrophages then release monokines which leads to inflammation.

• Direct attack by Tc cells can also occur• Not tissue specific

– Depends on where the antigen is and the route of the administration

Type IV HypersensitivityT-cell Mediated

Diagram

Types of T-cell Mediated Immunity

Contact dermatitis: – e.g. poison ivy erythema, papules, vesicles, warm, swollen,

exudation, crusting • Not immediate, have been sensitized where it came into contact with skin• Takes a while to react because the T cells must be activated

– Latex allergy

Response to the Tuberculin test:

- Erythema and induration within 8-12 hours at site of injection

Granulomatous inflammation with large, insoluble Antigens:

- e.g. splinter, silica, tuberculosis bacteria

Which type of hypersensitivity disorder is related to ABO antigen blood transfusion

reactions?

Which type of hypersensitivity disorder is related to ABO antigen

blood transfusion reactions?

une Com

Alle...

25% 25%25%25%1. Antibody

mediated

2. IgE-mediated

3. Immune Complex Allergic Disease

4. T-cell mediated

Host vs. Graft Disease

• Recipient attacks donor cells: e.g. you receive liver and your body rejects it

• Cell-mediated responses: Th Tc (Type IV Hypersensitivity)

– Tc and Th severely respond to the graft

Results of Host vs. Graft Disease

• Th cells activate the production of antibodies through B cells which circulate and target graft vasculature. This causes:

1. Complement-mediated toxicity (Type II reaction)

2. Antigen-antibody complexes (Type III reaction)

3. Antibody-mediated cytolysis (Type II reaction)

Autoimmunity

• Breakdown of immune system cannot differentiate between self and non-self– Breakdown in the immunosurveillance

• Can lead to localized or systemic injury depending on what you have an autoimmune reaction to

• Response may be T cell-mediated or involve Ag-Ab complexes that precipitate Type III or even anaphylactic response depending on the severity and type of reaction

• More common in females and elderly

• May be tissue specific: e.g. Graves’ disease (thyroid), myasthenia gravis (neuromuscular junction)

• May be system specific: e.g. systemic lupus erythematosis (SLE), rheumatoid arthritis

• Causes unclear:– Possibly due to an inheritance in the alterations of MHC Genes. – However, individuals may still need a trigger event

Rheumatoid Arthritis (RA)

• Systemic, inflammatory disease

• Affects ± 0.3 – 1.5% of population

• Affects all races

• Women 2-3 times more than men

• Prevalence with age:

– Peak for women: 40-60 YOA– Peak for men: 30-50 YOA

• Etiology of RA– Not sure, but:

• Many patients (not all) have specific genes (although some people have these genes and do not develop RA)

• Environment: virus, bacteria

Rheumatoid Arthritis (RA)Diagram

Pathogenesis of Rheumatoid Arthritis (RA)

• 70-80% of patients have Rheumatoid Factor (RF): RF is an Antigen against IgG that is found in blood, synovial fluid and synovial membrane

– Antigen against protein in own body that is highly enriched in the synovial fluid and membrane, it makes sense that you would get joint problems

• Problems could also happen in similar membranes around the heart and lung

• RF + IgG form immune complexes which leads to synovitis and the development of PANNUS (granulation tissue) swollen and puffy joint

– Complex activates complement, settles in joints, recruits immune cells, inflammation, MAC

• Cartilage and subchondral bone get destroyed

• Surrounding muscles, ligaments and tendons weaken, and cannot function well.

• Reduced joint motion and possibly ankylosis (fusion of joint) due to calcification and inflammation

• Pannus differentiates RA from other arthritis (granulation tissue)– This is what separates RA from OA

Signs and Symptoms of Rheumatoid Arthritis (RA)

• Mild: May last only few months or 1-2 yrs

• Moderate: Flares and remissions

• Severe: Active most of time for many yrs; causes serious joint damage and disability

Extra-articular Manifestations in RA

Systemic

Extra-articular Manifestations in RA

Systemic• Fatigue• Anorexia• Weight loss• Aching of muscles and joints• Stiffness ESR due to significant burden• Anemia • Rheumatoid nodules: Bumps under skin close

to joints. There are Granulomatous lesions that develop around small BVs ± ¼ of patients

• Vasculitis, pleuritis, pericarditis

Emotional and Mental Symptoms of RA

• Depression

• Anxiety

• Feelings of helplessness

• Can’t perform ADL or work (arthritis self-management programs help patients cope)

Diagnosis of RA

1. Morning stiffness for > 1 hour2. Swelling of >3 joints for >6 weeks3. Symmetric joint swelling

- because this is systemically based, it is present bilaterally

4. Rheumatoid nodules present (around small blood vessels)

5. Presence of serum rheumatoid factor (RF) antibody

Evaluation of RA

• History

• Physical exam

• Radiographs are NOT diagnostic

• Lab tests (RF is NOT diagnostic)

• Check for Cloudy synovial fluid330

Goals of RA Treatment

• Relieve pain

• Reduce inflammation (anti-inflammatories)

• Slow down or stop joint damage

• Improve a patient’s sense of well-being and ability to function (Educate patient!)

