Immuno-Innate defenses
Terms
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- What is immunity?
- All mechanisms by which the body protects against foreign agents
- Two “arms†of immune response
-
Innate immunity(non-specific)
-born with
-fast acting
-barriers, cells, and serum proteins
Acquired (adaptive) immunity(specific)
-improves with exposure
-primarily mediated by lymphocytes (T and B cells) - Examples of Innate defenses
-
-Barriers (e.g. skin, mucous membranes)
-Chemical mediators
-Interferon (fight viral
infection)
-Complement (C.L.I.O)
-Phagocytosis
-Toll-like receptors
-Inflammation
-NK cells (recognize tumor or viral cells – “altered-self cells†- Barriers
-
Two major surfaces by which most microbes/Ag enter body:
-Skin
-Mucous membranes - Epidermis
- Live and Dead cells with keratin
- Epidermis is renewed every _____ days
- 15-30
- When Epidermis is damaged it secretes _______ and _____
- IL-8 / Tumor Necrosis Factor(TNF) (inflammatory)
- Dermis is ________ and contains (3) _________
-
Vascularized
Hair follicles,
Sweat glands, &
Sebaceous glands (oil can coat microbes) - Langerhans cells (DC) in skin
- move Ags to LN
- Normal flora in skin
- Can inhibit pathogenic microbes
- Restriction enzymes
- enzymes in skin that restrict growth of viruses
- Bacteriocins
- inhibit bacteria in skin (ex. colicins)
- Innate defenses of skin
-
Epidermis
Dermis
Langerhans cells (DC)
Normal flora - Mucous membranes
- Respiratory, Digestive, Genitourinary Tracts
- sIgA (secretory immunoglobulin) is an ________ componant of mucus membrane immune function
- adaptive
- Mucin
- coats (traps) microbes
- Mucociliary escalator
- – movement of mucous up to be expelled (cough/sneeze) or swallowed
- examples of 2 pathologies associated with mucociliary escalator
-
Cystic fibrosis patients – abnormal cilia and mucous
Smoking – temporary paralysis of cilia - Lysozyme functions by
- cleavage of bacterial cell wall (b1,4 linkage of peptidoglycan)
- immune defences in mucus membranes
-
secretory immunoglobulin [sIgA](adaptive)
& Mucin and Lysozyme - Respiratory tract contains ________ which is important in immune function
- Surfactants
- Surfactants
-
-Pathogen-binding proteins
-Important in alveolar function - Surfactants are members of ________ family
- Collectin
- Surfactants bind _______ and ________
- pathogen and phagocytes
-
Surfactants binds pathogen and phagocytes using
Globular lectin-like “head†to bind _____ and a Collagen-like “tail†to interact with ______ - microbe/Macrophage
- an example of surfactant is __________ which can activate complement proteins
- Mannan-binding lectin (MBL)
- Chemical mediators of innate defenses
-
Stomach acid/digestive enzymes
Lysozyme
Interferon
Complement cascade - Lysozymes are involved in
- destruction of microbes
- Interferon has _______ activity
- antiviral
- Complement cascade has _______ activity and consists of (3)
- antimicrobial/Cell lysis, opsonization, inflammation
- the low _____ of stomach acid helps to kill microbes
- pH
- Reduced acid production increase risk for ______ infections
- Salmonella
- Some microbes can overcome the low pH of the stomach. For example, ___________ creates microenvironments where pH is not as low
- Helicobacter pylori
- Interferon has _________ properties
- Anti-viral
- Interferon causes cells to become resistant to viral infection by inducing changes in _________ and inhibiting _________
- cell surface receptors/viral replication
- Interferon inhibits viral replication by (2) ________
-
inducing CHANGES in host cell molecules needed for viral replication and
stimulating of APOPTOSIS of infected cells - types of interferon
- alpha, beta, and gamma
- a and b IFN have ________ than g IFN
- more potent antiviral properties
-
a and b IFN are involved in activation of ______ activity and
increased activity (class I presentation) - NK cell /TAP
- g IFN is involved in
- immune system activation
- g IFN is produced by
- Th1 cells
- TAP
- series of enzymes that chop up proteins for presentation w/ class I, role inCD8+ cells
- What are the three activities of alpha and beta IFN
-
1) induce resistance to viral replication in all cells by destroying viral mRNA
2)Increase MCH class I expression and Ag presentation in all cells by increased recognition of CTL or cytotoxic T lymphocytes.
