[DISCUSSION] MODULE 2 UNIT 1 Flashcards
Innate immunity
NATURAL IMMUNITY
Ability of the individual to resist infection
NATURAL IMMUNITY
Normally present body functions
Ability of the individual to resist infection
NATURAL IMMUNITY is Considered:
• Non adaptive
• Nonspecific
Same for all pathogens or foreign substances
NATURAL IMMUNITY
• No prior exposure is required
NATURAL IMMUNITY
• No prior exposure is required
• Response does not change = same magnitude every time
NATURAL IMMUNITY CHARACTERISTICS:
- Components are preformed
- Standardized
- Without memory
- Nonspecific
NATURAL DEFENSE SYSTEM
• TWO PARTS:
• External defense system
• Internal defense system
EXTERNAL DEFENSE SYSTEM
• Composed of:
- Anatomic barriers
- Physiologic barriers
• Prevent most infectious agents from entering the body
Anatomic barriers
Anatomic barriers Examples:
• Intact skin
• Mucous membranes
Physiologic barriers
• Temperature
• Low pH
• Physiologic functions → coughing, sneezing, vomiting, diarrhea,
shedding of cells
• Oxygen tension
• Age
• Hormonal balance
• Chemical mediators → lysozyme, interferon, complement, toll-like
receptors, collectins
Physiologic functions
coughing, sneezing, vomiting, diarrhea,
shedding of cells
Chemical mediators
lysozyme, interferon, complement, toll-like
receptors, collectins
• Cleaves bacterial cell wall
• Lysozyme
• Induces antiviral state in uninfected cells
• Interferon
• Lyses microorganisms or facilitates phagocytosis
• Complement
• Recognize microbial molecules
• Toll-like receptors
• Signal cell to secrete immunostimulatory cytokines
• Toll-like receptors
→ disrupt cell wall of pathogen
• Collectins
• Second line of defense
INTERNAL DEFENSE SYSTEM
• Cells and soluble factors
INTERNAL DEFENSE SYSTEM
• Designed to recognize molecules that are unique to
infectious organisms
INTERNAL DEFENSE SYSTEM
• Phagocytosis
INTERNAL DEFENSE SYSTEM: Second line of defense
INTERNAL DEFENSE SYSTEM
Designed to recognize molecules that are unique to
infectious organisms
mannose found in microorganisms
enhanced by soluble factors called acute phase reactants
Phagocytosis
• Ability to recognize a given class of molecules
PATTERN RECOGNITION
• Ability to immediately recognize and combat invaders displaying such molecules is a strong feature of innate immunity
PATTERN RECOGNITION
Molecules with pattern recognition
PATTERN RECOGNITION
bind PAMPs
PRRs
• Molecules with pattern recognition
• May be soluble
complement, lysozyme
• Molecules with pattern recognition
• Cell-associated receptors
toll-like receptors (TLR’s)
• normal serum constituents
ACUTE PHASE REACTANTS
• increase rapidly by at least 25% due to infection, injury, or trauma to the tissues
ACUTE PHASE REACTANTS
• produced primarily by hepatocytes (liver parenchymal
cells)
ACUTE PHASE REACTANTS
• within 12 to 24 hours
ACUTE PHASE REACTANTS
• within 12 to 24 hours
• in response to an increase in certain intercellular signaling polypeptides called
cytokines
cytokines
IL-1β, IL-6, TNF-α
• most abundant of the coagulation factors in plasma
Fibrinogen
• forms the fibrin clot
Fibrinogen
• dimer with a molecular weight of 340,000 daltons
Fibrinogen
Fibrinogen Normal levels range from
100 to 400 mg/dL
• Promote healing process
Fibrinogen
• Prevents spread of microorganisms
Fibrinogen
• alpha2
-globulin with a molecular weight of 100,000 daltons
Haptoglobin
• bind irreversibly to free hemoglobin released by intravascular hemolysis
Haptoglobin
Preventing loss of free hemoglobin
Haptoglobin bind irreversibly to free hemoglobin released by intravascular
hemolysis
Haptoglobin
• Normal plasma concentrations range from
40 to 290 mg/dL
Haptoglobin plays an important role in:
• protecting the kidney from damage