Treatment of RALifestyle

• Rest and exercise• Joint care• Stress reduction• Balanced diet

Treatment of RAMedications

• NSAIDs • DMARDs (Disease Modifying Anti-

Rheumatic Drugs) reduce joint destruction and retard disease progression

• Reduced number of immune cells (methotrexate)• Block cytokines (anti-TNF (anti-cytokine);

Etanercept) decreases inflammation

• Immunosuppressants• Corticosteroids• New approach: Combination therapy

Treatment of RASurgery

• Joint replacement

• Tendon reconstruction and synovectomy

• Arthrodesis (joint fusion)

Osteoarthritis

Osteoarthritis• Degenerative Joint Disease; Osteoarthrosis

• Most common form of arthritis

• Second to CV disease for chronic disability in US

• 1/3 of all adults in US show OA on X-rays

• Only affects articular cartilage and subchondral bone of diarthrotic joints– Shows reduction of bone and calcification, not pannus

Influences on Osteoarthritis

• In age: Men affected at younger age than women, but rate for affected women exceeds that of men by middle age

• Occupation

• Obesity

• Heredity (e.g. hand OA) 342

Causes of Osteoarthritis

• Primary OA: Idiopathic; no identified risk factors

• Secondary OA: Associated with risk factors:• Joint stress (obesity, sports injuries)• Congenital abnormalities• Joint instability leads to chronic stress of

a joint over time• Trauma

Pathogenesis of OA

•Joint cannot absorb mechanical stress.– This leads chondrocytes to release cytokines which causes release of enzymes and more joint damage. –Articular cartilage breaks down and wears away. –Bone wears on bone Pain, swelling, loss of motion.

•Other results:–Osteophytes–Fragments–Microfractures–Loss of capability to secrete synovial fluid–Joint immobility lubrication more cartilage atrophy

Signs of Symptoms of OA

•Sudden or insidious

•Mild synovitis

•Mostly hips, knees, lumbar and cervical regions, proximal and distal joints of hand, first CMC joint and first MTP joint

•Joint enlargement

•Joint feels hard 348

Process of OADiagram

Warning Signs of OA

• Steady or intermittent pain in a joint• Stiffness > bed• Joint swelling or tenderness in 1 or > joints• Crepitus (a grinding sound in the joint)• Hot, red, or tender?? No….. probably not

OA, maybe RA• Not always pain

Diagnosis of OA

• No single test

• History

• X-rays

• Lab tests (usually normal)

Treatment Goals of OA

• Control pain

• Improve joint care

• Maintain acceptable body weight

• Achieve healthy life style

Joint with OADiagram

Differences between RA and OA

OA is different because...• No or very little synovitis• No systemic signs and symptoms• Normal synovial fluid (no pannus)• Affects cartilage and subchondral bone

only• Not always symmetric• Not always polyarticular• Hardness around joint

Differences between RA and OA

Diagram

Congenital Immunodeficiency

• Congenital (primary)

– Lymphocyte development disrupted in fetus or embryo (rare)

• T cell• B cells

Acquired (Secondary) Immunodeficiency

1. Immune /inflammatory deficiency after birth.

2. Not related to genetic defects:• Nutritional

• Need folate in order to help properly dividing cells develop healthily

• Iatrogenic Deficiencies• Medical treatment - chemotherapy - immunosuppression• Trauma: - Burn victims• Stress - sympathetic lymphoid innervation - cortisol• Acquired Immunodeficiency Syndrome (AIDS)

Human Immunodeficiency Virus (HIV)

A retrovirus unknown until early 1980s:• Contains only RNA; no DNA• Most infections caused by HIV-1 variant of the virus• Cannot replicate outside of living host cells

Infection leads to relentless destruction of immune system AIDS: One of leading causes of death in US and in other countries

Patients infected with HIV are at risk for illness and death from:• Opportunistic infections• Neoplastic complications

Mainly present in blood, genital secretions, breast milk

Presence in saliva, tears, urine, sweat is not important or a high risk for transmission

Transmission of HIV

Transmission of HIV• Sex: Semen, vaginal secretions, cervical secretions, and rectal

secretions

• Blood: Open wound, injection with contaminated needle, blood transfusion (<1985)

• Perinatally:1. In utero2. Inoculation during birth and delivery due to the mixing of blood3. Breast-feeding

• NOT TRANSMITTED BY:1. Casual contact2. Mosquitoes or other insects

• Occupational transmission is very rare 370

HIV Structure

HIV Structure• Viral genome: Two short strands of RNA with

three major genes that encode enzymes:– Reverse transcriptase (Makes mistakes

mutations HIV variants)– Protease: breaks down proteins– Integrase: incorporates viral DNA into host

genome to make more virus

• Outer lipid envelope with surface projections containing gp120 antigen which binds to CD4 proteins of Th

– CD4 are part of the T cell receptor in T helper cells– When the HIV virus gets into the body, it seeks out

cells with the CD4 receptor, and the virus incorporates into contents into the host’s cell, lying dormant and waiting for more virus to be made

