Innate Immune System

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- Has two key roles:
1. It uses Pattern Recognition Receptors (PRRs):
• Recognize Pathogen-Associated Molecular Patterns (PAMPs) & Damage-
Associated Molecular Patterns (DAMPs)
• Include:
✓ Collectin:
❖ Globular lectin-like heads that can bind to sugars on microorganisms
❖ Long collagen-like tails that bind to phagocytes or complement
❖ Example: Mannan-Binding Lectin (MBL) + Surfactant
2. It activates other parts of the immune system & tissues throughout the
body
- :
1. SKIN:
• The skin is typical of innate immune system components in its ability to respond rapidly to stimulation
and activate and inform the adaptive immune response
• The dense outer layer of dead keratinocytes prevents penetration of these organisms into deeper tissues
• These keratinocytes if they are damaged ,secrete cytokines:
✓ InterLeukin 8 (IL-8)
✓ Tumor Necrosis Factor (TNF)
• Such cytokines are responsible for the inflammation
• Contains Langerhans cells:
✓ Sentinel cells of the dendritic cell lineage
✓ After exposure to microorganisms, these cells migrate to the local LN & present antigen to T cells
• Sebaceous gland: Produce sebum (acidic)
• Sweat gland: Secrete sweat (NaCl) which interfere with microorganisms growth
• Lacrimal gland: secrete tears, which contains lysosome that kill microorganisms
2. RESPIRATORY TRACT:
NOTE: TOBACCO Plant
• The UPPER respiratory tract:
when you grow it in soil
✓ Begins at the nose & ends in the bronchioles
, it will absorbed
✓ Protected by the MucoCiliary escalator:
radioactive uranium &
❖ Mucus:
radioactive balonium
 Secreted by goblet cells
 Traps microorganisms
NOTE: Smoking is the
 Mucus secretion is abnormal in:
most common cause
▪ Cystic fibrosis ➔ recurrent respiratory tract infections
of chronic obstructive
❖ Cilia:
lung disease
 Push the mucus toward the mouth & nose
 Then, trapped organisms are cleared by sneezing or coughing
 Destroyed by smoking (TOBACCO)
 Cilia are defective in:
▪ Primary ciliary dyskinesia ➔ recurrent respiratory tract infections

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 • The lower respiratory tract:
✓ Include terminal bronchioles & alveoli
✓ The main defenses here are surfactants:
❖ Secreted by type II pneumocytes.
❖ Mixture of proteins and phospholipids that prevent alveoli from collapsing during expiration
❖ Contain pathogen-binding proteins (members of the COLLECTIN family)
3. GastroIntestinal (GI) Tract
• The low pH (2) of the stomach:
✓ Is one of the main defenses against infection of the gut
✓ Achieved by gastric acid (HCl)
✓ Patients who are unable to secret gastric acid have a high risk for Salmonella infection
• The lower gut:
✓ colonized by trillions of bacteria
✓ These bacteria are normally harmless and inhibit the growth of pathogenic bacteria
• The gut epithelium also secretes Transformation Growth Factor beta (TGF-β)

• InterFeroNs (IFNs):
✓ Interferes with viral replication
✓ Double strand RNA (ds-RNA) is the strongest motivator for the production of IFN
✓ Type I IFN:
❖ Include: IFN-α and IFN-β
❖ Have more potent antiviral effects:
 Activation of two intracellular enzyme pathway that degrade the viral genome
 Inhibit transcription of viral mRNA
❖ Activate natural killer (NK) cells & macrophages
❖ Increased expression of MHC class I
❖ Secreted by a wide range of cells (e.g. epithelial cells lining the gut )
❖ Plasmacytoid dendritic cell (APC) ➔The most efficient producers of type I IFNs
❖ Recombinant IFN-α:
 Biopharmaceutical (aka a biologic medical product, or biologic)
 Used to Treat viral hepatitis, in combination with more conventional antiviral drugs
 Used to treat malignancies (most often chronic myeloid leukemia) by:
▪ Induce either apoptosis or maturation of malignant cells.
✓ Type II IFN:
❖ Include: IFN-γ:
 The only type II interferon in humans
 More potent at activating the TH1 arm of the adaptive immune response
• Complement proteins
✓ There are nine basic complement components, numbered C1 to C9.
✓ When they become activated, complement components are split into2 fragments
❖ Small fragment:
▪ Referred as C3a, C4a, etc...
▪ Act as chemotactic or Anaphylatoxins
❖ Large fragment:

