I & I Flashcards
Innate immunity in health and disease by Dr. Deborah Chong
What are Natural Killer Cells?
*LOB: Describe the main features of natural killer cells
- From a lymphoid lineage
- recognise infected and stressed cells
- kills irus infected cells and malignant transformed cells
- express cytotoxic enzymes
- produce interferon γ
Innate immunity in health and disease by Dr. Deborah Chong
What are the features of Natural Killer Cells?
*LOB: Describe the main features of natural killer cells
- complex for activation
- granules in cytosol of
- perforin (perforate)
- cytolitic enzymes (granzymes A and B)
Innate immunity in health and disease by Dr. Deborah Chong
What is Mφ ΝΚ cooperation?
*LOB: Explain the mechanisms underlying target cell recognition by natural killer cells
- Mφ produce IL-12
- IL-12 activates NK
- NK produce IFN γ
- IFN γ helps to activate Mφ
Innate immunity in health and disease by Dr. Deborah Chong
How do NK recognise cells?
*LOB: Explain the mechanisms underlying target cell recognition by natural killer cells
integration of signals from inhibitory
and activating receptors
Inhibitory receptors recognise ligands on healthy cells
Activating receptors recognise infected/stressed cells
Innate immunity in health and disease by Dr. Deborah Chong
What are the inhibitory receptors of NK Cells
*LOB: Explain the mechanisms underlying target cell recognition by natural killer cells
- KIRs (killer inhibitory receptors)
- NKG2A (C type lectin receptors)
- Leucocyte Ig-like receptors (LIRs)
Inhibitory receptors recognise ligands on healthy cells
These are the receptors on the NK cell that recognise MHC class 1 on self cells.
The aim of these receptors is to PREVENT NK cell killing “healthy” cells
Innate immunity in health and disease by Dr. Deborah Chong
What are activating receptors of NK Cells
*LOB: Explain the mechanisms underlying target cell recognition by natural killer cells
- NKG2D, KIRs, CD16
- Adaptor proteins: DAP10, DAP12
Activating receptors recognise infected/stressed cells
Innate immunity in health and disease by Dr. Deborah Chong
How do NK not affect healthy cells?
*LOB: Explain the mechanisms underlying target cell recognition by natural killer cells
- All healthy autologous cells have MHC class 1
- Inhibitory receptors recognise MHC 1
- This blocks the recognition from activation receptors
- so NK do not attack autologous cells
Innate immunity in health and disease by Dr. Deborah Chong
So how do cells lose the protection of MHC class 1?
*LOB: Describe the main molecules and steps involved in target cell killing by natural killer cells
- Virus infected cells: downregulate MHC I
- Malignant (cancer) cells: downregulate MHC I
- inhibitory receptors are not ligated by MHC class I
- Do not down regulate the activation receptors (NKG2D)
Therefore are killed
However, this doesnt mean NO MHC class 1, rather a lot fewer MHC1 than activating receptors. So signals from activating receptors may overwhelm the signals from inhibitory receptors.
Innate immunity in health and disease by Dr. Deborah Chong
What is the biochemical mechanism of NK activation?
*LOB: Describe the main molecules and steps involved in target cell killing by natural killer cells
- Both inhibitory and activatory receptors have intracellular and extracellular portions (immunoreceptor tyrosine-based inhibitory/activatory motif)
- Inhibitory (ITIM) phosphatases block signalling
-
Activatory (ITAM) engage protein tyrosine kinase-mediated signalling
events
Innate immunity in health and disease by Dr. Deborah Chong
What do the NK use to “kill”
*LOB: Describe the main molecules and steps involved in target cell killing by natural killer cells
At the site of contact between NK and Target
1) Perforin: forms pores
2) allows Granzymes A, B, C in
3) Granzymes activate Caspases
Innate immunity in health and disease by Dr. Deborah Chong
What are the roles of Granzymes A B and C?
*LOB: Describe the main molecules and steps involved in target cell killing by natural killer cells
Granzyme B: can trigger
mitochondrial apoptotic
pathway
Innate immunity in health and disease by Dr. Deborah Chong
NK Disease and Defects
*LOB: Describe defects in various components of the innate immune response and explain the mechanisms by which they cause disease
- immuno-deficiencies (e.g. Chediak-Higashi)
- complete absence of circulating NK cells
- functional NK cell deficiencies (normal numbers)
Innate immunity in health and disease by Dr. Deborah Chong
Innate lymphoid cells (ILCs)
*LOB: Give some examples of lymphocytes with limited antigen recognition capacity
similar functions to lymphocytes
Lymphocyte-like cells
* ready to act → main mechanism: produce cytokines
* do not express TCRs (T cell receptors)
* responses are faster → innate immunity
* different types of ILCs depending on type of cytokines
ILC1 (Th1-like; IFN-γ); NK cells are related to ILC1
ILC2 (Th2-like; IL-5, IL-13)
ILC3 (Th17-like; IL-17)
* no clonal expansion (proliferation) & no differentiation
LCs do not possess rearranged antigen-specific cell receptors (T-cell receptor [TCR] or B-cell receptor [BCR]), but they mirror T helper (Th) cell diversity
Innate immunity in health and disease by Dr. Deborah Chong
What are the roles of ILC
*LOB: Give some examples of lymphocytes with limited antigen recognition capacity
ILCs cross talk with the resident tissue by sensing the cytokines present in their microenvironments and subsequently secreting a plethora of cytokines that regulate innate immunity
Innate immunity in health and disease by Dr. Deborah Chong
Examples of lymphocytes with limited diversity
*LOB: Give some examples of lymphocytes with limited antigen recognition capacity
γδ (gamma/delta) T cells
NK-T cells
Mucosa-Associated Invariant T (MAIT) cells
B-1 B cells
Marginal zone B cells
Innate immunity in health and disease by Dr. Deborah Chong
Chronic granulomatous disease
*LOB: Describe defects in various components of the innate immune response and explain the mechanisms by which they cause disease
mutation in NADPH component and defect in oxidative burst
Innate immunity in health and disease by Dr. Deborah Chong
Chediak-Higashi syndrome
*LOB: Describe defects in various components of the innate immune response and explain the mechanisms by which they cause disease
- defective phagosome-lysosome fusion
- Neutropenia and giant granules on film
- genetic, rare LYSosomal Trafficking regulator (LYST) errror
Innate immunity in health and disease by Dr. Deborah Chong
Leucocyte adhesion defects
*LOB: Describe defects in various components of the innate immune response and explain the mechanisms by which they cause disease
- Defect in 2-chain integrins (LFA-1, Mac-1)
- Defective neutrophil chemotaxis
- Defect in sialyl-Lewis X (selectin ligand)
decreased levels of integrins on phagocytes - Impaired clearance of pathogens
Innate immunity in health and disease by Dr. Deborah Chong
Complement deficiencies
*LOB: Describe defects in various components of the innate immune response and explain the mechanisms by which they cause disease
- C2, C4, C1q deficiency → SLE-like syndrome
- C3 deficiency → frequent serious infections with pyogenic bacteria (e.g. Staphylococcus aureus, etc.)
- C5-C9 (MAC) deficiency → disseminated infections with Neisseria (N. meningitidis, N. gonorrhoeae)
- C1 INH deficiency → hereditary angioedema
- increased cleavage C4, C2
- DAF, CD59 deficiency → paroxysmal nocturnal haemoglobinuria:
- recurrent intravascular haemolysis (RBC lysis)
Development of Immune Cells by Dr José Saldana
Overview of development of Innate Immune Cells
*LOB: Present an overview of the development of innate and adaptive immune cells
Derived from hematopoietic stem cells (HSCs) in the bone marrow.
Common myeloid progenitor (CMP) gives rise to innate immune cells such as:
Neutrophils, monocytes/macrophages, dendritic cells, mast cells, and natural killer (NK) cells.
Granulocyte-macrophage progenitor (GMP) specifically produces neutrophils, monocytes/macrophages, and dendritic cells.
Development of Immune Cells by Dr José Saldana
Overview of Development of Adaptive Immune Cells
*LOB: Present an overview of the development of innate and adaptive immune cells
Also originates from HSCs in the bone marrow.
Lymphoid progenitor cells differentiate into:
B lymphocytes (B cells) in the bone marrow, where they undergo gene rearrangement to generate diverse antigen receptors.
T lymphocytes (T cells) that migrate to the thymus for maturation and selection of T cell receptors (TCRs).
Development of Immune Cells by Dr José Saldana
T cell maturation checkpoints
*LOB: Describe the main stages of T and B lymphocyte maturation and selection
1) No Antigen produced -> DIE
2) Partial anitgen produced -> CLONE
3) CLONE doesnt produce partial Ag -> DIE
4) Full Antigen Produced
5) Full Antigen WEAK -> LIVE (Full Mature T Cell)
6) Full Antigen STRONG -> targeted to die to prevent autoimmune
Development of Immune Cells by Dr José Saldana
What are the stages in T Cell maturation?
*LOB: Describe the main stages of T and B lymphocyte maturation and selection
Development of Immune Cells by Dr José Saldana
What are the stages in T Cell selection?
*LOB: Describe the main stages of T and B lymphocyte maturation and selection
Development of Immune Cells by Dr José Saldana
Define positive selection
*LOB: Understand the concept of self/immunological tolerance
Only lymphocytes that express Ag receptors that can recognise Ags/MHC molecules mature & are retained in repertoire
Development of Immune Cells by Dr José Saldana
What is negative selection?
*LOB: Understand the concept of self/immunological tolerance
Lymphocytes with Ag receptors that recognise self Ags/MHC molecules too strongly are eliminated (die by apoptosis)
PREVENTS AUTOIMMUNE
Development of Immune Cells by Dr José Saldana
What is death by neglect?
