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NONSPECIFIC DEFENSES OF THE HOST. Innate Immunity (Non-Adaptive Immunity). (Pre-existing immunity) Immunity you are born with Does not change/adapt during life in response to infection. HOST IMMUNE SYSTEM.

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slide2

Innate Immunity

(Non-Adaptive Immunity)

(Pre-existing immunity)

Immunity you are born with

Does not change/adapt

during life in response to infection

slide3

HOST IMMUNE SYSTEM

There are over 400 known pathogens of man and each of us is likely to come into contact with at least 150 of them within our life span

Include:

    • Viruses (10-20 nm)
  • Bacteria (1-2 um)
  • Protozoa (50-100um)
  • Fungi (10um-10cm)
  • Parasites (Worms & Flukes) (>10cm)
slide4

Why Do We Need An Innate Immune System?

Replication rate of extracellular bacteria with an average doubling time of 20 minutes

Dead within 24hrs !!!

= 2 x 1021

slide5

Innate Immune System comprises

of a

Cellular arm(cells)

and

a

Humoral arm (soluble factors)

slide6

IMMUNOLOGY

Study of how the body limits invasion by non-self and

recognises and eliminates altered self

- damaged cells and cancer cells

HAEMATOLOGY

Study of blood cells and their origins and

the homeostatic mechanisms that control coagulation

Most types of blood cell are components of the immune system

slide7

INFECTION

  • Differences between infectious agents and
  • their sites of replication necessitate
  • different immune mechanisms for their control
  • VIRUSES (DNA & RNA, intracellular replication)
  • BACTERIA (intracellular / extracellular replication)
  • FUNGI
  • PROTOZOA
  • WORMS
slide8

DEFENCE AGAINST INFECTION

  • Physical barriers
  • Non-adaptive (Innate) immunity
  • Adaptive immunity
nonspecific resistance
NONSPECIFIC RESISTANCE
  • Defenses that protect the host against ANY pathogen
    • Mechanical factors
    • Chemical factors
specific resistance
Specific Resistance

Specific Resistance, or immunity is based on antibody production

It is a defense against a particular microorganism

mechanical factors
Mechanical Factors

The intact skin consists of the dermis, an inner thicker portion composed of connective tissue, and the epidermis, an outer, thinner portion consisting of several layers of epithelial cells

The top layer of epidermal cells contains the protein keratin (remember—fungi produce keratinase)

slide12
SKIN
  • Dermis
    • Inner thicker portion
  • Epidermis
    • Outer, thinner portion
  • Keratin (waterproofing)
skin infections
SKIN INFECTIONS
  • Rare in unbroken skin
  • Sweat washes microbes off
  • Cuts and burns may get infected
    • Subcutaneous infections
    • Staphylococcus spp.
mucosal surfaces
MUCOSAL SURFACES
  • Epithelial layer
  • Connective tissue

Bronchi

Intestine

mucosal surfaces cont
MUCOSAL SURFACES (cont.)
  • Gastrointestinal tract
  • Respiratory tract
  • Urinary tract
  • Reproductive tract
mucosal surfaces cont1
MUCOSAL SURFACES (cont.)
  • Mucus traps microorganisms
  • Physical barrier
  • Cilia lower respiratory tract
  • Washing (sweat)
mucosal surfaces cont2
MUCOSAL SURFACES (cont.)
  • Mucosal irritation or damage facilitates infection (smoking)
  • Substances produced by pathogens
    • Treponema pallidum
flushing of cavities
Flushing of Cavities
  • Prevents colonization
    • Tears (lysozyme—breaks down NAG/NAM)
    • Saliva
    • Urine
    • Feces
    • Sebum (unsaturated fatty acids of sebum inhibit growth of certain pathogens)
chemical factors
CHEMICAL FACTORS
  • Skin
    • Sebaceous glands
      • Unsaturated fatty acids
      • pH 3-5
lysozyme
LYSOZYME
  • Enzyme that degrades peptidoglycans
    • Gram positives more susceptible than Gram negatives
lysozyme cont
LYSOZYME (cont.)
  • Sweat
  • Saliva
  • Tears
  • Nasal secretions
gastric juice
GASTRIC JUICE
  • Hydrochloric acid (pH 1.2 to 3)
    • Helicobacter pylori
      • Neutralizes acidic pH
  • Enzymes
  • Mucus
blood
BLOOD
  • Iron-binding proteins
    • Lactoferrins
    • Transferrins
      • Iron unavilable for pathogens
slide24

