The Innate Immune System by xor16863


									                                                     Mechanical Barriers to
                                                      •Skin epithelial cells joined by
The Innate Immune System                               tight junctions
                                                      •Intestinal epithelium
                                                      •Longitudinal flow of air or
                                                       fluid across epithelium
                                                      •Constant flushing of the
                                                       urinary bladder
                              Jan 19, 2005

     Substances that inhibit
        microbial growth                              Acute Phase Response
• Lysozyme in the blood, saliva, sweat,        • The acute phase response involves a
                                                   shift in the proteins secreted by the
• Acidic pH in stomach                             liver into the blood plasma.
• Digestive enzymes, pepsin in the stomach     •   In the acute phase response, levels of
• Antibacterial peptides (defensins) in            some plasma proteins go down, while
                                                   levels of others increase. It occurs in
• Friendly flora in gut, reproductive tract,       response to infection, burns, trauma,
  skin,intestine compete for attachment
  and nutrients, and themselves can                and neoplasia.
  produce anti-microbial substances

      Acute Phase Response                            Acute Phase Response
 • TNF, IL-1, and IL-6 are produced by         • TNF and IL-1 induce haptocytes to
   activated macrophages (including                produce one set of acute phase
   Kupfer cells in the liver), i.e.,               proteins including serum amyloid
   macrophages that have been                      protein.
   stimulated by LPS, C5a, or                  •   IL-6 induces another set including
   chemokines.                                     fibrinogen, C-reactive protein,
                                                   mannose-binding protein.

IL -6 a n d T N F
               L IV E R                                                                      Tumor Necrosis Factor
                                                A c u te p h a s e p ro te in s
                                             S e r u m a m y lo id p ro te in          • TNFα (cachetin) is selectively cytotoxic
                                                     C -re a c t iv e p ro te in
                                                                 F ib r in o g e n         for many tumor cells. Secreted by
                                           M a n n o s e -b in d in g p ro te in           macrophages, monocytes, T and B
               B one M arrow

                                             N e u t ro p h il m o b iliz a t io n
                                                                                           TNFβ (lymphotoxin, LTa) 35% homologous
                                                              P h a g o c y to s is        with TNFα. Important as a mediator of
               H y p o tha la m us
                                                                                           inflammation. Sources are T and B

               L y m p h o c y te s
                                      I n c re a s e d B o d y T e m p e ra t u re
                                                                                       •   Each binds to TNF-RI and TNF-RII
                                                     I n c re a s e a c tiv a t io n
                                                   D e c re a s e d v ira l a n d
                                                   b a c te r ia l re p lic a t io n

         Acute Phase Proteins
• Two acute phase proteins are important                                                      Acute Phase Proteins
    because they mimic the action of
    antibodies.                                                                        • C-reactive protein, mannose-binding
•   The acute phase protein, C-reactive                                                    protein.
    protein, binds to phosphorylcholine on                                             • These two acute-phase proteins
    microbial surfaces (and not mammalian
                                                                                           mimic some of the properties of
    cells) to opsonize the microbe, and initiate
    the complement cascade.                                                                antibodies before an antibody
                                                                                           response has a chance to become
•   A second protein, mannose-binding
    protein , is a calcium-dependent lectin                                                established.
    that binds to mannose moieties on
    bacterial surfaces.

      CRP -Acute Phase Proteins                                                                   Contact System
                                                                                       • Inflammation can be activated by the
                                                                                           Contact System, solid, anionic surface
                                                                                           can initiate a cascade of events
                                                                                           leading to inflammation.
                                                                                       •   Synthetic or foreign materials that
                                                                                           can incite this response include: glass,
                                                                                           plastics, dextran sulfate,
                                                                                           carrageenan, and cellulose sulfate.

           Contact System                                   Contact System
• Naturally occurring substances             •   The end results of the liberation of bradykinin
                                                 by the kallikrein-kinin system include
    include:                                     constriction of:
    • sodium urate (the inciting                  • uterine and gastrointestinal smooth muscle,
      metabolite of gout);                        • constriction of coronary and pulmonary
    • calcium pyrophosphate crystals
                                                    vasculature, mucosal inflammation,
                                                  • bronchoconstriction, edema,
      (pseudogout);                               • hypotension, flushing, pain, and rhinitis.
    • homocysteine (homocystinuria).

