Inflammation and the Immune System

9 / 4 lecture

how does the body protect itself against disease

• innate immune system

• inflammation

• adaptive immune system

• chronic inflammation

innate immunity

• first line of defense

• the natural defenses in place to provide protection against pathogens and stressors from the environment

• include physical, mechanical, and biochemical mechanisms designed to mitigate or prevent growth of pathogens and exposure to external stressors

• in place at birth

• fast acting

innate immunity: physical barriers

• epithelial cells

  • tightly bound

  • line the surfaces of the skin and the GI tract

  • prevent deep penetration by pathogens

• low temperature of the skin

  • inhibits pathogen growth

• low pH of the skin and stomach

  • inhibits pathogen growth

innate immunity: mechanical barriers

• mechanisms for cleaning pathogens from the surfaces of epithelial cells

  • vomiting → clears pathogens from the GI tract

  • urination → clears pathogens from the GU tract

  • goblet cells of upper respiratory tract → secrete mucous that traps pathogens

    • ciliated cells then brush out the mucous and pathogens

innate immunity: biochemical barriers

• substances synthesized by and secreted by epithelial cells designed to trap or destroy pathogens

  • antimicrobial fatty acids and lactic acid → secreted by sebaceous glands of skin

  • antimicrobial peptides → secreted by epithelial cells

  • lysozyme → component of perspiration, tears, and saliva

innate immunity: normal microbiome

• bacteria and fungi colonize the surfaces of the body

  • unique to a given area

  • non-pathogenic under normal circumstances

  • compete with other microorganisms for resources and space (block attachment to the epithelium)

    • secrete chemicals (ammonia, etc.) that inhibit growth of pathogens

  • immune system also suppresses growth of normal microbiome (aka normal flora)

innate immunity: failure due to medications

• use of broad-spectrum antibiotics can kill the body’s normal microbiome

  • organisms that are resistant to the antibiotic have the opportunity to replicate and may lead to opportunistic infections

    • candida albicans = thrush

    • clostridium difficile = pseudomembranous colitis

  • immunosuppressant medications (meds that block the immune system) can also lead to opportunistic infections

innate immunity: the genitourinary tract

• urinary tract is normally sterile

• urination flushes bacteria from system and disrupts adhesion

• increased risk of bacterial growth if there is:

  • short urethra

  • reflux/retrograde flow

  • obstruction

innate immunity: respiratory tract

• mucociliary blanket lining nose and upper respiratory tract trap microbes (smoking damages this)

• goblet cells secrete mucous and trap microbes

• cilia in upper airway move encapsulated bacteria to back of throat where they are swallowed or expelled

• alveolar macrophages destroy small organisms that travel down airway

innate immunity: gastrointestinal tract

• gastric acid destroys pathogens in stomach (creates low pH)

• viscous mucous layer coats gut and entraps microbes

• pancreatic enzymes and bile detergents destroy organisms

• IgA secreted by mucous membranes in gut

• normal bacterial flora compete with pathogens for nutrients

inflammation

• second line of defense

• programmed response to tissue injury

• integrated system of humoral (dissolved in blood) and cellular responses designed to:

  • limit tissue damage

  • destroy pathogens

  • initiate adaptive immune system

  • begin healing

• rapid response in vascularized tissue (begins in seconds)

  • broken into vascular and cellular components

cells of inflammation: endothelial cells

• layer of cells lining blood vessels

• connected to underlying connective tissue

  • release nitric oxide (NO) to promote vasodilation

  • release inflammatory mediators (interleukins, prostaglandins, etc.) to regulate cellular changes during inflammation

  • regulate movement of cells through endothelial layer

  • release tissue factor in response to injury (activates extrinsic pathway of clotting cascade)

cells of inflammation: mast cells

• cells that lie in connective tissue near blood vessels

• when activated, mast cells:

  • degranulate (release inflammatory mediators stored in cellular granules)

    • immediate

    • primarily histamine

  • synthesize new inflammatory mediators

    • delayed

what is histamine responsible for

(released by mast cells)