• preventing the loss of iron by urinary excretion
Haptoglobin Most important function
to provide protection against oxidative
damage mediated by free hemoglobin
• single polypeptide chain with a MW of 132,000 daltons
Ceruloplasmin
• Principal copper transporting protein
Ceruloplasmin
• Essential to collagen formation & the extracellular cross-linking and
maturation of collagen and elastin
Ceruloplasmin
• Protect the matrix of healing tissue against superoxide ions
Ceruloplasmin
• Protease inhibitor
Alpha-2-macroglobulin
• Binds to proteolytic enzymes released from damaged tissues and
from phagocytic cells
Alpha-2-macroglobulin
• Scavenger protease inhibitor that binds excess molecules that
cannot be handled by the intended inhibitor
Alpha-2-macroglobulin
• homogeneous molecule with a MWof 118,000 daltons
C-Reactive protein (CRP)
• increases rapidly within 4 to 6 hours following infection, surgery, or
other trauma to the body
C-Reactive protein (CRP)
C-reactive protein (CRP)
• Capable of:
- Opsonization
- Agglutination
- Precipitation
- Activation of complement by the classical pathway
• Apolipoprotein synthesized in the liver (30mg/ml)
Serum amyloid A
• Precursor to amyloid deposition
Serum amyloid A
• Reported to cause adhesion and chemotaxis of phagocytic cells and
lymphocytes
Serum amyloid A
• Bind to lysosomal enzymes released during inflammation
Serum amyloid A
• Increased levels found to be a risk factor for heart attack in women
Serum amyloid A
• Can increase almost 1000-fold
Serum amyloid A
• Serum proteins that are normally present
Complement
• Mediation of inflammation
Complement
Complement Major functions:
- Opsonization
- Chemotaxis
- Lysis of cells
Trimer that acts as an opsonin that is Ca-dependent
Mannose-binding protein
Recognize foreign carbohydrates such as mannose and a number of
sugars
Mannose-binding protein
Mannose-binding protein
Recognize foreign carbohydrates such as mannose and a number of
sugars present in:
• Bacteria
• Some yeasts
• Viruses
• Several parasites
• Widely distributed in mucosal surfaces throughout the body
Mannose-binding protein
• Binding activates complement cascade and helps to promote phagocytosis
Mannose-binding protein
• High carbohydrate content and MW 44 kD
Alpha-1 acid glycoprotein
• Exact function not known
Alpha-1 acid glycoprotein
• Binds progesterone and may be important in its transport or metabolism
Alpha-1 acid glycoprotein
• Able to bind drugs such as lidocaine, keeping them in an inactive
circulating pool
Alpha-1 acid glycoprotein
CELLULAR DEFENSE MECHANISMS
• Neutrophils
• Eosinophils
• Basophils
• Mast cells
• Monocytes
• Tissue macrophages
• Dendritic cells
• Polymorphonuclear neutrophilic leukocyte (PMN)
NEUTROPHILS
• 50 – 70% of the total peripheral wbcs
NEUTROPHILS
• Diameter: 10 – 15 mm
NEUTROPHILS
• Nucleus: 2-5 segments
NEUTROPHILS
• Large number of neutral staining granules
NEUTROPHILS
NEUTROPHILS granules
• Primary granules
• Secondary granules
NEUTROPHILS
Primary granules (azurophilic) contain:
• Myeloperoxidase
• Lysozyme
• Proteinase 3
• Elastase
• Cathepsin G
• Lysosomal acid hydrolases
• Defensins
Small proteins that have antibacterial activity
Defensins
NEUTROPHILS
Secondary (specific) granules contain:
• Collagenase
• Lysozyme
• Lactoferrin
• Reduced NADPH oxidase
• Alkaline phosphatase
NEUTROPHILS
Tertiary granules contain:
gelatinase & plasminogen
activators
• Normally, half of the total neutrophil population is found in
a marginating pool on the walls of blood vessels
NEUTROPHILS
• The rest circulate freely for approx. 6 – 10 hours
NEUTROPHILS
• Capable of moving from the circulating blood to the
tissues
NEUTROPHILS
movement through blood vessel walls
DIAPEDESIS→