DEAD TISSUE leads to INFECTION

Mechanical, chemical or thermal injury

Debride wounds

Interruption of blood supply – infarction

slide25

DEFENCE AGAINST INFECTION

  • Physical barriers
  • Non-adaptive (Innate) immunity
  • Adaptive immunity

A variety of immune mechanisms utilising

proteins and cells that act in concert

to control and eradicate infection

Immune mechanisms are targeted by

molecular recognition of micro-organisms

slide26

INNATE IMMUNITY

  • Mast cells
    • increase blood flow and vascular permeabilitybring components of immunity to site of infection
  • Phagocytes
  • engulf (phagocytose) and destroy micro-organisms
  • Complement
  • activate mast cells, attract phagocytes, opsonize
  • and lyze micro-organisms
  • Acute phase proteins
  • activate complement and opsonise
slide27

1011 different receptors

1011 different antigens

1

3

1

3

2

2

4

4

SPECIFIC IMMUNITY

For each different antigen there is a specific receptor

slide28

Exposure to infection Resistance to infection

  • Climate
  • Vectors
  • Population
  • Housing
  • Water / sewage
  • Public health
  • Mutation
  • Age
  • Previous exposure
  • Vaccination
  • Nutrition
  • Disease
  • immunodeficiency
phagocytosis is the body s second line of defense
PHAGOCYTOSIS is the body’s second line of defense
  • Ingestion of particulated matter by a cell
    • Phagocytes (white blood cells)
    • Phagocytosis derived from the Greek work “to eat” and “cell”
formed elements in blood
Formed Elements in Blood

--Blood fluid is called plasma

--Cells and cell fragments of the blood are the formed elements

--Most important ones in Immunology are the leukocytes (WBC)

--Decreased leukocyte counts are called leukopenia (I.e.Thrombocytopenia)

slide32

A differential white blood count detects leukocyte number changes

Leukocytes are subdivided into three categories

GRANULOCYTES---have granules in their cytoplasm (neutrophils, basophils, eosinophils)

LYMPHOCYTES (are note phagocytic—occur in lymphoid tissue)

MONOCYTES (lack granules & are phagocytic only after maturing into MQ)

phagocytes
PHAGOCYTES
  • Neutrophils (60-70%)
    • Initial phagocytic cells
  • Monocytes/Macrophages (3-8%)
    • Final phagocytic cells
slide34

Granulocytes

Eosinophil

(0-2%)

Neutrophils

(45-74%)

In Blood

slide35

Eosinophils Target – Worms and flukes

Filarial Nematode Larvae

Wucheria bancrofti

Migrates within tissues

slide36

Granulocytes are mostly neutrophils that wander in the blood and can pass through capillary walls to reach trauma sites

MQ are highly phagocytic cells called wandering MQ’s b/c of their ability to migrate

Fixed MQ’s (histiocytes) enter tissue/organs and remain there (I.e. Kupffer cells in the liver)

phagocytosis
PHAGOCYTOSIS
  • Chemotaxis
  • Adherence
  • Ingestion
  • Digestion
avoiding contact with phagocytes
Avoiding Contact with Phagocytes
  • Bacteria can avoid the attention of phagocytes in a number of ways
  • Pathogens may invade or remain confined in regions inaccessible to phagocytes. Certain internal tissues (e.g. the lumens of glands, the urinary bladder) and surface tissues (e.g. the skin) are not patrolled by phagocytes.
  • Some pathogens are able to avoid provoking an overwhelming inflammatory response. Without inflammation the host is unable to focus the phagocytic defenses.
slide39
Some bacteria or their products inhibit phagocyte chemotaxis