• vasodilation

• increased capillary permeability

• bronchoconstriction

cells of inflammation: neutrophils

• first phagocytic cells to arrive in inflammation**

• main function

  • phagocytosis of pathogens

    • these aren’t able to survive the acidic environment of inflammation for long

    • they become a component of purulent exudate (pus)

what is the first inflammatory mediator in a wound

histamine

what is the first cell in a wound

neutrophils

cells of inflammation: eosinophils

• two main functions

  • defense against parasites

  • regulate changes associated with allergic reactions (mast cells, eosinophils, histamine, etc.)

• mildly phagocytic

• worms, wheezes, and weird diseases

cells of inflammation: dendritic cells

• aka Langerhan cells

• link between innate and adaptive immune system

• two main functions

  • function as antigen-presenting cells (APCs) to initiate adaptive immunity

  • phagocytosis (mild)

cells of inflammation: monocytes/macrophages

• monocytes are the precursor to macrophages

• capable of surviving in acidic environments

  • last longer than neutrophils

• if it’s in your blood, it is a monocyte

• if it comes out into the tissues, it is a macrophage

main functions of monocytes / macrophages

• clear pathogens and debris from injured tissue/wounds

• function as antigen-presenting cells (APCs) to initiate adaptive immunity

chemical mediators of inflammation

• responsible for coordination of vascular and cellular aspects of inflammation

• tightly regulated

chemical mediators of inflammation: histamine

• first inflammatory mediator released

• produced by mast cells

• responsible for

  • vasodilation

  • increased vascular permeability

  • bronchoconstriction (contraction of bronchial smooth muscle)

• temporary

• leukotrienes will take over once synthesized

chemical mediators of inflammation: bradykinin

• initiated by activation of Hageman factor (factor XII)

• responsible for

  • vasodilation

  • increased vascular permeability

  • bronchoconstriction

  • pain **

chemical mediators of inflammation: clotting factors

• produced by liver

• induces the clotting cascade

• chain of events that leads to production of fibrin clot

chemical mediators of inflammation: complement proteins

• plasma proteins

• present in inactive form

complement proteins as part of inflammation

• increase vascular permeability

• promote chemotaxis (movement of cells following concentration gradient)

  • like when u float bc u smell a pie <3

complement proteins as part of immune system

• act as opsonins and facilitate phagocytosis

• create holes in cell membrane of pathogens (membrane attack complex → MAC)

  • basically sprinkles on a pathogen which attract the body’s response to eat the pathogen

chemical mediators of inflammation: arachidonic acid metabolites

• fatty acids present in the cell membrane

• metabolized by one of two pathways

  • cyclooxygenase (COX) pathway

    • produces prostaglandins and thromboxane

      • prostaglandins are responsible for pain

      • thromboxane = platelet aggregation

    • aspirin/NSAIDs block COX pathway

      • will stop you from feeling pain and blood coagulation

  • lipoxygenase pathway

    • produces leukotrienes

chemical mediators of inflammation: prostaglandins and leukotrienes

promote:

• vasodilation

• increased capillary permeability

• bronchoconstriction

chemical mediators of inflammation: thromboxane

promotes:

• platelet aggregation

chemical mediators of inflammation: IL and TNF

• interleukins and tumor necrosis factor

  • many kinds

  • some are pro inflammatory (IL-1β, IL-6) **

  • some are anti inflammatory (IL-4, IL-10) **

• many overlapping functions

  • recruitment and activation of leukocytes (WBCs)

