Lecture 32 - Innate immunity II Flashcards
3 layers of immune defence
1 - physical and chemical barriers (skin, mucosal membranes)
2- the innate immune system
3-the adaptive immune system
The inflammatory response
For example a foreign object manages to bypass the physical barrier of the skin therefore the bacteria have been able to get past this layer of defence
Chemical signals from the tissue- resident cells act to attract more cells from the circulation to the site of injury of infection (they do this by creating a chemical gradient by releasing chemical mediators and this gradient is able to attract the extra cells needed)
Neutrophils enter the blood from the bone marrow (neutrophils are circulating through the blood normally but then they are able to detect the chemical gradient)
Neutrophils cling to the capillary wall (neutrophils, after detecting the concentration gradient, slow down and cling on to the capillary walls, so instead of shooting past like normal they start slowing down and rolling along the capillary walls)
Chemical signals from tissue-resident cells dilate blood vessels and make capillaries ‘leakier’ (so things can get out of these vessels and into the tissue more easily) (Therefore a common feature of inflammation is the skin going red due to dilating and increased blood flow into this area also causes heat) (dilating which means making them buffer therefore more blood is getting to that area)
Neutrophils squeeze through the leaky capillary wall and follow the chemical trail to the injury site
Then neutrophils phagocytose
Diapedesis
Immune cells get from the blood to the site of infection called a process called diapedesis
Neutrophilia
During bacterial infections the number of neutrophils circulating in the blood increases
Neutrophilia is an increase in circulating neutrophils above that expected in a healthy individual. Neutrophuls are the primary white blood cells that respond to bacterial infection, so the most common cause of neutrophilic is a bacterial infection, especially pyrogenic infections. Neutrophils are also increased in any acute inflammation (increase in neutrophils should increase the body’s ability to phagocytose)
Phagocytosis
Cell eating
Many _______ cells are phagocytic
Myeloid
Stages of phagocytosis
1- Phagocyte adheres to pathogens or debris
2- Phagocyte forms pseudopods that eventually engulf the particles, forming a phagosome (pseudopod is a foot like projection that goes out and wraps itself around particles) (phagosome is the little vesicle after pseudopod wraps around the molecule)
3- Lysosome fuses with the phagocytic vesicle, forming a phagolysosome (lysosome is full of enzymes that will break down pathogens + acidic) (the membrane of the lysosome is able to bind with the membrane of the phagosome - fills the phagosome with digestive enzymes which are very toxic to the pathogens therefore they breakdown and destroy the pathogens)
4 - Toxic compounds and lysosomal enzymes destroy pathogens (now the nucleic acid will be visible once it has been broken down into all its components that represents whether it is a virus or a bacteria so the toll-like receptors can send signals through to the cell to start regulating its gene transcription and start up regulating transcription of IL-1 etc that causes fevers and starts down regulating thing that do need to be made at that exact moment. So in this way the pathogen is destroyed but the immune cell is also able to illicit effective functions on lots of other cells by the chemical mediators it is able to produce)
5- Sometimes exocytosis of the vesicle removes indigestible and residual material (ejects the material)
Importance of phagocytosis
Important for destroying the organism but it is also important for cell communication because it can regulate genes and talk to other cells and allows the innate cells to communicate with the adaptive cells of the immune system
Killing and digesting of phagocytksed microbes
Low pH - acid environment - this is a good way of killing microbes. The lysosome is very acidic and the formation of the phagolysosome therefore creates an acidic environment that is antimicrobial
Reactive oxygen (hydrogen peroxide) and reactive nitrogen intermediates (nitric oxides) - this is very toxic to bacteria
Enzymes (digestive enzymes) - proteases ( good at breaking down proteins), Lipases (good at breaking down fats) and nucleases (good at breaking down nuclear material I.e. DNA or RNA)
The complement system/the complement cascade
Complement - 9 major proteins/protein complexes (C1-9) act in sequence to clear pathogens from blood and tissues
Label pathogens = opsonisation
Recruit phagocytes = chemotaxis
Destroy pathogens = lysis
Complement provides a major mechanism for destroying foreign substances in the body. Its activation unleashes inflammatory chemicals that amplify virtually all aspects of the inflammatory process. Activated complement also lyses and kills certain bacteria and other cell types. Although complement is a nonspecific defensive mechanism, it ‘complements’ (enhances) the effectiveness of both innate and adaptive defences
A group of blood borne proteins that when activated…lyse microorganisms, enhance phagocytosis by opsonisation and intensify inflammatory and other immune responses
Opsonisation
Coats pathogen surfaces which enhances phagocytosis
Chemotaxis
Recruitment of phagocytes by creation of a chemical gradient
Lysis
Destroying of pathogens
disruption of cellular membranes, leading to cell death and the release of cytoplasmic compounds in the extracellular space
What are the three complement pathways?
