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
How does bystander activation lead to autoimmunity?
T and B cells with low affinity for self-antigen escape selection and go to the periphery. Antigen alone cannot activate these cells. Inflammation/ infection causes co-stimulatory molecules to be expressed by antigen presenting cells (APC). These APC overcome T cell anergy. The T cells become activated and attack self
How does epitope spreading lead to autoimmunity?
Immune reactions to infection or self-antigens leads to damage to self-cells.This can lead to release and presentation of more cryptic self-antigens or normal self-antigens at unusually high concentrations. This can lead to activation of more T and B cells of different specificities – the immune response spreads
How does antigen as also a DAMP lead to autoimmunity?
Some autoantigens are also DAMPs (Toll-Like Receptor ligands) – such as unmethylated CpG nucleic acid. Host unmethylated CpG usually only becomes available during cell death (apoptotic chromatin). If the unmethylated CpG is not cleared quickly, a self-reactive B cell could receive signals through the TLR and BCR - and become activated
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 key microscopic features of acute inflammation?
Infiltration of neutrophils. Also: evidence of edema in tissue, vascular congestion.
What are the key histological features of granulomatous inflammation?
Central necrosis in caseating immune granulomas; no necrosis in non-caseating immune granulomas. Aggregation of macrophages with different phenotypes: multinucleate giant cells, foamy macrophages, epithelioid macrophages. Lymphocytes - generally arranged outside the main aggregation of macrophages
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 are the different types of IgA class switching?
T-dependent (CD40L, TGF-B) and T-independent (BAFF, APRIL- produced by dendritic cells)
What is the gut immune response to pathogenic bacteria?
What is fecal microbiota transplantation (FTM)?
Donor is screened for infectious diseases and feces turned into a preparation for administration. Infused into recipient through nasoenteric tube, enema or colonoscopy. Also oral capsules
What is the role of short chain fatty acids in the gut microbiota?
What are the types of short chain fatty acids?
Acetate
- Substrate for synthesis of cholesterol and long chain fatty acids (LCFAs)in the liver
- Modulates the activity of immune cells
Propionate
- Substrate for gluconeogenesis in the liver
- Influences the secretion of appetite-regulating hormones
Butyrate
- Energy source for colonic epithelial cells
- Promotes gut barrier integrity
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 5 causes of cell injury and death?
1.Lack of factors essential for normal cell function
o blood (ischaemia)
o oxygen (ischaemia, hypoxia)
o nutrients eg vitamin deficiencies
o neural stimulation eg muscular dystrophies
2.Physical
trauma, heat/cold
3.Chemical
drug injury (prescription and recreational) -toxins eg alcohol metabolites
4. Inflammation- Autoimmune Inflammation
5. Metabolic and genetic disorders-eg. diabetes mellitus, obesity, glycogen storage disease
What are the cellular effects of injury?
What are the features of cell death?
- deranged tissue/organ function
- detection of leaked intracellular contents in blood (when severe membrane damage has occurred)
- Morphological changes in the tissue
- Light microscopic changes
- Gross changes in surgical specimens/PM
Apoptosis vs necrosis
Apoptosis-
- Physiological process
- Specific enzymes break down cells -Caspases
- Neat and tidy Typically single cells
- Cell suicide programme
- Activated by some types of injury
Necrosis-
- Not physiological
- Uncontrolled cell breakdown-non- specific enzyme activation
- Messy process
- Typically large groups of cells
- Mass murder
- Common pattern following injury
What are the 2 types of necrosis?
Coagulative- most common, less rapid shrinking of cells, tissue, structure transiently preserved but tissue weak and non- functional. Necrotic tissue- pale with yellow colour from acute inflammatory cells
Liquifactive- rapid degradation of cells to liquid mass(mush)
What are the possible outcomes of necrosis?
- ECM in tact → return to normal
- ECM damaged → repair and scar
- Tissues that have no regenerative capacity repair and fibrous scarring
What are the cellular changes in apoptosis?
- Cell shrinks, cytoplasm stains darker
- Chromatin condenses under the nuclear membrane and DNA fragmentation
- Cell membrane blebs and then cell fragments in to membrane bound bodies
- Apoptotic cell bodies express macrophage attractants and are phagocytosed by macrophages
Reduced vs increased apoptosis
Reduced apoptosis- Mutations in pro-apoptotic or anti- apoptotic proteins that allow cells with damaged DNA to survive eg in cancers,
Mutations in Fas/FasL in autoimmune disorders
Increased apoptosis- Seen in ischemic injury (MI, Stroke) where pathway is activated. Neurodegenerative diseases
What are the mechanisms of cell injury?