For example, Streptococcal streptolysin suppresses neutrophil chemotaxis, even in very low concentrations

Fractions of Mycobacterium tuberculosis are known to inhibit leukocyte migration.

slide40
Some pathogens can cover the surface of the bacterial cell with a component which is seen as "self" by the host phagocytes and immune system. Such a strategy hides the antigenic surface of the bacterial cell.
  • Phagocytes cannot recognize bacteria upon contact and the possibility of opsonization by antibodies to enhance phagocytosis is minimized.
  • Staphylococcus aureus produces cell-bound coagulase which clots fibrin on the bacterial surface
  • Treponema pallidum, the agent of syphilis, binds fibronectin to its surface.
  • Group A streptococci are able to synthesize a capsule composed of hyaluronic acid. Hyaluronic acid is the ground substance (tissue cement) in connective tissue.
chemotaxis
CHEMOTAXIS
  • Chemical attraction of phagocyte to microorganism
    • Microbial products
    • Damaged tissue
    • White blood cell components
adherence engulfment ingestion
ADHERENCE & ENGULFMENT (INGESTION)
  • Attachment of phagocyte plasma membrane to microorganism
ingestion
INGESTION
  • Pseudopods extend from phagocyte plasma membrane and engulf the microorganism forming the phagosome
slide44
A pathogen is only a pathogen if it “tricks” the immune system’s defense missiles (phagocytes)
inhibition of phagocytic engulfment
Inhibition of Phagocytic Engulfment
  • Some bacteria employ strategies to avoid engulfment (ingestion) if phagocytes do make contact with them
  • Many important pathogenic bacteria bear on their surfaces substances that inhibit phagocytic adsorption or engulfment
  • Clearly it is the bacterial surface that matters
  • Resistance to phagocytic ingestion is usually due to a component of the bacterial cell surface (cell wall, or fimbriae, or a capsule).
classical examples of antiphagocytic substances on the bacterial surface include
Classical examples of antiphagocytic substances on the bacterial surface include
  • Polysaccharide capsules of S. pneumoniae, Haemophilus influenzae, Treponema pallidum and Klebsiella pneumoniae
  • M protein and fimbriae of Group A streptococci
  • Surface slime (polysaccharide) produced as a biofilm by Pseudomonas aeruginosa
  • O polysaccharide associated with LPS of E. coli
  • K antigen (acidic polysaccharides) of E. coli or the analogous Vi antigen of Salmonella typhi
digestion
DIGESTION
  • Within cytoplasma the phagosome fuses with lysosome (digestive enzymes) forming the phagolysosome
lysosome contents
Lysozyme

Lipases

Proteases

Hypochlorous acid

Toxic O2

Nucleases

LYSOSOME CONTENTS
survival inside of phagocytes
Survival Inside of Phagocytes

Some bacteria survive inside of phagocytic cells, in either neutrophils or macrophages

Bacteria that can resist killing and survive or multiply inside of phagocytes are considered intracellular parasites

In this case, the environment of the phagocyte may be a protective one, protecting the bacteria during the early stages of infection or until they develop a full complement of virulence factors

The intracellular environment guards the bacteria against the activities of extracellular bactericides, antibodies, drugs, etc.

