Wk2 - Immunology Flashcards
What are the different factors involved in innate immunity
Soluble factors: Antibacterial factors (lysozyme (enzyme present at mucosal surfaces, active in breaking down the gram positive cell wall) and lactoferrin (Protein found at mucosal surfaces, chelates iron and therefore reduces soluble iron in the GI/respiratory tract, Inhibits the growth of bacteria)) Compliment system (Active at mucosal surfaces and also in blood, enzymatic cascade)
Cellular factors: Scavenger phagocytes (mainly macrophages and neutrophils)
The 3 outcomes of the compliment cascade
Recruitment of inflammatory cells
Opsonization of pathogens
Killing of pathogens
How are macrophages able to carry out their function?
When might macrophages not be able to carry out their function?
They express TLR (a pattern recognition receptor)
Pattern recognition receptors:
Recognise molecules found commonly in micro-organisms
Able to recognise extracellular and intracellular threats
Respond to bacteria, fungi and yeasts
May not be able to carry out their function due to highly pathogenic bacteria or due to structural failure (e.g. surgery or injury that allows the bacteria to enter the body)
Macrophages have 2 main functions
Macrophages are involved in…
1) Clearance of micro-organisms
2) Getting help - by releasing hormones e.g. cytokines and neutrophils
Involved in:
Phagocytosis - specialises in destruction of pathogens. Also removes harmless debris e.g. tattoo pigment.
Antigen presentation - processes engulfed particles, travels to draining lymph nodes and presents T cell to MHC II
Cytokine production - M1- inflammatory, TNF alpha; M2- Regulatory, IL10
Inflammation is (in general terms)…
Universal response to tissue damde.
Damage can be caused by infection, necrosis or trauma
Explain how changes in the vasculature and cells occur with inflammation
1) Vascular dilatation - histamine and prostaglandins released –> arterioles dilate increasing blood flow, fluid passes into tissues causing swelling
2) Neutrophil activation - chemotaxis, phagocytosis and bactericidal
3) Endothelial activaiton - 5HT, histamine, bradykinin, C3a, C5a, leukotriene. Activates vascular endothelium; increased cell adhesion molecules; increased leakiness of endothelium; Plasma proteins travel into tissues including immunoglobulins, compliment and fibrinogen
5 cardinal signs of inflammation
Redness - hyperaemia Swelling - fluid exudate and hyperaemia Heat - hyperaemia pain - bradykinin and PGE2 Loss of function - combination. Pain and swelling prevent movement
Types of exudates
Neutrophilic exudate (supportive/purulent) Fibrinous exudate Serous inflammation (in peritoneal cavity or pleural cavity)
Spread of infection
Natural barriers
Air borne
Blood borne
Immune factors
Sequelae of acute inflammation
Abscess, chronic inflammation
Define chronic inflammation
Results from persisting tissue damage and ongoing acute inflammation or de novo (by viral infection).
Associated with a chronic inflammatory cell infiltrate including lymphocytes, macrophages and plasma cells.
Often leads to fibrosis or scarring.
Granulomatous inflammation is a subtype of chronic inflammation with a specific histological appearance (granulomatous inflammation associated with caseous necrosis)
Granulomatous inflammation
Defined by the presence of granulomas, collection of epitheloid macrophages and multinucleate giant cells
Subtypes include necrotising, non-necrotising, foreign body granulomas
Describe the antibacterial (soluble) factors of innate immunity
Lysozyme - enzyme present at mucosal surfaces; Active in breaking down the gram positive cell wall
Lactoferrin - Protein found at mucosal surfaces; Chelates iron and therefore reduces soluble iron in the GI/respiratory tract; Inhibits the growth of bacteria
Describe features of neutrophils
Have a multi-lobed nucleus Release DNA tangles Kills bacteria but also kills the surrounding cells Makes up 60-70% of WBCs Provides a rapid response to infection
The process of neutrophils killing bacteriats
Chemotaxis - migrate towards bacterial products (e.g. LPS), chemokines and ‘danger signals’ (e.g. compliment components)
Phagocytic: Will ingest and destroy pathogens using proteases, reactive oxygen species, lysozymes etc.
Degranulate: Release toxic granules intracellularly
Die locally: producing characteristic pus
Features of eosinophils
Process of eosinophil
Classically respond to parasites
1-6% of WBCs
Pathological role in allergy
Chemotaxis: migrate in response to chemokines e.g. eotaxin
Degranulation: release toxic substances into the surface of parasites e.g. major basic protein, eosinophil cationic protein, eosinophilic peroxidase
Cytokine production: drive inflammation - IL1, IL2, IL4, IL8, TNF alpha
Process of basophils/mast cells
(Have an important role in allergy)
Degranulation: Rapid release in pre-formed granules containing cytokine and mediators e.g. histamine - Wheal and Flare reaction
Cytokine release: store many pre-formed cytokines that are ready for release that attract and drive the subsequent immune response
Innate immunity overview
Capable of containing vast majority of interactions with micro-organisms.