• Margination & adherence to the vessel wall
DIAPEDESIS
• Formation of pseudopods, squeeze through junctions of the endothelial
cells
DIAPEDESIS
• Wander randomly through the tissue or be attracted to a specific area by
chemotactic factors
DIAPEDESIS
chemical messengers that cause migration
of cells in a particular direction
Chemotaxins
Chemotaxins
5 days
Once in tissues, neutrophils’ life span: about
5 days
Once in tissues, neutrophils’ life span: about 5 days
12 to 16 mm
EOSINOPHILS
1 – 3%
EOSINOPHILS
EOSINOPHILS Numbers increased during:
• Allergic reaction
• Response to many parasitic infections
Eosinophils Nucleus
• Bilobed or ellipsoidal
• Eccentrically located
• Take up the acid eosin dye
EOSINOPHILS
Cytoplasm is filled with large orange to reddish-orange
granules
EOSINOPHILS
EOSINOPHILS granules
• Acid phosphatase
• b-glucuronidase
• Arylsulfatase
• Phospholipase
• Peroxidase
• Histaminase
• Aminopeptidase
• Ribonuclease
Capable of phagocytosis but much less efficient than
neutrophils
EOSINOPHILS
EOSINOPHIL phagocytosis
• Smaller numbers
• Lack of digestive enzymes
EOSINOPHILS MOST IMPORTANT ROLE:
• Neutralizing basophil and mast cell products
• Killing of certain parasites
ADCC
Eosinophils
• Less than 1% of all circulating wbcs
BASOPHILS
• Smallest of the granulocytes
BASOPHILS
• 10 to 14 mm in diameter
BASOPHILS
• Contain coarse densely staining deep bluish purple
granules that often obscure the nucleus
BASOPHILS
• Constituents of granules: histamine, eosinophil
chemotactic factor of anaphylaxis (ECF-A), and a small
amount of heparin
BASOPHILS
• Induce and maintain immediate hypersensitivity
reactions
BASOPHILS
BASOPHILS
vasoactive amine that contracts smooth
muscle
HISTAMINE
BASOPHILS anticoagulant
HEPARIN
stream• Granules: lack hydrolytic enzymes although peroxidase
is present
BASOPHILS
• Capable of phagocytosis
BASOPHILS
• Only present for a few hours in the blood
BASOPHILS
• Resemble basophils
MAST CELLS
• May share a common stem cell precursor
MAST CELLS
• Larger with a small round nucleus and more granules
than the basophil
MAST CELLS
• Found in connective tissue, especially around blood and
lymphatic vessels
MAST CELLS
• Long life span
MAST CELLS
• May be capable of proliferation in the tissues
MAST CELLS
• The enzyme content of the granules distinguish them from
basophils because they contain acid phosphatase,
alkaline phosphatase, protease & serotonin
MAST CELLS
• Play a role in hypersensitivity reactions
MAST CELLS
• Largest cells in the peripheral blood
MONOCYTES
• Diameter: 12 to 22 mm, ave. 18 mm
MONOCYTES
• Irregularly folded or horseshoe-shaped nucleus occupying
almost ½ of the entire cell’s volume
MONOCYTES
• Abundant cytoplasm stains a
dull grayish-blue with a ground
glass appearance
(fine granules)
MONOCYTES
One type of granules contain peroxidase, ACP,
arylsulfatase (similar to neutrophils)
MONOCYTES
• Other type of granules contain b-glucuronidase,
lysozyme, lipase, but NO alkaline phosphatase
MONOCYTES
• Make up 4 to 10% of total circulating wbc
MONOCYTES
• Stay in the peripheral blood for up to 70 hours then
migrate to the tissue and become macrophages
MONOCYTES
• All tissue macrophages arise from monocytes
TISSUE MACROPHAGES
• Transition from monocyte to macrophage is characterized
by progressive cellular enlargement to between 25 and 50
mm
TISSUE MACROPHAGES
• Increase in ER, lysosomes, & mitochondria
TISSUE MACROPHAGES
• Unlike monocytes, macrophages contain NO
PEROXIDASE AT ALL
TISSUE MACROPHAGES
Lung
Alveolar macrophages
Liver
Kupffer cells
Brain
Microglial cells
Connective tissue
Histiocytes
Kidney
Mesangial cells
Bone
Osteoclast
Spleen
Littoral cells
Joints
Synovial A cells
• Life span: months
TISSUE MACROPHAGES
