Immunology Flashcards
Physiology of vasodilation
occurs due to histamine being released by mast cells acting on smooth muscle in blood vessels
Vascular permeability is increased by…
histamine, bradykinin, prostaglandins and leukotrines. Endothelial cells contract and the tight junctions between them are disrupted
What is vascular stasis and how does it help?
Is the slowing of blood flow which allows cells to line up near the endothelium (margination)
Physiology of pain in inflammation
Action of inflammatory mediators (prostaglandins and cytokines) on free nerve endings either directly activating them or sensitising them
Physiology of loss of function in inflammation
Damage to cells necessary for tissue function (esp. parenchyma; also stroma)
What is leukocyte extraversion?
is moving out of the vascular lumen to the tissue and then towards the site if injury
Role of a neutrophil in acute inflammation
predominate first few hours, nucleus has 2-5 lobes, they phagocytose microbes, dead cells, cell debris, produce neutrophil extracellular traps and secrete cytokines
How to identify a monocyte histologically
are large with bean shaped nucleus
Role of macrophages in acute inflammation and how to distinguish from monocyte
are large with bean shaped nucleus but have more cytoplasm than monocytes, they are phagocytic, secrete lots of pro inflammatory cytokines and can activate T cells
What are 2 therapeutic interventions for acute inflammation?
COX-inhibitors(such asaspirinandibuprofen)
MoA:inhibitprostaglandin synthesis;particularlyeffective attreatingpain
Steroids(such as dexamethasone)
MoA:bind to glucocorticoid receptors in innate immune cells, inhibiting inflammation
Hallmarks of serous inflammatory response
Characterised by accumulation of exudate in a cavity (e.g., peritoneal or space created by injury). Exudate is derived either from plasma or mesothelium. Exudate is essentially sterile and free of leukocytes
Hallmarks of fibrinous inflammatory response
Characterised by large deposition of fibrin. Typically occurs at lining of certainbodycavities (e.g.,pleural and pericardial). Highvascularleakage +procoagulantstimulileads tofibrin deposition. If notresolved, a scar may form that can disrupt tissue function
Hallmarks of purulent (suppurative) inflammatory response
Characterised by the formation of pus, whichcomprisesnecroticdebris(dead/dying neutrophils, tissue cells and usually bacteria)andtissuefluid. An abscessis alocalisedcollection ofpus buried inside a tissue. If inflammation is chronic, repair processes may initially surround and then eventually replace the abscess with fibrotic connective tissue. Often causedby infection with pyogenic bacteria
Hallmarks of ulcerative inflammatory response
An ulcer is a localdefect in a tissue causedsloughingoff or disintegrationinflamed necrotic tissue. Foundwhere inflammation and necrosis can occur at ornearasurface (e.g.,the mucosa ofthegastrointestinal tract). Acute and chronic inflammatory processes may be going on simultaneously in distinct areas of ulcers (e.g., peptic ulcers)
What are the outcomes of acute inflammation?
Resolution
Repair by fibrosis
Progression to chronic inflammation
Formation of granuloma
Causes of chronic inflammation
persistent infection, unresolved acute inflammation, continual exposure to stimulus, hypersensitivity disease
Features of chronic inflammation
tissue infiltration by mononuclear cells (monocytes, macrophages, dendritic cells and lyphocytes), destruction of normal tissue architecture and angiogenesis and fibrosis
What are the 4 treatment options for chronic inflammation?
NSAIDs E.g., naproxen for the treatment of ankylosing spondylitis. Corticosteroids E.g., inhaledbudesonide for chronic asthma. Immunosuppressants E.g., methotrexate for rheumatoid arthritis. Biologics E.g., adalimumab for severe active Crohn’s disease
What happens in T cell development?
CLP→ proliferation in thymus→ double negative thymocyte→ arrange beta chain D-J→ continue to arrange with surrogate alpha → stop rearranging and start proliferating → double positive thymocyte→ start rearrangement of alpha chain→ check self recognition (positive selection) → apoptosis if no recognition → negative selection to determine either CD4 (MHCII) or CD8 (MHCI) → but if strong affinity then apoptosis→ T reg if low affinity to MHCII
What happens in B cell development?
What are central vs peripheral mechanisms of immune tolerance?
