Immunology Flashcards
What is inflammation?
What is its purpose in a nut shell?
bodies protective response against injury or infection
It…
- Mobilises defensive cells
- Limits pathogen spread
- Kills pathogens
How does inflammation present?
- Redness
- Heat
- Swelling (oedema)
- Pain
What causes pain when inflammation occurs?
Swelling puts pressure on the nerve endings
How does chronic inflammation lead to an autoimmune disease?
Inflammation targets and destroys healthy tissue leading to cardiovascular diseases, asthma, diabetes, arthritis and even cancer
Give some inflammatory mediator examples:
- Bradykinin
- Histamine
- Leukotriene D4
- Prostaglandin E2
What causes blood vessels to vasodilate during the immune response and why do they do this?
What clinical presentation does this cause?
Inflammatory chemicals increase blood flow and enhance permeability allowing plasma fluid and immune cells to get through and accumulate at site
Causes redness, swelling and heat
As well as vasodilation, what is the other job of the inflammatory chemicals?
Attract specific white blood cells to the site of injury which is helped by the increased blood flow
What is the basic response that occurs to trigger acute inflammation?
- Immune cells in tissue (eg. macrophage) come across inflammatory stimuli (pathogens, toxins, injured host cells)
- Stimulus binds to immune cell receptor
- Signal cascade activated
- Produces cytokines and inflammatory mediators
What causes the activation of complement proteins?
Foreign cells
What are complement proteins?
Substance that is produced by a predecessor protein or in response to the presence of foreign material in the body and that triggers or participates in a complement reaction
In summary, when inflammation occurs what does plasma do?
Moves out of the vessels into the site with antimicrobial mediators, platelets and blood clotting factors to destroy microbes and stop potential bleeding
What are neutrophils?
Major phagocytes (WBC) involved in first line defence
In summary, when inflammation occurs what doe neutrophils do?
Endothelial cells of blood vessels attach to the neutrophils slowing them down and then getting them through the vessel walls. Chemical ques guide them to site, and they engulf bacteria destroying them with enzymes or toxic peroxides.
They can also release reactive oxygen species, oxidative bursts, which is faster and more effective.
Once finished they die via apoptosis.
In summary, when inflammation occurs how do monocytes react?
Arrive and differentiate into macrophages which remove pathogens, injured cells and the dying neutrophils. Then they are cleared by the lymphatic system.
After monocytes have finished at a sight of injured or infected tissues, how does the lymphatic system clear them out?
The increased fluid at the site forces lymphatic capillaries to open their one-way valves allowing lymphatic drainage. The lymph passes through lymph nodes which filters out the macrophages before returning to the blood stream.
What is the name given to describe neutrophils and monocytes?
They are said to be phagocytic - they can remove bacteria and debris by engulfing or swallowing them
What drives the termination of inflammation once the site is clear?
Immune cells stop producing pro-inflammatory chemicals and produce anti-inflammatory mediators (eg. lipids), preventing chronic inflammation
What causes neutrophils to attach to the endothelial wall and then end up at the site of inflammation?
- Chemokines released at site of injury/inflammation activating capillary endothelial cells
- Endothelial cells express adhesion molecules which neutrophils respond to by expressing receptors that weakly bind to the endothelial wall
- Neutrophil adheres to vessel wall and rolls along its surface slowly (still moves due to blood flow)
- Neutrophil leaves vessel, and chemical signals direct them to sight of inflammation
What circulates in the lymphatic system?
Lymph = excess tissue fluid (plasma), white blood cells, nutrients, waste products, damaged cells
What is the lymphatic system?
What’s it made up of?
1 way system that’s part of the circulatory system. Carries lymph back to the circulating blood after being filtered by the lymph nodes.
It’s made up of a network of capillaries, vessels, ducts, nodes and tissues
What are the 3 main functions of the lymphatic system?
- Mechanism for removing excess interstitial (tissue) fluid, filtering it and putting it back into blood
- Transportation of fats
- Immune defence – presentation of foreign materials to the immune system & circulation of lymphocytes
Why is it important that lymph capillaries are intertwined with the circulatory capillaries?
- fluid and dissolved gasses are passing out of circulatory capillaries into interstitial tissues
- excess is removed from the tissue by the lymphatic system
- interstitial fluids enter lymph capillaries via openings between adjacent endothelial cells
How does lymph flow is the lymph vessels?
