Test 2 Concepts Flashcards
Sensitization of Type 1 HS
Allergen breached tissue barrier
Phagocytosed by immature D cell
Travels to lymph node
Naive T cells recognise allergen derived pMHC on mature DC and become activated, differentiate into Th2 effector cells that help activate B cells. Activated B and Th2 cells leave the lymph node
Travel to where allergen entered body
Th2 cells produce cytokines that instruct plasma cells to produce IgE
IgE can bind directly to allergen or FCR on mast cells. Mast cells are sensitised for the effector stage
Excess IgE taken up by lymphatics
IgE encounters basophils in the blood and binds to FcRs to sensitise them
IgE encounters mast cells in other tissues and binds to FcRs to sensitise them
Effector stage of Type 1 HS (early stage)
Allergen enters tissue where sensitised mast cells are present
Allergen binds IgE molecules attached to mast cells via FcRs
Mast cells degranulate and secrete cytokines/chemokines
Breakdown of mast cells releases platelet-activating factor
Tissue-specfic symptoms of allergic response
Additional leukocyte recruited (eig eosinophils and sensitised basophils)
Type 1 HS
IgE medited, allergy atopy
<1-30min
Allergens cross-link IgE bound on mast cells and basophils induce degranulation
Asthma, hay fever, eczema, hives, food allergies
Type II HS
Direct antibody- mediated cytotoxic HS
Antibody (IgG or IgM)
5-8hr
IgM or IgM bind to cell-bound antigen, cell is destroyed by phagocytosis, complement activation or ADCC
Hemolytic anemias, Goodpasture’s syndrome
Antibody-mediated cytotoxic hypersensitivity
Autoantibodies against cell surface Ag
Complement-dependent cell lysis
C3b-opsonised phagocytosis
FcR-mediated antibody-dependent cell-mediated cytotoxicity, ADCC (NK cells and macrophages)
Type III hypersensitivity
Immune complex-mediated HS
Antibody (IgG or IgM)
4-6 hr
Immune complexes trigger complement activation; phagocyte FcR engagement leads to release of lytic mediators
Arthus reaction, aspects of rheumatoid arthritis and systemic lupus erythematosus
Immune complex-mediated hypersensitivity
Ab binds antigen in the blood (IC). Insoluble ICs form by cross-linking that lodge in small vessels. ICs enter tissues (kidneys, joints), drives local inflammation/tissue damage
How does pos and neg selection occur?
Positive selection occurs in the cortex when thymocytes are double positive for CD4 and CD8.
Thymic cortical epithelial cells mediate positive selection.
Developing T cells bearing antigen receptors that recognise self MHC with sufficient affinity survive.
T cells bearing TCRs that strongly recognise self peptide, self MHC are negatively selected.
DP cells express a successfully rearranged TCR with CD4 and CD8 on their surface
Positive selection rescues the T cell from default ‘death by neglect’
Those with high affinity interactions with dendritic cells presenting self MHC with self peptide undergo negative selection
Education of B cells
Educated to not recognise self antigens during their development,
Developing B cells with BCRs strongly recognize multivalent cell-surface self antigen undergo selection
B cell precursor rearranges its immunoglobulin genes
Immature B cell bound to self cell-surface antigen is removed from the repertoire
Mature B cell bound to foreign antigen is activated
Activated B cells give rise to plasma cells and memory cells
What happens when an APC presents self-peptide
DCs present self antigens derived from host cells, in the absence of pathogen attack
In the absence of pathogen attack the DC is not activated
DC encounters an autoreactive T cell that recognises the self MHC, self peptide combination it inactivates it
How do bacteria stick
Non-specific adhesion molecules (often reversible)
Specific adhesins - Gram-negative bacteria - Pili and Fimbriae. Outer membrane adhesins
Gram positive bacteria - cell wall proteins - Microbial surface components recognising adhesive matrix molecules
Enteropathogenic E.Coli attachment
Initial contact with intestinal cells mediated through bundle forming pilus (BFP)
Attaching - effacing lesion
- characterised by effacement of brush border microvilli and intimate attachment of bacteria to cell.
Mimicking - binding Ig
Staph - Protein A binds to antibody Fc region
Inhibits the activation of complement, phagocytosis and ADCC
Cell now covered in layer of host proteins = recognised as self
Mimicking - binding factor H
If C3b forms on a cell it can target it for complement-mediated damage.
Serum factor H binds to our cells and degrades any C3b forming on the surface to protect us from damage
H. pylori gastric coloniser
Attaches to gastric epithelium via Lewis b carbohydrate receptor with BabA adhesin
Chronic infection: Immune evasion methods
Evade host defense
LPS = poorly recognised by TLR4 -> low levels of cytokine production
Flagellum subunits = poorly recognised by TLR5 -> low levels of cytokine production
Vacuolating toxin A (VacA)
Inhibits phagosomal maturation. T/B cell proliferation, iNOS generation
Coating with plasminogen and cholesterol -> mimic host
H. pylori and genetic instability of epithelial cells
Irregular AID expression
Double-strand DNA breaks
Impaired DNA mismatch repair
Irregular DNA methylation
miRNA regulation
H. pylori CagA
Phosphorylated in gastric cell
CagA-P stimulates phosphorylation cascades, apoptosis, morphological change, cytokine production, cell proliferation
Promotes release of ROS from mitochondria. Stimulates oncogenic pathways
Guanine nucleotide-binding (G) proteins
Binding of hormone produces a conformational change in receptor.
Receptor binds to G protein
Binding induces a conformational change - GDP is replaced by GTP.