                                                        Complement Pathway
           Physical Trauma
• If Mast Cells are damaged or                   • Complement components may become
    activated, they release Histamine.               activated by two pathways:
•   This causes vascular endothelial cells       •   the classical complement pathway,
    to become permeable to plasma fluids.            and
•   Extravasation                                •   the alternative (or properdin)

        Complement Pathway .
                                                        Complement Pathway

                                                 •See handout on the
                                                     complement system.

• The inflammatory response results in:        Inflammation
• the leakage of fluids into the
    extravascular space (edema);               • A primary activity of the
•   The leakage of macromolecules such             inflammatory response is often to
    as fibrinogen and formation of an              activate neutrophils--and to cause
    extravascular matrix (induration);             them to migrate from the blood
                                                   vasculature to the extravascular
•   The migration of cells (primarily              tissues.
    neutrophils) from the postcapillary
    venules to the extravascular space
    (extravasation).                           • The absence of neutrophils is
                                                   essentially incompatible with life.

              Neutrophils                                    Neutrophils

                                               • Neutrophils are distinct from other
                                                   white blood cells, because of the
                                                   presence of enzyme containing
                                                   granules in the cytoplasm.
                                               •   There are about 3 to 6 x 103
                                                   neutrophils present per milliliter of
                                               •   Each day 1011 neutrophils are released
                                                   into the bloodstream.

              Neutrophils                                    Neutrophils
                                          •   Some chemoattractants that stimulate neutrophils
• An important element in the                 • products of the complement system (specifically
    normal attack of the neutrophil is        • formyl-methionyl-leucyl-phenylalanine (FMLP),
    chemotaxis because it allows the          • antigen-antibody complexes,
    phagocytic cell to come into close        • bacterially derived factors (LPS),
    proximity with the                        • products from the lymphocyte series (MAF),
                                                Interleukin 8 (IL8),
    microorganism, abnormal cell, or
                                              • products of arachadonic acid specifically
    necrotic tissue, to allow for cell          Leukotriene B4, and
    killing and digestion.                    • Platelet Activating Factor (PAF).

                 Neutrophils                                        Neutrophils

• On the surface of the neutrophil plasma          • There are two different types of granules
    membrane are opsonins                              which are distinct from one another on the
    • such as C3b (a complement component) or          basis of enzyme content, morphology, and
    • the Fc portion of immunoglobulins.               phase in which they emerge during
• When these receptors are engaged by                  neutrophil maturation.
    opsonized bacteria, the membrane               •   The two types are the azurophilic granules
    invaginates and forms a phagosome.                 and the specific granules.

    Azurophilic granules                                      Azurophilic granules

                                                   • Some of the enzymes released by the
• Comprise one third of all mature granules            azurophilic granule include
    and are not synthesized in the later stages    •   myeloperoxodase (MPO),
    of neutrophil maturation.
                                                   • elastase,
•   They are predominantly microbicidial and
                                                   • neutral proteases,
    digestive in function with their enzymes
    working                                        • lysozyme, and
                                                   • several acid hydrolases.

           Azurophilic granules
• Myeloperoxidase: is a abundant granular
    enzyme (accounts for 5% of dry weight of
    the neutrophil).

• This enzyme combines hydrogen peroxide
    with chloride ions to form hypochlorous acie

           Azurophilic granules                            Azurophilic granules

                                                 • Lysozyme: like MPO is a microbicidial
• Elastase: is a serine protease which           • Lysozyme digests debris from cell walls of
    specifically hydrolyzes elastin.                 bacteria that have already been processed
•   Elastin is the major component of elastic        by other enzymes.
    fibers whcih stretch in the walls of blood   •   Another function of lysozyme is to modulate
    vessels, lungs, and ligaments.                   inflammation by suppressing neutrophil
                                                     chemotaxis and oxidative metabolism.

                                                        •Macrophages are Phagocytic
     • Endothelial cell,                                •They express Fc Receptors and
     • Kupfer cells,                                     receptors for complement
     • histiocytes,                                      components
     • microglia,                                       •They can fuse to become
     • alveolar macrophages, and                         multinucleated giant cells
     • multinucleate phagocytes in the bone             •Macrophages can secrete anti-
       are called osteoclasts.                           microbial substances such as
                                                         reactive oxygen species, nitric
                                                         oxide, and prostaglandins.