Flow is unidirectional and passive so contraction of surrounding muscles, arteries and respiratory pump help with return flow
How do lymph vessels compare to blood vessels, similarities and differences?
Lymph vessels also have valves to prevent back flow
Lymph vessels are similar in structure to veins but have thinner walls (more delicate)
Lymph vessels are not visible
The flow of lymph is a continuous cycle, draw out the process it follows from beginning to end:
Which duct is the largest in the lymphatic system?
What is the other important duct to note?
The thoracic duct
- Originates from the cisterna chyli in dorsal abdomen
- Drains into cranial vena cava around vicinity of left brachiocephalic vein
The tracheal duct
- Takes lymph from the head
(duct can also be called trunk)
What is the most common congenital disease of lymph vessels?
Lymphoedema = localised fluid retention due to obstructions/pathology of the system (other problems usually due to trauma)
What is the name given to lymph from the digestive system and what does it contain?
What is its identifying feature and why is this?
Chyle - contains protein coated lipid droplets called chylomicrons
Milky appearance due to emulsified fats
Where does chyle (digestive lymph) drain into?
Drains into lymphatic capillaries known as lacteals in the small intestine which return it to the chyle cistern (cisterna chyli)
What is the chyle cistern?
A lymphatic sac (not a node or duct) that is also the origin of the thoracic duct
What is chylothorax?
Leakage of Chyle into thoracic cavity. Linked to underlying conditions (heart disease, blood clots, heart worms or tumours)
What are the lymph organs, split them into primary and secondary:
Primary
- Thymus
- Mature bone marrow
- Birds = Bursa of Fabricius
Secondary
- Spleen
- Lymph nodes
- MALT
- GALT
- Ileal Peyers patches
Which lymphoid tissue produces B cells and which produces T cells?
Are these primary or secondary lymphoid tissues?
B cells - Mature in Bone marrow, Bursa of Fabricius (birds)
T cells - Mature and are ‘educated” in Thymus (Ileal Peyers Patches in some species)
Primary
Where is the thymus in animals?
How does the thymus change with age (same in birds)?
Caudal neck and cranial thoracic regions
Can see it in young animals but as they mature it is replaced with fat tissue
What are the main 3 features of the thymus (histology)?
- Cortex, medulla
- Connective tissue capsule and strands form incomplete lobules
- Hassall’s corpuscle
What travels to the thymus to become T-cells?
Bone marrow derived lymphocytes travel into the cortex of thymus
Here they mature to T-cells
What is the largest lymphoid organ?
Where is it located?
The spleen
Closely attached to greater curvature of the stomach on left side of cranial abdomen sitting superficially (bean shaped in birds)
What are the 4 main functions of the spleen?
- Storage of platelets
- Destruction of old red blood cells and platelets
- Reacts to blood borne antigens
- Main source of circulating antibodies: secondary lymphoid organ
What is a splenectomy?
Why would you perform a splenectomy?
Total removal of the spleen (Can survive without spleen as other organs can take over)
tumour, trauma, GDV (bloat and twisting of stomach)
What are the 6 main features of the spleen (histology)?
- Smooth muscle capsule (squeezes to push things in circulatory system)
- Trabeculae
- Central arteries
- Red pulp – vascular sinuses (blood capillaries)
- White pulp – mass of lymphoid tissue (T and B lymphocytes) looks more purple
What are lymph nodes enclosed in, what is the exception?
Enclosed be a capsule, tonsils are not
What happens as lymph passes through a lymph node?
Lymphocytes are added, and macrophages act as filters to remove microorganisms in an attempt to halt the spread of infection and tumours
Once lymph reaches the lymph node how does it travel into it?
Afferent vessels open into subcapsular sinus (as well as efferent)
The moves into trabecular sinuses into medulla and medullary sinus
What are the main 3 features of the lymph node structures (histology)?
- Capsule and subcapsular sinus
- Cortex – B-cell centres
- High endothelial venules (HEVs)
-> Characterised by plump endothelial cells
-> Allow lymphocytes from blood to enter directly into a lymph node
Why when there is an infection, do lymph nodes become swollen?
Infection causes a large production in lymphocytes so large lymph nodes indicates high filtration occurring as they are efficient filters so flow through them is slow as the
How does metastasis occur in lymph nodes?
