Explain the fundamental differences in innate and adaptive immunity
There are 4 fundamental differences in innate and adaptive immunity which are specificity (what kind of receptors are identified), receptors genes coding, kinds of receptors and differentiation between self and non self.
Innate immune response identify structures that are shared by an entire class of microbes or damaged tissues. These structures are necessary for pathogen infection or when a cell is damaged. The patterns are PAMPs (pathogen associated molecular patterns) and DAMPs (damage associated molecular patterns). The receptors for these are encoded in germline, which gives rise to limited diversity in these receptors. The distribution of these receptors are non clonal, there are identical receptors on all of the cells involved in innate immune response. For adaptive immunity the structure detail of microbial molecules are recognized. These are encoded by genes produced by somatic recombination of gene segments that gives rise to greater diversity. This results in a clonal response with cells having distinct specificities and different receptors. Both of the immune systems can differentiate between self and non self.
What are the intial barriers for innate immunity
There are physical and chemical barriers. Physcial can be the epithelial layer on our skin whereas chemical barriers can be proteases in our saliva and tears in our eyes
How does the epithelial leyer play a role in innate immunity.
It is a physical barrier and it also kills microbes by secreting antibodies such as defensins. Suprisingly there is also some extent of adaptive immune response associated with the epithelial layer of our skin where intraepithelial lymphocytes called the gamma, delta T cells secrete specific antibodies.
What is the role of neutrophils in innate immune response
These are the fastest white blood cells, they are the main phagocytes, neutrophils first respond to a bacterial or fungal infection. Their production is rapidly increased when there is an infection, production is increased by an increase in the prodcution of G-CSF (Granulocyte Colony Stimulating Factor).
Dead neutrphils form pus.
What is a band neutrophil?
How are they significant
It is an immature neutrophils. Their significance is that when we see alot of band neutrophils in the blood that means the body is experiencing a bacterial (she kept saying bacterial specifically) infection. Neutrophils live only for a few hours, band neutrophils go to the circulatory system where they mature.
Name the disease assocaited with neutrophils. What happens in that disease?
It is called Severe Congenital Neutropenia. This disease is associated with severe and recurrent bacterial and fingal infections and also sepsis. This is due to neutropenia (abnormally small number of neutrophils present in the blood). The disease is caused by a dysfucntion in the neutrophil generation mechanism.
The answer is A and D. It is important to know why. In some conditions patients may experience a lack in the prodcution of G-CSF whereas in other cases the actual stem cells are less or faulty which leads to the development of neutropenia.
Name the 2 causes of neutropenia
Increased destruction of neutropils or low rate of prodcution of neutrophils
How do you clinically differentiate between the 2 causes of neutropenia in a patient
We can look at their bone marrow and determine if the rate of production of neutrophils is fast enough or not
Describe the role of macrophages. What kind of cells do they arise from
They arise from monocytes. They have a variety of different roles:
1. Tissue resident macrophages
2. In all healthy tissues
3. Survive for months
4. Make cytokines to regulate other immune cells
5. Clear dead cells
6. They are also involved in tissue repair
Name some of the common PAMPs
These are basically essential cellular structure components that the microbes have, they are essential for infections and proliferation of the microbes. A few of these examples are:
2. Lipopolysaccharide (LPS), it is an endotoxin
3. Terminal mannose residues
4. Unmethyated CG rich DNA
What recognizes the PAMPs
PRRs: Pattern Recognition Receptors
The first class of these receptors is the Toll like receptors (TLRs). These can be either on the cell surface membrane to identify bacterial and fungi or they can be in the inside of the cells to identify intracellular parasites such as viruses and plasmodium.
Intracellular TLRs are called Endosomes
Explain the process of TLR singaling
I believe what she described here was a cell surface membrane TLR.
This receptor has a protein associated with called the MyD88 which interacts with IRAKF. Then there is cascade of signaling factors involved which eventually leads to NF kappa B transcription factor triggering gene transcription that induces an inflammatory response.
It is important to know that there are rare inherited conditions that are associated with faulty TLR singaling that predisposes an individual to a higher risk of infections
What receptors are found inside the cells that are assocaited with detecting EXTRAcellular microbes
These are called NOD like receptors
Explain the mechanism of action of NOD like receptors
The one that we need to know about in this lecture is called NLRP-3. It detects extracellular bacteria by sensing for bacterial products, K+ efflux, reactive oxygen species or crystals.
NLRP3 forms the NLRP3 inflammasome which causes activation of caspase 1. Caspase 1 then cleaves IL 1 beta (from pro-IL1 beta). This activates IL1 beta which then leads to the development of acute inflammation in that region.
What are the functions of IL1beta
It induces fever, it induces inflammation at the site of infection and it recruits neutrophils and monocytes to the site of infection
What are some of the other receptors that are employed to idenitfy extracellular microbes (other than TLRs and NLRs)
1. Mannose receptors - recognize terminal manose residues
2. Dectins - recognzie fungal glycans
3. Complement System
What are the 3 pathways to activate Complement system
1. Classical pathway - antibodies bind to the microbe
2. Alternate pathwya - proteins binds to the microbe
3. Lectin pathway - manose binding lectin (MBL) bind to the terminal manose residue on the glycoproteins present on the surface of the microbes
Describe the mechanism of compliment system in detail. What specific substances are involved in this pathway and what are their functions?
This consists of a system of proteolytic enzymes, which upon activation cleaves other protein that leads to an amplification of the signal and a cascade of events. The eventual end product of this cascade is that C3B binds to the microbe that facilitates its opsonization. Some other chemicals worth remembering:
1. C3A and C5A causes inflammation
2. C5 leads to the development of MAC complex on the microbe that leads to its lysis.
Define the acute phase response
It is part of the compliment system, an important part of the innate immunity where plasma proteins leads to the lysis of microbes that are present in the circulatory system.