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 ▪ Referred as C3b, C4b, etc...
▪ Act as enzyme
✓ Activation of Complement:
1. The lectin pathway
❖ Mannan-binding lectin (MBL) is a collectin that is able to bind mannose present on bacteria
❖ MBL collagen-like domain indirectly activates:
 C2 → C2a & C2b
 C4 → C4a & C4b
❖ C4b binds to C2b → C4b2b ; C3 convertase
❖ C4b2b (C3 convertase) activate:
 C3 → C3a & C3b
❖ C3b bind to C4b2b → C4b2b3b; C5 convertase
❖ C4b2b3b (C5 convertase) activate:
 C5 → C5a & C5b
❖ C5b bind to C6 , C7, C8 & C9 → Forms Membrane Attack Complex (MAC):
 Creates a pore in the plasma membrane
 This allows free passage of water and solutes across the membrane, killing the cell
2. The classical pathway (discovered first)
❖ Triggered by immune complexes of antibody & antigen
❖ Only 2 IgG or IgM can activate it
❖ C1 binds to the Fc portion of immunoglobulin (Ig):
 This is most likely to occur when an antigen binds several Ig molecules (more Fc potions)
 Because \IgM (pentamer) has 5 Fc portions; is particularly good at C1 binding
 C1 activate:
▪ C2 → C2a & C2b
▪ C4 → C4a & C4b
❖ C4b binds to C2b → C4b2b ; C3 convertase
❖ C4b2b (C3 convertase) activate:
 C3 → C3a & C3b
❖ C3b bind to C4b2b → C4b2b3b; C5 convertase
❖ C4b2b3b (C5 convertase) activate:
 C5 → C5a & C5b
❖ C5b bind to C6 , C7, C8 & C9 → Forms Membrane Attack Complex (MAC)
 creates a pore in the plasma membrane
 This allows free passage of water and solutes across the membrane, killing the cell
3. The alternative pathway
❖ Spontaneous activation of(cobra venom):
 C3 → C3a & C3b
 In normal cell:
▪ Express surface complement inhibitors that prevent spontaneous C3 activation
▪ OR C3b bind to Factor H → C3bH
➔ Factor I destroyed C3bH
 Pathogen lack surface complement inhibitors
❖ D-protein, split B protein into;
 Bb & Ba

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 ❖ C3b bind to Bb → C3bBb (C3 convertase)
❖ C3bBb; C3 convertase activate:
 C3 → C3a & C3b
❖ C3b binds to C3bBb → C3bBb3b; C5 convertase
❖ C3bBb3b (C5 convertase) activate:
 C5 → C5a & C5b
❖ C5b bind to C6 , C7, C8 & C9 → Forms Membrane Attack Complex (MAC):
 creates a pore in the plasma membrane
 This allows free passage of water and solutes across the membrane, killing the cell
✓ C3 is the KEY complement of the 3 pathways & has the largest concentration in serum
✓ Complement Regulators:
 In normal cell:
▪ Express surface complement inhibitors that prevent spontaneous C3 activation
▪ C1 inhibitor prevent C1 from activating C4 & C2
▪ OR C3b bind to Factor H → C3bH
➔ Factor I destroyed C3bH
✓ Complement act as Anaphylatoxins:
❖ C3a & C5a:
 Come from the complement activation
 Cause Mast cell degradation
 Consequences:
▪ Increase vessel permeability
▪ Increase Leukocyte adhesion
✓ Properdin:
❖ Stabilized C3 convertase
❖ Increase the time of complement activation
✓ Complement act as Chemotaxis:
❖ C5a:
 come from the complement activation
 Functions:
▪ Recruitment of Neutrophils
✓ Complement Receptors (CR):
❖ Present on a variety of cells & bind early complement components
❖ Epstein-Barr virus uses CR2 as its receptor to enter to B-cell
❖ Serve the following functions:
1. Opsonization:
 Facilitate the phagocytosis
 Opsonins:
▪ Molecules that enhance phagocytosis
▪ Include:
a) C3b: the most important opsonin
b) IgG

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 2. Immune complex clearance:
 Immune complexes
▪ = Antibody + Antigen
▪ Insoluble, so we need to remove it to avoid any disease
 Complement helps to remove immune complexes in two ways:
▪ Large insoluble complexes: high numbers of C3b interrupt the lattice of the immune
complex, making them soluble
▪ C4 & C3 present in solubilized immune complexes can bind to CR1 on red cells, which
transport the immune complexes to organs rich in fixed phagocytes (liver & spleen)
3. B-cell stimulation:
▪ Binding of C3 to the CR2 receptor on B cells provides co-stimulation & decreases the
threshold for B-cell activation a thousandfold
✓ Complement Deficiencies:
❖ Cause recurrent bacterial infection
❖ Deficiencies of the MAC lead to a specific higher risk for infection with Neisseria species
❖ Deficiencies in the early lectin & classic pathways cause type III hypersensitivity (immune
complex disease)
❖ Deficiency of early complement components can cause the autoimmune disease systemic
lupus erythematosus (SLE)
❖ Low levels of complement are more usually the result of consumption, rather than reduced
production, of complement components in the liver
❖ Complement is consumed when immune complexes are produced, such as during infections
or in autoimmune diseases

