Lecture 5 Flashcards
What are the key components of the innate immune response?
Barriers, Sentinel cells in tissue, circulating phagocytes and granulocytes, blood proteins, cytokines
Sentinel cells in tissues
Dendritic cells, macrophages, natural killer cells
What do circulating phagocytes and granulocytes do?
Cells that can recognize groups of pathogens (ingest foreign matter)
Examples of circulating phagocytes and granulocytes
Neutrophils, monocytes, eosinophils, basophils
What do blood proteins do?
Mediate inflammation
What do cytokines do?
Signal, stimulate, and regulate the immune response
Barrier: saliva properties
Antibacterial enzymes
Barrier: tears properties
Antibacterial enzymes
Barrier: skin properties
Prevents entry
Barrier: mucus properties
Lining traps dirt and microbes
Barrier: stomach acid properties
Low pH kills harmful microbes
Barrier: “good” gut bacteria properties
Out compete the bad bacteria (kills it)
What are the main sites of interaction between individuals and their environment?
Skin, GI tract, Respiratory tract, and the Genitourinary tract
Role of epithelial cells
Defence against pathogens
What makes up the epithelial barrier?
Tight junction, Mucous, and Keratin layers (physical barrier)
Defensins
Host defence peptides with either direct antimicrobial activity, immune signalling activities, or both
Cathelicidins
A polypeptide that is primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes
Where do all immune cells originate
Bone marrow
Phagocytes’ objective:
Identify, ingest and destroy pathogens
The role of a Phagocyte
Recognition of microbes (PRR), Ingestion of microbe by phagocytosis, Destruction of ingested microbe, Secretion of cytokines to promote and/or regulate immune response, Recruitment of cells to site of infection
Examples of professional phagocytes
Marcophages and neutrophils
Where are macrophages found?
Present under your skin, tissues in lungs and intestines
Macrophages found in bone:
Osteoclasts
Macrophages found in the central nervous system
Microglia
Macrophages found in connective tissue
Histiocytes
Macrophages found in the chorion villi of the placenta
Hofbauer cells
Macrophages found in the kidney
Mesangial cells
Macrophages found in the liver
Kupffer cells
Macrophages found in the peritoneal cavity
Peritoneal macrophages
Macrophages found in the pulmonary airway
Alveolar macrophages
Macrophages found in the skin
Epidermal and dermal macrophages
Macrophages found in the spleen
Marginal zone macrophages, metallophilic macrophages, red pulp macrophages, and white pulp macrophages
What stages do macrophages exist?
Resting (patrolling mode), activated (antigen presentation mode), hyperactivation (destroyer mode)
Resting macrophage stage
Digest dead/non-functional cells and wound healing
Activated macrophage stage
Upregulation of antigen molecules (MHC 1/2), Invaders are destroyed and pieces are displayed to activate T cells
Hyperactivation macrophages stages
Increased in size to focus on destruction (increased lysosomes)
Neutrophils
Most abundant white blood cells (40-70%) specialized for killing
How long is the life span of a neutrophil
Short (5-7 days)
Monocytes
Circulate in blood to be recruited to sites of infection to mature into macrophages
Where are NK cells found?
Blood, spleen, and liver
What is the role of NK cells
“on call” and recruited to the sites of infection, produced cytokines to help in pathogen defence and activation of macrophages. They destroy infected/cancerous cells/parasites/bacteria/fungi
True or false: Natural Killer cells secrete fas ligand killing to induce apoptosis
True
Where are mast cells found?
In tissues
What is the role of mast cells
Inflammation, release cytokines, increased vascular permeability, promotes recruitment and activation of immune cells, parasitic infections through IgE/IgG binding and FC receptor cross linking
Where are Basophils/Eosinophils found?
Blood (low proportion of WBC)
What do Basophils/Eosinophils release?
Histamine and cytokines
What is Inflammation?
Recruitment of leukocytes and plasma proteins from the blood which accumulates in tissues. Activation of mediators occurs to destroy microbes/wound
repair
Signs of inflammation
Dolor (pain), Calor (heat), Rubor (redness), Tumor (swelling), Functio laesa (loss of function)
Causes of inflammation characteristics
Vasodilation/ Increased blood flow (heat, redness), Fluid accumulation (swelling), Chemical activation /cytokine release (ie histamine, bradykinin) that stimulates nerve endings (pain, loss of function)
The purpose of inflammation
Eliminate the initial cause of cell injury (infection), clear out necrotic cells and tissues, initiate tissue repair.
Process of Inflammation
- Mast cells initiate this process
- Macrophages/neutrophils, and dendritic cells to release inflammatory mediators
- Mediators cause inflammation signs to allow for increased permeability to allow cells to cross
- Immune cells are activated
True or False: IL-1 and IL-6 are not produced by endothelial and epithelial cells
False, they are produced by endothelial and epithelial cells
What happens if there are any disturbances in the tissue repair process
Aberrant repair
Outcome of Inflammation
Resolution, Repair, Areas of destruction replaced by scar tissue, Mediators intensify the inflammatory process, Mediators generate more mediators
Mast cells
Specialized connective tissue cells with granules filled with histamine, a vasodilator (promotes the dilatation of blood); initiate the process of inflammation
What are the chemical mediators of Inflammation?