What are the primary, secondary and tertiary wound healing?
Closure by Primary Intention
Usually refers to deliberate closure of a wound that isn’t too large; edges of wound are aligned
Closure by Secondary Intention
Extensive tissue loss; no deliberate closure; ‘healing on its own’. Repair is prolonged, with formation of much granulation tissue
Tertiary Intention Healing
Intentional delay of wound closure – typically because of risk of infection, decontamination etc. Wound closure is performed after interventions and formation of granulation tissue
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 are the stimultaneous processes in proliferation?
Angiogenesis
Formation of granulation tissue
Fibroblast migration
Collagen deposition
Epithelialisation
Wound contraction
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 is granulation tissue?
Initially the capillaries are fragile and permeable and contribute to tissue oedema and the appearance of healing granulation tissue. The resulting pink, vascular, fibrous tissue which replaces the clot at the site of a wound is termed granulation tissue.
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 happens in collagen deposition?
In wounds closed by primary intention, collagen deposition is maximal by day 5 and this can often be palpated beneath the skin as a wound ridge. When a wound ridge is not palpable, this is an indication that the wound is at risk of dehiscence (re-opening). Overproduction of collagen can lead to the development of a hypertrophic scar. Hypertrophic scars remain raised and erythematous but remain within the confines of the original wound. Keloid scars do not remain within the wound confines. Risks for development of scars include wound infections
and wounds where there is excessive tension
What happens in Epithelialisation?
n wounds that are primarily closed, this phase can be completed within 24 hours. Cytokines and growth factors at the wound site stimulate basal epithelial cells at the wound edge to migrate across the wound bed. They adhere to the deposited ECM. They then proliferate, differentiate and stratify to repopulate epithelial cell levels and complete wound repair. A process called epithelial-mesenchymal transition (EMT) allows epithelial cells to gain motility and travel across the wound surface. In wounds that heal by secondary intention, the area lacking epithelial cells can be large. The wound must contract significantly before epithelialisation can be completed. In some cases this might never occur - skin grafting might be appropriate
What happens in wound contraction?
Wounds begin to contract about ~ 7 days after injury. Mediated mainly by myofibroblasts. Cell bodies are pulled closer together decreasing the area of tissue needing to heal. This is influenced by wound shape, with linear wounds contracting fastest and circular wounds the slowest. Disorders of this phase of healing can lead to deformity and the formation of contractures
What happens in remodelling?
- Involves a balance between synthesis and degradation of collagen and other proteins which become increasingly well organised.
- Wounds never achieve the same level of tissue strength
- Normal epithelium & maturation
of scar tissue - As the scar matures, the level of vascularity decreases and the scar changes from red to pink to grey with time
- Factors influencing scarring outcome: type of wound, wound size, wound location
What are the stages of bone healing?
Haemostasis- haematoma forms, stabilises fracture; matrix for cells infiltrating; source of signalling molecules to initiate inflammation, coagulates in between and around the broken ends of the bone
Inflammation- vasodilation and increased vascular permeability, influx of inflammatory cells, removal of debris, formation of granulation tissue (blood vessels, fibroblasts and new ECM), osteoprogenitor cells are recruited to the site (mesenchymal cells)
Proliferation- soft callus (cartilaginous and bridges fracture ends) formation, chondrocytes lay down cartilage, capillaries connect to callus, after time soft callus is resorbed and replaced by hard callus (woven bone), cartilage matrix is progressively calcified and reabsorbed and replaced by bone, more mechanically rigid
Maturation/ remodelling- woven bone is resorbed by osteoclasts and remodelled into lamellar bone by osteoblast deposition, mechanical stress is important
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 mediator of type 1 hypersensitivity and what are examples of it?
IgE
- allergic rhinitis
- allergic asthma
- eczema
What is the mediator of type 2 hypersensitivity and what are examples of it?
IgG
- drug allergies
- chronic urticaria
What is the mediator of type 3 hypersensitivity and what are examples of it?
IgG
- serum sickness
- arthus reaction
What is the mediator of type 4 hypersensitivity and what are examples of it?
Cell mediated
- allergic contact dermatitis (+ to poison ivy)
- chronic asthma
- chronic rhinitis
- graft rejection
What is the normal function of IgE?
What are the cells involved in Type I hypersensitivity?