Cells migrate from primary tumours and enter the lymphatic vessels, they lodge and grow as secondary tumours in lymph nodes (especially if they are well vascularised with slow blood flow)
Identify the following lymph nodes:
Identify the following lymph nodes in cattle:
What does an enlarged mammary gland usually indicate?
Mastitis
Why is the retropharyngeal lymph node important in horses and where is it located?
Drain larynx and pharynx collecting centre for other nodes of the head (often infected if horse has strangles)
Medial group lie at roof of pharynx and lateral related to guttural pouch in horse (lots of smaller collections)
Where is the bursa of fabricius located in birds?
Dorsal surface of cloaca
Are lymph nodes and vessels in birds the same as mammals?
No, birds have fewer nodes and vessels some even have no nodes and their thymus is lobed and accompanies the jugular vein
What are the stages of lymphocytes maturation in the following lymph organs:
Bone Marrow (BM)
Primary lymphoid organ (PLO)
Secondary lymphoid organ (SLO)
BM - Immature lymphocytes
PLO - Maturation of lymphocytes
SLO - Adaptive immune response
What is the fundamental property of cancer?
Cancer cells divide continuously (in defiance of the normal restraints on cell division) and have an altered metabloism
When do cancer cells start to spread?
If the environmental and nutritional conditions of the tumour deteriorate
What is neoplasia?
Uncontrolled, abnormal growth of cells and tissues in the body
What is a tumour?
Sweeping, usually without inflammation caused by an abnormal growth of tissue
What is mutagenesis?
When an organisms DNA changes causing a gene mutation
What is oncogenesis?
Formation of cancer where normal cells are transformed into cancer cells
What is angiogenesis?
Process of body forming new capillaries out of existing blood vessels
What are the differences between benign and malignant tumours?
- mitotic rate
- metastasis
- effect on tissues
- is the mass differentiable?
- cell pleomorphism and nuclei
What is the difference necrosis between apoptosis?
Necrosis: Lethal cell injury or accidental cell death in the living organism
Apoptosis: Programmed cell death
What are 6 causes of necrosis?
- Injury (mechanical, chemical, heat (burns), lack of O2 and nutrients)
- Infection
- Cancer
- Infarction (death of tissue due to lack of blood supply)
- Toxins
- Inflammation
How do necrotic cells damage other cells?
What enzymes are released in accompany to cell necrosis?
They release harmful chemicals that damage the other cells
Lysosomal enzymes which digest cell components
What happens to the cell when it is undergoing necrosis?
They start to swell because the control of ion passage and water is disrupted
Then the internal structures such as the mitochondria swell
Then the content leaks out causing inflammation of the surrounding tissues
What is a clinical example of cell necrosis?
Equine hepatitis
- hepatic necrosis due to bacterial infection
- Necrotic hepatocytes exhibiting nuclear pyknosis (condensation + reduction in size nucleus) and karyorrhexis (nuclear fragmentation with scattering of cytoplasm pieces)
What cells are destroyed during apoptosis?
What processes is apoptosis involved in?
- Unnecessary cells
- Infected cells
- Transformed cells
- Embryo development
- Tissue turnover
- Pathological stages:
–> decrease = neoplasia
–> increase = atrophy
Apoptotic cells are recognised by characteristic patters (morphological, biochemical, molecular) that have 3 distinct stages, early, intermediate and late. Describe what happens in each stage:
EARLY
- decreased cell size (dehydrated)
- altered membrane function
- large DNA stands break
- increase in cellular calcium levels
INTERMEDIATE
- DNA cleavage
- further decrease in cell size
- decrease in pH
LATE
- loss in membrane function
- formation of apoptotic bodies
- phagocytosis (no inflammation)
What is the difference between intrinsic and extrinsic signals for apoptosis?
Intrinsic = stress induced damage
- acts inside cell
- p53 recognises damage DNA
- mitochondria contributes to the trigger
Extrinsic = surface death receptor mediated
- act outside of the cell but then leads to chain of events inside cell
What is a clinical example of apoptosis?
During development:
Limb development, eg the interdigital mesoderm, initially formed between fingers and toes, is removed by programmed cell death
What are the differences between apoptosis and necrosis?
- physiological or pathological
- no. of cells
- change in size of cell
- what happens to membrane
- mitochondria involved?
- leakage of lysosomal enzymes?
- what happens to nuclei?
- what ingests the dead cells?
- cascade protease involved?
What echogenicity does the spleen appear as on an ultrasound?
