Mechanical Barriers to
IL -6 a n d T N F
               L IV E R                                                                      Tumor Necro...
Contact System                                   Contact System
• Naturally occurring substances             •   The end r...
• The inflammatory response results in:        Inflammation
• the leakage of fluids into the
Neutrophils                                        Neutrophils

• On the surface of the neutrophil plasma          • There...
Azurophilic granules                            Azurophilic granules

                                                 • L...
                                                    Adhesion Proteins
  • Macrophages serve as antigen         ...
              Names     expressed by   bind to              INTEGRINS
                                               NAMES               E...
            • L-selectin   down regulated by IL-1

            • P-selectin up-...
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The Innate Immune System


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Transcript of "The Innate Immune System"

  1. 1. Mechanical Barriers to microorganisms •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 tears 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 intestine 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. 1
  2. 2. 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 lymphoctyes. • 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 lymphocytes. 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. 2
  3. 3. 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) pathway. Complement Pathway . Complement Pathway •See handout on the complement system. 3
  4. 4. Inflammation • 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 blood. • 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 C5a), 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). 4
  5. 5. 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 • 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 (HOCl). 5
  6. 6. Azurophilic granules Azurophilic granules • Lysozyme: like MPO is a microbicidial enzyme. • 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. Macrophage Macrophage •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. 6
  7. 7. Macrophage 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 response. 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 INTEGRINS The majority of adhesion molecules fall into one of four families; • cadherins. • integrins, • immunoglobulin superfamily (IgSF), • selectins 7
  8. 8. INTEGRINS Names expressed by bind to INTEGRINS Important roles: • tumor metastasis, • platelet • tissue migration aggregation, during embryogenesis. • 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 8
  9. 9. IMMUNOGLOBULIN SUPERFAMILY 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 system IMMUNOGLOBULIN SUPERFAMILY IMMUNOGLOBULIN SUPERFAMILY • 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 SELECTINS 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 9
  10. 10. SELECTINS SELECTINS • 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 SELECTINS 10