TISSUE MACROPHAGES Role →
initiating and regulating IR
TISSUE MACROPHAGES Functions:
- Microbial killing
- Tumoricidal activity
- Killing of intracellular parasites
- Phagocytosis
- Secretion of cell mediators
- Antigen presentation
• Covered with long membranous extensions making them
resemble nerve cell dendrites
DENDRITIC CELLS
DENDRITIC CELLS Main function:
• Phagocytose antigen and present it to helper T lymphocytes
• Believed to be descendants of the myeloid line
• Classified according to tissue location
• E.g., Langerhans’ cells → skin and mucous
DENDRITIC CELLS
skin and mucous membranes
Langerhans’ cells
▪Interstitial dendritic cells
heart, lungs, kidney, GIT
Toxins released via phagocytosis
Leukocidin
Listeriolysin
Streptolysin
M. bacterium leptae and MBT contains this material that does not fuse with lysosome
Pristiophorus vacuole
Catalase
Staphylococcus aureus
▪Interdigitating dendritic cells
T lymphocyte areas
of the secondary lymphoid tissue and the thymus
▪After capturing Ag in the tissue by
phagocytosis or endocytosis,
they
migrate to the blood or the lymphoid
organs & present Ag
▪Most potent phagocytic cell in the tissue
DENDRITIC CELLS
also known as large granular lymphocytes (LGL)
NK (Natural Killer) Cells
identified by the presence of CD56 and CD16 and a lack of CD3
cell surface markers
NK (Natural Killer) Cells
capable of killing virus-infected and malignant target cells
NK (Natural Killer) Cells
upon exposure to IL-2 and IFN-gamma, NK cells become
lymphokine-activated killer (LAK) cells
NK (Natural Killer) Cells
capable of killing malignant cells
lymphokine-activated killer (LAK) cells
not a morphologically distinct type of cell
K (Killer cells)
• any cell that mediates antibody-dependent cellular cytotoxicity (ADCC)
K (Killer cells)
• have on their surface an Fc receptor for antibody and thus they can
recognize, bind and kill target cells coated with antibody
K (Killer cells)
Killer cells which have Fc receptors include (?) which have an Fc receptor for IgG antibodies and
eosinophils which have an Fc receptor for IgE antibodies
NK, LAK, and macrophages
Additional mechanism recently discovered on certain cells,
enhancing natural immunity
TOLL-LIKE RECEPTORS (TLRs)
→ a protein originally discovered in the fruit fly
Toll
Highest concentration occurs on monocytes, macrophages
and neutrophils
TOLL-LIKE RECEPTORS (TLRs)
→ recognizes techoic acid and peptidoglycan in g+ bacteria
TLR2
→ recognizes LPS
TLR4
Monocytes, macrophages, endothelial cells, epithelial cells
Interleukin 1 (IL-1)
Vasculature (inflammation); hypothalamus (fever); liver (induction of acute phase proteins)
Interleukin 1 (IL-1)
Macrophages
Tumor Necrosis Factor-alpha (TNF-alpha) & Interferon alpha (IFN-alpha)
Vasculature (inflammation); liver (induction of acute phase proteins); loss of muscle, body fat (cachexia); induction of death in many cell types; neutrophil activation
Tumor Necrosis Factor-alpha (TNF-alpha)
Macrophages, dendritic cells
Interleukin 12 (IL-12)
NK cells; influences adaptive inmmunity (promotes TH1 subset)
Interleukin 12 (IL-12)
Macrophages, endothelial cells
Interleukin 6 (IL-6)
Liver (induces acute phase proteins); influences adaptive immunity (proliferation and antibody secretion of B cell lineage
Interleukin 6 (IL-6)
This is a family of molecules
Interferon alpha (IFN-alpha)
Induces an antiviral state in most nucleated cells; increases MHC class I expression; activates NK cells
Interferon alpha (IFN-alpha) & Interferon beta (IFN-beta)
Fibroblasts
Interferon beta (IFN-beta)
Involves engulfment and destruction of pathogens and particulate matter by cells of the mononuclear phagocyte
system
PHAGOCYTOSIS
Macrophages release monokines like (?)
