NONSPECIFIC DEFENSES OF THE HOST

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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
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)

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

Innate Immune System comprises of a

Cellular arm (cells)
and a Humoral arm (soluble factors)

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

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

DEFENCE AGAINST INFECTION

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

NONSPECIFIC RESISTANCE • Defenses that protect the host against ANY pathogen – Mechanical factors – Chemical factors

Specific Resistance
Specific Resistance, or immunity is based on antibody production It is a defense against a particular microorganism

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)

• Dermis – Inner thicker portion • Epidermis – Outer, thinner portion • Keratin (waterproofing)

SKIN

SKIN INFECTIONS
• Rare in unbroken skin • Sweat washes microbes off • Cuts and burns may get infected –Subcutaneous infections –Staphylococcus spp.

MUCOSAL SURFACES
• Epithelial layer • Connective tissue

Bronchi

Intestine

MUCOSAL SURFACES (cont.)
•Gastrointestinal tract •Respiratory tract •Urinary tract •Reproductive tract

MUCOSAL SURFACES (cont.) • Mucus traps microorganisms • Physical barrier • Cilia lower respiratory tract • Washing (sweat)

MUCOSAL SURFACES (cont.) • Mucosal irritation or damage facilitates infection (smoking) • Substances produced by pathogens –Treponema pallidum

• Prevents colonization –Tears (lysozyme—breaks down NAG/NAM) –Saliva –Urine –Feces –Sebum (unsaturated fatty acids of
sebum inhibit growth of certain pathogens)

Flushing of Cavities

CHEMICAL FACTORS

• Skin –Sebaceous glands •Unsaturated fatty acids •pH 3-5

LYSOZYME

• Enzyme that degrades peptidoglycans –Gram positives more susceptible than Gram negatives

LYSOZYME (cont.) • Sweat • Saliva • Tears • Nasal secretions

GASTRIC JUICE
• Hydrochloric acid (pH 1.2 to 3) –Helicobacter pylori •Neutralizes acidic pH • Enzymes • Mucus

BLOOD
• Iron-binding proteins –Lactoferrins –Transferrins • Iron unavilable for pathogens

DEAD TISSUE leads to INFECTION

Mechanical, chemical or thermal injury Debride wounds
Interruption of blood supply – infarction

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

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

SPECIFIC IMMUNITY
For each different antigen there is a specific receptor

1011 different antigens
1 2 3 4

1011 different receptors
1 2 3 4

Exposure to infection •Climate •Vectors •Population •Housing •Water / sewage •Public health •Mutation

Resistance to infection •Age •Previous exposure •Vaccination •Nutrition •Disease •immunodeficiency

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
--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)

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 • Neutrophils (60-70%) –Initial phagocytic cells • Monocytes/Macrophages (38%) –Final phagocytic cells

Granulocytes

Eosinophil (0-2%) Neutrophils (45-74%) In Blood

Eosinophils Target – Worms and flukes Filarial Nematode Larvae

Wucheria bancrofti

Migrates within tissues

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 • Chemotaxis • Adherence • Ingestion • Digestion

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.

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.

• 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

CHEMOTAXIS
• Chemical attraction of phagocyte to microorganism –Microbial products –Damaged tissue –White blood cell components

ADHERENCE & ENGULFMENT (INGESTION)
• Attachment of phagocyte plasma membrane to microorganism

INGESTION

• Pseudopods extend from phagocyte plasma membrane and engulf the microorganism forming the phagosome

A pathogen is only a pathogen if it ―tricks‖ the immune system’s defense missiles (phagocytes)

• 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).

Inhibition of Phagocytic Engulfment

• 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

Classical examples of antiphagocytic substances on the bacterial surface include

DIGESTION

• Within cytoplasma the phagosome fuses with lysosome (digestive enzymes) forming the phagolysosome

LYSOSOME CONTENTS
• Lysozyme • Hypochlorous acid • Lipases • Toxic O2 • Proteases • Nucleases

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.

BACTERIAL INTRACELLULAR PATHOGENS Organism Disease Mycobacterium tuberculosis Mycobacterium leprae Listeria monocytogenes Salmonella typhi Shigella dysenteriae Tuberculosis Leprosy Listeriosis Typhoid Fever Bacillary dysentery

Yersinia pestis Brucella species Legionella pneumophila Rickettsiae
Chlamydia

Plague Brucellosis Pneumonia Typhus; Rocky Mountain Spotted Fever Chlamydia; Trachoma

• 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

• 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
• Replicate inside phagocyte • Shigella • Mycobacterium

• Mycobacteria (including M. tuberculosis) have waxy, hydrophobic cell wall and capsule components (mycolic acids), which are not easily attacked by lysosomal enzymes

• 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 • Toxins • Staphylococcus –Actinobacillus

• 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

• Escape from the phagosome • Early escape from the phagosome vacuole is essential for growth and virulence of some intracellular pathogens

• 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.

