Enclonar, Kimberly / MLS 3A

• Damage Associated Molecular Patterns (DAMPs)

Innate Immunity o Molecules that are released from damaged or
January 21, 2021 necrotic "self" cells
Lean Kristin Ugdang, RMT o Normally they are released in small amounts
following sporadic host cell damages due to
First-line of defense: Physical barriers trauma or necrosis
• Lined by continuous epithelia o Pathologic cell death can lead to increase
o Natural antibiotic peptides - Catalysidins and release of these molecules, and can play a role in
defensins the development of autoimmune disease
• Skin - keratinization and constant renewal of the
skin's epithelial cells assist in the protective function Neutrophils
of the skin • Short-lived circulating PMN - for phagocytosis under
• Secretions the influence of chemotactic
o Mucus - adhering the nose and nasopharynx molecules/chemotaxins/chemoattractants
o Sebum - consists of lactic and fatty acids • Principal phagocyte and has protective effect against:
maintain the pH of the skin (pH 3-5) inhibit the bacteria and fungi
growth of pathogenic microorganisms • Found in
• Earwax (cerumen) - protect auditory canal from o Circulating pool
infection o Marginal pool
• Lysozymes • Half of the neutrophils are found in the marginating
o Attacks cell wall of microbes, especially gram+ pool - adherent to the walls of the blood vessel (for
o Lysozyme digests the Beta(1-4) glycosidic bond diapedesis or extravasation)
between N-acetyl miramic acid (NAM) and N- o Selectin molecules facilitates adhesion
acetyl-glucosamine (NAG) • The rest of the population are circulating freely in the
• Saliva, Tears, Mucous secretions - wash away blood stream for 6-10hrs
potential invaders and also contain antibacterial or
antiviral substances Granules
• Elimination of liquid and solid wastes (defecation,
Primary (azurophilic) Myeloperoxidase
urination, sneezing)
Elastase
• Cilia
o Hair-like protrusions of the epithelial cell Proteinase 3
Lysozymes
membranes. The synchronous movement of cilia
Cathepsin G
propels mucus-entrapped microorganisms from
Defensins
these tracts
• Acidity Secondary (azurophilic) Collagenase
o Vaginal (lactic acid) pH 5 Lactoferrin
o Stomach (HCl) pH 1 Lysozyme
• Resident flora Reduce NADPH oxidase
o Non-pathogenic organisms (bacteria or yeast) in
Tertiary Gelatinase
some parts of the body through competitive Plasminogen activator
exclusion
• Physiologic Factors
o pH Neutrophil diapedesis
o Body temperature 1. Rolling
o Injured tissues and nearby cells release chemical
o Oxygen tension
o Hormonal balance mediators that activate endothelial cells to
o Age express molecules on the surface
o Carbohydrate ligand (receptor in neut) bind to
selectin molecules on the inner wall
Second-line of defense: Cells & Humoral Factors o Neutrophil express P-selectin glycoprotein ligand
• Cells from the bone marrow 1 (PSGL) and binds to P-selectin in EC
• Mast cells - do not rise from the myeloid progenitor, o Causes the leukocyte to slow down and roll
they originate from mesenchymal cell 2. Tight adhesion
• Lymphoid - NK and dendritic cell o Chemokines activate rolling leukocyte and cause
• Humoral defense - cytokines them to express high affinity integrin molecules
o Integrin binds to integrin ligand (intracellular
How do cells in the innate immune response recognize self adhesion molecule 1 ICAM1)
from non-self? o Margination - Accumulation of neutrophils
• Pathogen/Microbe Associated Molecular Patterns 3. Transmigration
(PAMPs/MAMPs) o Mast cells release histamine causing vasodilation
o Microbial molecules that stimulate innate o Leukocyte forms pseudopods and platelet
immunity endothelial cell adhesion molecule 1 (PECAM-1)
o Present only in microbes
interact
o Examples: LPS, peptidoglycan, and other o Interaction pulls leukocyte causing them to
virulence factors completely transmigrate
• Pattern Recognition Receptors (PRRs) o Extravasation - change in shape to fill in the gaps
o Receptors of the cells of the innate immune o They interact with chemotaxins to reach the site
system that recognize PAMPs/MAMPs of injury
o Examples: toll-like receptors in phagocytic cells
(toll in grosophila flies)
 Enclonar, Kimberly / MLS 3A
Phagocytosis (ICEDE)
• Initiation stage
o Formation of cell surface receptors on
phagocytes
o Formyl-methionyl-leucyl-phenylalanine (FMLP)
receptors
▪ FMLP is a bacterial peptide
o CR3 receptors and Fc portion receptors
o Opsonized/Indirect phagocytosis
▪ Phagocytes express receptor for Fc portion
of antibody molecule
▪ Fragment antigen binding (Fab) portion
binds on the surface of pathogen or
epitope
▪ For phagocytes to bind, it must interact to
the Fc region of the antibody (Fragment • Digestion/Cytopepsis
crystallizable) o Increase in O2 consumption (respiratory burst)
▪ Phagocytes should express Fc receptors via the hexose monophosphate pathway
▪ C3b - complement product that acts as o NADPH is reduced to NADP+; O2 is reduced to
opsonin, therefore it should express C3b O2- or superoxide anion (unstable oxygen
receptors radical)
o Superoxide dismutase (SOD) - converts O2- to
H202
o Myeloperoxidase - converts H2O2 to HClO
o Reactive oxygen species (ROS) - toxic
□ Superoxide
□ Hydrogen peroxide
□ Hypochlorite
o Nitric oxide - produced only by activated
macrophages
▪ Inducible nitric synthase converts arginine
to nitric oxide