Medium echogenicity
What is this an ultrasound image of?
The spleen
What non-cellular components are involved in the innate immune system?
- complement
- cytokines
- lactoferrin
- acute phase protein
What cells are involved in the innate immune system?
- Neutrophils
- Monocytes (and therefore macrophages)
- Eosinophils
- Basophil
- Mast cells
- Dendritic cell
- Natural Killer cells
What is lactoferrin?
Iron binding protein
Produced by epithelial cells of mucus, membrane and neutrophils
Anti bacterials as deprives bacteria of iron which is essential for bacterial growth and damages bacterial membrane
How many proteins are involved in the complement system?
30 proteins found in all bodily fluids
What are the 3 main roles of the complement system?
Cripples enemies
Rips holes in membrane
Activates the immune system
What steps occur in the complement system before C3 changes into C3a ad C3b?
C3 in passive state. Changes shape when activated. Protein cascade occurs activating other proteins. Activation cab be random or due to proteins or antibodies. Once active becomes C3a + C3b.
What does C3b do for the complement system?
Act on bacteria, fungi and viruses. Neutralised by water if target not found. Anchors to target, changes shape and creates a protein cascade. Platform on target called C3 convertase. This ativates more C3 creating an amplification loop until bacteria is covered, slow and helpless.
What does C3a do for the complement system?
Moves away from site activating passive immune cells which follow protein tracts back to target site (more C3a they encounter the more aggressive they become) - OPSONISATION
How does the complement system help phagocytes with phagocytosis?
Phagocytes arrive first of the immune cells to engulf the bacteria but they are slippery and don’t want to be caught. Complement acts like glue binding to complement receptors on the phagocyte.
Once the complement system helps the phagocytes, what does it do?
C3 complex on bacteria surface changes shape to recruit new proteins (cascade). This forms a membrane attack complex. Spear shaped proteins attach to this and anchor deep into the membrane ripping a hole in it - CELL LYSIS. Fluid rushes in and insides burst out.
Give an example for both bacteria and a virus has adapted to avoid being targeted by the complement system:
Virus = When vaccinia virus infects a cell it forces the cell to produce a protein that shuts down the complement activation system, creating a safe zone so has higher chance of success
Bacteria = some bacteria steals molecules from blood that keep complement system calm becoming invisible
Out of the following, which is the complement system most effective at destroying and why?
Bacteria
Fungus
Virus
Virus
Moves by travelling from cell to cell, during the transitions between they are defenceless waiting to bump into next cell, this is when the complement system attacks
How is innate immunity linked to adaptive immunity?
The complement system works with antibodies, this links the two systems
Immune Response
Acquired vs. Innate
Which is specific and which is faster?
Acquired
- specific
- slow the 1st time then once system knows a particular pathogen secondary response is RAPID
Innate
- non-specific
- fast
What are the 3 types of complement pathways, where do they all interlink?
- classical (antibody dependant)
- alternative (antibody-independent)
- lectin (antibody-independent)
At the C3 step
There are 3 types of antibody pathways, some are anti-body dependant and some are antibody-independent what is the difference?
Anti-body dependant = Effect of compliment strongly amplified in the presence of an adaptive immune response and links innate & adaptive immunity
Antibody-independent = Activated directly by microbial carbohydrates
What makes C3?
Is it found in high concentrations?
The macrophages in the liver
Yes, highest concentration of serum complement proteins in species
How is C3 removed from circulation the. it is no longer required as a preventative measure against unnecessary cascades?
Can bind to Factor H on host cells
What is the name given to C3a since it recruits immune cells to areas of infection?
Chemoattractant or a Anaphylotoxin
As well as recruiting immune cells, what other roles does C3a have?
- Change in smooth muscle so easier for cells to migrate from blood to tissues
- Increases vasodilation – more blood accessing site of infection, so more innate immune cells
- Activates mast cells or neutrophils
- Increases fluid in the tissue and speeds up lymph flow
What is canine C3 deficiency?
Inherited disorder - missing C3 in serum
Struggle to make certain antibodies, more susceptible to infection and higher chances of pneumonia, sepsis etc.
What is Porcine Factor H Deficiency?
Inherited recessive autosomal disease - factor H stops C3b activation
Carriers born normal for a few weeks then production problems occur
C3 accumulates on surface and basal membranes of kidneys but not in serum
Die of anaemia and renal failure
Where does initial lymphocyte development occur before bone marrow?