• 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 • 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

• 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

• A localized protective response of the body to tissue injury –Pain –Heat –Redness –Swelling –Loss of function

INFLAMMATION

INFLAMMATION FUNCTIONS • To destroy invading agents • Walling off invading agents • Repair or replace damaged tissue

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

THE COMPLEMENT SYSTEM part II

• 30 different serum proteins involved in: –Lysis (destruction) of foreign cells –Inflammation –Phagocytosis Serum Blood clot

COMPLEMENT SYSTEM

Blood

• Two cascade activation paths: –Classical (immune system) •Antibodies –Alternative •Interaction with Polysaccharides (mostly bacterial) •Protein C3 activates both the alternative & the classical pathway

COMPLEMENT SYSTEM

•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)

Classical pathway

Alternative pathway

•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

What is opsonization?
• Increases the susceptibility of microorganisms to ingestion by phagocytes

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
• Cytolysis –Formation of membrane attack complexes by the complement proteins –Damage of plasma membrane • leakage and death of the cell

COMPLEMENT SYSTEM FUNCTIONS
• Inflammation –Triggers histamine release • Increased blood vessel permeability • Promotes migration of cells to site of inflammation

(Humoral) classical pathway

Alternative pathway

SPECIFIC DEFENSES OF THE HOST: THE IMMUNE RESPONSE

IMMUNITY • Specific response to foreign microorganisms or substances –Antibodies –Specialized lymphocytes (B and T)

ANTIGENS

• Foreign substances or microorganisms that provoke an immune response

Types of immunity
Acquired immunity

Natural

Artificial

Active

Passive

Active

Passive

Infection Colostrum Vaccines Antiserum

COLOSTRUM

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

SERUM • Fluid remaining after blood has clotted • Fluid where most antibodies are found –Antiserum
Blood
Serum Blood clot

SEROLOGY

• The study of antibodies and antigens

IMMUNE SYSTEM
• Humoral or antibodymediated –B lymphocytes • Cell-mediated –T lymphocytes (TH & TC)

HUMORAL IMMUNE RESPONSE • Against: –Bacteria –Bacterial toxins –Viruses outside of cells

• Against: –Intracellular agents –Fungi –Protozoa –Helminths –Viruses inside cells

CELLULAR IMMUNE RESPONSE

ANTIGENS

• Proteins • Polysaccharides • Lipids and nucleic acids only if combined with proteins or polysaccharides

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
• 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) • Y-shaped proteins made in response to an antigen • Antibodies specifically bind to that antigen by two antigen-binding sites

Receptor for macrophages

CLASSES OF IMMUNOGLOBULINS • IgG • IgM • IgA • IgD • IgE

IMMUNOGLOBULIN G (IgG) –80% of all Igs –Cross blood vessels and enter tissue fluids –Cross human placenta

IMMUNOGLOBULIN G (IgG) (cont.) • Protects against circulating bacteria and viruses • Neutralizes bacterial toxins • Trigger the complement system • Facilitates phagocytosis

• 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 by a j chain • Do not cross placenta b/c too big

IMMUNOGLOBULIN M (IgM)

• 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

IMMUNOGLOBULIN M (IgM) (cont.)

IgM pentamer

―J‖ chain

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.) • Dimer (2 ―Y‖s) joined by a j chain • Prevents attachment (adherence) of pathogens to mucosal surfaces

IgA dimer
Secretory component

―J‖ chain

IMMUNOGLOBULIN E (IgE) • 0.002% of all Igs • Bind to mast cells and basophils • Involved in allergies • Effective against parasitic worms

IMMUNOGLOBULIN D (IgD) • Structurally similar to IgG • Unknown function in serum • Antigen receptor on B cell surfaces

IgM

IgA

IgG

IgE

IgD

• Neutralization –Viruses and toxins • Agglutination (clumping of AG &AB so phagocytes can ingest them better) –Bacterial cells • Precipitation –Soluble antigens

ANTIGEN-ANTIBODY REACTION

viruses (b) Neutralization of viruses by antibodies No access to cell receptors

IMMUNE SYSTEM

• Humoral or antibodymediated –B lymphocytes • Cell-mediated –T lymphocytes

B CELLS AND HUMORAL IMMUNITY • Stem cells in bone marrow –Adults • Liver –Fetuses

CLONAL SELECTION OF B CELLS

Activated B cell (Lymphocyte)

Memory cells

Plasma cells (Igs-producing)

CLONAL DELETION

• During fetal development, clones of lymphocytes that react with self antigens are eliminated (self-tolerance)

PLASMA CELLS

• Secrete antibodies (Igs) against specific antigens • Short lived • Produce 2000 antibodies per second

T-CELL MEDIATED IMMUNITY • Derived from stem cells –Adults •Bone marrow –Fetuses •Liver

T-CELL MEDIATED IMMUNITY (cont.) • Mature and differentiate in thymus • Mature T cells migrate to lymphoid organs

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

• Cytotoxic (TC) CD8 –Kill altered cells • Helper (TH) CD4 –Activate B, TH, and TC cells

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 • Non-T lymphocytes • Not specific • Kill altered cells

CYTOKINES (INTERLEUKINS) • Chemical messengers of the immune system –Interleukin-1 •Stimulates TH cells –Interleukin-2 •Proliferation of TH cells


				
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