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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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Nonspecific defenses of the host
NONSPECIFIC DEFENSES OF THE HOST


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


Nonspecific defenses of the host

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)


  • Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    Innate Immune System comprises

    of a

    Cellular arm(cells)

    and

    a

    Humoral arm (soluble factors)


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    • 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


    Nonspecific defenses of the host


    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)


    Nonspecific defenses of the host
    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


    Nonspecific defenses of the host

    DEAD TISSUE leads to INFECTION

    Mechanical, chemical or thermal injury

    Debride wounds

    Interruption of blood supply – infarction


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    • 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


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    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)


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    Granulocytes

    Eosinophil

    (0-2%)

    Neutrophils

    (45-74%)

    In Blood


    Nonspecific defenses of the host

    Eosinophils Target – Worms and flukes

    Filarial Nematode Larvae

    Wucheria bancrofti

    Migrates within tissues


    Nonspecific defenses of the host

    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 and can pass through capillary walls to reach trauma sites

    • Chemotaxis

    • Adherence

    • Ingestion

    • Digestion


    Avoiding contact with phagocytes
    Avoiding Contact with Phagocytes and can pass through capillary walls to reach trauma sites

    • 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.


    Nonspecific defenses of the host

    Some bacteria or their products and can pass through capillary walls to reach trauma sitesinhibit phagocyte chemotaxis

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

    Fractions of Mycobacterium tuberculosis are known to inhibit leukocyte migration.


    Nonspecific defenses of the host

    • 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 with a component which

    • Chemical attraction of phagocyte to microorganism

      • Microbial products

      • Damaged tissue

      • White blood cell components


    Adherence engulfment ingestion
    ADHERENCE & ENGULFMENT (INGESTION) with a component which

    • Attachment of phagocyte plasma membrane to microorganism


    Ingestion
    INGESTION with a component which

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


    Nonspecific defenses of the host

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


    Inhibition of phagocytic engulfment
    Inhibition of Phagocytic Engulfment 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).


    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 bacterial surface include

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


    Lysosome contents

    Lysozyme bacterial surface include

    Lipases

    Proteases

    Hypochlorous acid

    Toxic O2

    Nucleases

    LYSOSOME CONTENTS


    Survival inside of phagocytes
    Survival Inside of Phagocytes bacterial surface include

    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.


    Nonspecific defenses of the host

    BACTERIAL INTRACELLULAR PATHOGENS bacterial surface include


    Nonspecific defenses of the host

    • 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


    Nonspecific defenses of the host


    Prevention of phagosome and lysosome
    PREVENTION OF PHAGOSOME AND LYSOSOME virtue of mechanisms which interfere with the bactericidal activities of the host cell.

    • Replicate inside phagocyte

    • Shigella

    • Mycobacterium


    Nonspecific defenses of the host

    • Mycobacteria (including virtue of mechanisms which interfere with the bactericidal activities of the host cell. M. tuberculosis) have waxy, hydrophobic cell wall and capsule components (mycolic acids), which are not easily attacked by lysosomal enzymes


    Nonspecific defenses of the host

    • In virtue of mechanisms which interfere with the bactericidal activities of the host cell. 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 virtue of mechanisms which interfere with the bactericidal activities of the host cell.

    • Toxins

    • Staphylococcus

      • Actinobacillus


    Nonspecific defenses of the host

    • B. abortus virtue of mechanisms which interfere with the bactericidal activities of the host cell. 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


    Nonspecific defenses of the host

    • Escape from the phagosome virtue of mechanisms which interfere with the bactericidal activities of the host cell.

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


    Nonspecific defenses of the host

    • This is a clever strategy employed by the Rickettsiae virtue of mechanisms which interfere with the bactericidal activities of the host cell.

    • 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.


    Nonspecific defenses of the host

    • Listeria monocytogenes virtue of mechanisms which interfere with the bactericidal activities of the host cell. 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 virtue of mechanisms which interfere with the bactericidal activities of the host cell.

    • 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


    Nonspecific defenses of the host


    Inflammation

    A localized protective response of the body to tissue injury

    Pain

    Heat

    Redness

    Swelling

    Loss of function

    INFLAMMATION


    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


    Nonspecific defenses of the host




    Nonspecific defenses of the host


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    Receptor for

    macrophages


    Classes of immunoglobulins
    CLASSES OF IMMUNOGLOBULINS

    • IgG

    • IgM

    • IgA

    • IgD

    • IgE


    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


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    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


    Nonspecific defenses of the host

    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



    Nonspecific defenses of the host

    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