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- Triggered by the release of IL-1, IL-6 & TNF from macrophages:
• These increase the body temperature (fever), which impairs pathogen reproduction
• Induce production of C-Reactive Proteins (CRP):
✓ Protein produced in the liver that binds to phospholipids on the surface of bacteria
✓ Activates the complement system through the lectin pathway
✓ CRP production increases dramatically during inflammation
✓ Good indicator of inflammation (e.g. appendicitis)
✓ Also increased by noninfectious diseases, such as in the autoimmune disease rheumatoid arthritis
✓ Provides a good way of monitoring disease activity and response to treatment.
✓ Acts as an opsonin
- Erythrocyte Sedimentation Rate (ESR):
✓ Measuring the ESR is one of the simplest ways of showing an acute-phase response
✓ The ESR takes longer than CRP to become abnormal during an inflammatory response.
- Granulocyte-Colony Stimulating Factor (G-CSF):
• Produced during the acute-phase response
• Leads to a rapid increase in the production of neutrophils in the bone marrow
- The acute-phase cytokines also contribute to a general activation of the adaptive immune response

- C1 inhibitor:
• Inhibit complement activation
• Inhibits the production of bradykinin
- Autosomal-dominant disease
- Caused by deficiency of C1 inhibitor (complement inhibitor)
- The deficiency of C1 inhibitor ➔ Increase activation of complement & bradykinin
- The result is excessive amounts of C2a & bradykinin production that leads to increased capillary permeability at
any site, causing swelling that is painful and sometimes life threatening
- Txt: Purified C1 inhibitor can prevent & treat attacks of hereditary angioedema

Neutrophils (PMN) Monocytes → In the blood stream

Macrophages → In the tissue
Production - Produced from the same stem cells in the bone marrow
- Many more neutrophils than monocytes are produced each day
- Their production stimulated by colony-stimulating factors (CSFs)
Life cycle - Single mature form - Various mature forms depending on tissue
- Highly variable production, increase in infection - Produced at a steady level
- Blood levels vary, increase in infection - Blood levels steady
- Migrate only into inflamed tissue (not found in normal tissue) - Migrate into tissue when no inflammation is present
- Die a few hours after migrating into tissue & encountering - May survive many years after encountering pathogen
pathogen - APC

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 Killing of - Phagocytosis: Phagocytosis:
pathogens • A phagosome is formed by the ingestion of particulate • A phagosome is formed by the ingestion of
matter particulate matter
• Phagosome merge with lysosome to from • Phagosome merge with lysosome to from
Phagolysosome Phagolysosome
- Kill pathogens using: - Kill pathogens using:
1. Oxidative (respiratory) burst 1. Oxidative (respiratory) burst
✓ O2 → O2.- (by NADPH oxidase) ✓ O2 → O2.- (by NADPH oxidase)
✓ O2.- → H2O2 (by superoxide dismutase) ✓ O2.- → H2O2 (by superoxide dismutase)
✓ H2O2 → HOCl (by myeloperoxidase) ✓ H2O2 → HOCl (by myeloperoxidase)
2. Enzymes: 2. Enzymes
✓ In lysosome ✓ In lysosome
✓ The main enzymes present are proteolytic ✓ The main enzymes present are proteolytic
✓ Contained in granules 3. Defensins are low-molecular-weight peptides
3. Neutrophil Extracellular Traps (NETs): that punch holes in bacteria
✓ This may be helpful when the pathogen is either Too 4. Lactoferrin binds to iron, depriving bacteria of this
large or too numerous to be phagocytosed important nutrient.
✓ the neutrophil breaks down its own cell membrane - Do not produce NETs
and extrudes chromatin, a mixture of DNA and
histones
✓ The chromatin unravels to produce a trap that
physically captures pathogens.
✓ The toxic molecules and proteolytic enzymes are also
restricted by the NETs, & so the pathogens are
destroyed
4. Defensins are low-molecular-weight peptides that
punch holes in bacteria
5. Lactoferrin binds to iron, depriving bacteria of this
important nutrient.
Communication - Short-lived secretion of chemokines recruits more neutrophils - Recruit neutrophils to the site of inflammation by
with other parts to the site of inflammation secreting IL-8, TNF, & IL-1
of the immune - Respond to IL-17 from the adaptive immune system - Respond to IFN-γ from the adaptive immune system
system - Do not provide many signals to the adaptive immune system - Stimulate the adaptive immune system by presenting
processed antigen, providing co-stimulation, and
secreting cytokines such as IL-12 and TNF
RECRUITMENT - By interleukin 17 (IL-17) secreted by T-helper 17 (TH17) cells
- By IL-8 from macrophage
- By C5a
Inflammatory - Pyogenic (pus-forming) reaction: Short-lived response, with - Chronic inflammation
Signaling pus formation
- PUS: largely composed of dead neutrophils