*LOB: Understand the concept of self/immunological tolerance
Lymphocytes that express Ag receptors that do not recognise Ags/MHC molecules are eliminated (do not receive survival signals through their Ag receptors and die by apoptosis )
Development of Immune Cells by Dr José Saldana
B Cell maturation and selection
*LOB: Describe the main stages of T and B lymphocyte maturation and selection
μ-> IgM -> IgM and IgG
Development of Immune Cells by Dr José Saldana
Immunological Tolerance
*LOB: Understand the concept of self/immunological tolerance
The ability to regulate immune cells to prevent autoimmune disease
Recognition of self.
Development of Immune Cells by Dr José Saldana
Central Tolerance
*LOB: Describe the main mechanisms that determine the induction of central tolerance of T and B lymphocytes
induction of tolerance to self Ags during lymphocyte development in central lymphoid organs
In the thymus as only self Ags can be encountered
peripheral tissue-restricted self Ags: AIRE (AutoImmune Regulator Protein)
allows expression of tissue restricted peripheral self Ags in thymic medullary
epithelial cells
Self tolerance – mechanisms (T cells)
Development of Immune Cells by Dr José Saldana
Define Anergy
*LOB: Describe the main mechanisms that determine the induction of peripheral tolerance of T and B lymphocytes
Functional unresponsiveness between immature immune cell and effector.
Development of Immune Cells by Dr José Saldana
Define Suppresion
*LOB: Describe the main mechanisms that determine the induction of peripheral tolerance of T and B lymphocytes
Block in activation of immature cell by TReg
Development of Immune Cells by Dr José Saldana
Peripheral Tolerance
*LOB: Describe the main mechanisms that determine the induction of peripheral tolerance of T and B lymphocytes
tolerance to self Ags is induced when mature lymphocytes respond to Ags in peripheral lymphoid organs or peripheral tissues
Development of Immune Cells by Dr José Saldana
What are the effector roles of mature lymphocytes?
*LOB: Describe the main mechanisms that determine the induction of peripheral tolerance of T and B lymphocytes
Development of Immune Cells by Dr José Saldana
Peripheral Tolerance and Receptor editing in B Cells.
*LOB: Describe the main mechanisms that determine the induction of peripheral tolerance of T and B lymphocytes
Immature B cells that recognise self Ags with high
avidity (strongly) in bone marrow can:
- change the specificity of their Ag receptors so that
they no longer recognise strongly self Ags
B cell central tolerance: receptor editing
- mechanism: rearranging the genes for the light chain
occurs in the
lymph nodes and spleen
Development of Immune Cells by Dr José Saldana
Key players in central tolerance?
*LOB: Describe the main mechanisms that determine the induction of central tolerance of T and B lymphocytes
T Cells: TCR CD4 CD8
Non-T Cells: MHC1 MHC2
Development of Immune Cells by Dr José Saldana
Peripheral Tolerance
*LOB: Describe the main mechanisms that determine the induction of peripheral tolerance of T and B lymphocytes
tolerance to self Ags is induced when mature lymphocytes respond to Ags in peripheral lymphoid organs or peripheral tissues
Inflammation by Dr Omar Janneh
Define prostanoid
*LOB: Define the terms prostanoid, leukotriene and eicosanoid
derived from arachidonic acid (20c chain)
include prostaglandins, prostacyclins, and thromboxanes
These steps are triggered by many agents, e.g. thrombin on platelets and antigen-antibody reactions on mast cells
Inflammation by Dr Omar Janneh
Define leukotriene
*LOB: Define the terms prostanoid, leukotriene and eicosanoid
formed from arachidonic acid
synthesized and released by immune cells, such as leukocytes (white blood cells) and mast cells.
Inflammation by Dr Omar Janneh
Define eicosanoid
*LOB: Define the terms prostanoid, leukotriene and eicosanoid
deriving from “eicosa,” which means twenty, referring to the 20 carbon chain arachadonic acid
Inflammation by Dr Omar Janneh
Timescale of Events in Inflammation
*LOB: Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
Inflammatory steps (5Rs)
Recognition of the injurious agent
Recruitment of leukocytes
Removal of the agent
Regulation (control) of response
Resolution (repair) – inflammation initiates repair
Inflammation by Dr Omar Janneh
Histamine Receptor G Proteins
*(not stated as required but might be useful to know)
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
H1 - Gq/PLC, PIP2 production, generation of DAG/IP3, PKC: smooth muscle, endothelium, CNS, sensory nerves
H2 - Gs/AC, generation of cAMP, stimulation of PKA: parietal cells, heart, uterus, mast cells, neutrophils
H3 - Gi, decrease in cAMP levels: neuronal presynaptic terminals (autoreceptor: ↓ release of histamine)
H4 - Gi, decrease in cAMP levels: basophils, bone marrow, gut
Pathogenesis of TB by Prof Phillip Butcher
History of TB
*LOB: Describe the natural history of tuberculosis infection and give pathological features of the disease
Exposure: TB spreads when someone with active TB coughs or sneezes, releasing bacteria into the air that can be inhaled by others.
Infection: Not everyone exposed gets infected. The immune system usually keeps the bacteria in check, leading to latent TB infection (LTBI).
**
Latent TB Infection (LTBI): In LTBI, bacteria are dormant, causing no symptoms, and individuals are not contagious. A chest X-ray is often normal. However, they can develop active TB if their immune system weakens.
**
Active TB Disease: Immune system compromise can lead to reactivation of the bacteria, causing active TB with symptoms like cough, fever, night sweats, weight loss, and fatigue. Active TB is contagious and spreads through the air.
Pathogenesis of TB by Prof Phillip Butcher
Pathogenesis of TB
*LOB: Describe the natural history of tuberculosis infection and give pathological features of the disease
- Inhalation
- Alveolar macrophages
- Lymph nodes
- Haematogenous spread to other parts of lung
via lymphatics and capillaries - A brief acute inflammatory response -
neutrophils, cytokine storms
macrophage recruitment and activation - recruitment of CD4, CD8 and NK cells - production of IFN-
- Down regulation of acute inflammation chronic inflammation
- Formation of granuloma - immune containment
- Caseation
- Liquifaction, cavitation and release
- Transmission
Pathogenesis
Inflammation by Dr Omar Janneh
Describe the role of histamine
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
All G-protein-coupled receptors which produce physiological effects by activating second messenger systems
Synthesised, stored and released from:
– Mast cells, which express receptors for IgE, C3a and C5a on cell
surface (connective tissues)
– Basophils (blood)
– Neurons in brain
– Histaminergic cells in gut (ECL, enterochromaffin-like cells)
Released by allergic reactions (IgE-mediated), production of
complement agents (C3a and C5a), insect stings, trauma, etc.
through a rise in [Ca2+]i
Inflammation by Dr Omar Janneh
Cyclooxygenases are important because….
*LOB: Define the terms prostanoid, leukotriene and eicosanoid
Conversion of Arachadonic Acid to prostanoids requires the enzyme cyclooxygenase (COX)
COX 1: Constitutively active, involved in regulation of peripheral vascular resistance, renal blood flow, platelet aggregation, gastric cytoprotection
COX 2: Needs to be stimulated (e.g. by inflammatory cytokines- IL-1, TNF)
- Responsible for role of PGs/TXs in inflammatory responses (pain and fever)
COX 3 is similar to COX 1 but pain perception of CNS
Inflammation by Dr Omar Janneh
What are the Effects of Stimulation of H1 and H2 Receptors
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
Cardiovascular
dilates arterioles, ↓ TPR (H1)
Increased permeability of post-capillary venules, ↓ BV (H1)
Increase in heart rate (H2) - in vivo reflex to try to retain BP to normal
Generally involved in ↓BP (↓ vascular resistance)
Non-vascular smooth muscle (airways, gut etc.)
Contraction (H1), e.g. bronchoconstriction
Algesia
Pain, itching, and sneezing caused by stimulation of sensory nerves (H1)
Associated exocrine secretions
Increased, due to increased blood flow
Gastric acid
Increase secretion (H2 –mediated effects are of interest)
Inflammation by Dr Omar Janneh
What is the Triple Response?
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
Characterised by reddening, wheal and flare.
Refers to LOCAL histamine response
Reddening (Rubor):
initial response to histamine release in the skin.
localized vasodilation
Increased blood flow leads to redness and warmth
Wheal:
raised, swollen, and palpable area at the site of histamine release
the increased permeability of capillaries, allows fluid to accumulate
Flare:
spreading of redness beyond the immediate area due to the dilation of larger blood vessels
Inflammation by Dr Omar Janneh
How is the Flare response co-ordinated (Triple Response)
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
Sensory nerves and C fibers, are involved in the perception of pain and sensory information during inflammation.
Substance P is released from C fibers
Substance P contributes to vasodilation
The orthodromic (normal direction) and antidromic (opposite direction) responses of sensory nerves can influence the spread of pain signals and inflammation.
This leads to a flare of the original inflammation beyond its micro localised area.
Inflammation by Dr Omar Janneh
How can the Flare response occur outside the site of inflammation? (Triple Response)
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
When histamine stimulates afferent fibres, it is known to stimulate an axon reflex: It orthodromically stimulates nerve impulse which travel towards the spinal cord and the dorsal root ganglia, passing antidromically down the other branches of sensory nerves. These antidromic impulses release nerve impulses → vasodilation (flare, reddening) distant from the site of irritation
This is now being explored as reasoning for migraines
dermatographia
Inflammation by Dr Omar Janneh
What is the vasodilator that is involved in Histamine response?
How is it synthesised?
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
Bradykinin
Synthesised by activation of:
Hageman factor (HF, factor XII) & production of plasma kallikrein (makes sense when you think of wound healing)
Production of lysylbradykinin by tissue kallikreins;
Action of cellular proteases
Inflammation by Dr Omar Janneh
What are the pharmacological affects of Bradykinin?