What in bone marrow gives rise to lymphocytes and other immune cells?
They yolk sac of the embryo and the fetal liver
Stem cells
Where in rabbits do B-cells mature? (different to other species)
Appendix
What is the function of the thymus?
How long does the thymus function for?
- eliminates T-cells from reacting to “self” antigens
- thymic education of T-cells
During foetal development and for the first few month of life and then it stops working
What does this picture show?
The thymus aging, shrinking and turning into fat and connective tissue
Once the thymus stops working are T-cells still produced?
No, once the thymus stops working that is all the T-cells that you will have fore life but they can clone to make more of themselves if needed
What is the function of red pulp?
What is the function of white pulp?
Red: Filters blood for foreign pathogens
White: Lots of cell types including T and B-lymphocytes
What is the main function of lymph nodes?
Presentation of antigen to lymphocytes and mount an immune response if necessary
(lymph nodes densely packed with T and B lymphocytes and have immune cells monitoring the lymph)
The MHC molecule on cells is what helps the immune system distinguish between healthy and infected cells, what changes between the two so that this identification can be made?
Healthy cells - the MCH groove is filled with a “self” peptide generated by the cell
Infected cells - the MCH groove is filled with a “non-self” peptide derived from the pathogens protein
There are two classes of MCCH molecules, MCH class l and MCH class ll?
MCH class l = on every nucleated cell – presents endogenous (‘self’)peptides
MCH class ll = on antigen presenting cells – presents exogenous (‘non-self’) peptides if infection has been found (if a macrophage had destroyed a cell then it shows that peptide but the cell is not destroyed the immune system goes and fights the infection)
During thymic education of T-lymphocytes some are eliminated, what properties would lead to elimination?
What is the name given to this type of selection?
T-lymphocytes that don’t interact with MHC
T-lymphocytes that respond to “self” peptides
Negative selection
During thymic education of T-lymphocytes some are kept, what properties would lead to this?
What is the name given to this type of selection?
T-lymphocytes that recognise the bodies MCH receptors
T-lymphocytes that ignore “self” peptides
Positive selection
As T-lymphocytes mature they express molecules on their cell membrane that determine what type of cell they will become, what are these two molecules?
CD4+ (T helper) or CD8+ (T cytotoxic)
What are the 3 outcomes of thyme education?
- Central tolerance
- T cells which do not react to their body’s own peptide antigens are selected (stops autoimmune disease) - Huge T cell diversity in peptide recognition
- T cells will recognise any non-self peptide, provided it is presented on an antigen presenting molecules MCH - Maturation of T cells
- T helper cells, cytotoxic T cells
What do cytotoxic T- cells express and which class do they respond to?
What do T-helper cells express and which class do they respond to?
CD8, interacts with MHC-Class l complexes on nucleated cells
CD4, interact with MHC-Class ll complexes on antigen presenting cells
In bone marrow self antigens are also presented but on stromal cells (cells that can becomeconnective tissuecells of anyorgan), what happens is a B-cell responds to this through it’s receptor?
- cell death by apoptosis
- receptor editing
B-cells have a specific receptor that responds* to self-antigens, what is the name given to it and what are the two forms in the membrane that it can be found in?
*or preferably does not respond
BCR
Bound or soluble
What is the correct order of CD4/CD8 expression in the development progenitor T-cell => cytotoxic T-cell?
CD4-/CD8- => CD4+/CD8+ => CD4-/CD8+
Which CD4/CD8 phenotype is characteristic for T helper cells?
CD4+/CD8-
What is junctional diversity in B and T-cells?
Addition of random extra nucleotides between the V, D and J regions, changing the structure of the variable regions that will be produced
What is randomly re-arranged when B-cells are at the B-cell progenitor stage ad T-cells are at the progenitor stage in the thymus?
Theirvariable(V),diversity (D), andjoining (J)genes allowing diversity to antigens as there are multiple copies of the gene that can be arranged differently very time
What determines the specificity of B-cells and T-cells allowing them to recognise a diversity of antigens?
determined by the shape of itsvariable region
What is the recombination process for BCR and TCR variation unique to?
It is unique to lymphocytes
Example – canine heavy chain repertoire:
41 V- segments (low number - usually hundreds)
6 D-segments
3 J-segments
How many variations could there be?
41 x 6 x 3 = 738