Recognise danger patterns with genetically determined receptors
Capable of inactiviating micro-orgnaisms through combination of secreted factors and phagocytosis
Can activate adaptive immunity if required.
What are the link between the innate and adpative immune system
Dendritic cells:
Derived from the same precursors as macrophages
Prototype Antigen Presenting Cell
Dendritic cells = cells of langerhans
Process of dendritic cells
Phagocytosis: unlike macrophages, dendritic cells are not specialised in destruction of pathogens. Instead they function mainly as antigen presenting cells (APCs)
Migration: sit in tissues constantly sampling environment. When activated will travel to draining lymph nodes.
Antigen presentation: presents to CD4 T cells and can initiate an adaptive immune response
Structure of antibodies
Light chains
Heavy chain
Fab region - antigen binding region
Fc region - binds to Fc receptors on phagocytes; Activates compliment
What are the 3 functions of antibodies?
opsonise for phagocytosis
Activates compliment for lysis
Neutralises toxins and pathogen binding sites
How do the antibody isotypes differ?
They differ in their Fc region
IgM antibody
Main antibody of primary immune system (is produced first)
Low affinity
Activates compliment
IgG antibofy
Main antibody of secondary immune system
High affinity as part of secondary response
Activates compliment, binds Fc gamma receptor on phagocytes (opsonises)
Crosses placenta
IgA antibody
‘antiseptic paint’
Present in secretions and lines epithelial surface
Neutralises by blocking binding of pathogens
Important in nose, lung, gut
IgE antibody
High affinity binding to mast cells through Fce receptor
Role in allergy
optimal B cell response requires T cell help
T cell help: Cloncal expnasion of specific B cells Progression to antibody secreting cells (plasma cells) Progression to memory B cells Isotype switching to IgG, IgA and IgE Affinity maturation
T cell receptor
the receptor is on the surface of T cells and only recognises antigen when it is presented in a MHc molecule
Recognises short peptide lengths, not whole three diensional molecules
T cells can only see antigen in context of MHC. Describe features of class I MHC, and class II
Class I:
Presents to CD8 T cells
Found on all nucelated cells
Presents intra-cellular antigen
Class II:
Presents to CD4 T cells
Presents extra-cellular derived antigen (phagocytosed)
Found on anitgen presenting cells: DC’s, macrophages, B cells
Activated CD4 T cells differentiate into…
Th1 cells - IFN-gamma secretion; host defense against intracellular microbes; inflammation.
Th2 cells- IL-4, Il-5, IL-3 secretion; host defense against helminths; allergic reactions
Th17 cells: IL-7 secretion; host defense against some bacteria; inflammatory disorders
T regulatory cells: Act to regulate function of other immune cells, in particular T cells
Primary and secondary organs of the adaptive immune system
Primary - thymus (T cell education), Bone marrow (B cell education)
Secondary - lymph nodes, spleen, mucosal associated lymphoid tissue of GI tract (MALT) and bronchial tract (BALT)
Overview of adaptive immune system
Provides specific antibodies to the innate immune system to enhance pathogen clearance.
Provides cytokines to the innate immune system to upregulate activity
Finishes off the job of clearing pathogens.
Develops a memory to prevent future infection
Secondary response
Memory B cells and memory T cells already present at high frequency.
Memory lymphocytes have lower threshold for activation and actively patrol the sites of previous pathogen entry.
Preformed antigen specific IgA prevents pathogen binding.
Preformed high affinity IgG rapidly opsonises pathogen for phagocytosis
Features of the 5 types of hypersensitivity
I - immediate, atopic - IgE mediated
II - cytotoxic, antibody dependent - IgM or IgG bound to cell/matrix Ag
III - immune complex - IgM or IgG bound to soluble Ag
IV - cell mediated - T cells (CD4+ & CD8+)
V - receptor mediated - IgM or IgG bound to receptors
Characteristics of type 1 hypersensitivity
Response to challenge occurs immediately.
Tends to increase in severity with repeated challenge.
Predominantly mediated by IgE bound to mast cells.