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
Potent vasoactive peptide with wide-ranging effects:
Increases vascular permeability
Promotes vasodilation (↓BP)
Pain
Contraction of visceral smooth muscle (gut and bronchus)
Stimulation of arachidonic acid metabolism (initiates phospholipase action → release of numerous lipid mediators of inflammation)
Chemotactic to leukocytes, which defend the body against infections
Dry cough (sensitization of airway sensory nerves via rapidly adapting stretch receptors and C-fiber receptors and substance P)
Metabolism of bradykinin: kininases, I and II (ACE, aminopeptidase P, carboxypeptidase)
Inflammation by Dr Omar Janneh
What are H1 and H2 receptor antagonists
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
H1 Antagonists – Treat Acute Inflammation
such as mepyramine, promethazine, diphenhydramine, Terfenadine
H2 Antagonists – Gastric Problems
such as cimetidine, famotidine
Inflammation by Dr Omar Janneh
What are major side effects of H1 and H2 receptor antagonists
*LOB: Describe the role of histamine in inflammation and outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
H1
Reduce minor inflammatory reactions (e.g. insect bites, hay
fever), BUT NO significant value in asthma
– 1st generation drugs are sedative – drowsiness is a major side
effect, but sometimes used as a therapeutic effect
– Some (e.g. promethazine) are anti-emetic – ‘motion sickness’
– Anti-muscarinic actions (common in 1st generation drugs) e.g.
atropine-like effects of blurred vision, constipation, etc.
H1 Antagonists – Treat Acute Inflammation
H2
Reduce gastric acid secretion in the treatment of duodenal
and gastric ulcers and Zollinger-Ellison syndrome (duodenum
& pancreas tumours increasing gastrin secretion)
– Increase INMT activity so more rapid breakdown of histamine
– Mental confusion, dizziness, tiredness & diarrhoea sometimes
as side effects
– Cimetidine decreases cytochrome P450 activity so potential
for adverse drug interactions; gynecomastia
Inflammation by Dr Omar Janneh
Describe the major pathway leading to prostaglandin
*LOB: Describe the major enzymatic pathways leading to the formation of prostaglandins and leukotrienes, with special reference to areas where drug therapy can be applied
Inflammation by Dr Omar Janneh
Describe the enzymatic pathways leading to leukotrienes
*LOB: Describe the major enzymatic pathways leading to the formation of prostaglandins and leukotrienes, with special reference to areas where drug therapy can be applied
Inflammation by Dr Omar Janneh
Where can drug therapy be applied to prostaglandins and leukotriene enzymatic pathways?
*LOB: Describe the major enzymatic pathways leading to the formation of prostaglandins and leukotrienes, with special reference to areas where drug therapy can be applied
NSAIDs
Glucocorticoids
Lipoxygenase inhibitors
Leukotriene antagonists
Conversion of AA to prostanoids requires the enzyme cyclooxygenase (COX)
COX-1 is constitutively expressed at low levels in many cell types.
The expression of COX-2 is highly regulated.
For example Aspirin interacts with thromboxane synthase and Epoprostenol
interacts with prostacyclin synthase*
Inflammation by Dr Omar Janneh
Main effects of eicosanoids
*LOB: Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
Inflammation:
Example: Prostaglandins and leukotrienes
Vasoconstriction and Vasodilation:
Example: Prostacyclin (PGI2) promotes vasodilation, and thromboxane A2 (TXA2) promotes vasoconstriction.
Pain and Fever:
Example: Prostaglandins sensitize pain receptors and raise body temperature, leading to fever.
Platelet Aggregation:
Example: Thromboxane A2 (TXA2)
Bronchoconstriction:
Example: Leukotrienes, particularly leukotriene D4 (LTD4)
Regulation of Blood Flow:
Example: Prostaglandins
Gastrointestinal Protection:
Example: Prostaglandins
Reproductive Function:
Example: Prostaglandins
Immunomodulation:
Example: Various eicosanoids can influence immune cell function, including prostaglandins and leukotrienes.
Inflammation by Dr Omar Janneh
Physiological effects of eicosanoids
*LOB: Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
Inflammation by Dr Omar Janneh
How does the eicosanoid prostaglandin have a paradoxical component?
*LOB: Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
This is important to allow resolution to occur.
Recruit monocytes for clearance
CyPG CYCLIC PROSTAGLANDINS – inhibits macrophage activation→ ↓ uncontrolled tissue damage; ↓NF-B activation (helps to ↓ activation of inflammatory genes)
Inflammation by Dr Omar Janneh
Eicosanoids with Haemostasis
*LOB: Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
Eicosanoids, such as thromboxane A2 (TXA2), play a crucial role in hemostasis.
Thromboxane A2 is produced by platelets and promotes vasoconstriction and platelet aggregation.
imbalance- clotting disorders
Inflammation by Dr Omar Janneh
Eicosanoids with Gastric cytoprotection
*LOB: Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
prostaglandins, are significant regulators of the gastrointestinal system.
Prostaglandins help maintain the integrity of the gastrointestinal mucosa by promoting the secretion of mucus and bicarbonate.
This protective action helps prevent damage to the stomach lining and the development of gastric ulcers.
NSAIDs that inhibit this can cause ulcers
Inflammation by Dr Omar Janneh
Why do Eicosainoids cause dry cough and bronchospasm as side effects?
*LOB: Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
↑ cellular infiltration of eosinophils, neutrophils
↑ mucus secretion
↑ bronchoconstriction (similar to vascular mechanism)
↑ airway oedema
Leuokotriene are more potent.
Smooth muscle cells in the bronchial airways express receptors for leukotrienes.
Gs -> PLC -> IP DAG
Inflammation by Dr Omar Janneh
What are the side effects of Leukotriene receptor antagonists
*LOB: Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
Receptor blockade is useful in following:
Prevention of mild to moderate asthma
Early to late bronchoconstrictor effects of allergens
Exercise-induced asthma and asthma provoked by NSAIDs
Side effects:
GI upset
Dry mouth, thirst
Rashes, oedema
Irritability
Pathogenesis of TB by Prof Phillip Butcher
Difference between Active and Latent TB
*LOB: Describe the natural history of tuberculosis infection and give pathological features of the disease
Pathogenesis of TB by Prof Phillip Butcher
Where can TB spread in body
*LOB: Describe the natural history of tuberculosis infection and give pathological features of the disease
Pleural disease
Lymph nodes – scrofula
Pericardial
Skeletal –Potts disease
Genitourinary
Gut
Peritoneal
Miliary
Meningeal
Pathogenesis of TB by Prof Phillip Butcher
Pathological features of the disease
*LOB: Describe the natural history of tuberculosis infection and give pathological features of the disease
**Granuloma Formation: **Immune response to M. tuberculosis leads to granulomas, organized collections of immune cells like macrophages and lymphocytes, containing the bacteria and preventing their spread.
**Caseous Necrosis: **Within granulomas, infected tissue undergoes caseous necrosis, a type of tissue death causing a cheese-like appearance. Accumulation of this necrotic material can create lung cavities.
**
Ghon Focus and Ghon Complex: **Initial infection can result in a Ghon focus, a small lung lesion where bacteria enter. If the immune response successfully controls the infection, it forms a Ghon complex, combining the Ghon focus with associated lymph node involvement.
Miliary TB: In severe cases, the infection can disseminate via the bloodstream, leading to miliary TB. It involves widespread distribution of small TB lesions throughout various organs, resembling millet seeds.
Fibrosis and Scarring: The immune system’s efforts to control the infection often lead to fibrosis and scarring, particularly in affected organs like the lungs.
Respiratory Tract Infections by Tim Planche
Global burden of resp inf.
*LOB: Demonstrate an appreciation of the global health burden of disease caused by respiratory infections
eading cause of morbidity and mortality worldwide
High prevalence in developing countries
Significant impact on children and the elderly
Increased risk in crowded or unsanitary living conditions
Major contributors to healthcare costs and economic burden
Respiratory Tract Infections by Tim Planche
Clinical presentation of bacterial respiratory infections
*LOB: Outline and differentiate between the clinical presentations of common upper and lower respiratory tract bacterial and viral infections
Sudden onset of symptoms
High fever
Productive cough with purulent sputum
Shortness of breath
Chest pain
Systemic symptoms (fatigue, malaise)
Respiratory Tract Infections by Tim Planche
Clinical presentation of viral respiratory infections
*LOB: Outline and differentiate between the clinical presentations of common upper and lower respiratory tract bacterial and viral infections
Gradual onset of symptoms
Low to moderate fever
Dry or minimally productive cough
Runny or stuffy nose
Sore throat
Headache and muscle aches
Respiratory Tract Infections by Tim Planche
Clinical presentation of upper respiratory infections
*LOB: Outline and differentiate between the clinical presentations of common upper and lower respiratory tract bacterial and viral infections
Nasal congestion
Sneezing
Runny nose
Sore throat
Cough (usually dry)
Mild fever
Generalized malaise
Respiratory Tract Infections by Tim Planche
Clinical presentation of lower respiratory infections
*LOB: Outline and differentiate between the clinical presentations of common upper and lower respiratory tract bacterial and viral infections
Persistent cough with or without sputum
Shortness of breath
Chest discomfort or pain
Wheezing or difficulty breathing
Fever and chills
Cyanosis in severe cases
Respiratory Tract Infections by Tim Planche
Organisms which cause community acquired pneumonia
*LOB: List organisms that commonly cause: community acquired pneumonia, croup, epiglottis, tonsillitis, pharyngitis (sore throat)
Streptococcus pneumoniae (most common)
Haemophilus influenzae
Mycoplasma pneumoniae
Chlamydia pneumoniae
Staphylococcus aureus
Legionella pneumophila
Influenza virus
Respiratory syncytial virus (RSV)
Klebsiella pneumoniae (especially in older adults and those with underlying conditions)
Respiratory Tract Infections by Tim Planche
Organisms which cause croup
*LOB: List organisms that commonly cause: community acquired pneumonia, croup, epiglottis, tonsillitis, pharyngitis (sore throat)
Parainfluenza viruses (especially type 1)
Para=beside flu- so Like the Flu
In some cases, other respiratory viruses like influenza, adenovirus, and respiratory syncytial virus (RSV)
Respiratory Tract Infections by Tim Planche
Organisms which cause epiglottis
*LOB: List organisms that commonly cause: community acquired pneumonia, croup, epiglottis, tonsillitis, pharyngitis (sore throat)
Haemophilus influenzae type b (Hib) used to be the most common cause in children (before the introduction of the Hib vaccine).