There are 3 major plasma proteins involved in this process
1. Collectins - which are MBL, binds to the terminal manose residue on the glycorproteins that are present on the cell wall or cell surface membrane of the micrbes. Lung surfactant is also calssified as a collectin.
2. C Reactive Proteins (CRPs) - they have 5 heads, binds to the phosphrylcholine which leads to opsonization of the microbes, they are also capable to activate the compliment system
3. Lastly some chemicals directly associated with acute phase response are TNF alpha, IL-1 and IL-6 induce this acute phase response such that collectins and CRPs are quickly made in the liver
What is the process of leukocyte extravasation
What does TNF and IL1 do
They induce vasodilation and inflammation
What are the clinical signs of inflammation
1. There is heat and redness due to vasodilation
2. There is swelling, pain and loss of function due to increased permeability
What are Lekocytes Adhesion Deficiencies (LADs)
There are inherited deficiencies in selectins and integrins which leads to poor leukocyte recruitment. This leads to increased susceptibility to bacterial and fungal infections and there are also defects in wound healing
What are the different ways in which a mircobe can be killed
1. MAC can be placed on the microbes, leading to lysis of the microbe
2. They can be phagocytosed
3. Cell lysis by granules release to extracellularly digest their cellular compartment, these granules are present in neutrophils and mast cells
4. There are Neutrophils Extracellular Traps (NETs) where the bacteria can get stuck and they are destroyed once they get stuck their
What is released in the phagosome to digest the microbes
1. NADPH oxidase to release ROS
2. iNOS to release ROS (converts arginine to NO)
3. Lysosomal proteases
Why doesnt all these ROS and proteases doesnt kill the mast cells or nutrophils
She said because all of these substances are contained within the phagolysosomes, they do not cross the membrane of the phagolysosome so they dont casue harm to the white blood cell itself.
What is the name of the disease associated with phagocytosis of the microbes and what is the associated mechanism of this disease
It is called Chronic Granulomatous Disease where there is a deficiency in the NADPH oxidase enzyme. So the neutrophils keep phagocytosing the microbes but they cant destroy it. This leads to an accumulation of neutrophils in a spot, the body eventually tries to wall off this site of infections which causes the formation of a granuloma.
What are NK cells and how do they function, it is important to know that these are NK cells, not NKT cells! (NKT cells express the TCR).
They are lymphocytes, however they represent only a small population of lymphocytes, about 10%, the rest of the lymphocytes are T cells and B cells. They do not express TCRs or BCRs. They enhance microbes destruction. When a macrophage ingests a microbe they release IL12 which binds to the receptors of NK cells and these NK cells release IFN gamma which then allows the macrophages to effectively destroy the microbe while it was in a phagosome.
What are some of the other lymphocytes associated with innate immune response
1. NKT cells, these are T cells but they all have the same receptor, they recognize microbial lipids on CD1
2. B-1 B cells, these are B lymphocytes which are in the peritoneal cavity and in mucosal tissue, they immediately start pumping out antibodies whenever they see a PAMP. They produce IgG antibodies.
What are the proteins that respond to PAMPs that get inside the cells
RIG-I, MDAS, MAVS and STING
What are the types of interferons
There are 2 types:
Type 1: These are interferon alpha and beta
Type 2: These are interferon gamma's
What are the functions of interferons alpha and beta
1. Induce resistance to cell division to virus affected cells
2. Increase expression of ligands for receptors of NK cells
3. Cause the NK cells to kill virus infected cells
It doesnt have to be a virus, there are also several well known intracellular bacteria that casues infection.
Explain the disease associated with type 1 interferons
Recurrent Herpes Simplex Encephalitus. In this disease the body is either unable to produce type 1 interferons or doesnt have the sensitivity (enough receptors) for type 1 interferons. This leads to recurrent infections by the HSV virus which can also invade the brain, which normally doesnt happen in HSV infections.
Also this disease is associated with faulty signaling of the TLR-3, downstream of this receptor.
What is the function of TLR-3 singaling
Induce the release of IFN alpha and beta to stimulate the NK cells and stop the infected cells from dividing
What does NK cells do when a cell is infected
They can kill the cell by granule dependent killing or they can induce apoptosis by death ligands
How do you regulate immune response
1. Make IL1 antagonist
2. Release antiinflammatory cytokines such as IL 10
Name some of the microbes that have evolved mechanisms to evade the innate immune response
1. Listeria Monocytogen can evade phagocytosis, it can come out of the phagosome.
2. Some microbes cell wall is resistant to compliment system proteins
3. Some cause degeneration of the receptors such as NKG2D, one example of the virus is Cytimegalovirus (CMG).
Name 2 examples where the innate immune system causes pathology
1. Gouts: body recognizes urate crystals as foreign and leads to an immune response that causes inflammation
2. Periodic fevers: IL1 overactivation or over activity causes periodic fevers.
What is the pathology associated with NLRs
Polymorphisms associated with NOD 2 can cause some inflammatory bowel disease such as Crohn's disease
What is Sepsis
It a microbe specific or sterile non specific immune response that causes inflammation all over the body. It is associated with organ dysfunction, hypoperfusion and hypotension.
What is septic shock? What is the biochemical basis that causes septic shock?
It is a sepsis induced shock, its criteria is hypotension even when the fluids are administered intravenously to the patient. It can be life threatening and lead to multiple organ failure. It caused by low contractile power of the heart together with vasodilation and increased leakge of the capillaries.
It is caused by increases levels of TNF alpha which causes all of the above and thrombus formation on the endothelium.