Mast cells, Histamine, serotonin, prostaglandins, leukotrienes
Chemical Mediators of Inflammation from blood plasma
Bradykinin and Complement
What is Complement
Series of proteins that interact in a regular sequence. They are activated by antigen-antibody reactions
Exudate
A mass of cells and fluid that has seeped out of blood vessels or an organ (important in inflammation)
What is in the fluid mixture of Exudate
Proteins, leukocytes and tissue debris
Serous exudate
Primarily fluid, little protein
Purulent exudate
Largely inflammatory cells (pus)
Fibrinous exudate
Rich in fibrinogen; coagulates and forms fibrin; produces a sticky film on surface of inflamed tissue
Adhesions exudate
Bands of fibrous tissue that bind adjacent tissue together
Hemorrhagic exudate
Increased red blood cells
How do immune cells communicate?
Cytokines
True or False: one cytokine influences the synthesis of other cytokines
True, produces a cascade
Cells that respond to cytokine
Autocrine (same cell), paracrine (nearby cell), or endocrine (distant cell)
Monokines
Cytokines produced by mononuclear phagocytic cells
Lymphokines
Cytokines produced by activated lymphocytes, especially Th cells
Interleukins
Cytokines that act as mediators between leukocytes
Chemokines
Type of cytokine that help in the host immune response and the movement of leukocytes and other cells
TNF-α
Induced by LPS; It is an important mediator of acute inflammation. It mediates the recruitment of neutrophils and macrophages to sites of infection
IL-1
inflammatory cytokine produced by activated macrophages.
(Similar to TNF-α; Helps activate T-cells)
IL-10
Interleukin 10 is produced by activated macrophages and Th2 cells (CD4); Inhibitory cytokine
What does IL-10 Inhibit?
inhibits production of IFN-γ by T cells, which shifts immune responses from attack to repair functions and cytokine production by activated macrophages and the expression of class 2 MHC
IL-12
Produced by activated macrophages and dendritic cells and stimulates the production of IFN-γ and induces the differentiation of Th cells to become Th1 cells
Type I interferons
Type I interferons (IFN-α and IFN-β) are produced by many cell types and they
function to inhibit viral replication in cells.
Pathogen Associated Molecular Patterns (PAMPs)
Activate Innate Immune Response; cell associated receptors mediated through toll-like receptors
Lipopolysaccharide
gram –ve bacteria cell membranes
Lipoteichoic acid
gram +ve bacteria
ds RNA
Virus
unmethylated CpG DNA sequences
Bacteria
Damage associated molecular patterns (DAMPs)
Tend to be nuclear/cytosolic proteins; Trigger inflammatory response in macrophages/neutoriphils/dendritic cells
PRR (Pattern Recognition Receptors)
TLR-Toll like receptor, RLR-Rig like receptor (IFNα/β), NLR-NOD like receptor (inflammatory), Lectin like receptors
Toll Like Receptors (TLR)
Bind/ react to a wide range of microbial targets not present in/on healthy cells
Which transcription factors does TLR signalling activate
IRFs and NF-kB
IRF (Interferon regulator Factors)
IFN α, IFN β
NF-κβ
TNFα (Tumor Necrosis Factor), IL-1, IL-6, Adhesion molecules
DAMP vs PAMP
intra/extra will activate different pathways to produce different cytokine profiles that will polarize Macrophages more suited to Killing (infection) or repair (healing), or both
The Complement System
Composed of 30+ proteins found in the blood; Synthesized by hepatocytes in the liver
Basic functions of complement
Opsonization (enhancing phagocytosis of antigens), Chemotaxis (activating macrophages and neutrophils) , Cell Lysis (rupturing membranes of foreign cells), Agglutination (binding pathogens)
What can complement proteins be activated by?
A cut, can work in milliseconds to start clotting; antigen antibody reaction
Membrane Attack Complex (MAC)
This compromises the integrity and in turn causes the destruction of the target bacterium
True or False: Innate Immunity has more effectiveness against intracellular pathogens vs. extracellular pathogens
False, has more effectiveness against extracellular pathogens (Intra = adaptive)
Type 1 Interferons
Secreted by cells in response to PAMP recognition; Most potent stimuli for type I interferon synthesis are viral nucleic acids
Types of Type 1 Interferons
Interferon α (mostly dendritic cells, macrophages) and
Interferon β (a wide range of cells)
Roles of Type 1 Interferons
Increase cytotoxicity of the “killers”, Upregulate expression of class I MHC molecules, Cause sequestration (keep producing them) of lymphocytes in lymph nodes, Improved resistance to infection (infected and uninfected cells)
Paracrine action
Virally infected cells secretes type I interferons to act and protect adjacent cells not yet infected
What do the cells of the Innate Immunity promote?
Differentiation, proliferation or T and B cells
Dendritic cells
Professional Antigen Presenting Cells (APC) located at common sites of entry of microbes (skin, mucosa, organ parenchyma)
Which cells do dendritic cells present antigens to?
After antigens have been captured and sent to the lymph nodes they are presented to T lymphocytes
X-presentation
Infected cells/debris engulfed, digested and presented