1. Tissue Macrophages
• Large cells with specialized granules and cytoplasmic compartments that are found in a wide range of sites.
• In some tissues, such as bone marrow and lymph nodes, these active macrophages are referred to as
histiocytes
2. Giant & Epithelioid Cells:
• Multinucleated
• Found in sites of chronic inflammation
• Under the influence of T-cell cytokines
• Characteristic of granuloma formation
• Participate in prolonging the inflammatory response by presenting antigen to T cells & by secreting cytokines.

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3. Fixed Macrophages:
• Line sinusoids in the spleen & liver.
• In the liver, these macrophages are referred to as Kupffer cells.
• Their role is to phagocytose circulating particulate matter and, in some situations, to phagocytose entire cells
4. Alveolar Macrophages
• Found in lungs
• They are involved in disease processes such as chronic obstructive pulmonary disease (COPD)
5. Glial Cells
• Long-lived macrophages resident in the nervous system.
• They are involved in clearing dead neuronal cells
6. Osteoclasts:
• Found in the bone
• The most specialized macrophages
• Participate in regulating calcium metabolism by resorbing bone & releasing calcium into the blood.

1. Toll-Like Receptors
TLR Expressed on Ligand Associated Pathogen
TLR-2 Widespread Sugars and lipoproteins A wide range of bacteria
TLR-3 Dendritic cells, epithelial cells Double-stranded RNA Viruses
TLR-4 Macrophages LPS (TLR-4 forms a complex with CD14) Gram-negative bacteria
TLR-5 Macrophages Flagellae Wide range of motile
bacteria
TLR-7 Dendritic cells, macrophages Single-stranded RNA Viruses
TLR-9 Dendritic cells, B cells Unmethylated cytosine and guanine Bacteria
sequences (CpG)
2. C-Lectin Receptors
• Lectins are sugar-binding proteins
• The sugars are recognized by C-lectin receptors as sequences on glycolipids or glycoproteins on
pathogen cell surfaces or dying mammalian cells
• Binding of C-lectin receptors activates the macrophages that lead to cytokines production
4. Receptors for Complement
• Phagocytes can bind to complements to:
✓ Opsonization
✓ Clear immune complexes
5. Receptors for Immunoglobulin
• Phagocytes can recognize immunoglobulin G (IgG) through their Fc receptors
• IgG stimulates phagocytosis and thus acts as an opsonin

- X-linked, primary immunodeficiency that affects neutrophil function

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- Characterized by recurrent bacterial & fungal infections in the presence of neutrophilia
- It is caused by mutations in the genes for Nicotinamide Adenine Dinucleotide PHosphate (NADPH) oxidase
- Screen for CGD:
• Nitroblue Tetrazolium Tests:
✓ If the leukocyte can convert O2 to O2.- → Blue (normal)
✓ If the leukocyte can not convert O2 to O2.- → colurless (CGD)

- Derived from an unknown precursor cell in the bone marrow under the influence of the T-helper 2 (TH2) cytokines
interleukin (IL)-3 & IL-4
- Home into a range of normal tissues
- Recruitment to these frontline sites is increased during worm infestations
- Recognize Fc portion of IgE by Fc receptors (FcεRI)
- Become activated:
• When surface IgE molecules are cross-linked by antigen
• By anaphylatoxins C3a and C5a
• Recruit Eosinophils (have toxic compounds)
• Mast cell activation results in degranulation, release of preformed substances from the granule (e.g histamine)

- Same linage as T & B cells

- Has Fc receptor (FcγRIII or CD16 )
- Activated when the MHC is low
- Kill the virus-infected cells & tumor cells
- Very similar to Cytotoxic T Lymphocyte
- Kill the pathogens by antibody-dependent cellular cytotoxicity (ADCC)
• The virus is bound to IgG
• The CD16 of NK cell bind to Fc portion of IgG
• The NK cell secrete:
1. Perforin
✓ Contained within the cytotoxic granules of NK cells (& CTL)
✓ Forms a pore that is inserted into the target cell membrane,
✓ These pores allow salts and water to flow into the target cell; more importantly, they give granzyme
access to the cytoplasm
2. Granzyme
✓ Activate the caspase enzyme system, which results in apoptosis.
- Fas Ligand (FasL):
• Found in surface of NK cell &CTL
• Is a potent inducer of apoptosis
• Kill infected cells and tumor cells by bind to Fas death receptor (CD95) on the target cells