Central-
- Thymus- education and selection of t cells
- Bone marrow- production and selection of B cells
- AIRE- AutoImmuneRegulator- Transcriptional regulatorwhich induces theexpressionofself-proteinsin thethymus. AIRE isexpressedin the nucleus of thymic medullarystromalcells.
Peripheral-
- Preventing aberrant immune responses in peripheral tissues
- iTreg suppress effector responses to innocuous foreign antigens and development of autoimmunity, secrete IL10 and TGF-B
What is APECED AutoimmunePolyEndocrinopathyCandidiasis EctodermalDystrophy?
Caused by mutation of AIRE. The immunesystemattacks multiple endocrinetissues: parathyroid glands, adrenal glands,pancreaticinsulin-producingcells
Primary vs secondary immunodeficiency
Primary (genetic eg. SCID, treated with bone marrow transplant), secondary (acquired eg. AIDS, starvation and drug acquired impaired immunity, managed with anti-microbials)
What is AIDS?
Caused bythehuman immunodeficiency virus(HIV). Receptor is CD4; obligatory co-receptors are CXCR4 and CCR5. Not rapidly cleared and ultimately cannot be chronically controlled. Initial infection of CD4+ cells at mucosa: T cells and dendritic cells. Spreads to lymph nodes, then systemically
What are the cells that are involved in a TB granuloma?
macrophages, monocytes, multinucleate giant cells (formed by fusion of macrophages) and lymphocytes
What is granulomatous inflammation?
Form of chronic inflammation, response to offending agent that is difficult to eradicate, characterised by organised collection of immune and other cells and aggregation of activated macrophages. Seen in TB, crohns and sarcoidosis.
What are the 2 types of granulomatus inflammation?
Foreign-body granuloma
- Reaction to inert foreign material (e.g., silica, sutures)
- No T cell-mediated immune response
Immune granuloma
- Caused by agents that are capable of eliciting a T cell mediated response
- Certain mycobacterial, fungal and parasitic infections produce immune granulomas
What are the outcomes of a granulomatous inflammation?
healing by fibrosis and consequent tissue and organ damage. They can calcify over time which is a type of scarring
What are the 4 stages of tissue repair?
What 2 things does the outcome of tissue repair depend on?
Nature of damage and nature of tissue
What is labile tissue? Give examples
(continually dividing) can easily regenerate as long as there are stem cells remaining
e.g., surface epithelium, haemopoietic cells in the bone marrow
What are stable tissues? Give examples
do not actively proliferate in their usual state but are capable of (limited) regeneration in response to injury e.g., endothelial cells, smooth muscle cells, parenchymal cells of some solid organs
What are permanent tissues? Give examples
are terminally differentiated and unable to regenerate e.g., neurons, cardiac myocytes
What is the process of tissue regeneration?
Existing, surviving functional cells proliferate. Stem cells located in specific niches in the tissue differentiate into the required lineages. Growth factors, produced at the site of injury by macrophages, epithelial cells and fibroblasts, drive the response
TGF-B function
Transforming growth factor beta
Fibrobalast migration
Collagen synthesis
Monocyte migration
PDGF function
Platelet derived growth factor
Fibroblast migration and proliferation
collagen synthesis
monocyte migration
angiogenesis
wound contraction
VEGF function
Vascular endothelial growth factor
Angiogenesis (endothelial cell migration and proliferation)
EGF function
Epidermal growth factor
Epithelial cell migration and proliferation, fibroblast proliferation, MMP synthesis
FGF function
Fibroblast growth factor
Fibroblast migration and proliferation, epithelial migration and proliferation, MMP synthesis, wound contraction
Damage to … means full regeneration cant be achieved
ECM
What is the mechanism of scar formation?
What are the factors influencing tissue repair?
• Infection (prolongs inflammation) I
• Disease (diabetes causes poor perfusion) Don’t
• Nutritional Status (protein deficiency) Need
• Glucocorticoids (less inflammation, less repair) Gloves
• Mechanical Factors (physical disruption) My
• Perfusion (reduced delivery of materials) Pinky
• Foreign-bodies (persistent stimulus) Finger
• Injury type and extent (loss of function) Itches
What are 5 examples of abnormal tissue repair?