Responsible for most allergies - asthma, eczema, hayfever
Describe the stages of allergy (type I hypersensitivity)
- Sensitisation
- Mast cells primed with IgE
- Re-exposure to antigen
- Antigen binds to IgE associated with mast cells
- Mast cells degranulate releasing - toxins (i.e. histamine), tryptase, pro-inflammatory cytokines, chemokines, prostaglandins, leukotrienes
- Pro-inflammatory process stimulates and amplifies future responses
Tissue effects to allergy - early effects
Occurs within minutes if exposure to antigen
Occurs largely as a result of histmaine and psotaglandins - casues smooth muscle contraction, increased vascular permeability
Tissue effects to allergy - late phase
Occurs hours to days after exposure to antigen.
Prinicipally mediated through recruitment of T-cells and other immune cells to site.
Results in - sustained asmooth muscle contraciton/hypertrophy & tissue remodellign
What is anaphylaxis?
Sever, systemic type 1 hypersensitivity:
Widespread mast cell degranulation caused by systemic exposure to antigen (i.e. penicillin)
Vascular permeability is prinicple immediate dander: soft tissue swelling threatening airway; loss of circulatory volume causing shock.
Can be rapidly fatal
Describe features of type II hypersensitivity
Causes by binding of antibodies directed against human cells - IgG is usual causes IgM, IgA)
Uncommon causes of allergy - drug associated haemolysis
Common cause of autoimmune disease e.g. bullous pemphigoid (deep blisters on skin)
Process of type II hypersensitivity
- Sensitisation
- Opsonisation of cells - generated antibodies opsonise cells.
- Cytotoxicity - compliment activation, inflammation, tissue destruction
- In some cases - direct biological activation with antigen (i.e. receptor activation, impaired enzyme action) - type V can do stage 4
Describe features of type III hypersensitivity
Mediated by immune complexes bound to soluble antigen.
Cause of autoimmune disease and drug allergy.
Aggregate in small blood vessels: direct occlusion, compliment activation, perivascular inflammation
Example = SLE
Describe features of type IV hypersensitivity
Example of Type V hypersensitivity
Process of Type IV hypersensitivity
Also known as delayed hypersensitivity
Presents several days after exposure
Mediated by the action of lymphocytes infiltrating the area
(type II, III and IV are all delayed hypersensitivity)
Example = DMT1, Allergic Contact Dermatitis
Example of type V = Graves disease
Process of type IV:
Contact-sensitizing agent penetrates the skin and binds to self proteins, which are taken up by Langerhans cells.
Langerhans cells present self peptides haptenated with the contact-sensitizing agent to Th1 cells, which secrete IFNgamma and other cytokines.
Activated keratinocytes secrete cytokines such as IL1 and TNFa and chemokines such as CXCL*, CXCL11, and CXCL9.
The production of keratinocytes and Th1 cells activated macrophages to secrete mediators of inflammation
Define autoimmune disease
harmful inflammatory response directed against ‘self’ tissue by the adaptive immune response.
Divided into:
- organ specific (e.g. T1DM, Myasthenia Gravis, Addison’s disease)
- systemic (e.g. RA, SLE, IBD, connective tissue disease, systemic vasculitis)
Describe T1DM - an organ specific autoimmune disease
Selective, autoimmune destruction of the pancreatic beta cells - often mix of type II and type IV.
Causes profound insulin deficiency and death if not treated with insulin replacement.
Inflammation of the islets of Langerhans precedes symptoms by many years
Describe mysathenia gravis - an example of organ specific autoimmun disease
Syndrome of fatigable muscle weakness - limbs, repsiratory, head and neck.
Causes by IgG against acetylcholine receptor.
antibody blcoks receptor at neuromuscular junction and prevents signal transduction
Give examples of systemic autoimmune disease
Rheumatoid arthritis Systemic lupus erythermatosus inflammatory bowel disease Connective tissue disease Systemic vasculitis
Examples of organ specific autoimmune disease
T1DM
Myasthenia Gravis
Addisons disease
Characteristics/signs and sympotms of RA
Pulmonary nodules and fibrosis Pericarditis and valvular inflammation Small vessel vasculitis Soft tissue nodules Skin inflammation Weight loss, anaemia
pathophysiology of RA
Rheumatoid factor: - IgM and IgA directed against IgG Fc region. Forms large complexes –> high concentration with in synovial fluid.
Inflammation leads to release of PAS from inflammatory cells.
Alters variety of proteins by converting alanine to citrulline
in RA, anti-citullinated protein/peptide antibodies are common.
Stages leading to inflammation in RA
Amplificaition of inflammatory cascade.
Furhter chemoattraction of inflammatory cells into synovium - macrophages, neutrophils, lymphocytes.
osteoclast activation and joint destruction.
Fibroblast activation and synovial hyperplasia.
Systemic inflammation.