Classical, alternative and lectin pathway
Classical pathway
Antibody bound to pathogen binds complement (triggers the first enzymatic reaction and then the cascade starts)
Activated by antipodies coating the target cell
Alternative pathway
Pathogen binds complement to surface/pathogen components (triggers the first enzymatic reaction and then the cascade starts)
Activated spontaneously. Lack of inhibitors on microorganism’s surface allows process to proceed
When C3b binds directly to a microbe
Lectin pathway
Carbohydrate components of microbes bind complement (binding to first protein/protein complex leads to enzymatic activity and leads to the cascade of enzymatic reactions)
Activated by lectins binding to specific sugars on the microorganism’s cell surface
Lectins = water soluble protein molecules
Complement pathways converge
Triggers - classical or alternative (properdin) or lectin
These all converge to the formation of …
Amplification - C3 converts (enzyme complex)
Outcomes - label (opsonisation), destroy (lysis) and recruitment (of white blood cells to phagocytose)
The three outcomes from the complement cascade
Label - opsonisation
Recruitment
Destroying of pathogen (lysis)
Label (opsonisation)
Coating of a microbe with antibody and/or complement fragment C3b
Opsonisations (labels pathogens which bind to complement receptors on phagocytes)
Mediated with C3b which is produced when C3 converts is enzymatically cleaved into C3b and C3a
Recruit
Complement proteins act as peptide mediators of inflammation and recruit phagocytes
Mediated by C3a and C5a. These act as chemotaxis agents, means that chemicals are present that basically have an attractive gradient to the phagocytes so they come to that area and help destroy the microbe
Phagocytes attracted into site. Mast cells are degranulated by C3a and C5a. (when these cells encounter C3a and C5a they release those chemical mediators….) Inflammatory mediators released including proteins that attract phagocytes.
Destroy
Membrane attack complex formation and this results in a pore in bacterial cells this therefore causes death in the pathogen because all the contents start leeching out
C9 forms the MAC
Microbes are coated with C3b are phagocytosed. Assembly of MAC complex causes lysis (C9 components of the complement cascade forming this)
Membrane attack complex
MAC forms and stabilises a hole in the membrane that allows a massive influx of water, lysing the target cell and forms a pore which foes through the target cell membrane and then all of the contents can leech out resulting in the death of this target cell
C3b
Act as opsonins which coat the microorganism, providing ‘handles’ that receptors on macrophages and neutrophils can adhere to. This allows them to engulf particles more rapidly
C9
Forms the membrane attack complex which causes a pore in the bacterial cell walls which causes death of the cell
C3a and C5a
Amplify the inflammatory response by stimulating mast cells to release chemicals and by attracting neutrophils and other inflammatory cells to the area
Phagolysosome
When a lysosome fuses with a phagosome
How might neutrophils recognise bacteria?
Bacteria have common patterns on their surfaces called PAMPS that pattern recognition receptors (toll-like receptors) on our phagocytes can recognise
Recognise a broad pattern over bacteria and viruses not specific species.
Toll-like receptors… some are internal and some are on surface. Bacteria usually recognised by a PAMP on the surface whereas virus because they invade our cells are more likely to be recognised by toll like receptors inside the cell
Explain the mechanism by which the entry of bacteria into the system causes an increase in body temperature
Increase in temperature means that bacteria will be less likely to grow
The mechanism of fever appears to be a defensive reaction by the body against infectious disease. When bacteria or viruses invade the body and cause tissue injury, one of the immune system’s responses is to produce pyrogens, which when introduced or released into the blood cause fever. Fever can support the immune system’s attempt to gain advantage over infectious agents, such as bacteria, and it makes the body less favourable as a host for replicating bacteria that are temperature sensitive