                Macrophage                                       Macrophage
     The scavenger function of
      macrophages prevents the
      contents of dying cells from
      causing damage or inflammation,                     •Macrophages produce
      in fact, macrophages are so                          cytokines such as: IFN;
      effective it is hard to find dead
      cells in healthy tissue--even in                     TNF; IL-1; IL-6;
      locations such as the thymus                        •Chemokines such as IL-8.
      where 98% of the cells die
      before leaving.

                                                    Adhesion Proteins
  • Macrophages serve as antigen           The majority of adhesion molecules fall
    presenting cells to activate T cells     into one of four families;
  • Activated T cells secrete cytokines    • cadherins.
    that activate most or all of the
    above functions of macrophages.        • integrins,
  • Thus, the T cells and macrophages      • immunoglobulin superfamily (IgSF),
    stimulate each other and this          • selectins
    greatly amplifies an immune

           CADHERINS                                    CADHERINS
                                           • There is strong evidence to suggest
• They play a fundamental role in              that cadherins may be involved in
 maintaining the integrity of                  invasion and metastasis of tumor
 multicellular structures and                  cells.

• areimportant in the diapedesis of
                                           •    Finally, cadherins may play a role in
                                               intercellular signalling due to the
 lymphocytes and neutrophils                   discovery of kinases regulating
                                               cytoplasmic cadherin phosphorylation.

         Adhesion Proteins
The majority of adhesion molecules
 fall into one of four families;
• cadherins.
• integrins,
• immunoglobulin   superfamily (IgSF),
• selectins

              Names     expressed by   bind to              INTEGRINS
                                                 Important roles:      • tumor metastasis,
                                                 • platelet            • tissue migration
                                                   aggregation,            during
                                                 • inflammation,       •   signalling
                                                 • immune                  pathways,
                                                   function,               transmitting
                                                 • wound healing,          signals both into
                                                                           and out from cells

          INTEGRINS                                         INTEGRINS
Lymphocyte function-associated                   • Expression of the β1 integrins
 antigen-1 (LFA-1, CD11a/CD18).                   increases significantly late in T-cell
                                                  activation, and they are thus often
This is thought to be the most                    called VLA for very late antigen and
 important adhesion molecule for                  play an important part in directing
 lymphocyte activation as antibodies              armed effector T cells to their target
 to LFA-1 effectively inhibit the                 tissues.
 activation of both naive and armed
 effector T cells.

          INTEGRINS                                     Adhesion Proteins
• Leukocyte  adhesion deficiency (LAD)           The majority of adhesion molecules
 is a rare inherited disorder in which            fall into one of four families;
 key functions of leukocytes are                 • cadherins.
 impaired, notably the migration of
 neutrophils to sites of extravascaular
                                                 • integrins,
 inflammation                                    • immunoglobulin   superfamily (IgSF),
                                                 • selectins

                                               IMMUNOGLOBULIN SUPERFAMILY
                                               NAMES               Expressed by          Bind to

• IgSF members are widely utilized in      •   CD2 (LFA-2)           T-cells                LFA-3
 two areas involving complex               •   ICAM-1 (CD54)         APCs, lymphocytes      LFA-1
 interactions among a diverse array of     •   ICAM-2 (CD102)        APCs, lymphocytes      LFA-1
 cell types;                               •   ICAM-3 (CD50)         APCs                   LFA-1
  • during nervous system                  •   LFA-3 (CD58)          APCs, lymphocytes      CD2
     development and                       •   VCAM-1 (CD106)        EC (activated)         VLA-4
  • in the regulation of the immune


                                               • ICAM-1     is expressed by antigen
                                                   presenting cells.
                                               •   Induced or upregulated by IFNγ, IL-
                                                   1β, TNFα and LPS.
                                               •   Ligands are CD11a/CD18,
                                    IgSF           CD11b/CD18, CD43 (mucin-like
                                                   vascular addressin).
                                               •   Adhesion is calcium dependent

       Adhesion Proteins
The majority of adhesion molecules                 • Are earliest expressed in
 fall into one of four families;                       inflammatory responses
                                                   •    Lead to neutrophil activation and
• cadherins.                                                   extravasation
• integrins,                                       •    L-selectin
• immunoglobulin   superfamily (IgSF),             •    E-selectin
• selectins                                        •    P-selectin
                                                   •    Bind to SLex of neutrophil

            • L-selectin   down regulated by IL-1

            • P-selectin up-regulated by thrombin,
             histamine, peroxides, TNF-α, IL-4,
             IL-1, and IFN-γ

            • E-selectin up-regualted IL-1β, TNFα
             and LPS



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