IL-1, IL-6 and TNFa
PHAGOCYTES:
• Fixed
• Wandering
• CHARACTERISTICS OF PHAGOCYTIC PROCESS:
- AMOEBOID MOVEMENT
- CHEMOTAXIS
•
Cell migration occurs in and out of blood vessels, and throughout the tissues
AMOEBOID MOVEMENT
• Movement of cells or organisms toward objects in response to
chemical agents called CHEMOTAXINS
CHEMOTAXIS
→ cell emigration from capillaries
Diapedesis
modified a.a. present in the a.a. termini of proteins of most types of
bacteria
Microbial/ bacterial products: N-formylmethionine residues
Attractants of phagocytes/chemotactic agents:
• Microbial/ bacterial products: N-formylmethionine residues
• Tissue components (leukotriene)
• Activated intermediates of the fibrinolysis, kallikrein, and
complement systems
Once a particle is close enough to the target, the cells engulf it
PHAGOCYTOSIS
STEPS IN PHAGOCYTOSIS
- Physical contact between the white cell and the foreign particle
- Formation of a phagosome
- Fusion with cytoplasmic granules to form a phagolysosome
- Digestion and release of debris to the outside
•
Digestion of engulfed material inside the phagolysosome
CYTOPEPSIS
•
Contents of the lysosome granules are important in breaking down
ingested material and in killing microorganisms
CYTOPEPSIS
TWO MECHANISMS FOR DESTROYING FOREIGN PARTICLES
- Oxygen-independent mechanisms
- Oxygen-dependent mechanisms
• Proteinases (hydrolytic enzymes)
• Cationic proteins
• Lysozyme
• Lactoferrin
OXYGEN INDEPENDENT MECHANISMS
OXYGEN DEPENDENT MECHANISMS
• Myeloperoxidase
• Hydrogen peroxide (H2O2)
• Superoxide anion (O2– )
→ toxic peroxidation of microorganisms
Myeloperoxidase
→ oxygen in which one of the electrons has
moved to an orbit of higher energy
Singlet oxygen (‘O2
)
→ a highly unstable oxidizing agent that
reacts with most organic molecules it encounters
Hydroxyl radical (OH–)
increase in overall oxygen consumption by the neutrophil
RESPIRATORY BURST/ METABOLIC BURST
• METABOLIC EVENTS DURING PHAGOCYTOSIS
• Accompanied by respiratory burst that involves the following:
1.
Increase in oxygen consumption
2.
Stimulation of HMP shunt activity
3.
Increase in production of hydrogen peroxide
4.
Superoxide anion production and singlet oxygen production
→ extremely toxic to bacteria and tissue; very unstable; quickly converted to H2O2 by SOD → catalase
Superoxide anion
The (?) combine and act synergistically
oxygen-dependent agents
→ Hypochlorite
Myeloperoxidase + H2O2 + Halide (I- or Cl -)
(?) is more antimicrobial than the three components alone
Hypochlorite
LIMITATIONS OF PHAGOCYTOSIS
- Presence of capsules
- Opsonization inhibited
- Release of toxins
- Phagolysosome formation inhibited
- Able to escape into cytoplasm by lysing lysosomal
membrane - Resistance to killing by producing anti-oxidants
PHAGOCYTOSIS
• IMPORTANCE:
- Destroy/ kill microorganisms
- Disposal of damaged and dying cells
- Suppression of the growth of spontaneously arising tumors
- Processing of antigens
- Removal of cancer cells
- Removal of debris from repairing wounds
- Removal of debris as embryonic tissues replace one another
• Process of enhancing phagocytosis via the presence of opsonins
OPSONIZATION
• Substances that promote phagocytosis
OPSONIZATION
• OPSONINS:
- C3b split product of complement cascade
- C5a and C5b67 → chemotactic factors that also aid
in the clearance of foreign materials - Antibodies (phagocytes have a receptor for the Fc
portion of IgG)
→ chemotactic factors that also aid
in the clearance of foreign materials
C5a and C5b67
Antibodies (phagocytes have a receptor for the Fc
portion of IgG)
•
IgG1 and IgG3
→ gp that opsonizes & acts like glue to cause neutrophils and their targets to stick together
Fibronectin
→ derivatives of arachidonic acid
Leukotrienes
• Several kinds, not all act as opsonins
Leukotrienes
• LTBy
is chemotactic
Leukotrienes