Mechanism of HIV InfectionDescription

• Gp 120 antigen binds to CD4 cell• Fusion of HIV virus with cell membrane• RNA is incorporated• Reverse transcriptase makes DNA• Protease breaks down proteins• Integrase integrates proteins into host’s viral genome

• Cell lies dormant• Cell at some time decides to make all of the proteins for HIV,

virus buds out of the host cell, killing the host cell (CD4) in the process, the virus incorporates some of the host’s cell markers with it, helping it to further evade detection• Kills T helper cells, which orchestrate the immune system,

release cytokines

Mechanism of HIV InfectionDiagram

Mechanism of InfectionDetailed Description

• gp120 of virus binds to CD4 molecule

- virus and host membranes fuse

- virus enters host and sheds protein coat

• Viral RNA is converted to viral DNA with reverse transcriptase

• After integration of proviral DNA, virus may remain latent for some time

• Eventually, productive virus synthesis occurs virions released (protease) T cell dies

• Virions invade other CD4 cells fast amplification first few years, destruction of millions of T cells release of millions of virions, but all T cells still get replaced

• After several years, however, T cell numbers begin to crash to very low levels.

Clinical Course of HIV Infection

• Latest classification based on CD4 cell count rather than signs and symptoms

• Primary or Initial Infection: -Window Phase: Between time of exposure to time Abs are

detectable

• Latent period 8-10 years -Acute Phase

-Latent Phase

-Clinically Apparent Disease with Constitutional Symptoms

• Full-blown AIDS380

Primary Infection with HIV

• Immune response HIV Abs (2 weeks to 6 months after infection) Patient will test positive for HIV Ab (seropositive)

• Acute phase that may go unnoticed or produce mild disease:– Acute mononucleosis-like syndrome (acute retroviral syndrome)– Fever, myalgia, sore throat, nausea, lethargy, lymphadenopathy, rash, headache– Symptoms after 1-2 months– Burst of viral replication (viremia) CD4 count (as low as 200), but then immune system

tries to control viral replication viremia CD4 cells rebound, but not to pre-infection levels

• The individual is then asymptomatic because the CD4 cells increase

• Both humoral and cell mediated responses play role in the primary infection phase

• Sometimes mistaken for flu or cold

Viral Load in the Blood (Viremia)

Clinical Latency of HIV

• May last 10 years

• Disease concentrates in lymph nodes– Lymph nodes are areas where T cell congregate

• Asymptomatic and little detectable virus in blood – There will not be an active viremia

• Gradual fall in CD4 count as more virus occurs

• Patient still tests seropositive for antibodies against HIV

Clinically Apparent HIV Disease

Clinically Apparent HIV Disease• Persistent generalized lymphadenopathy (PGL) (>3mos.)

: Lymph nodes swell; not life threatening

• Fatigue, weight loss, night sweats, diarrhea, fungal infections of mouth and nails– These occur because immunosurveillance is decreased

• CD4 count < 500 cells/l (normal 800-1000)

Full-Blown or Clinical AIDS

• CD4 count < 200 cells/l

• Confirmed by a variety of lab tests

• Opportunistic infections (risk correlated with CD4 count)

Full-Blown or Clinical AIDSLungs

• PCP: Pneumocystis carinii pneumoni: Fever, chest pain, sputum,

tachypnea

• TB: Mycobacterium tuberculosis

Full-Blown or Clinical AIDSGI Tract

• Esophageal candidiasis, thrush: painful swallowing; retrosternal pain

• Diarrhea or gastroenteritis

Full-Blown or Clinical AIDSNervous System

• Toxoplasmosis: Toxoplasma gondii (parasite): affects CNS; fever, altered mental status, seizures, motor deficits

• AIDS Dementia: Ataxia, tremor, spasticity, paraplegia

• Cerebral atrophy

Full-Blown or Clinical AIDSNeoplastic Malignancies

• Kaposi’s sarcoma - Neoplasm of endothelium

- Opportunistic cancer

- Small discolored elevated tumors of skin that invade viscera

• Lymphoma398

Full-Blown or Clinical AIDSWasting Syndrome

Wasting syndrome (Cachexia):– Emaciation, severe diarrhea, chronic weakness, fever, fatigue,

lethargy, severe negative nitrogen balance

Patients with HIV disease are most likely to die from:

Neopla

plicat

rtunis

tic in

33% 33%33%1. Neoplastic

complications

2. Opportunistic infections

3. Neurological disease

4. Wasting

All of the above

Diagnosis of HIV Infection

• HIV antibody test (ELISA: enzyme-linked immunosorbent assay):– Detects Abs produced in response to HIV

infection• Western Blot (done if ELISA is positive):

– Identifies Abs specific to viral Ags• CD4 count• Based on symptoms

Treatment of AIDS

• No cure; no vaccine

• Treat opportunistic infections with drugs

• Therapeutic management:– Inhibit reverse transcriptase

– Inhibit protease

– Inhibit integrase

– Prevent transcription from host DNA into viral RNA

– Vaccine??

Treatment of HIVDiagram

1.Fusion inhibitor

2.RT inhibitor

3.Protease inhibitor

4.Under development

5. Integrase inhibitor

The Immune Response:

Documents