-Mast cells- are tissue resident cells found predominantly in mucosal tissues near body surfaces and in connective tissues near blood vessels. IgE becomes bound to FcεRI (a type of Fc receptor) on mast cells. One mast cell can have on its surface pre-bound IgE antibodies covering a range of specificities. When the bound IgE is cross-linked, mast cells release histamine and other mediators (prostaglandins, leukotrienes, cytokines and enzymes)
-
Eosinophils- present in small numbers in the blood. Resident in connective tissues under mucosal surfaces. Like mast cells, eosinophils have receptors for IgE on their surface. Contain pre-formed toxic mediators (e.g., MBP and ECP) in granules, which they release on receptor crosslinking. They can also secrete cytokines. Th2 cells regulate the eosinophil arm of the immune response:
• secrete cytokines (e.g., IL-5) that promote development and
survival of eosinophils.
• promote recruitment of eosinophils to sites of inflammation by stimulating release of chemokines (e.g., eotaxin) by
activated endothelial and epithelial cells. - Basophils- a minor population in peripheral blood and not usually found in large numbers in peripheral tissues. Recruited to sites of inflammation, and activated in several ways: by PAMPs, cytokines and lipid mediators and … also by IgE. They bear FcεRI and degranulate on receptor crosslinking. Release histamine amongst other mediators. Cytokine production by basophils (specifically early secretion of IL-4 and IL-13) may be important in the initiation of Th2 responses
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?
Why do we react this way to some antigens?
- Most multicellular parasites infect through skin and mucosal tissues.
- These tissues are predisposed to developing Th2 responses.
- Parasitic worms can use proteases to access the body.
- We respond to several proteases as allergens e.g., Der p 1 in faeces of house dust mites.
- Many allergens are soluble in the mucosa and present at low doses. Low antigen doses favour Th2 over Th1.
- Parasites often need to be expelled by muscle contraction and enzymatic breakdown
What is atopy?
tendency to develop allergic diseases
- In Caucasian populations of Europe and North America, up to 40% of people are atopic.
- Atopic individuals have higher levels of IgE and eosinophils in their blood.
- Strong genetic component to risk – polymorphisms of multiple genes including on chromosomes 5, 6 and 11
- MHC II – Enhanced presentation of allergen peptides
- IL-4R – Increased signaling from IL-4
- IL-4 – Variation in IL-4 expression
- FcεRI – IgE binding
- On chromosome 5, there is a cluster of cytokine genes (including IL-3,-4,-5 and -13) which are all involved in regulating components of the allergic immune response
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.
What is the immunopathological mechanism in peanut allergy?
This is a type 1 hypersensitivity to a foreign but harmless antigen. There is no autoimmune component. IgE mediated crosslinking of FceRI causes mast cells to become activated and degranulate, releasing histamine(preformed) and leukotrienes (synthesised de novo) – causing smooth muscle contraction and increased vascularpermeability. Histamine can activate nerve endings directly to cause itching. Eosinophils may be recruited to the tissue and can accumulate in chronic disease. They release mediators such asMBP which are very damagingBasophils have an important role in systemic anaphylaxis, which can occur in this condition. Th2 cell infiltrate in the tissue characteristic of chronic allergy. They release cytokines including IL-4, IL-5 and IL-13
What are the signs and symptoms of a peanut allergy?
Itching, Swelling, Airway constriction, Pulse and blood pressure changes (in anaphylaxis, systemic vasodilation and increased vascular permeability can causehypovolemic shock)
What is the immunopathological mechanism in myasthenia gravis?
autoimmunity
Failure of central and/ or peripheral self-tolerance mechanisms mean that an antibody response is mounted to self antigens at the postsynaptic terminal of the neuromuscular junction
Plasma cells secrete IgG antibodies (mostly IgG1, but also IgG3 and other types) which bind to the nicotinic acetylcholine receptor. There are other autoantigens, including MuSK and LRP4
Antibody binding can lead to various effects: internalisation and degradation of the receptors; direct blockage of ACh binding; and activation of complement which damages the postsynaptic membrane
The consequence is impairment of signalling required to trigger muscle contraction. This may be manifested in ptosis(extraocular muscles; less severe) or difficulty breathing (diaphragm and other respiratory muscles; more severe)
What is the treatment for myasthenia gravis?