→ tetrapeptide split product of IgG that stimulates chemotactic and phagocytic activities
Tuftsin
• Complex series of non-specific soluble and cellular events
INFLAMMATION
• Promotes elimination of the foreign entity
INFLAMMATION
• Initiated by chemical mediators whenever phagocytosis
alone fails to prevent infection or when tissues are injured
INFLAMMATION
INFLAMMATION Induced by:
pathogen attack, inert tissue injury, products of
complement activation, or by cytokines released by innate or
adaptive leukocytes that were activated elsewhere
Five cardinal signs/clinical symptoms: (Celsus)
- Redness (rubor)
- Swelling (tumor)
- Heat (calor)
- Pain (dolor)
- Loss of function (functio laesa)(Galen)
• Major Events associated with inflammation:
- Increased blood supply to the infected area
- Increased capillary permeability caused by retraction of
endothelial cells lining the vessels - Migration of white blood cells (mainly neutrophils) from the
capillaries to the surrounding tissue - Migration of macrophages to the injured area
EVENTS OF INFLAMMATION
- Histamine released from mast cells
- Inreased permeability of the vessels
- Soluble mediators
- Amplification
- Coagulation system and fibrinolytic system
SIGNS OF INFLAMMATION
- Redness and heat
- Swelling and pain
→ Cause dilation of the blood vessels & additional flow to affected area
Histamine released from mast cells
→Fluids to leak out to the tissues
Inreased permeability of the vessels
→Stimulation of the pain receptors (skin) by peptide mediators
Inreased permeability of the vessels
initiate and control the response
Soluble mediators
occurs through formation of clots
Amplification
involvement
Coagulation system and fibrinolytic system
→ vasodilation, increased vascular permeability, smooth muscle contraction, pain
Kinins (e.g., bradykinin)
→ activates macrophages (from NK cells)
IFNg
→ perpetuate the inflammatory
response
TNF, IL-1, IL-6
→ from hepatocytes responding to TNF and IL-6; initiates complement cascade via C1 activation
CRP
MEDIATORS OF INFLAMMATION
- Kinins (e.g., bradykinin)
- IFNg
- TNF, IL-1, IL-6
- CRP
- C3a & C5a → anaphylatoxin
- C3b
- Leukotrienes and prostaglandins
- Serotonin (5-hydroxytryptamine)
→ provokes mast cell degranulation and consequent release of heparin and vasoactive amines (HISTAMINE) that induce
Vasodilation increases vascular permeability
C3a & C5a → anaphylatoxin
opsonin
C3b
→ increase vasodilation and promote neutrophil chemotaxis
Leukotrienes and prostaglandins
→ vasodilation
Serotonin (5-hydroxytryptamine)
• Neutrophils
• Macrophages
ACUTE INFLAMMATION
• Mobilized within 30 to 60 minutes after the injury
Neutrophils
• Neutrophil emigration lasts (?) hours
24 to 48
• Proportional to the chemotactic factors present in the area
Neutrophils
• Attempt to clear the area through phagocytosis
Macrophages
• Most cases: healing process is completed with a return of normal
tissue structure
Macrophages
Migration occurs several hours later and peaks at (?) hours
16 to 48
• Prolonged inflammatory response
CHRONIC INFLAMMATION
• Tissue damage and loss of function may result
CHRONIC INFLAMMATION
• Often follows acute inflammation but can be the only inflammatory
response in certain viral infections and hypersensitivity reactions
CHRONIC INFLAMMATION
• Characterized by infiltration of tissue with macrophages,
lymphocytes and plasma cells, or eosinophils
CHRONIC INFLAMMATION
Infection: neutrophils. Macrophages
Allergy: eosinophils, mast cells
ACUTE
Macrophages, lymphocytes
CHRONIC
Complement, kinins, prostaglandins,
leukotrienes, acute phase cytokines,
chemokines
ACUTE
Cytokines from macrophages and T cells
CHRONIC
Rash, pus, abscess
ACUTE
Rash, fibrosis, granuloma
CHRONIC
Response to infection, hypersensitivity response
ACUTE
Autoimmunity, response to intracellular bacterial infection
CHRONIC