Streptococcus pneumoniae and Streptococcus pyogenes (Group A Streptococcus) can also cause epiglottitis.
In adults, various bacteria, including Staphylococcus aureus and Streptococcus species, can be responsible.
Respiratory Tract Infections by Tim Planche
Organisms which cause tonsillitis
*LOB: List organisms that commonly cause: community acquired pneumonia, croup, epiglottis, tonsillitis, pharyngitis (sore throat)
Bacterial Tonsillitis:
Streptococcus pyogenes (Group A Streptococcus) is a common bacterial cause of tonsillitis. It can lead to a condition known as streptococcal pharyngitis or strep throat.
Viral Tonsillitis:
Numerous respiratory viruses can cause viral tonsillitis, including:
Rhinovirus (common cold)
Adenovirus
Epstein-Barr virus (EBV, causing infectious mononucleosis)
Influenza virus
Herpes simplex virus
Cytomegalovirus (CMV)
Other Possible Causes:
Fungal infections, although rare, can lead to tonsillitis. Candida species are typically responsible for fungal tonsillitis.
Respiratory Tract Infections by Tim Planche
Organisms which cause pharyngitis
*LOB: List organisms that commonly cause: community acquired pneumonia, croup, epiglottis, tonsillitis, pharyngitis (sore throat)
Viral Pharyngitis:
Rhinovirus (common cold)
Adenovirus
Influenza virus
Epstein-Barr virus (EBV, causing infectious mononucleosis)
Enteroviruses
Coronavirus (including SARS-CoV-2, which causes COVID-19)
Bacterial Pharyngitis (Strep Throat):
Streptococcus pyogenes (Group A Streptococcus) is the most common bacterial cause of pharyngitis in children and adults.
Other Bacterial Causes (Less Common):
Mycoplasma pneumoniae
Chlamydia pneumoniae
Neisseria gonorrhoeae (usually in the context of sexual transmission)
Arcanobacterium haemolyticum
Corynebacterium diphtheriae (causing diphtheria, a rare but serious condition)
Respiratory Tract Infections by Tim Planche
laboratory investigation and diagnosis of respiratory tract infections
*LOB: Outline the principles of laboratory investigation and diagnosis of respiratory tract infections
Laboratory Investigations:
Respiratory Viral PCR Testing:
Collect respiratory specimens (nasopharyngeal swabs, sputum) for PCR testing.
Identify common viruses like influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 (COVID-19).
Microbiological Cultures:
Obtain sputum or tracheal aspirates for bacterial culture and sensitivity testing.
Useful for diagnosing bacterial pneumonia and determining appropriate antibiotics.
Blood Tests:
Complete Blood Count (CBC): Evaluate white blood cell count and differential to assess for infection.
C-reactive protein (CRP) and Procalcitonin: Markers of inflammation and infection.
Chest X-ray:
Consider a chest X-ray for patients with severe or atypical symptoms.
Useful for detecting pneumonia and assessing lung involvement.
Additional Investigations (if indicated):
Pulse Oximetry: Measure oxygen saturation, especially in patients with respiratory distress.
Arterial Blood Gas (ABG) Analysis: Assess oxygen and carbon dioxide levels in severe cases.
Bronchoscopy: May be necessary in select cases for obtaining deeper respiratory samples.
Viral Serology:
In some cases, serological tests may be used to detect past infections or antibodies (e.g., for Mycoplasma pneumoniae or other atypical pathogens).
Molecular Testing:
Polymerase chain reaction (PCR) testing for atypical pathogens like Mycoplasma pneumoniae, Chlamydia pneumoniae, or Legionella pneumophila may be considered in specific clinical scenarios.
Urine Antigen Tests:
Utilize urine antigen tests to diagnose Streptococcus pneumoniae or Legionella pneumophila in certain cases.
Consider Comorbidities:
Evaluate underlying conditions (e.g., chronic lung disease, immunosuppression) that may influence diagnosis and management.
Patient Isolation:
Based on clinical and laboratory findings, implement appropriate infection control measures to prevent the spread of contagious RTIs.
Consultation:
Collaborate with microbiologists, radiologists, and infectious disease specialists for challenging cases.
Antibiotic Stewardship:
Prescribe antibiotics judiciously, guided by laboratory results and clinical assessment, to combat antibiotic resistance.
Respiratory Tract Infections by Tim Planche
COPD and resp inf.
*LOB: Explain how COPD may be exacerbated by respiratory infections.
Increased Inflammation
Mucus Production
Bronchospasm
Worsening Airway Obstruction
Reduced Lung Function
Exacerbation of Symptoms
Increased Risk of Hospitalization
Prolonged Recovery
Potential for Long-Term Damage
Clinical Aspects of TB by \_\_\_\_\_\_\_\_\_
TB symptoms
*LOB: Describe symptoms and signs found in people affected with pulmonary tuberculosis
Persistent Cough: A cough that lasts for more than three weeks is one of the most common symptoms of TB.
Coughing Up Blood or Phlegm: Sometimes, coughing may produce blood-tinged sputum.
Chest Pain: Pain or discomfort in the chest, often localized.
Fever: Low-grade or high-grade fever, especially in the afternoon or evening.
Night Sweats: Profuse sweating, particularly during the night.
Unintentional Weight Loss: Significant weight loss without diet or exercise changes.
Fatigue: Persistent tiredness and weakness.
Loss of Appetite: A reduced desire to eat and a general feeling of malaise.
Shortness of Breath: Difficulty breathing or shortness of breath, especially with physical activity.
Swelling of Lymph Nodes: Enlarged and tender lymph nodes, typically in the neck or under the armpits.
Clinical Aspects of TB by \_\_\_\_\_\_\_\_\_
invesitgating TB
*LOB: Outline the investigation of a patient with suspected TB
Tuberculin Skin Test (TST) or Interferon-Gamma Release Assay (IGRA)
Chest X-ray
Sputum Smear Microscopy
Sputum Culture
Nucleic Acid Amplification Tests (NAATs)
Bronchoscopy
Tissue Biopsy
Blood Tests
HIV Testing
Drug Susceptibility Testing (DST)
Chest CT Scan
Tuberculosis Contact Tracing
Humoural Immunity by Dr Tasneem Rahman
How do B Cells mature?
*LOB: Understand the basic principles of B cell maturation and antibody generation
Mature naïve B cells express a membrane-bound IgM
Ag recognition by membrane IgM => activation of signalling pathways => B cell activation
Humoural Immunity by Dr Tasneem Rahman
What do mature naive B Cells co express and why?
*LOB: Understand the basic principles of B cell maturation and antibody generation
Co express IgD and IgM
IgM is the 1st immunoglobulin to be produced; Ag receptor
Humoural Immunity by Dr Tasneem Rahman
How are antibodies generated?
*LOB: Understand the basic principles of B cell maturation and antibody generation
CD40L (T) and CD40 (Healthy) = Isotype Switching via molecules (IFN γ IL 4, TGFβ)
Humoural Immunity by Dr Tasneem Rahman
What is isotype switching?
*LOB: Understand the principles of generation of antibody diversity
During an immune response B cells become capable to produce Abs of different classes but without changing specificity (respond to the same Ag)-
IgM switch to => IgG, IgA, IgE
IgG switch to => IgA, IgE
Isotype switching does not alter specificity for Ag !
Isotype switching does not alter the light chain !
Humoural Immunity by Dr Tasneem Rahman
What is Clonal Selection?
*LOB: Understand the principles of generation of antibody diversity
Humoural Immunity by Dr Tasneem Rahman
How do T Cells help isotype switching
*LOB: Understand the principles of generation of antibody diversity
- CD40L on T cell interacts with CD40 on activated B cells
- Cytokines produced by T cell
IFN-γ => switch to IgG1, IgG3
IL-4 => switch to IgE
TGF-β, IL-5 => switch to IgA
Humoural Immunity by Dr Tasneem Rahman
How do antibodies know to isotype?
*LOB: Understand the principles of generation of antibody diversity
Abs retain already rearranged variable regions whilst exchanging constant regions for different Ig classes
Humoural Immunity by Dr Tasneem Rahman
What role does somatic DNA recombination play in diversity of antigens
*LOB: Understand the principles of generation of antibody diversity
Limited no of genes for diversity of antigen receptors.
Variable regions= gene segments.
- VH encoded in 3 gene segments (V, D, J)
- VL encoded in 2 gene segments (V, J)
- Gene segment recombination => Ab diversity
Gene segment recombination = random arrangement of gene segments in different combinations:
SOMATIC DNA RECOMBINATION
T and B cells
Gene segments rearrangements (VDJ/VJ) take place during B cell development in bone marrow
Immature B cells:
1st: successful VDJ rearrangement => heavy chain produced
2nd: successful VJ rearrangement => light chain produced
Mature naïve B cells express full IgM/antigen receptor
Humoural Immunity by Dr Tasneem Rahman
What is the Germinal centre?
*LOB: Understand the basic principles of B cell maturation and antibody generation
Sustained B cell proliferation and differentiation.
Plasma cells or memory B cells.
Grows in size with immune response, disappears when infection cleared.
3-4 weeks
More effective antibodies vs primary focus.
Dark zone vs light zone
Somatic hypermutation and Affinity maturation.
Survival of B cell that has a high affinity for the antigen.
Humoural Immunity by Dr Tasneem Rahman
Antibody diversity is….