  • induce acute-phase responses of systemic inflammation

    • fever, increased HR, anorexia, increased neutrophils, increased cortisol)

which IL and TNF are pro inflammatory

(IL-1β, IL-6)

which IL and TNF are anti inflammatory

(IL-4, IL-10)

chemical mediators of inflammation: interferons

• produced by virus-infected cells

• enhances defense against viruses

• inhibits DNA/RNA synthesis

• some active immune cells to destroy viruses

chemical mediators of inflammation: nitric oxide

• produced by endothelial cells

• promotes smooth muscle relaxation and vasodilation

what are the two types of inflammation

• acute

• chronic

acute inflammation

• early, short term and self limiting

• occurs before adaptive immunity can exert its effect

• designed to remove injurious agent and limit extent of damage

• neutrophils predominate in first 24 hours

chronic inflammation

• late, long-term and self-perpetuating

• usually the result of recurrent inflammation/irritation or slow processes that falls to induce an acute response

• macrophages and lymphocytes are more common

acute inflammation: vascular response

• following tissue injury

  • initial vasoconstriction (controls loss of blood)

  • vasodilation

    • increase flow of blood to the area

    • makes area warm and red **

  • increased vascular permability

    • endothelial cells contract

    • fluid leaks through gaps between cells → meant to dilute the pathogen

      • initially plasma with little protein (transudate)

      • quickly followed by movement of protein-rich fluid (exudate)

    • outflow of protein draws water from vessels to surrounding tissue (edema)

what are the stages of cellular response in acute inflammation

1. endothelial activation

2. margination

3. tethering

4. rolling

5. firm adhesion

6. diapedesis/transmigration

7. chemotaxis

8. leukocyte activation

9. phagocytosis

every month thunderstorms rolling from Dallas, Texas can leave puddles

endothelial activation

• first stage of acute inflammation cellular response

• inflammatory mediators (histamine, interleukins, etc.) promote expression of integrins on surface of leukocytes (mostly neutrophils → first responder)

• also promotes expression of selectins and intracellular adhesion molecules (ICAM) on surface of endothelial cells

• Endothelial cells have selectins and leukocytes have integrins

margination

• second stage of acute inflammation cellular response

• circulating leukocytes are swept against blood vessel wall

tethering

• third stage of acute inflammation cellular response

• integrins on leukocytes bind loosely to selectins on endothelium

rolling

• fourth stage of acute inflammation cellular response

• leukocytes move from selectin to selectin

  • just rolling across the endothelial cells

firm adhesion

• fifth stage of acute inflammation cellular response

• integrins on leukocyte attach firmly to ICAM

• after rolling, the leukocyte will eventually come into contact with an intracellular adhesion molecule which traps the leukocyte and stop the rolling

diapedesis/transmigration

• sixth stage of acute inflammation cellular response

• leukocyte moves through gap between endothelial cells

chemotaxis

• seventh stage of acute inflammation cellular response

• leukocytes follow chemical gradient to the site of injury

  • chemicals are released by immune and non-immune cells

• the smell of pie

leukocyte activation

• eighth stage of acute inflammation cellular response

• a chain of events that leads to attachment of a leukocyte to a pathogen and phagocytosis

  • through one of two ways

    • pattern recognition receptors (PRRs)

    • opsonization

leukocyte activation via PRRs and PAMPs

• a way for phagocytic cells to recognize pathogens

• pattern recognition receptors (PRRs) are toll-like receptors

• molecules on the surface of phagocytic cells that recognize pathogen-associated molecular patterns (PAMPs) on surface of pathogens

  • PAMPs are not present on mammalian cells

• PRR attachment to PAMP stimulates activation of the phagocytic cell and phagocytosis

leukocyte activation via opsonization

• ex. complement proteins, cytokines, c-reactive protein

• soluble molecules that bind to particles on surface of pathogens

• phagocytic cells bind to opsonins on the surface of pathogen

• opsonin attachment stimulates activation of the phagocytic cell and phagocytosis

phagocytosis

• ninth stage of acute inflammation cellular response

• engulfment of pathogens by leukocytes

  • engulfment: once activated, pseudopods extend around pathogen and enclose it in a phagocytic vacuole (phagosome)

