23 Innate immunity Flashcards
1) Recognize and eliminate damaged and dead host cells
2) Stimulate the adaptive immune responses and influence the nature of the adaptive response
Are the functions of the ___
Innate immune system
Enable recognition of foreign microorganisms
Receptors
___ are mounted to eliminate the foreign microorganisms
Effector components
o Receptors are encoded in the germline
o Limited diversity
o Pattern recognition receptors (PRRs)
Recognizes structures shared by various microbes
Innate immune system receptors
o Epithelial barriers and secreted antimicrobial proteins are always present and do not need to be activated
o All other components of the innate immune system must be
Effector functionsd of the innate immune system
o Activated by sequential proteolysis (activation)
o Activation is inhibited by regulatory proteins that are present on normal host cells and absent from microbes (minimize damage to host cells)
Complement system
Cleaves complement component 3 (C3), which releases C3b and C3a as products.
C3 convertase
Stimulates mast cell degranulation, thus triggering an immune response. Attracts phagocytic cells to the site of inflammation
C3a
• The larger of the two elements formed by the cleavage of complement component 3. ___ covalently bonds to microbial cell surfaces within an organism’s body. Binds with the C3 convertase, forming the C5 convertase
C3b
Cleaves complement component 5 (C5), releasing C5a and C5b as products
C5 convertase
Diffuses away from the C5 convertase reaction and attracts phagocytic cells to the site of inflammation
C5a
Stays bound to the surface of the microorganism and continues the complement cascade (ends with the creation of a pore in the surface of the microorganism –the membrane attack complex)
C5b
Allows liquids, electrolytes, and other cellular components to exit/enter the microorganism, causing cell lysis
Membrane attack complex (MAC). Note: formation of the MAC is not effective against microorganisms that have a protective layer of carbohydrates, or an extra-thick membrane
Loss of liver function (e.g. alcoholic cirrhosis or chronic hepatitis B) leads to decreased complement protein synthesis and reduced complement function patients are predisposed to infections caused by ___ bacteria
Pyogenic bacteria
Part of the adaptive immune response (b/c antibodies are necessary to detect antigen on the pathogen surface and eventually form C3 convertase
Classical pathway
C3 is normally around (normally hydrolyzed). However, C3 may become attached to the surface of microorganisms, attracting factor B (which gets cleaved and attracts factor D which also gets cleaved). The end cleavage product is the C3 convertase
Alternative pathway
The mannose-binding lectin (MBL) is made by the liver. It is able to bind lectin (which is bound to carbohydrates of the microorganism membrane). It attracts C2, and C4, and the end cleavage product is C3 convertase.
MB-lectin pathway
Attaches to the surface of the microorganism, attracting C5b, C6, C7, C8, and C9 (forms the membrane attack complex, which lyses the pathogen)
C3b
May also be recognized by the C3b receptors of phagocytic cells, causing opsonization and phagocytosis
C3b
Allows for removal of antigen-antibody complexes and aids the B cells to identify pathogens
Cooperation w/ adaptive immune system
Inactivates protease activity of C1. This inhibits the classical pathway. A deficiency in C1 inhibitors leads to upregulation of the classical pathway (hereditary angioedema). In this disease, there are increased C3a, C4a, and C5a concentrations, leading to excessive inflammation, vasodilation, and vascular permeability, leading to edema
C1 inhibitor
Disease resulting from upregulation of the classical pathway. There are increased C3a, C3a, and C5a concentrations, leading to excessive inflammation, vasodilation, and vascular permeability, leading to edema
Hereditary angioedema
Binds to C4b and C4b, limiting the formation of C3 and C5 convertases. A deficiency leads to increase C3 and C5 convertase formation. This leads to complement-mediated hemolysis (paroxysmal nocturnal hemoglobinura is the resulting disease and is due to increased RBC lysis)
Decay accelerating factors
Disease caused by deficient decay accelerating factor levels, and the resulting increase in C3 and C5 convertase formation
Paroxysmal nocturnal hemoglobinura
Patients w/ C5-C9 complement deficiencies have increased susceptibility to only certain types of infections ( ___ and ___ infections)
Meningococcal & Neisseria-gonorrhea
A phagocytic cell w/ a C3b receptor will increase its recognition of the pathogen to which the C3b protein is bound. Note: iC3b or Ab individually will enhance phagocytosis of the pathogen. However, both iC3b and Ab together will enhance phagocytosis of the pathogen even more
Opsonization (enhanced phagocytosis)
1) Formation of the MAC
2) Opsonization
3) inflammation
Functions of the complement system
Stimulated by C3a and C5a. All below factors are involved:
Contraction of smooth muscle
Increase vascular permeability
Increase expression of cell-adhesion molecules (CAM) on endothelial cells
Activate mast cells and basophils to produce inflammatory mediators (i.e. histamine, Tumor necrosis factors (TNFa))
C5a: acts directly on phagocytic cells to increase adhesion and extravasation
Inflammation
A variety of ROSs are generated (toxic to microorganisms). Hydrogen peroxide, hydroxyl radicals, activated halides (Cl-, I-, etc), and NO are all used
Oxygen dependent killing
Lysosomal enzymes and acidic pH destroy the microorganism.