*LOB: Understand the principles of generation of antibody diversity
Over 10^7-10^9 different types of B cells generated randomly
Each of these B cells makes a different antibody
B cells generated in bone marrow where they go through different developmental stages
Naive B cells populate lymph nodes/spleen and ‘wait’ for antigens
In the presence of Infection, Antigens are recognised by lymphocyte clone with the specific antigen receptor for that antigen
=> expansion of antigen-specific clone
=> generation of Abs specific for that Ag only
Humoural Immunity by Dr Tasneem Rahman
Structure of Antibodies
*LOB: Describe the structure of antibodies and their role (ie main effector mechanisms) in the immune system
two identical heavy chains + two identical light chains
held together by disulphide bonds
5 types of heavy chains: μ,γ,α,δ,ε (IgM, IgG, IgA, IgD, IgE)
2 types of light chains: κ,λ
Heavy chain (H):
3-4 constant (C) domains + 1 variable (VH) domain
Light chain (L):
1 constant domain and 1 variable (VL) domain
Variable domains: amino acid sequence varies highly between different immunoglobulins
Antigen binding site: VL + VH
Humoural Immunity by Dr Tasneem Rahman
What is somatic hypermutation?
*LOB:Understand the process of affinity maturation
Process of introducing mutations in the variable region of Immunoglobulins (rearranged VDJ/VJ)
Initiated by enzyme AID expressed in Germinal centre B cells only.
Mutations with decreased affinity for binding to Ag= NEGATIVE selection (majority)
Mutations with decreased affinity for binding to Ag= POSITIVE selection
higher affinity antibodies => stronger cell signalling; faster proliferation of B cells => advantage over low affinity B cells
Role of T cell in selection
Humoural Immunity by Dr Tasneem Rahman
What is affinity maturation?
*LOB:Understand the process of affinity maturation
Goal: Production of high affinity antibodies = more efficient.
Abs produced early during primary (1st) immune response have lower affinity (weak binding) for antigen
Later 1st immune response/ 2nd immune responses => production of high affinity antibodies
Achieved through process of Somatic Hypermutation
Humoural Immunity by Dr Tasneem Rahman
What are the subtypes of B Lymphocytes?
*LOB:Understand the process of affinity maturation
Follicular B cells
recognise protein antigens => antibodies (anti-protein Ag)
produce mainly high-affinity IgG class/switched antibodies
Marginal zone B cells
recognise polysaccharide; glycolipid; nucleic acid antigens
produce mainly IgM class antibodies
B-1 cells
peritoneal cavity, mucosal tissues
recognise polysaccharide; glycolipid; nucleic acid antigens
produce mainly natural low-affinity IgM class antibodies
The Complement System by Dr. Tasneem Rahman
What is the Complement system?
*LOB: Define the complement system
Innate System
Cascade complex
Activation of small soluble heat sensitive protein that can combine and create complexes with proteolytic activity.
RECOGNITION
OPSONISATION
EFFECTOR- inflammation, phagocytosis and membrane attack
The Complement System by Dr. Tasneem Rahman
What is the function of Complement?
*LOB: List the main functions of complement in the immune response
RECOGNITION
Innate recognition of non self
Antibodies
Apoptopic cells
OPSONISATION
EFFECTOR- Lysis, Inflammation,
Phagocytosis.
OTHER FUNCTIONS:
Chemotaxis, adhesion of inflammatory cells
Vascular permeability, contraction of smooth muscle cells
Disposal of waste- clearance of immune complexes and apoptotic cells
The Complement System by Dr. Tasneem Rahman
What are the main pathways of complement?
*LOB: Describe the main pathways of complement and the terminal complement pathway
3 DISTINCT PATHWAYS
Antibody triggered (Classical)
Presence of pathogen alone (Alternative)
Lectin type protein activation (Lectin)
1 COMMON PATHWAY
-Terminal pathway- lysis
The Complement System by Dr. Tasneem Rahman
What is the classical pathway?
*LOB: Describe the main pathways of complement and the terminal complement pathway
When antibodies bind
Formation of C1 Complex
Cascade Activation: C1 activation sets off a series of reactions (a cascade), leading to the activation of other complement proteins, like C4 and C2.
C3 Convertase Formation: The activated C4 and C2 proteins join together to form a new complex called C3 convertase.
C3 Activation: C3 convertase then activates a protein called C3, splitting it into C3a and C3b.
Effector Functions: C3b helps tag the invader for destruction by immune cells and also contributes to the formation of a membrane attack complex (MAC) that punches holes in the invader’s membrane, leading to its destruction.
The Complement System by Dr. Tasneem Rahman
What is the alternative pathway?
*LOB: Describe the main pathways of complement and the terminal complement pathway
Spontaneous Activation: “always-on” mode of the complement system, activated by small amounts of complement proteins present in the blood.
C3 Activation: Spontaneous activation causes a protein called C3 to split into C3a and C3b, similar to the classical pathway.
Effector Functions: C3b helps tag invaders for destruction and contributes to the formation of the membrane attack complex (MAC), which can damage and kill invaders.
The Complement System by Dr. Tasneem Rahman
What is the lectin pathway?
*LOB: Describe the main pathways of complement and the terminal complement pathway
Lectins recognize sugar molecules on the surface such as bacteria.
Complex Formation
Cascade Activation leading to the activation of complement proteins like C4 and C2.
C3 Activation: The activated C4 and C2 proteins combine to form C3 convertase, which then activates C3, splitting it into C3a and C3b.
Effector Functions: C3b helps label the invader for destruction and contributes to the formation of the membrane attack complex (MAC), which can damage and kill the invader.
The Complement System by Dr. Tasneem Rahman
What is the terminal pathway?
*LOB: Describe the main pathways of complement and the terminal complement pathway
Formation of MAC
membrane attack complex
a group of complement proteins that come together and create holes in the membranes of invaders
The Complement System by Dr. Tasneem Rahman
Why must complement be regulated?
*LOB: Understand the need for regulation of complement activation, and outline how this is achieved
Protection against Self-Attack
Avoidance of Excessive Inflammation
Prevention of Autoimmunity
Minimization of Infection Risk
Tissue Homeostasis
Prevention of Allergic Reactions
Protection of Host Microbiota
Preservation of Cellular Integrity
Fine-Tuning of Immune Responses
Avoidance of Chronic Inflammation
Minimization of Secondary Tissue Damage
The Complement System by Dr. Tasneem Rahman
How is complement regulated?
*LOB: Understand the need for regulation of complement activation, and outline how this is achieved
The Complement System by Dr. Tasneem Rahman
Examples of disease in Complement errors.
*LOB: Understand how loss of control of the complement system can lead to disease and relate to clinical examples
Atypical haemolytic uraemic syndrome AHUS
Genetic Defects:
Thrombocytopenia
Microangiopathic haemolytic anaemia
Acute renal failure
Failure to control the alternative pathway
Paroxysmal Nocturnal Haemoglobinuria (PNH)
Lack of glycosylphosphatidylinositol protein in host cells walls reduces anchoring of CD55 and CD59 control factors on erythrocytes
Susceptible to lysis
C3b accumulates on Erythrocyte Surface
Activation of complement Terminal/ Mac pathway
Destruction of Erythrocytes
Antigen recognition by T lymphocytes by Dr Deborah Chong
How are antigens recognised by T Cells
*LOB: Discuss the differences between recognition of antigens by T and B cells
T cells recognise antigen processed and presented by APC
APCs process antigens into peptides (for αβ T cells)
peptides bind to MHC molecules
peptide:MHC complexes are presented on the APC surface
CD4+ helper T cells: antigens (peptides) displayed by MHC class II
CD8+ cytotoxic T cells: antigens (peptides) displayed by MHC class I
Antigen recognition by T lymphocytes by Dr Deborah Chong
How are antigens recognised by B Cells
*LOB: Discuss the differences between recognition of antigens by T and B cells
B cells recognize antigens directly through their surface immunoglobulins
Antigen recognition by T lymphocytes by Dr Deborah Chong
What are the main APC and their roles?
*LOB: Describe the main antigen presenting cells and the signals that they provide to T cells
Dendritic cells → the only APCs capable to present to naïve T cells (occurs in lymph node)
Macrophages → present to previously activated effector T cells (Ag presentation to effector CD4+ T cells (Th1))
B cells → present to previously activated effector T cells (presentation peptides to effector CD4+ T cells (Th2)) (- regulate class switch (e.g. IFN-γ & IgG; IL-4 & IgE))
Antigen recognition by T lymphocytes by Dr Deborah Chong
What are the signals for naive T cell activation?
*LOB: Describe the main antigen presenting cells and the signals that they provide to T cells
MHC:peptide // TCR
(B7 family) CD80:CD86 // CD28
Cytokines (IL-12)
Antigen recognition by T lymphocytes by Dr Deborah Chong
What is the structure of a T Cell Receptor and MHC?
*LOB: Discuss the main structure of T cell receptors and MHC molecules and their role in antigen recognition by CD4+ and CD8+ T cells
2 chains: α and β (most common TCR type)
(γ and δ (TCR in γδ T cells) )
each chain: 1 variable (V) domain + 1 constant (C) domain
Antigen binding site formed by: Vα + Vβ
V and C domains of TCR and BCR are homologous
Antigen recognition by T lymphocytes by Dr Deborah Chong
What is MHC
*LOB: Discuss the main structure of T cell receptors and MHC molecules and their role in antigen recognition by CD4+ and CD8+ T cells
MHC I: presentation of peptides to** CD8**+ T cells
composed of α chain + β2-microglobulin
MHC I: all nucleated cells
MHC II: presentation of peptides to CD4+ T cells
composed of α chain + β chain
MHC II: antigen presenting cells: dendritic cells
macrophages
Antigen recognition by T lymphocytes by Dr Deborah Chong
What is exogenous antigen processing?
*LOB: Describe the exogenous antigen processing and presentation pathway (MHC II and CD4+ T cells)
Extracellular antigens are engulfed by APCs.
Antigens are broken down into peptides in endosomes.
Peptides are presented by MHC II to CD4+ T cells.