  • fusion: phagosome merges with lysosome

  • killing of ingested pathogen: enzymes inside of the lysosome degrade the pathogen

local manifestations of inflammation

• occur as the result of vasodilation and increased vascular permeability

  • heat → due to vasodilation

  • redness → due to vasodilation

  • swelling → due to increased capillary permeability

  • pain → due to increased capillary permeability

    • exudate compresses nerves in tissue

    • presence of prostaglandins and bradykinin

  • loss of function

what are the systemic manifestations of inflammation

• fever → early response induced primarily by IL-1 acting on the hypothalamus

• leukocytosis

  • increase in leukocytes to fight infection

  • may be accompanied by “left shift” in severe infections

    • most of your WBC get killed off and are replaced by immature cells that aren’t able to fight off pathogens as well

• plasma protein synthesis

  • fibrinogen, prothrombin, clotting factors, plasminogen, complement proteins, etc. (produced by liver)

chronic inflammation

• persistent infections (>2 weeks)

  • acute response may have been unable to control the infection or clear foreign objects (splinter, dirt, asbestos, etc.)

• also may occur independently

  • some microorganisms can survive and replicate inside phagocytic cells

  • activates chronic inflammation

what organisms can survive and replicate inside phagocytic cells

• mycobacterium tuberculosis, mycobacterium leprae, salmonella typhi

acute vs. chronic inflammation (cell types)

• acute: characterized by high numbers of neutrophils (but they can’t survive very long)

• chronic: neutrophils are replaced by macrophages and lymphocytes

  • take over for neutrophils (bc they are stronger)

what is a granuloma

• happens during chronic inflammation

• if macrophages cannot destroy the organism, the body attempts to contain the organism in a granuloma

  • core of macrophages surrounded by lymphocytes

  • may contain fibroblasts that produce collagen

  • may become calcified

  • center of granuloma can become necrotic

acute inflammation key points

• fast, early

• characterized by:

  • infiltration by neutrophils

  • protein rich exudates

chronic inflammation key points

• slow, late

• characterized by:

  • infiltration by macrophages and lymphocytes

  • presence of fibroblasts that secrete collagen

  • can become calcified

  • core can become necrotic

adaptive immunity

• third line of defense

• process designed to create a specialized immune response against a particular pathogen

• augments protection already in place and prepares long term protection

• major components

  • cells of adaptive immune system

  • antibodies

what are the two branches of adaptive immunity

• cell mediated → mediated by T-lymphocytes

• humoral → mediated immunoglobulins (antibodies) produced by plasma cells

antigen presenting cells (APC)

• immune cells that initiate adaptive immunity

  • macrophages

  • dendritic cells

  • some B lymphocytes

• bind to an antigen, engulf them, break them down into protein fragments

• attach a protein fragment to a molecule of major histocompatibility complex (MHC)

• presents the MHC/protein fragment to T lymphocytes for activation

major histocompatibility complex (MHC)

• aka human leukocyte antigen (HLA)

• glycoproteins on the surface of cells responsible for antigen presentation and helping the immune system differentiate native cells from foreign cells

• has a groove that accommodates the protein fragment derived from an invading pathogen

• when the MHC/protein fragment complex of an APC is presented to T-cells, the T-cells become activated

what are the two main MHC glycoproteins

• MHC II: on APCs

  • activate CD4+ cells to become T-helper cells

• MHC I: on all nucleated cells

  • activate CD8+ cells to become cytotoxic T cells

B lymphocytes

• part of the adaptive immune system

• when activated, differentiate into plasma cells and make antibodies

T lymphocytes

• part of the adaptive immune system

• several types differentiated by “cluster of differentiation” (CD) protein on the surface (CD4+ vs CD8+)

CD4+ T lymphocytes

• when presented with antigen peptide/MHC II complex by APCs they differentiate into T-helper cells

• function: regulate adaptive immune system and create memory

CD8+ T lymphocytes

• when presented with antigen peptide/MHC I complex by virus infected cells or cancer cells, they differentiate into cytotoxic T cells

• function: release reactive oxygen species and enzymes to destroy infected cells

pathogen recognition by T helper cells: cell-mediated immunity

1. APCs engulf pathogen, break it down, bind a protein fragment to MHC II

• antigens can be microbial (virus, bacteria, fungi) or non-microbial (plant pollen, poison ivy resin)