Biologic therapy for autoimmune diseases
Infliximab - monoclonal antibody; Target = soluble cytokine
Etanercept - a soluble receptor ; Target - soluble cytokine
Rituximab - monoclonal antibody; Target - surface marker
Effect of biological therapies on autoimmune disease for RA
Reduces joint swelling and pain
Decreases systemic inflammation
Delays and prevents appearance of erosions and one deformity
Cost - increased risk of infection, esp TB
Genetic predispostion to autoimmune disease
Genes involved:
MHC-1 and II (HLA locus)
Cytokine and their receptors, i.e. TNF alpha
Environmental factors for autoimmune disease
Infection - molecular mimicry; tissue damage exposing self-antigens
Geographical factors: Vitamin D mediated through sunlight exposure
Modifiable personal risk factors - smoking
Enzymes and proteins involved with inflammation in RA
Presence of antibodies of citrullinated proteins strongly predicts RA
Citrullinated proteins develop due to action of enzymesinduced during inflammation
Associated with conversion of alanine to citrulline
A bacterium is inoculated into tissue, leukocytes leave the vasculature and migrate to the site of bacterial inoculation. The movement of leukocytes is most likely to be mediated by which of the following substances A) Bradykinin B) Chemokines C) Histamine D) Prostaglandins E) Complement C3a
Chemokines
A patient has a fever, productive cough and O2 sats of 92%. Auscultation demonstrates crackles at the right base. CXR demonstrates consolidation at the right base. Which of the following inflammatory cell types is most likely to be seen in greatly increased numbers in a sputum specimen? A) Macrophages B) Neutrophils C) Mast cells D) Small lymphocytes E) Multinucleate giant cells
Neutrophils
A man dies two weeks following an acute myocardial infarction. At post mortem, a histological section of the infarct shows that the necrotic myocardium has largely been replaced by capillaries, fibroblasts and collagen. Which of the inflammatory cells in this lesion has the most important role in the healing process? A) Macrophages B) Plasma cells C) Neutrophil polymorphs D) Eosinophils E) Lymphocytes
Macrophages
A man develops infective endocarditis. Blood cultures grow Streptococcus viridans. Microbes are opsonised and cleared. Which of the following mediators is the most important in this process? A) Bradykinin B) CRP C) IFN-gamma D) NO E) Complement F) TNF
Complement
A man becomes increasingly breathless. A CXR shows that fluid has accumulated in his right pleural space. A pleural tap shows that the fluid is composed of neutrophil polymorphs in the majority. Which of the following mechanisms contributes to the accumulation of fluid in the pleural space? A) Lymphatic obstruction B) Neutrophil release of lysosomes C) Promotion of platelet adherence D) Arteriolar vasoconstriction E) Endothelial contraction
Endothelial contraction
What could have caused the appendix to perforate? A) Acute necrotising inflammation B) Rupture of a diverticulum C) Vasculitis D) A parasitic infection E) All of the above
All of the above
A 42 year old man presents with a dry cough of several months duration
What is your differential diagnosis?
What simple tests can be performed?
What is your differential diagnosis?
Asthma, COPD, ILD, Sarcoid, Reflux
What investigations will you ask for
Peak flow, PFTs, CXR, CT, HRCT, Serum ACE, Endoscopy
In this granulomatous condition (granulomatous inflammation), what is main cell type involved? A) Neutrophil polymorph B) Macrophage C) Lymphocyte D) Eosinophil E) Basophil
Macrophage
A man injures his finger and it becomes red, hot and swollen.
What process is this?
What are the five cardinal signs
What is your differential diagnosis?
What process is this? Acute inflammation What are the five cardinal signs Pain, heat, redness, swelling, loss of function What is your differential diagnosis? Arthritides, infection, gout, tumour
What mediator permits diapedesis of inflammatory cells A) Serotonin B) VEGF C) Nitric oxide D) Endothelin-1 E) Integrins
integrins
A 66 year old female presents with early morning pain and stiffness in her joints On examination, the following are noted (ulnar deviation of digits) What is this condition A) Osteoarthritis B) Rheumatoid arthritis C) Psoriatic arthritis D) Gout E) Septic arthritis
RA
A biological therapy called anti-TNF alpha is recommended
What is the mechanism of action?
What are the side effects?
What is the mechanism of action?
Apoptosis, cytotoxicity, diminished cell influx or a reduction in chemotatic molecules
What are the side effects?
Mild rash/pain, autoantibody production, TB, skin cancer, lymphoma
Brief steps to forming a protein from DNA
DNA polymerase - causes DNA replication
RNA polymerase - Transcription - forms RNA from DNA.
Translation occurs on the ribosome –> protein