CD4+ T cells are activated to help B cells and other immune responses.
Antigen recognition by T lymphocytes by Dr Deborah Chong
What is endogenous antigen processing?
*LOB: Describe the endogenous (cytosolic) antigen processing and presentation pathway (MHC I and CD8+ T cells)
Intracellular antigens are processed by the proteasome.
Peptides are transported to the endoplasmic reticulum and loaded onto MHC I.
MHC I-peptide complex is presented on the cell surface for CD8+ T cell recognition.
CD8+ T cells are activated to kill infected cells.
Antigen recognition by T lymphocytes by Dr Deborah Chong
Why is co-stimulation necessary?
Prevention of Anergy: Co-stimulation helps prevent the induction of anergy (unresponsiveness) in T cells. In the absence of co-stimulatory signals, T cells may become tolerant to the antigen and lose their ability to mount an immune response
Also:
* Discrimination Between Self and Non-Self
* Immune Tolerance
* Immune Memory
* Balancing Immune Responses
* Preventing Hyperactivation
Antigen recognition by T lymphocytes by Dr Deborah Chong
If both MHC I and MHC II are produced and assembled in ER how come MHC II can’t load peptides that derive from cytosolic pathogens (viruses) and MHC I can’t load peptides that derive from phagocytosed extracellular pathogens?
I&I Blood Group Antigens and Antibodies by James Uprichard.
What is ABO?
Include genetics
*LOB: Describe the genetics of blood group antigens: ABO and Rh systems.
All blood cells have antigens
A and B antigens very common (55% UK)
Anti-A, anti-B or anti-A,B antibodies very common (97% UK)
AA or AO -> A
BB or BO -> B
OO -> O
AB -> AB
I&I Blood Group Antigens and Antibodies by James Uprichard.
What is Rh?
Include genetics
*LOB: Describe the genetics of blood group antigens: ABO and Rh systems.
Most important antigen is called D.
People with D antigen are D positive (85% of UK)
People who do not produce any D antigen are D negative (15%)
The other 4 main Rh antigens are known as C, c, E and e
D antigen is very immunogenic and anti-D is easily stimulated
I&I Blood Group Antigens and Antibodies by James Uprichard.
What is the mechanism of Haemolytic disease of the newborn?
*LOB: Outline the mechanisms of haemolytic disease of the newborn and current guidelines for prevention of the disease.
Rh antibodies are usually IgG and can cause haemolytic disease of the newborn.
Anti-D is still most common cause of severe HDN
D antigens from the developing fetus can enter the mother’s blood during delivery
The mother will produce anti-D antibodies
In a following pregnancy anti-D antibodies will cross the placenta and damage the fetus
I&I Blood Group Antigens and Antibodies by James Uprichard.
How is haemolytic disease of the newborn prevented?
*LOB: Outline the mechanisms of haemolytic disease of the newborn and current guidelines for prevention of the disease.
Through blood tests.
If a mother is Rh-negative and has not been sensitized, she is usually given a drug called Rh immunoglobulin, or RhoGAM.
An injection of anti-D will bind to and remove any fetal D positive red cells in the circulation
In some hospitals 2 smaller (500 iu) doses are given at 28 and 34 weeks instead of the 1 larger dose
Anti-D is also given after any event that may cause a feto-maternal haemorrhage (bleed between mum and fetus) such as:
Abdominal trauma
Intrauterine death
Spontaneous or therapeutic abortion
I&I Blood Group Antigens and Antibodies by James Uprichard.
What are the consequences of mis-matched blood transfusions?
*LOB: Explain the possible consequences of mis-matched blood transfusionsDescribe testing for ABO blood group
An acute immune hemolytic reaction
ABO antibodies can activate complement causing INTRAVASCULAR HAEMOLYSIS
I&I Blood Group Antigens and Antibodies by James Uprichard.
How are ABO tested?
*LOB: Describe testing for ABO blood group
- Test patient’s red cells with anti-A, anti-B and anti-D
- Agglutination shows that a particular antigen is on the red cells
- No agglutination shows the antigen is absent
I&I Blood Group Antigens and Antibodies by James Uprichard.
How is antibody screening carried out?
*LOB: Describe testing for ABO blood group
Patients serum is mixed with 3 selected screening cells, incubated for 15 minutes at 37oc and then centrifuged for 5 minutes.
Any clinically significant antibodies reacting at body temp should be detected and then identified using panel of known phenotyped red cells.
I&I Blood Group Antigens and Antibodies by James Uprichard.
What is the indirect antiglobulin test?
*LOB: Describe testing for ABO blood group
Used to detect IgG antibodies
Uses low ionic strength saline
Results in agglutination
Used for:
Screening for antibodies
Identifying antibodies
Cross-matching donor blood with recipient plasma when there are known antibodies or a previous history of antibodies.
NOTE COOL SCIENCE
IgM antibodies can span the gap between RBCs
IgG can not, because too small to overcome ZETA potential (+ve charge)
LISS (low ionic strength saline) is negatively charged, so neutralises positive ZETA potential.
Therefore IgG can now span the gap.
I&I Blood Group Antigens and Antibodies by James Uprichard.
Why is low ionic strength saline required for cross matching?
*LOB: Describe testing for ABO blood group
Trying to detect IgG
IgM antibodies can span the gap between RBCs
IgG can not, because too small to overcome ZETA potential (+ve charge)
LISS (low ionic strength saline) is negatively charged, so neutralises positive ZETA potential.
Therefore IgG can now span the gap.
I&I Blood Group Antigens and Antibodies by James Uprichard.
What is Cross-matching?
*LOB: Describe testing for ABO blood group
Immediate spin cross-match (ISX)
Antibody screen is negative
Checking donor red cells against patients plasma
ABO check
Incubate for 2 – 5 minutes (room temp), spin and read.
Full Indirect Antiglobulin test (IAT) cross-match
Antibody screen positive or patient has known antibody history.
Select antigen negative donor red cells and incubate with patient serum for 15 minutes at 37oC
I&I Blood Group Antigens and Antibodies by James Uprichard
How are antibodies to blood groups produced?
*LOB: Describe the production of naturally occurring antibodies to blood group antigens.
Natural genetic variance causing variance in blood group
I&I Investigating Infections by Dr Peter Riley
Define Differential Media
*LOB: Define the terms: differential, selective and enriched media and give examples
Media that allow the differentiation of different bacterial species based on specific growth characteristics or biochemical reactions.
Example: MacConkey’s agar, which differentiates lactose fermenters from non-fermenters based on the ability to produce acid and turn the agar pink.
I&I Investigating Infections by Dr Peter Riley
Define selective media
*LOB: Define the terms: differential, selective and enriched media and give examples
Media that selectively inhibit the growth of certain types of bacteria while allowing others to thrive.
Example: Mannitol salt agar, which selects for halophilic bacteria like Staphylococcus species while inhibiting the growth of most other bacteria.
I&I Investigating Infections by Dr Peter Riley
Define enriched media
*LOB: Define the terms: differential, selective and enriched media and give examples
Media that provide additional nutrients to support the growth of fastidious or nutritionally demanding bacteria.
Example: Blood agar, which contains blood to support the growth of a wide range of bacteria, including those with complex nutritional requirements.
I&I Investigating Infections by Dr Peter Riley
Define alpha and beta hemolysis
*LOB: Define the terms: alpha and beta haemolysis; lactose fermenter; anaerobe, and explain how these properties can be shown by culture techniques
Incomplete hemolysis of red blood cells, resulting in a greenish discoloration around bacterial colonies on blood agar.
Complete hemolysis of red blood cells, leading to a clear zone around bacterial colonies on blood agar.
I&I Investigating Infections by Dr Peter Riley
Define lactose fermenter
*LOB: Define the terms: alpha and beta haemolysis; lactose fermenter; anaerobe, and explain how these properties can be shown by culture techniques
Bacteria that can metabolize lactose to produce acid and gas.
I&I Investigating Infections by Dr Peter Riley
Define anaerobe
*LOB: Define the terms: alpha and beta haemolysis; lactose fermenter; anaerobe, and explain how these properties can be shown by culture techniques
Bacteria that can grow in the absence of oxygen.
I&I Investigating Infections by Dr Peter Riley
What is blood agar and why is it important?
*LOB: Explain the value of blood agar and MacConkey’s agar in bacterial identification
: Blood agar is valuable for identifying bacterial species based on their hemolytic activity (alpha or beta hemolysis) and their ability to utilize blood components for growth. It can help differentiate between different Streptococcus species and other pathogens.
I&I Investigating Infections by Dr Peter Riley
What is MacConkey’s agar and why is it important?
*LOB: Explain the value of blood agar and MacConkey’s agar in bacterial identification
MacConkey’s agar is useful for identifying lactose fermenters from non-fermenters. It is commonly used in the identification of Enterobacteriaceae, including Escherichia coli, based on their ability to ferment lactose.
I&I Investigating Infections by Dr Peter Riley
What is the relationship between bacteria numbers in specimen and UTI?
*LOB: Explain the relationship between bacterial numbers in a urine specimen and urinary tract infections
An increased number of bacteria in a urine specimen, especially in midstream or catheterized samples, is often indicative of a urinary tract infection (UTI). Normally, urine is sterile or contains only a small number of commensal bacteria.
The extent of bacterial growth can be quantified by colony-forming units (CFUs) per milliliter of urine, with a high CFU count indicating a more severe infection.
I&I Investigating Infections by Dr Peter Riley
What are the commensal organisms found in the nasopharynx
*LOB: List commensal organisms commonly found in: nasopharynx, skin, gut, vagina (see previous lecture Principles of Infection)
: Commensal bacteria commonly found in the nasopharynx include Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus.
I&I Investigating Infections by Dr Peter Riley
What are the commensal organisms found in the skin
*LOB: List commensal organisms commonly found in: nasopharynx, skin, gut, vagina (see previous lecture Principles of Infection)
Commensal organisms on the skin can include Staphylococcus epidermidis, Corynebacterium species, and various yeast species like Candida.