2. APCs present MHC II/antigen complex to CD4+ T lymphocyte

3. CD4+ cell becomes an active “T-helper cell”

what does a T-helper cell do

• cytokines are released that activate B cells

  • B cells become plasma cells which make antibodies (these specific antibodies target the antigen that was presented by the MHC II)

• cytokines are released to make memory T cells

• cytokines are released to recruit CD8+ T cells

cytotoxic T-cell response: cell mediated immunity

1. recruited CD8+ cells bind to MHC I / antigen complex of infected cell

2. CD8+ cell becomes an active “cytotoxic T cell”

3. cytotoxic T cells releases enzymes/cytokines that destroy the infected cell

humoral immunity

• dissolve in your blood

• the immune response is mediated by antibodies

• antibodies form complexes with antigens

• complexes may result in precipitation of antigen-antibody complexes, agglutination of pathogens, phagocytosis or lysis of infected cells

humoral primary immune response

• first exposure to an antigen

• slow to develop

• results in memory B cells

humoral secondary immune response

• subsequent exposure to the antigen

• much quicker response

immunoglobulins

• aka antibodies

• proteins produced by plasma cells in response to an antigen

  • IgG

  • IgA

  • IgM

  • IgD

  • IgE

IgG

• most abundant (75%)

• arrives late

  • but stay around after the pathogen is already gone (G=gone) + stays with you the rest of your life

• binds to infected cells and promotes lysis of infected cells

• only one that crosses placenta

IgA

• common in mucous membranes and secretions

• provides local immunity

IgM

• first to appear in response to antigen

  • for when you are the most miserable

  • fade away and get replaced by IgG

  • promote agglutination of organisms for lysis or phagocytosis

IgD

• on B cells

• required for B cell maturation

IgE

• binds to Fc receptors on mast cells releasing histamine

• inflammation, allergic responses, and parasites

• eosinophils

  • worms, wheezes, and weird diseases

active immunity

• immunity developed by vaccination or having the disease

• body exposed to antigen and develops IT’S OWN immunity

  • pathogen may be weakened or killed

• immune system of the host responds by creating antibodies to the antigen (may be a vaccine)

• long term

passive immunity

• immunity is from another

• fetus is protected by IgG of mother

• hyperimmune serum (IVIg)

• short term

what are the disorders of immune response

• hypersensitivity disorders

• transplant rejection

• autoimmune disease

• HIV

hypersensitivity disorders

• excessive inappropriate activation of immune system

• 4 types

  • Type I: anaphylactic/atopic/allergic (IgE mediated)

  • Type II: antibody mediated

  • Type III: immune complex mediated

  • Type IV: delayed, t cell-mediated

type I hypersensitivity: initial exposure

• IgE mediated, immediate, atopic and anaphylactic

• rapid allergic reactions (minutes)

• localized (atopic) → localized edema and vasodilation (rhinitis, food allergies)

• systemic (anaphylaxis) → widespread edema, vasodilation

• initial exposure (sensitization)

  • IgE produced by plasma cells in response to antigen

  • IgE binds to mast cells

Type I Hypersensitivity: subsequent exposure

• allergen binds to IgE bound to mast cells

• stimulates release of histamine and other mediators (prostaglandins, leukotrienes, etc.) from mast cells

• histamine → vasodilation, increased capillary permeability, bronchoconstriction

type I hypersensitivity: primary/initial phase

• within 5-30 mins

• vasodilation

• increased vascular permeability (leakage)

• smooth muscle contraction (bronchoconstriction may occur)

type I hypersensitivity: secondary/late phase

• onset 2-8 hrs after resolution of initial phase

• continued vasodilation

• more intense infiltration with eosinophils and other immune cells

• chemicals released by eosinophils promote tissue damage

• severity of reaction depends on degree of sensitization

Type II hypersensitivity

• antibody mediated

  • mediated by IgG or IgM (no IgE) directed against target antigens on cells

  • location of the target defines the response

• examples

  • ABO/Rh incompatibility: antibody binds to cell-surface antigen and causes cell destruction