Diagnosis of the condition involves looking at the clinical picture (muscle weakness, commonly ocular initially) and thenperforming antibody tests (specificity and titre). There is a minor subgroup of seronegative MGPyridostigmine (oral treatment) is an anticholinesterase. By inhibiting the breakdown of acetylcholine, is increases theamount of it available to signal at the NMJ. It is used for symptomatic controlPrednisolone is a glucocorticoid immunosuppressant. Low dose treatment produces a significant clinical response inmost patients with mild to moderate disease. It ultimately suppresses the immune response, reducing autoantibodyproduction and consequently muscle degenerationIntravenous immunoglobulins (IVIg) neutralises the autoreactive antibodies (preventing them from binding their target)and also neutralises cytokines and blocks activating Fc receptors. It is used in the situation of a severe acuteexacerbation of myasthenia gravis
What are the signs and symptoms of myasthenia gravis?
For diagnosis, muscle weakness particularly with repetitive use. Ocular muscles often involved with th consequences of doubledivision (diplopia) and droopy eyelids (ptosis). Muscles in face, limbs and trunk can be involvedRespiratory distress is indicative of myasthenic crisis and is a potentially life threatening exacerbation
What is the immunopathological mechanism in Systemic Lupus Erythematosus?
This is a type 3 hypersensitivity (sometimes also manifesting as type 2) to self antigens. It is an autoimmunityFailure of central and/ or peripheral self-tolerance mechanisms mean that an antibody response is mounted to selfantigens normally found in the cell nucleus – for example dsDNA, histones, and ribonucleoproteinsPlasma cells secrete IgG antibodies (IgG1, G2 and G3 may all be present) which bind for example to dsDNAreleased from dying/dead cells. This leads to formation of immune complexes (antigen, antibody, complement)which can deposit in vasculature.Several different organs can be damaged: lupus nephritis progressing to end stage kidney disease; jointinflammation progressing to erosive arthritis; and pleuritis and pericarditis affecting the lung and heart
What is the treatment for SLE?
Diagnosis is based on the clinical picture (skin, joint, kidney, serosa) and the presence of anti-nuclear antibodies (usually anti dsDNA is present)
Corticosteroids are immunosuppressives. They suppress the adaptive immune response and also reduce the inflammation and tissue injury consequent to immune complex deposition (activation of complement; tissue damage by myeloid cells and so on
Belimumab is a monoclonal antibody therapy which blocks (binds and neutralises) the B cell survival and stimulatory factor BAFF/BLyS. It causes B cell apoptosis and reduces autoantibody levels
What are the signs and symptoms of SLE?
Wide ranging symptoms but rash on the face, and arthritis, are classic presentations
The arthritis in the case will have been an early manifestation of SLE. This disease perhaps should have been diagnosed sooner
What is the immunopathological mechanism in acute lung transplant rejection?
This is a type 4 hypersensitivity (driven by T cells). It is not autoimmune as the immune response is against harmless alloantigens.
Those antigens are from the donor and are therefore foreign to the recipient
Direct allorecognition is central to acute rejection. Donor APC that are carried with the donor organ present allo MHC directly to the recipient T cells. Allo MHC I will activate cytotoxic CD8 T cells, which will then damage the graft. Allo MHC II will activate helper CD4 T cells, which assist the cytotoxic T cell response and also secrete inflammatory cytokines
In indirect recognition, recipient APC phagocytose, process, and present donor antigens to T cells. This is slower, but can result in cytotoxic T cell, helper T cell and also T-dependent antibody responses against the graft
What is the treatment for acute lung transplant rejection?
The patient has been on a triple immunosuppressant regime since transplantation to prevent organ rejection:
Tacrolimus is a calcineurin inhibitor and inhibits the activation of T cells
Mycophenolate mofetil inhibits the synthesis of guanosine monophosphate and therefore inhibits cell proliferation
Prednisolone is a corticosteroid and suppresses inflammation and immunity
Bronchoscopy + biopsy or bronchiolar lavage would be performed to look for immune cell infiltration into the graft - and to look for signs of infection. This will help discriminate infection from rejection. Impaired immunity in a patient under immunosuppression results in a much higher risk of serious infection
What are the signs and symptoms of acute lung transplant rejection?
Reduced organ function, pain at the site
Systemic symptoms of inflammation: fever and flu like symptoms
What is the treatment for peanut allergy?
Key to identify the allergen in order to know what to avoid. In this case the Ara peanut allergens are the most likely.These may also be present in other foods. Adrenaline given. It binds adrenergic receptors – critically here the b2 receptors on bronchial smooth muscle,causing bronchodilation and preventing asphyxia. Chlorphenamine is an H1 histamine receptor antagonist administered subcutaneously, intramuscularly or intravenously (relief from swelling and itching). Hydrocortisone is a corticosteroid which suppresses the inflammatory response. It is given to reduce inflammation inthe late phase and reduce the chance of a subsequent severe reaction (e.g., anaphylaxis)