slide51
Many intracellular parasites have special (genetically-encoded) mechanisms to get themselves into host cells that are nonphagocytic
  • Intracellular pathogens such as Yersinia, Listeria, Salmonella, Shigella and Legionella possess complex machinery for cellular invasion and intracellular survival
  • These systems involve various types of non-toxin virulence factors
  • Sometimes these factors are referred to as bacterial invasins
  • Still other bacteria such as Bordetella pertussis and Streptococcus pyogenes, have recently been discovered in the intracellular habitat of epithelial cells
slide52
Intracellular parasites survive inside of phagocytes by virtue of mechanisms which interfere with the bactericidal activities of the host cell.
prevention of phagosome and lysosome
PREVENTION OF PHAGOSOME AND LYSOSOME
  • Replicate inside phagocyte
  • Shigella
  • Mycobacterium
slide54
Mycobacteria (including M. tuberculosis) have waxy, hydrophobic cell wall and capsule components (mycolic acids), which are not easily attacked by lysosomal enzymes
slide55
In Salmonella typhimurium, the pH that develops in the phagosome after engulfment actually induces bacterial gene products that are essential for their survival in macrophages.
killing of phagocyte
KILLING OF PHAGOCYTE
  • Toxins
  • Staphylococcus
    • Actinobacillus
slide57
B. abortus and Staphylococcus aureus are vigorous catalase and superoxide dismutase producers, which might neutralize the toxic oxygen radicals that are generated by systems in phagocytes
  • S. aureus produces cell-bound pigments (carotenoids) that "quench" singlet oxygen produced in the phagocytic vacuole
slide59
Escape from the phagosome
  • Early escape from the phagosome vacuole is essential for growth and virulence of some intracellular pathogens
slide60
This is a clever strategy employed by the Rickettsiae
  • Rickettsia enter host cells in membrane-bound vacuoles (phagosomes) but are free in the cytoplasm a short time later, perhaps in as little as 30 seconds
  • A bacterial enzyme, phospholipase A, may be responsible for dissolution of the phagosome membrane.
slide61
Listeria monocytogenes relies on several molecules for early lysis of the phagosome to ensure their release into the cytoplasm
  • These include a pore-forming hemolysin (listeriolysin O) and two forms of phospholipase C
  • Once in the cytoplasm, Listeria induces its own movement through a remarkable process of host cell actin polymerization and formation of microfilaments within a comet-like tail
killing phagocytes before ingestion
Killing Phagocytes Before Ingestion
  • Many Gram-positive pathogens, particularly the pyogenic cocci, secrete extracellular enzymes that kill phagocytes
  • Many of these enzymes are called hemolysins because their activity in the presence of red blood cells results in the lysis of the RBC
slide63
Extracellular proteins that inhibit phagocytosis include the Exotoxin A of Pseudomonas aeruginosa which kills macrophages
  • bacterial exotoxins (Bacillus anthrax toxin EF & Bordatella pertussis toxin AC) which decrease phagocytic activity
inflammation functions
INFLAMMATION FUNCTIONS
  • To destroy invading agents
  • Walling off invading agents
  • Repair or replace damaged tissue
vasodilatation increased permeability of blood vessels
Vasodilatation & Increased Permeability of Blood Vessels

-Vasodilatation is the 1st stage of inflammation

-It involves an increase in blood vessel diameters  more blood flow to the injured area

-Responsible for the redness, heat, edema (swelling), & pain of inflammation

-Histamine is released by injured cells & increases permeability of immune system cells to the site of injury

complement system

Serum

Blood clot

Blood

COMPLEMENT SYSTEM
  • 30 different serum proteins involved in:
    • Lysis (destruction) of foreign cells
    • Inflammation
    • Phagocytosis
complement system1
COMPLEMENT SYSTEM
  • Two cascade activation paths:
    • Classical (immune system)
      • Antibodies
    • Alternative
      • Interaction with Polysaccharides (mostly bacterial)
      • Protein C3 activates both the alternative & the classical pathway
slide71

Major components of the classical pathway are C1 and C9

  • Classical pathway is initiated by the binding of AB’s to Ag
  • Alternative pathway is initiated by the interaction of foreign particle with the protein factors (important in combating enteric G- MO)
slide74

Endotoxin (Lipid A) trigger the alternative pathway

  • The alternative pathway is often known as the lectin pathway
  • MQ interacting w/ the foreign particle stimulate the liver to secrete lectin, which assists in the opsonization of MO
slide75

What is opsonization?