Oxygen-independent killing
Defect –NADPH oxidase activity (inability to form hydrogen peroxide). Consequence: Lack of oxidative burst and defective bactericidal activity. Leads to buildup of macrophages that are not able to kill microorganisms (granulomas)
Chronic granulomatous disease
Defect –Myeloperoxidase (lack of hypochlorite production). Consequence: phenotype is mild b/c of the presence of other reactive oxygen species that can handle microorganisms
Myeloperoxidase deficiency
May be activated by pathogens (lipopolysaccharides and mannose in the microorganism membrane) themselves or by the cells of the immune system.
Macrophages
A macrophage that has been activated by an antigen will increase in size and in its capacity for phagocytosis. It will also produce and secrete more cytokines that are normally produces by macrohpages
Hyperactivated macrophage
A macrophage that has been activated by T cells or NK cells (interferin-gamma mediated) will have enhanced expression of antigen presentation (increased expression of MHC2). They will also have increased phagocytic capacity
Primed macrophage
T/F. Activated macrophages secrete a number of cytokines that promote inflammation (IL-1 and TNF-alpha)
True
1) Inhibition of fusion w/ the lysosome
2) Prevention of acidification of endosomes
3) Escape the endosome
4) Prevent presentation of antigen
5) Therefore, a bacteria that would’ve normally developed in the extracellular space now develops inside macrophages
Mechanisms developed by pathogens to enter and survive inside macrophages
o About 70% of cells in the blood (most abundant cells in the blood)
o Shorter half-life compared to macrophages (b/c they are too dangerous to keep around for long)
o Attracted to the site of inflammation by interleukin-1 and TNF-alpha (both are secreted by macrophages), C5a, and by microorganisms (lipopolysaccharides)
o Function: phagocytosis
Neutrophils
Defect –integrin beta chain/CD18 (type 1) and selectin (type 3). Consequence: poor adhesion of neutrophils to endothelium. Leukocytes also have poor adhesion. Therefore the endothelium is affected (low quality integrin attached) so are several cells involved in the immune response
Leukocyte adhesion deficiency
The process by which leukocytes and circulating plasma proteins are brought into sites of infection and activated to destroy and eliminate the offending agents
Inflammation
Function to induce apoptosis in infected host cells (w/ virus, bacteria, or cancerous cells) and damaged cells
o Different than T-CD6 cells in that there is no T-cell receptor (no education)
o Markers: CD16 (Fc-IgG), CD56. Found on the surface of these cells
o Migrate to tissues (roll, stop, enter)
o Recognize target cells by checking the balance b/t kill vs. non kill signals
Kill signals: e.g. foreign molecules (lipopolysaccharides –LPS)
Non-kill signals: e.g. MHC1
Activated by interleukin 2 (IL2 –stimulates proliferation of all T cells), interferon (IFN alpha & IFN beta)
o Cytokine production: e.g. IFN-gamma, for differentiation of Th1 cells (helper T cells)
Natural killer cells
consists of changes in cells that prevent virus replication and increase susceptibility to killing by lymphocytes, thus eliminating reservoirs of viral infection
o A cell that has been infected by a virus will synthesize interferon which travels to neighboring cells, activating the IFN receptors and thus activating the antiviral response. The below are functions of the antiviral response
Cells whose IFN receptors have been activated synthesize antiviral proteins that sit in the cytosol. Thus they are “ready for” the invasion of viral proteins and will degrade any viral proteins that end up in their cytosol
o Other functions:
Increase antigen presentation (increase MHC1 expression)
Induce chemokine release to recruit lymphocytes
Activates NKC
Antiviral defense
The link b/t innate and adaptive immunity
o (NOT macrophages) Take up bacterial antigens in the skin (and tissues) and move to enter a draining lymphatic vessel
o Bearing antigen, these cells enter the draining lymph node where they settle in the T-cell areas
Dendritic cells
Not formed in host cells b/c of a protective response (specialized molecules) that prevents these holes from forming in the membrane
Membrane attack complex
As a result of infection, these cells increase in concentration in the blood
Neutrophils
What is the order in which immune cells are activated during an infection?
1) Resident macrophages are activated first
2) Neutrophils are the first cells recruited to the site of infection by macrophage cytokines
3) Monocytes are then recruited so that they can differentiate into more macrophages
4) Lymphocytes are then recruited to deal with the infection
___-gamma is involved in the interplay b/t macrophages & NK cells. ___ type-1 (alpha or beta) Is involved in the antiviral response
Interferon (IFN)
- Innate immune response: LPSs found on the surface of bacteria can activate the system. Neither antibodies nor T cell receptors are involved
- Adaptive immune response: The most potent means of activating this sytsem. This occurs when antibodies bind to the antigen at the surface of a cell. This exposes the Fc region of the antibody in a way that allows the first complement protein (C1) to bind
Activation of the complement system
Complement peptides. Ex: C3a, C4a, and C5a
Anaphylatoxin
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