I&I Investigating Infections by Dr Peter Riley
What are the commensal organisms found in the gut
*LOB: List commensal organisms commonly found in: nasopharynx, skin, gut, vagina (see previous lecture Principles of Infection)
Bacteroides, Firmicutes, and Escherichia coli.
I&I Investigating Infections by Dr Peter Riley
What are the commensal organisms found in the vagina
*LOB: List commensal organisms commonly found in: nasopharynx, skin, gut, vagina (see previous lecture Principles of Infection)
Lactobacillus species, which help maintain the acidic pH and prevent overgrowth of pathogenic bacteria.
Non-Steroidal Anti-Inflammatory Drugs by Omar Janeh
What are the uses of NSAIDS?
*LOB: Describe the mechanism of action and uses of non-steroidal anti-inflammatory drugs
Analgesic
Anti-pyretic
Anti-inflammatory
Treat: Low grade pain, Bone pain, Fever, Inflammation
Non-Steroidal Anti-Inflammatory Drugs by Omar Janeh
What is the mechanism of action of NSAIDS?
*LOB: Describe the mechanism of action and uses of non-steroidal anti-inflammatory drugs
COX converts AA to PGs and TXs
COX-1 (constitutively active, platelets)
COX-2 (inducible enzyme e.g. by IL-1β & TNFα)
Inhibition of COX-2 reduces PGs/TXs inflammatory agents
Aspirin acts irreversibly on COX; others act reversibly and this is significant in its use as a prophylactic in cardiovascular disease
Non-Steroidal Anti-Inflammatory Drugs by Omar Janeh
How are NSAIDS antipyrexic?
*LOB: Describe the mechanism of action and uses of non-steroidal anti-inflammatory drugs
Endotoxins from bacteria release IL-1β
IL-1β at hypothalamus releases PGE2
PGE2 depresses temperature sensitive neurons and causes fever by elevating end point of body temp
NSAIDs block PGE2 production
Reduces fever back to normal body temperature.
Doesnt affect core Body Temp
Non-Steroidal Anti-Inflammatory Drugs by Omar Janeh
How are NSAIDS analgesic?
*LOB: Describe the mechanism of action and uses of non-steroidal anti-inflammatory drugs
PGs sensitise and stimulate nociceptors
PGs interact with other pain producing substances (e.g. kinins, 5-HT, histamine) to produce hyperalgesia and pain sensitivity
Blockade of PG production leads to pain relief
Non-Steroidal Anti-Inflammatory Drugs by Omar Janeh
How are NSAIDS Anti-inflammatory?
*LOB: Describe the mechanism of action and uses of non-steroidal anti-inflammatory drugs
PGE2 and PGI2 have powerful acute inflammatory effects
Aspirin inhibits the activation of NF-κB
Inhibition of their formation reduces redness and swelling
NSAIDs provide only ‘symptomatic relief’
Non-Steroidal Anti-Inflammatory Drugs by Omar Janeh
Is paracetamol an NSAID?
*LOB: Describe the mechanism of action and uses of non-steroidal anti-inflammatory drugs
Not really
Weakly inhibits COX-3 in CNS
Analgesic
Not anti-inflammatory
Non-Steroidal Anti-Inflammatory Drugs by Omar Janeh
What are the side effects of NSAIDS?
*LOB: Outline the major side effects of NSAIDs
↓ mucus secretion:
↓ HCO3-:
↑ acid secretion:
↑ LT production:
↑ blood loss:
Interfere with tissue healing (COX-2 inhibition)
Nausea, dyspepsia, GI contraction (COX-1 inhibition)
Mechanisms of Bacterial Pathogenesis I by TIm Planche
Give examples of exotoxins
*LOB: List the 3 main types of bacterial exotoxins. Explain their mechanism of action and how this results in disease
I&I Investigating Infections II by Dr Peter Riley
What is disc diffusion test?
Explain the microbiological principles and clinical relevance of the following terms: disc diffusion test; MIC; MBC; serum bactericidal test
The isolate is inoculated on semisolid agar medium with antibiotic impregnated discs and incubated for 18-20 hours. The diameter of the zone of inhibition of growth around the disc is measured and the bacterium is categorised as resistant, intermediate or susceptible depending on the zone size and pre-defined criteria
I&I Investigating Infections II by Dr Peter Riley
What is MIC?
Explain the microbiological principles and clinical relevance of the following terms: disc diffusion test; MIC; MBC; serum bactericidal test
Disc diffusion zones correspond to minimum inhibitory concentrations (MIC)
MIC have been pre-determined by testing large numbers of organisms using disc-diffusion and quantitative methods in parallel.
Each antibiotic has a “breakpoint” MIC for a particular bacterial species.
If the concentration needed to inhibit the bacterium is below the breakpoint, the bacterium is susceptible.
If the concentration is higher than the breakpoint, the bacterium is resistant.
I&I Investigating Infections II by Dr Peter Riley
Why do antibiotic blood levels need to be measured?
*LOB: Discuss why antibiotic blood levels sometimes need to be measured and how this might be accomplished
As the amount of antibiotics that bind to serum proteins will vary between individuals
determine the precise amount of the drug that is bound to serum proteins
and how much is free in the blood, in order to be able to accurately calculate the optimum dosage
avoid the risks associated with potentially toxic levels
I&I Investigating Infections II by Dr Peter Riley
How can antibiotic blood levels be measured?
*LOB: Discuss why antibiotic blood levels sometimes need to be measured and how this might be accomplished
Nanotechnology, Assays, Breath tests,
I&I Investigating Infections II by Dr Peter Riley
Compare and contrast bacteriostatic and bacteriocidal.
*LOB: Distinguish between a bactericidal and a bacteriostatic antibiotic. Explain why both types of antibiotics are useful
I&I Antibiotics by Dr Kirwan
How are antibiotics chosen for use.
*LOB: Describe the considerations for the choice of an antibiotic
Distribution in body - relative to distribution of bacteria
- some not absorbed from gut
- many do not cross blood-brain barrier
- some do not penetrate abscess
- few accumulate inside cells
Spectrum of activity - cidal or static
Toxicity
Excretion
Patient age (renal capacity)
Route of administration (oral , i/v i/m, topical)
Clinical condition
Type of bacteria
Sensitivity of bacteria - mechanism of action of antibiotic
- resistance mechanisms
Cost
Specialist - Medical Microbiologist - Local Policies
I&I Antibiotics by Dr Kirwan
Define therapeutic index
*LOB: Explain the microbiological principles of the following terms: therapeutic index, selective toxicity, spectrum of activity, therapeutic index
Therapeutic index (TI) = a ratio comparing the blood concentration at which a drug becomes toxic and the ratio at which it is effective
active dose (MIC) versus toxic effect
The larger the TI, the safer the drug
I&I Antibiotics by Dr Kirwan
Match a component of bacteria cell wall to antibiotic action
*LOB: Outline the components of the bacteria cell wall and describe their roles in antibiotic action
I&I Antibiotics by Dr Kirwan
Outline the role of penicillin binding proteins (transpeptidases) in the synthesis of peptidoglycan
*LOB: Outline the role of penicillin binding proteins (transpeptidases) in the synthesis of peptidoglycan and the action of penicillin’s and cephalosporins
Cross links: PBPs catalyze the cross-linking of adjacent peptide chains within the peptidoglycan layer.
This provides structural integrity
However, PBPs are a target for antibiotics like penicillins and cephalosporins. These antibiotics contain a β-lactam ring, which binds to and inhibits PBPs.
I&I Antibiotic Resistance by Professor Lindsay
What are biofilms?
*LOB: Give an example of each of the following mechanisms of drug resistance: Antibiotic inactivating enzymes, altered target, by-pass metabolic routes, altered transport of drug
Often polymicrobial
Often form at site of foreign bodies e.g. prosthetic joints
Bacteria secrete a protective matrix
Decrease in gradient of nutrients and oxygen -> decrease in metabolic activity -> elevates proportion of persistent bacteria
I&I Antibiotic Resistance by Professor Lindsay
Transduction
*LOB: Explain the following bacterial genetic processes involved in acquisition of antibiotic resistance: transduction, conjugation, transformation
the process by which a virus transfers genetic material from one bacterium to another. Viruses called bacteriophages
I&I Antibiotic Resistance by Professor Lindsay
Conjugation
*LOB: Explain the following bacterial genetic processes involved in acquisition of antibiotic resistance: transduction, conjugation, transformation
a major horizontal gene transfer mechanism through which DNA is transferred from a donor to a recipient bacterium by direct contact.
I&I Antibiotic Resistance by Professor Lindsay
Transformation
*LOB: Explain the following bacterial genetic processes involved in acquisition of antibiotic resistance: transduction, conjugation, transformation
transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material from its surroundings through the cell membrane.
I&I Antibiotic Resistance by Professor Lindsay
History of MRSA
*LOB:Describe the history of methicillin resistant Staphylococcus aureus (MRSA)
I&I Glucocorticoids by Omar Janneh
Describe the mechanisms of action of glucocorticoids
*LOB: Describe the mechanisms of action of steroids, with reference to changes in gene regulation
1) Interaction of steroid/receptor with promoter regions
- these gene promoters have ‘glucocorticoid response elements’ (GREs) and occupancy of GREs turn on/off certain genes
2) Steroid/receptor complexes PREVENT gene activation by other transcription factors
- e.g. AP-1, NFkB: transcription factors involved in switching on COX-2; PLA2, IL-1, ICAM-1, IL-8, eotaxin, IκB-α etc.
Induction of IκBα (inhibitor of NF-κB) which causes NF-κB repression
Morphology and Biology of Viruses by Christina Baboonian
what is the replication cycle of HIV?
Revise replication cycle of herpes simplex and HIV
- Binding
- Fusion
- Reverse Transcription
- Integration
- Replication
- Assembly
- Budding
Morphology and Biology of Viruses by Christina Baboonian
Summarise the features of key viruses.