  • Increases the susceptibility of microorganisms to ingestion by phagocytes
complement system inflammation
Complement system & inflammation
  • C5a is the most potent complement protein triggering inflammation
  • It causes mast cells to release vasodilators such as histamine so that blood vessels become more permeable
  • it increases the expression of adhesion molecules on leukocytes and the vascular endothelium so that leukocytes can squeeze out of the blood vessels and enter the tissue (diapedesis)
  • it causes neutrophils to release toxic oxygen radicals for extracellular killing; and it induces fever
complement system functions
COMPLEMENT SYSTEM FUNCTIONS
  • Cytolysis
    • Formation of membrane attack complexes by the complement proteins
    • Damage of plasma membrane
      • leakage and death of the cell
complement system functions1
COMPLEMENT SYSTEM FUNCTIONS
  • Inflammation
    • Triggers histamine release
      • Increased blood vessel permeability
      • Promotes migration of cells to site of inflammation
immunity
IMMUNITY
  • Specific response to foreign microorganisms or substances
      • Antibodies
      • Specialized lymphocytes (B and T)
antigens
ANTIGENS
  • Foreign substances or microorganisms that provoke an immune response
slide85

Types of immunity

Infection

Colostrum

Vaccines

Antiserum

colostrum
COLOSTRUM
  • Fluid rich in protein and immune factors, secreted by the mammary glands during the first few days of lactation
serum

Serum

Blood clot

Blood

SERUM
  • Fluid remaining after blood has clotted
  • Fluid where most antibodies are found
    • Antiserum
serology
SEROLOGY
  • The study of antibodies and antigens
immune system
IMMUNE SYSTEM
  • Humoral or antibody-mediated
    • B lymphocytes
  • Cell-mediated
    • T lymphocytes (TH & TC)
humoral immune response
HUMORAL IMMUNE RESPONSE
  • Against:
    • Bacteria
    • Bacterial toxins
    • Viruses outside of cells
cellular immune response
CELLULAR IMMUNE RESPONSE
  • Against:
    • Intracellular agents
    • Fungi
    • Protozoa
    • Helminths
    • Viruses inside cells
antigens1
ANTIGENS
  • Proteins
  • Polysaccharides
  • Lipids and nucleic acids only if combined with proteins or polysaccharides
epitopes or antigenic determinants
EPITOPES OR ANTIGENIC DETERMINANTS
  • Antibodies specifically combine with a small segment of the antigen called the antigenic determinant or epitope to form an antigen-antibody complex
  • The antigen-antibody reaction is characterized by specificity
hapten
HAPTEN
  • Small molecule that needs a large molecule carrier to behave as an antigen
  • Drugs and pesticides are low molecular weight molecules and can be treated as haptens
  • By conjugation to larger carrier molecules (albumin), low molecular weight drugs and pesticides can be made antigenic
  • Not antigenic unless attached to a carrier molecule
    • Penicillin
    • Penicillin binding to certain blood proteins (albumin) can become antigenic  Penicillin allergy
antibodies or immunoglobulins igs
ANTIBODIES OR IMMUNOGLOBULINS (Igs)
  • Y-shaped proteins made in response to an antigen
  • Antibodies specifically bind to that antigen by two antigen-binding sites
slide96

Receptor for

macrophages

immunoglobulin g igg
IMMUNOGLOBULIN G (IgG)
  • 80% of all Igs
  • Cross blood vessels and enter tissue fluids
  • Cross human placenta
immunoglobulin g igg cont
IMMUNOGLOBULIN G (IgG) (cont.)
  • Protects against circulating bacteria and viruses
  • Neutralizes bacterial toxins
  • Trigger the complement system
  • Facilitates phagocytosis
immunoglobulin m igm
IMMUNOGLOBULIN M (IgM)
  • 1st AB that appears in response to an AG—however their conc. declines rapidly
    • Used for diagnosis
  • 5-10% of all Igs
  • Pentamer (5 “Y”s) joined bya j chain
  • Do not cross placenta b/c too big
immunoglobulin m igm cont
IMMUNOGLOBULIN M (IgM) (cont.)
  • Predominant AB in the blood typing process rx
  • Hi IgM conc. Represents an active disease
  • Aggregates antigens
  • Triggers the complement system
  • Facilitates phagocytosis
  • Antigen receptor of B cell
slide102