What are the causes and consequences of low grade systemic inflammation?
Causes
- Ageing – ‘inflammaging’. Immunosenescence and mitochondrial dysfunction likely contribute
- Poor diet. Alteration of the gut microbiome and excess adipose tissue
- Stress. Prolonged elevation of cortisol promotes inflammation and attenuates tissue repair
Consequences
- Sickness behaviours and physiological responses, such as fatigue and raised blood pressure
- Breakdown of tolerance leading to autoimmune diseases and IMID
- Dysregulation of normal cellular and tissue physiology, predisposing to metabolic diseases and cancer
Immunodeficiency vs autoimmunity
Immunodeficiency- poor or no response to pathogens
Autoimmunity- inappropriate response to self antigens
What is the loop in which chronic autoimmunity develops?
What are the genes associated with self-tolerance?
What are the environmental factors associated with self-tolerance?
- Smoking
- Chemicals
- UV
- Infection
How does cryptic antigens lead to autoimmunity?
Some antigens are hidden within cells or are altered in changing environmental conditions (e.g., hypoxia). These appear differently in the bone marrow and thymus and therefore look like non-self in the periphery. These are cryptic antigens. They can activate T and B cells to cause damage and further antigen release
How does molecular mimicry lead to autoimmunity?
Some pathogen antigens structurally resemble self antigens and may bind BCR/TCR with higher affinity. Infections can activate cross reactive responses to self antigens and initiate autoimmunity. Eg. Ankylosing spondylitis and guillian-barre syndrome
What are the mechanisms of damage for the immune system?
Graves’ disease and myasthenia graves are…mediated
Antibody
Rheumatoid arthritis immune mechanism
Type one diabetes is… mediated
Cytotoxic t cell
What are the phyla of bacteria present in the gut of a healthy person?
What are the factors associated with the composition of the gut microbiota?
What are the 5 ways in which commensals bacteria contribute to health?
What are the factors that can tip the microbiota balance?
Small vs large intestine gut immunity
Small intestine- loose mucus layer (not as well differentiated), digestive factors, shorter transit time, paneth cells produce more AMPs, less pathogens [compared to large intestine]
Describe the innate immunity in the gut
What do dendritic cells do in the gut?
Antigen delivered via M cells, via transcytosis of ab-ag conjugates, via directly sampling from gut and via uptake of apoptotic cells
What do T cells do in the gut?
T cells in Peyer’s Patches; and IELs (intraepithelial lymphocytes). Th17 cells are a component of normal epithelial defense; aberrant lumen, Th17 generation linked to immune-mediated inflammatory disease
What is the gut immune response to pathogenic bacteria?
What is the role of short chain fatty acids in the gut microbiota?
What is Crohn’s disease? Symptoms and cause
- Immune mediated inflammatory disease
- Affects the epithelium, lamina propria and other layers of the bowel wall. It can affect any part of the gut, but most commonly the terminal ileum / first part of colon
- Can see non-caseating granuloma
- Symptoms- abdo pain, fever, mouth ulcers, loss of appetite, fistulas
- Genetic and environmental factors interact to produce disease. Potentially a role for an environmental trigger (e.g., infection with a pathogen; stress). Significant genetic associations with susceptibility and protection. NOD2. An intracellular PR involved in recognition of bacterial infection (specifically MDP). IL-23R. Th17-skewing cytokine receptor
What is coeliac disease?
What are the cellular effects of injury?
What are the mechanisms of cell injury?
What happens in haemostasis?
- At the time of trauma, vascular injury occurs on a microvascular -/+ macrovascular scale
- The immediate response of the body is to prevent exsanguination -> promote haemostasis
- Damaged arteries rapidly constrict through the contraction of smooth muscle triggered by SNS and vasoconstrictors released locally –thromboxane A2 and endothelin
- Vessels up to a diameter of 5 mm can be completely closed through contraction, although this can only occur if the injury is in a transverse plane
- In a few minutes, the reduced blood flow mediated by artery and arteriole constriction leads to tissue hypoxia and acidosis which
promotes the production of vasoactive metabolites e.g., nitric oxide and adenosine which cause vasodilatation and relaxation of the arterial vessels. At this point coagulation is needed for haemostasis
What happens in early inflammation?