Gs dissociates from rest of G
Gs binds AC synthesis of cAMP; hormone dissociated
Hydrolysis of GTP to GDP causes Gs to disassociate from AC and bind to the rest of G
Cholera toxin mechanism
Locks G protein cause NAD+ -> ADP-ribose
ADP-ribosylation of Gsa causes constant activation of cyclase, resulting in increased levels of cAMP.
This activates Protein Kinase A
causes active secretion of chloride ions via CFTR and loss of water by osmosis
Shiga-like toxins
Toxins that cause cell death
Bind to Gb3 in digestive tract = bloody diarrhoea
and kidney = HUS (kidney failure)
Mechanisms of action of Shiga toxins
B subunits bind to Gb3 in cell membrane
A subunit transported to ER
Subunit cleaved by protease to make enzymatically active
Removes a single adenine from 28s rRNA = irreversibly inactivates ribosome inhibiting protein synthesis
Results in cell death
Alternative mechanism of action of shiga toxin
B subunits bind to Gb3 in cell membrane
Inactivates ADAMTS 13
Accumulate multimers of Von Willebrand’s Factor on endothelial surface, leads to clumping of platelets
Alternative Alternative mechanisms of action. Shiga toxin
Bind to Factor H
Prevent inactivation of C3b
Persistent C3b activity
Increased alternative pathway complement activation, leads to increased endothelial inflammation
Shiga-like toxin overview
Toxin mediated disease
Shiga-like toxin belongs AB5 family
5xB subunits: binding and entry
1xA subunit: enzymatic activity
Transported from cell surface to cytosol via Golgi and ER
Stops protein translation
Inflammation of intestinal epithelium and apoptosis, loss of barrier function
Physical damage
Digestive tract = bloody diarrhoea
Kidney = HUS
TLR signalling
LPS binding protein binds to LPS/LOS, delivers to CD14 then to TLR-4 which induces pro-inflammatory cytokines (IL-1B, TNF-a)
Immune damage of meningococcal disease
Alteration of coagulation pathways
Intravscular coagulation
Weakened epithelium
Bleeding under skin
Phagocytic cells release ROI and enzymes
Extensive tissue damage and necrosis
Treatable with antibiotics
Multiple organ failure
No vaccine protects against all types
Superantigens
Activates 2-30% of T cell population
Massive production of proinflammatory cytokines
No enzymatic activity
Act from outside cell by binding to MHC class II on APC and TCR on non-specific T cells
Systemic acute inflammation, toxic shock syndrome
Endothelial cells promoting haemostasis by…
Produce endothelin which causes vasoconstriction
Loss of endothelial barrier, activating platelets and coagulation cascade
Produce von Willebrand factor, promoting platelet adhesion to ECM exposed by vessel injury
Produce tissue factor = thromboplastin which activates coagulation cascade
Platelets promote haemostasis by
They become activated by ECM proteins
Secrete chemical signals including Thromboxane A2, vasoactive amines and ADP
Signals promote combination of vasoconstriction and platelet aggregation
Ischaemia causes decreased ATP by
Decreased oxidative phosphorylation with down the line leads to ER swelling, cellular swelling, loss of microvilli, blebs, clumping of nuclear chromatin and lipid deposition
O2 regulated gene expression
Anoxia causes increased HIF transcription system activity. This increases NFkB activity and pro-survival target RNAs
Timing of infarction
<24 hours - neutrophils develop from viable margins
1-3 days macrophages and lymphocytes appear
Fibroblasts and endothelial cells are then recruited (organisation) to form granulation tissue
6-8 weeks the infarct is organised and replaced by a fibrous scar
Some tissues (e.g liver) may attempt regeneration
Treatment of myocardial infarction
Thrombolytic agents (streptokinase or tissue-type plasminogen activator)
Mechanical re-expansion of the occluded vessel or coronary artery bypass grafting
Problem of further damage by reperfusion injury
Smoking and damage to endothelial cells
Chemical insult from free radicals and oxidants. Create a pro-oxidative environment.
Superoxide anion reacts with NO to form peroxynitrite & leads to protein nitration. Damaged & dysfunction endothelial cells. Leads to increased deposition of oxidized lipids
Left sided heart failure results in
Decreased emptying of LV
Increased volume in LV and PV
Increased volume in pulmonary capillaries
Movement of fluid from capillaries into the alveoli
Rapid filling of the alveolar spaces = pulmonary oedema
Breathlessness
Right sided failure
Increased pressure in the pulmonary system will eventually lead to right-sided heart failure
Causes back pressure on systemic venous circulation
Observed as venous congestion of visceral organs
Lower legs oedema
Triglycerides being broken down process
Perilipin controls access of enzymes to lipid droplets
First fatty acid is removed by adipose tissue triglyceride lipase (ATGL)
The second fatty is removed by hormone sensitive lipase (HSL)
The third fatty acid is removed by monoglyceride lipase (MGL)
Adrenergic receptors activate…
Protein kinase A which phosphorylates perilipin and increases access of lipases to lipid droplets. PKA phosphorylates and increases the activity of HSL.
Insulin stimulates lipid accumulation by shutting down HSL
Leptin
Receptors are mainly found in two sets of neurons in the arcuate nucleus of the hypothalamus
Leptin acts to shut down the production of the appetite promoting hormone AGRP
Alpha-MSH binds to melanocortin 4 receptors (MC4R) in nearby neurons
Together they suppress appetite
Reduced food intake and leptin
Leptin -> LEPR which goes to the arcuate nucleus to the NPY neuron. AGRP acts on MC4R which stimulate SIM1 in the paraventricular nucleus.
Increased energy expenditure and leptin
Leptin -> LEPR which goes to the arcuate nucleus to the POMC neuron. a-MSH acts on MC4R which stimulates SIM1 in the paraventricular nucleus.