IgM

pentamer

“J” chain

immunoglobulin a iga
IMMUNOGLOBULIN A (IgA)
  • 10 - 15% of all Igs
  • Most common in mucous membranes and body secretions
    • Mucus, saliva, tears and milk
immunoglobulin a iga cont
IMMUNOGLOBULIN A (IgA) (cont.)
  • Dimer (2 “Y”s) joined bya j chain
  • Prevents attachment (adherence) of pathogens to mucosal surfaces
slide105

IgA dimer

Secretory

component

“J” chain

immunoglobulin e ige
IMMUNOGLOBULIN E (IgE)
  • 0.002% of all Igs
  • Bind to mast cells and basophils
  • Involved in allergies
  • Effective against parasitic worms
immunoglobulin d igd
IMMUNOGLOBULIN D (IgD)
  • Structurally similar to IgG
  • Unknown function in serum
  • Antigen receptor on B cell surfaces
slide108

IgA

IgM

IgD

IgG

IgE

antigen antibody reaction
ANTIGEN-ANTIBODY REACTION
  • Neutralization
    • Viruses and toxins
  • Agglutination (clumping of AG &AB so phagocytes can ingest them better)
    • Bacterial cells
  • Precipitation
    • Soluble antigens
slide110

viruses

(b) Neutralization of viruses by antibodies

No access to cell receptors

immune system1
IMMUNE SYSTEM
  • Humoral or antibody-mediated
    • B lymphocytes
  • Cell-mediated
    • T lymphocytes
b cells and humoral immunity
B CELLS AND HUMORAL IMMUNITY
  • Stem cells in bone marrow
    • Adults
  • Liver
    • Fetuses
slide118

Activated B cell (Lymphocyte)

Memory

cells

Plasma cells

(Igs-producing)

clonal deletion
CLONAL DELETION
  • During fetal development, clones of lymphocytes that react with self antigens are eliminated (self-tolerance)
plasma cells
PLASMA CELLS
  • Secrete antibodies (Igs) against specific antigens
  • Short lived
  • Produce 2000 antibodies per second
t cell mediated immunity
T-CELL MEDIATED IMMUNITY
  • Derived from stem cells
    • Adults
      • Bone marrow
    • Fetuses
      • Liver
t cell mediated immunity cont
T-CELL MEDIATED IMMUNITY (cont.)
  • Mature and differentiate in thymus
  • Mature T cells migrate to lymphoid organs
t cell mediated immunity cont1
T-CELL MEDIATED IMMUNITY (cont.)
  • Clonal selection determines proliferation of T cells that carry out cell-mediated immunity
  • Respond only to antigens presented by macrophages
types of t cells
TYPES OF T CELLS
  • Cytotoxic (TC) CD8
    • Kill altered cells
  • Helper (TH) CD4
    • Activate B, TH, and TC cells
types of t cells cont
TYPES OF T CELLS (cont.)
  • Delayed Hypersensitivity (TD) CD4 and CD8
    • Anti-cancer, allergies
  • Suppressor (TS) CD4 and CD8
    • Suppress immune response
natural killer nk cells
NATURAL KILLER (NK) CELLS
  • Non-T lymphocytes
  • Not specific
  • Kill altered cells
cytokines interleukins
CYTOKINES (INTERLEUKINS)
  • Chemical messengers of the immune system
    • Interleukin-1
      • Stimulates TH cells
    • Interleukin-2
      • Proliferation of TH cells
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