- Mast cells degranulate releasing histamine
- Increases vasodilatation and increases vascular permeability
- Entry of inflammatory cells into the wound
- Complement is activated
- Neutrophils infiltrate the wound within an hour of the insult and migrate over the first 48 hours
- Neutrophils carry out phagocytosis, degranulation and NETosis
What happens in late inflammation?
- Macrophages are pro-inflammatory in the first days of wound healing (M1 phenotype) and become anti-inflammatory / more pro-resolution in later stages (M2)
- Lymphocytes appear in the wound (~72 hours +) and are involved in regulation of wound healing (as well as adaptive response to infection). Persist until wound healed
- Dendritic Epidermal T Cells (γδ T-cells) secrete keratinocyte growth factor (stimulates keratinocytes to proliferate) and IGF-1 (differentiation). Non-conventional T cell
- Products of arachidonic acid metabolism have anti-inflammatory properties which dampen the immune response and allow the next phase of wound healing to arise
What happens in angiogenesis?
Initially the centre of the wound is avascular and relies on diffusion of oxygen and nutrients from the undamaged capillaries at the wound edge. Later a rich vascular network of capillaries is formed throughout the wound from offshoots of healthy vessels. Angiogenesis is triggered from the moment the haemostatic plug has formed: platelets release VEGF as well as TGF-β, PDGF and FGF. Hypoxia is a key driver. VEGF is secreted by macrophages, fibroblasts and other cells, stimulating endothelial cells to proliferate and migrate forming tubes. MMPs are important for remodelling of the ECM.
What happens in fibroblast migration?
By the third day, the wound becomes rich in fibroblasts which proliferate and migrate in response to growth factors (FGF, PDGF, also TGF-b). They lay down extracellular matrix proteins (collagen, fibronectins and proteoglycans) – TGF-b very important for stimulation of this. Fibroblasts release MMPs: collagenases MMPs 1, 8 and 13. Collagens synthesised by fibroblasts are the key component in providing strength to tissues. The resulting pink, vascular, fibrous tissue which replaces the clot at the site of a wound is termed granulation tissue. Once sufficient matrix has been laid down, fibroblasts change to a myofibroblast phenotype and become more spindle-shaped. They connect to the surrounding cells and ECM proteins (e.g., fibronectin and collagen)
What is hypersensitivity and the different types?
- A hypersensitivity reaction is an overreaction to a harmless substance(s) which results in an immune response that causes inflammation and tissue damage.
- The many hypersensitivities can be classified into four groups, I to IV.
- All hypersensitivities involve components of the adaptive immune system.
What is the normal function of IgE?
What mediates mast cells?
What happens in type 1 hypersensitivity?
First exposure is asymptomatic
What is the reaction to IV, SC, inhalation and ingestion of allergen?
What happens in allergic asthma?
What happens in type 2 hypersensitivity?
What happens in type 3 hypersensitivity?
Similar to Type II except antibodies bind to soluble antigen (not attached to cells)
What happens in type 4 hypersensitivity?
What happens in transplant rejection?
What is graft vs host disease?
What is type 4 a,b,c and d hypersensitivity?
Type IVa
Classic Th1 immune reaction where sensitised T cells will secrete IFN-γ and TNF-⍺ leading to macrophage activation. Th1 cells can also act as co-stimulators for CD8 T cell responses as seen in Type IVc
Type IVb
Driven by Th2 cells which will secrete IL4, 5 and 13 to promote B cell production of IgE and IgG4. IL5 enhances eosinophil activation, degranulation and cytotoxicity
Chronic asthma is a Type IVb reaction which results in the activation of eosinophils. Upon activation, eosinophils will degranulate and cause further inflammation and recruitment of additional inflammatory cells resulting in chronic inflammation of the airways.
Type IVc
CD8 T cells function as the effector cells and cause direct damage through perforin, granzyme and Fas-ligand dependent mechanisms. Often occurs with other Type IV reactions
Type IVd
T cells activate sterile neutrophilic inflammation. CXCL8/GM-CSF producing T cells are activated by antigen. These recruit neutrophils via CXCL8 and promote survival through GM-CSF which will then create a neutrophil rich environment.