• Exocytosis
o Release of degradation products of
microorganisms
o Release of phagocytic proteolytic enzymes and
• Chemotaxis reactive oxygen species
o Movement of neutrophils to the site of injury or ▪ Harmful to the body
infection o Neutrophil Extracellular Traps (NETs)
o From low chemokine concentration gradient to ▪ Neuts spew contents that traps nearby
high concentration gradient bacteria and fungi that were not engulf
o Chemotactic factors:
▪ Host immune humoral factors, products of Eosinophils
cell damage, bacterial products (FMLP) • Responds to parasitic infections and allergic reactions
o Chemotactic receptors • Neutralizes basophil and mast cell products
▪ CCR5 - expressed on white blood cells • Primary granules
• Engulfment o Acid phosphatase
o Physical contact of phagocytes to microbe: o Arylsulfatase
Direct or indirect • Specific granules
o Direct - PAMPS and PRRs o Major Basic Proteins (MBP) - for destroying
o Indirect - opsonins through opsonization parasites
o Phagocytes engulf the foreign o Eosinophilic Cationic protein - for destroying
substance/pathogen parasites
o Active membrane evagination or pseudopodia o Eosinophil peroxidase
formation o Eosinophil derived neurotoxins
o Results to phagosome formation
o Lysosome + phagosome = phagolysosome
 Enclonar, Kimberly / MLS 3A
Frustrated Phagocytosis
• Not as efficient as neutrophils in phagocytosis due to
o Eosino are smaller in numbers
o Lacks digestive enzymes
o Parasitic larvae are too large - Phagocytes can
only digest up to 0.5um
• Cannot directly interact with surface of parasitic
larvae
o Interact to opsonized larvae - IgE
o IgE-Fc receptors
• Phenomenon happens when a phagocyte fails to
engulf the opsonized target and out of frustration will
release its toxic chemical agent
• It will digest the opsonized larva externally resulting
to fragmentation
• Macrophage can then scavenged them

Basophils
• Granules contain:
o Histamine - inflammation
o Heparin (small amounts)
o Eosinophil chemotactic factor of anaphylaxis
(ECF-A) Brain Microglia
Eye Intraoccular macrophage
Mast Cells Lungs Alveolar macrophage or dust cells
• Same function with basophils
• Mesenchymal origin Liver Kupffer cells
• Found in connective tissues Spleen Splenic macrophage
• Longer lifespan of between 9-18 months
Small intestine Intestinal macrophage
• Contains:
o Histamine Bone marrow Osteoclast
o Acid phosphatase
Lymph node Subcapsular sinusoidal macrophages
o Alkaline phosphatase
Medullary macrophages
o Protease
Skin Langerhans cells
Monocyte-Macrophage System
• Presence of the fine dust like granules Dendritic Cells
o Contains digestive vacuoles • Localized in tissues
o Migrate to tissues to become macrophages • Most efficient phagocytes in tissues
• Type 1 granules • Main function: antigen presentation - professional
o Peroxidases antigen presentating cells (APCs)
o Acid phosphatase B-cell can also perform antigen presentation
o Arylsulfatase • Serves as bridge between the innate and the adaptive
• Type 2 granules immune response
o B-glucoronidase • Langerhans cells - DC in skin and mucus membranes
o Lysozyme • Interstitial dendritic cells - DC in major organs (heart,
o Lipase - make them potent phagocyte for killing lungs, liver, kidney, GI tract)
MTB which contains high lipid • Migrate to lymphatic vessels carrying the antigen
causing the T cells to proliferate and differentiate to
Macrophage effector cells
• Scavenger cells
• Secondary phagocytes Natural Killer (NK) cells
o Not as efficient as neutrophils, but are more • Play an important role in innate defense against stress
persistent cells (cancer and viral infections)
• Found in tissues • Releases:
• Functions o Perforin
o Microbial killing o Granzyme
o Tumoricidal activity • Mechanism of Cytotoxicity
o Intracellular parasite eradication o Determined via balance between activation and
o Phagocytosis inhibitory receptors
• Macrophage and dendritic cell - most important ▪ Inhibitory receptors - deliver inhibitory
• Classically activated macrophage (M1) signals to NK cells
o TLR and IFN-y ▪ Ex: KIR (killer cell Ig receptors), ILP-LIR,
o For microbial actions and inflammation CD94 NKG2A
• Alternatively activated macrophage (M2) ▪ Activating receptors - deliver activating
o IL-13 and IL-14 signals thus killing target cells
o Anti-inflammatory effects; wound repair o Recognize MHC class I on normal cells via
inhibitory receptor and delivers inhibitory
response
 Enclonar, Kimberly / MLS 3A
o Cancer cells lacks or contains altered MHC class Interferon
1 triggering activation • Interferes viral replication
o Stress cells also express stress proteins: MICA • Type 1 interferon
(MHC Class 1 polypeptide related sequence A) o IFN-a and IFN-B
and MICB o Produce by dendritic cells and virally infected
o Activation receptors (CD94 NKG2C and NKG2D) cells
bind to MICA and MICB and sends signals to NK o Interferes viral replication and cell division
cells to release perforins and granzymes. • Type 2 interferon
o Released perforins are pore-forming proteins o IFN-y (immune interferon)
that polymerized in the presence of Calcium and o Release by T-cytotoxic and T helper cell type 1
forms channels/holes (Th1)
o Granzymes (serine proteases) mediates
apoptosis

• Antibody Dependent Cell Cytotoxicity (ADCC) of NK

cells
o Similar to frustrated phagocytosis but NK cells
are not phagocytic
o NK cells recognized target cells opsonized with
IgG
o CD16 receptors target Fc portion of IgG releasing
perforins and granzymes.