    • IgM/IgG binding activates complement cascade → lysis of RBC

  • graves disease: antibody binds to TSH receptor on thyroid follicle cells and activates it

  • myasthenia gravis: antibody binds to acetylcholine receptor on skeletal muscle cell and prevents activation

type III hypersensitivity

• immune complex mediated

  • antigen/antibody complexes formed in bloodstream

  • complexes are eventually deposited in vascular endothelium or extravascular tissue

  • initiates inflammation

• the location of the deposited antigen-antibody complex defines the response

• EX

  • systemic lupus erythematosus (SLE)

  • glomerulonephritis

type IV hypersensitivity

• delayed or t-cell mediated (no antibodies involved)

  • sensitized T lymphocytes

  • take time to develop, which is why it is “delayed’

  • e.g. contact dermatitis → poison ivy, nickel, etc

type IV hypersensitivity: initial exposure (sensitization)

• APCs process antigen (e.g. poison ivy toxin, medication)

• APCs present antigen to CD4 cells and activate them

• CD4 cells become t-helper cells and produce memory t-cells

type IV hypersensitivity: subsequent exposure

• rapid reactivation of memory t-cells

• memory t-cells recruit phagocytic cells

  • phagocytic cells destroy tissue

• memory t-cells activate cytotoxic t-cells

  • cytotoxic t-cells secrete enzymes that destroy tissue directly

stevens-johnson syndrome

• rare cutaneous reaction to medications

• type IV hypersensitivity

• pathophysiology

  • APCs take a portion of medication, bind it to a molecule of MHC and express it on the surface

  • MHC I / medication complex activates cytotoxic T cells

    • cytotoxic T cells infiltrate tissue and release enzymes that promote cell destruction

  • MHC II / medication complex activates T helper cells

    • recruit macrophages/neutrophils that destroy cells

transplant rejection

• process involving cell-mediated and humoral immunity

• most common is t-cell mediated and is known as cellular rejection

  • donor antigens are presented to recipient T lymphocytes by APCs

  • antibodies will be created that target the donor tissue

  • may be expedited if previously sensitized (ABO mismatch or prior organ rejection)

  • APCs may come from recipient or from the donor

transplant rejection: direct pathway

• antigen is pre-processed

• APCs come from the DONOR

• T cells (CD4 and CD8) of the RECIPIENT recognize foreign MHC molecules and antigens on the APCs of the DONOR TISSUE

• T helper cells secrete cytokines that are responsible for 3 things

  • cytotoxic T cells release enzymes and kill foreign tissue

transplant rejection: indirect pathway

• antigen needs to be processed first

• APCs come from the RECIPIENT (host)

• RECIPIENT APCs process the antigen from DONOR tissue

• RECIPIENT APCs present antigen to T cells

• T cells of the RECIPIENT recognize foreign antigen on the APCs and are activated

• T helper cells secrete cytokines that are responsible for 3 things

  • cytotoxic T cells release enzymes and kill foreign tissue

• this is a slower reaction

graft vs host disease

• cells with functional immune capacity are transplanted into someone who is immunocompromised

• the grafted tissue (the graft) rejects the recipient (the host)

• 3 requirements

  • tissue must have functional immune component

  • recipient must have antigens foreign to donated tissue

    • like if you were to get a transplant from someone related to you, it would be less likely for it to be foreign

  • recipient must be immunocompromised

• t cell mediated

autoimmune disorders

• tissue specific (graves disease) or may affect several systems

• tolerance → the ability of the immune system to differentiate self from non-self

  • central tolerance: apoptosis of autoreactive cells prior to release into circulation

    • t cells removed in the thymus

    • b cells removed in the bone marrow

  • peripheral tolerance: mechanisms in place to eliminate autoreactive cells that escape the thymus or bone marrow