Describe the structure of; Human Immunodeficiency virus, herpes viruses, hepatitis A, B and C viruses, influenza virus, rota virus, norovirus, measles, mumps and rubella viruses, enteroviruses, rhinovirus and adenovirus
Morphology and Biology of Viruses by Christina Baboonian
what diseases are caused by the key viruses:
Outline clinical features caused by these viruses
Herpes Simplex Virus (HSV):
Cold sores
Genital herpes
Influenza Virus:
Influenza (flu)
Hepatitis A Virus (HepA):
Hepatitis A
Hepatitis B Virus (HepB):
Hepatitis B
Hepatitis C Virus (HepC):
Hepatitis C
Rotavirus:
Gastroenteritis (especially in children)
Norovirus:
Gastroenteritis
Mumps Virus:
Mumps
Measles Virus:
Measles
Rubella Virus:
Rubella (German measles)
Enteroviruses:
Various, including hand, foot, and mouth disease
Adenovirus:
Respiratory and gastrointestinal infections
Mechanisms of viral infection and Pathogenesis by Christina Baboonian
How do viruses spread within the body?
Using Varicella Zoster virus as an example describe mechanisms that viruses use to spread within the body
Direct Cell-to-Cell Spread: VZV can move directly between cells, often in neurons, to evade immune surveillance.
Bloodstream Dissemination: The virus can enter the bloodstream, facilitating systemic spread.
Neuronal Transport: VZV can use neurons to travel to different areas of the body, leading to latent infections and reactivation.
Respiratory Spread: VZV can be expelled from the respiratory tract during infection, leading to transmission to other hosts.
Mechanisms of viral infection and Pathogenesis by Christina Baboonian
What viral mechanisms are used to remain in host?
Describe mechanisms used by viruses to persist within the host and relate to clinical examples
Latency: Some viruses, like VZV and herpes simplex virus, establish latency in neurons, avoiding immune detection.
Immune Evasion: Viruses can adapt to evade host immune responses.
Cell-to-Cell Spread: Viruses can use cell-to-cell transmission, reducing exposure to the immune system.
Antigenic Variation: Some viruses mutate their surface proteins, making them less recognizable to the immune system.
Release decoy particles
I&I Microbial Immune Evasion Mechanisms by Jose Saldana
How do pathogens avoid the innate immune system
*LOB: Outline, with bacterial and viral examples, survival strategies used by pathogens to avoid the adaptive and innate immune systems
Staphylococcus: leucocidins kill Mφ and protein A binds Fc of IgG to prevent opsonisation.
Meningococcus and Hib: capsules block contact with immune cells.
Intracellular pathogens:
Promote own uptake (safe) - CR3; mannose lectin receptors
Prepares cell for invasion - Shigella
Inhibit Phagosome-lysosome fusion - M. tuberculosis
Escape Phagosome-lysosome to cytoplasm - Listeria
Resist oxidative killing - produce catalases/peroxidases
I&I Diagnosis of Viral Infections by Dr Cassie Pope
Loop-Mediated Isothermal Amplification (LAMP):
*LOB: Demonstrate an appreciation of the advantages and limitations of the different viral diagnostic tests allowing the most appropriate sample and test to be chosen and the correct diagnosis to be made
*LOB: Understand the science behind the different methods of diagnosing viral infections.
Method: LAMP is an isothermal nucleic acid amplification technique that amplifies DNA at a constant temperature. It uses multiple primers and a DNA polymerase with strand-displacement activity.
Advantage: LAMP provides quick results, requires less expensive equipment, and is well-suited for resource-limited settings.
Disadvantage: It is limited to certain viruses, and specificity can be an issue, especially when dealing with closely related strains.
Human African Trypanosomiasis, various parasitic diseases.
I&I Clinical Use of Antiviral Drugs by Dr Peter Riley
Diseases and Antivirals
*LOB: List other agents used for the treatment of viral infections
I&I Disorders of Immune System by C Baboonian
Compare Immunodeficiency 1’ and 2’
*LOB: Distinguish between primary and secondary immunodeficiency
Primary immunodeficiency is genetic, present from birth, and often requires specific treatments, while secondary immunodeficiency is acquired, can develop at any age, and is typically managed by addressing the underlying cause.
I&I Maternal Health and Infectious Disease by Bernice Langdon
What is maternal mortality?
*LOB: Explain why maternal morbidity and mortality is important
- annual number of female deaths
- from any cause related to or aggravated by pregnancy or its management (excluding accidental or incidental causes)
- during pregnancy and childbirth
- or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy.
NICE: compared with white women (8/100,000), the risk of maternal death during pregnancy and up to 6 weeks after birth is:
4 times higher in black women (34/100,000)
3 times higher in women with mixed ethnic background (25/100,000)
2 times higher in Asian women (15/100,000; does not include Chinese women)
I&I Maternal Health and Infectious Disease by Bernice Langdon
What is STORCHH
Think Virals
*LOB: List key microbes that can cause maternal, congenital, and neonatal infection
Syphilis
Toxoplasmosis
Other
Rubella
Cytomegalovirus (CMV)
Herpes simplex virus (HSV)
HIV
I&I Maternal Health and Infectious Disease by Bernice Langdon
Which Vaccinations are given in pregnancy and why?
*LOB: Identify the vaccinations relevant to pregnant women in the UK schedule and explain why they are given
There is a difference in Immune Susceptibility when Pregnant
’The Government has accepted JCVI advice that the seasonal COVID-19 vaccine should be offered this autumn to all pregnant women – because they are at higher risk of severe COVID-19 infection.
’Wherever possible, vaccinations for flu, COVID-19 and pertussis should be offered at the same time
I&I Maternal Health and Infectious Disease by Bernice Langdon
What is Sepsis and how to manage
*LOB: Demonstrate an understanding of the key importance of sepsis during pregnancy and childbirth and outline typical microbial causes such as Group A Strep and Group B strep
Sepsis is a life-threatening reaction to an infection. It happens when your immune system overreacts to an infection and starts to damage your body’s own tissues and organs.
.
1.Oxygen to keep oxygen saturations above 95%
2.Blood cultures, also FBC, U&E, LFT, coagulations, glucose, other cultures
3. Lactate measurement
4 .IV fluids bolus20ml/Kg normal saline stat. If no response repeat unless there are signs of pulmonary oedema
5. IV antibioticsprescribe and commence within 60 minutes from triage/time of diagnosis. Do not wait for results of investigations.
6. Monitoring; respiratory rate, oxygen saturations, BP, heart rate, temperature, consciousness, fluid balance, urinary output.
I&I A Patient Presents with Suspected COVID...
COVID investigations
*LOB: Outline the relevant investigations that should be undertaken for a patient with suspected COVID-19
Blood tests - including Full Blood Count, Urea & Electrolytes, Liver Function Tests, CRP and Blood
Cultures
SARS-CoV-2 PCR swab
Respiratory viral panel PCR swab - testing for alternative respiratory viruses including rhinovirus, influenza amongst others
**Chest X-ray
**
ECG (to screen for features of heart failure, pericarditis etc.)
Urine dipstick (to exclude a urinary infection as the cause of his fevers/lethargy)
CRP is raised (which is a non-specific marker of inflammation but is usually elevated in moderate-severe COVID), and the normal procalcitonin level makes a bacterial infection less likely.
I&I Disorders of the Lymphatic System by Dr Kristiana Gordon
Functions of lymphatics
*LOB: Describe the functions of the lymphatic system
- drainage system of interstitial fluid
- Protein and fluid homeostasis
- Cellular drainage from tissues
- Immune surveillance
- Regulation of inflammation
- Fat homeostasis
I&I Disorders of the Lymphatic System by Dr Kristiana Gordon
Staging lymphodema
*LOB: Describe the pathophysiological mechanisms of common lymphatic conditions
I&I Disorders of the Lymphatic System by Dr Kristiana Gordon
Causes of Primary Lymphodema
*LOB: Describe the pathophysiological mechanisms of common lymphatic conditions
developmental abnormality of the lymphatic system,
- It is not just one disease. Phenotypes vary in age
of onset, site, inheritance patterns, associated
features. - Multiple causal genes identified
Classified * Associated with other genetic syndromes.
* Associated with systemic lymphatic problems.
* Congenital (swelling present at birth).
* Late-onset (onset after 1 year of age).
* Lymphatic malformations +/- overgrowth disorders.
I&I Disorders of the Lymphatic System by Dr Kristiana Gordon
Klippel-Trenaunay Syndrome
*LOB: Describe the pathophysiological mechanisms of common lymphatic conditions
I&I Disorders of the Lymphatic System by Dr Kristiana Gordon
Managing Lymphodema
*LOB: * Outline the management of chronic lymphoedema
I&I Principles of Selective Toxicity by Dr Omar Janneh
Mehcnism of penicillin
*LOB: Explain how antibiotics inhibit cell wall synthesis in bacteria
Side chain from the βlactam ring determins the properties of different penicillin but:
penicillin binds to PBP (penicillin binding proteins) which inhibits peptide cross links in the microbial cell wall.
Essentially inhibits transpeptidation- which prevents peptide bridge forming. (NAG and NAM)
I&I Principles of Selective Toxicity by Dr Omar Janneh
Mechanism of Aminoglycosides (streptomycin and gentamicin)
*LOB: Explain how antibiotics inhibit protein synthesis in bacteria
Binds to essential portions at the transcription process.
Streptomycin changes 30S: mRNA incorrectly read
Tetracyclin changes how tRNA and mRNA bind
Think s for 30s and t for trna
I&I Principles of Selective Toxicity by Dr Omar Janneh
What are the site of action for antifungal agents?
*LOB: Explain why some drugs selectively inhibit fungal growth
Meningitis Workshop
CSF changes
*LOB: Describe the changes in the CSF glucose, protein and white cell count in the cases of bacterial and viral meningitis