3)Activate NK cells to kill virus-infected cells - CTL
- cytotoxic T lymphocytes.
- phagocytosis involves ________ by _________
- Recognition, ingestion, and digestion/Monocyte/macrophage, neutrophil
- Resident (tissue) macrophages (Mf)
- First cells to encounter microbe
- Resident (tissue) macrophages (Mf) are activated by
-
-molecules on microbes binding to toll-like receptors (TLRs)
-Antibodies (Abs) coating microbe - e.g., of Resident (tissue) macrophages (Mf)
- alveolar Mf (lung), Kupffer cells (liver), osteoclasts (bone), microglial cells (brain), histiocytes (CT), mesangial cells (kidney)
-
Neutrophils vs. Monocytes/Mf?
Rapid increase during the acute phase response - Neutrophils
-
Found in healthy tissues
Macrophage or Neutrophil? - Macrophages
-
Short lived (die after phagocytosis)
Macrophage or Neutrophil? - Neutrophils
-
Rapidly form pus
Macrophage or Neutrophil? - Neutrophils
-
Long lived (survive phagocytosis)
Macrophage or Neutrophil? - Macrophages
-
Only found in inflamed tissues
Macrophage or Neutrophil? - Neutrophils
-
Slowly form granuoloma (with T cell help
Macrophage or Neutrophil? - Macrophages
-
Slight increase in blood during inflammation
Macrophage or Neutrophil? - Macrophages
- How do macrophage/neutrophils recognize of microbes
-
1) Changes in adhesion molecules
Extravasation (neutrophils go through the endothelial cells to get to microbe)
2) Acute phase proteins-
Opsonize microbe
3) Microbe specific receptors
CR4 and CD14 – neutrophil binding to LPS
Toll-like receptors - Mf recognition of microbes
-
Most receptors on Mf bind microbe molecules NOT
found on human cells - Toll-like receptors
-
-transmembrane signalling protein on Mf or neut used in innate defenses for recognition of microbes
-Many different forms (~10)
-Can bind to many substances (LPS, DNA, RNA, yeast cell wall components) - Upon stimulation of TLRs
- get inflammatory response
- Neutrophil localization to site of infection
- Neutrophil “rollingâ€
- Chemokine
-
(a/k/a IL-8)
small molecule involved in inflammation - Neutrophil recognition of microbes
-
CR = complement receptors
FcR = binds to Fc region of Ab - Cytokines (e.g., IL-1B; TNF-a) are
- regulatory produce a variety of responses including fever, inflammation etc.
- Acute phase response
- some cytokines produced by macrophages (IL-6, TNF-alpha, IL-1) float away from site of inflammation/damage to the liver and cause hepatocytes to produce C-reactive protein (CRP) and MBL (mannan-binding lectin). These molecules bind to sugars on microbe to allow for opsonization & complement activation
- Septic shock
- Occurs when TLR and other receptors on Mf & neuts recognize microbe and over produce inflammatory cytokines (e.g., TNF-alpha) resulting in a systemic inflammatory reaction.
- Destruction of ingested microbe results in
- Respiratory burst (increased oxygen consumption) within phagocytic cell and production of reactive oxygen and nitrogen intermediates designed to kill the microbe
- Purpose of inflammation-
- vasodialation draw more WBCs to area
- Granuloma
- chronic inflammation
- NK cells
-
-Considered to be a lymphocyte but NOT antigen specific.
-Kill virally-infected cells and tumor cells (altered self cells-changes in surface proteins)
-once bind to cell they release lytic mediators - How does NK cell know to kill altered self cell
- altered self cell will be lacking some sort of surface marker
- Temporal relationship between innate and adaptive immunity
-
Temporal relationship between innate and adaptive immunity
Some damage occurs in the body for example the epithelial cells. (t=0) Phagocytic cells (neutrophils, monocytes) get called to the area. They release cytokines.(t=2hr) Cytokines stimulate inflammation.(t=4hr) Cytokines can activate compliment (cell lysis, inflammation, opsinization). Cytokines call in NK cells. (t=12hr ) The story may stop here. If microbe not destroyed, then B or T cells called to the area (t=1D). The B cells then produce effector antibodies and the T cells produce effector cytokines.