Week 19 - TB Flashcards
What is chronic inflammation?
Long lasting inflammatory response (weeks, months)
May follow acute inflammation or not
Marked by significant tissue destruction
What are the potential causes of chronic inflammation?
Failure to close acute inflammatory reactions - Persistent infections
Misdirected inflammatory reaction - harmless environmental substances, autoimmune diseases
Underlies many disorders - cancer, atherosclerosis, alzheimer’s, etc
Acute vs chronic inflammation
Chronic involves adaptive more than acute
Chronic may include necrosis, fibrosis, scarring and angiogenesis
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What sort of cells are most often involved in chronic inflammation?
What is their role?
Monocytes - which become macrophages in cell
Activate other cells, secrete inflammatory cytokines, produce growth factors (tissue repair)
Other cells can be there - depends on what the response is to
When are eosinophils involved in chronic inflammation?
infections with parasites, IgE-mediated allergic reactions
When are mast cells involved in chronic inflammation?
present in connective tissue, close to vessels
Involved in acute as well
When are neutrophils involved in chronic inflammation?
some types of chronic inflammation: suppurative inflammation (abscess, osteomyelitis); lung disease smoking/irritants
What is the cytokine that activates macrophages?
Interferon-gamma
Types of chronic inflammation (4)
Non-specific - H.Pylori associated gastritis
Autoimmune - Rheumatoid arthritis
Chronic suppurative - abscess, osteomyelitis
Chonic granulomatous - TB, sarcoidosis
Outline non-specific chronic inflammation
Acute inflammation fails to clear properly such as h.pylori which body tries to fight with neutrophils. They do not effectively fight it so start to attack epithelial cells, leading to ulceration
Outline inflammation in autoimmune disease
Immune response to self-antigens
Outline chronic suppurative inflammation
Persisting pus-forming inflammation
Outline chronic granulomatous inflammation
Usually develop when causing agent can’t be eradicated
Granuloma forms to isolate and prevent spread of agent (usually made up of macrophages, lymphocytes, fibroblasts, necrotic tissues)
Types of granulomas
Immune - Infection or autoimmune (usually T cell activation)
Foreign bodies - no T cells
Diseases of unknown aetiology - sarcoidosis
Potential outcomes of granulomatous inflammation
Causing agent eradicated - tissue healing with some scarring / fibrosis
Causing agent persists - ‘walled off’ by fibrous tissue, infection kept in check by T cells and macrophages
Stages of tissue repair (3)
Acute inflammation
Dead organisms / cells are phagocytosed and cleared
Organisation, formation of granulation tissue
Resolution, repair (scarring)
Outline healing of skin wounds - primary and secondary intention
Primary - small, limited to epithelial layer, regeneration
Secondary - more extensive, repair by regeneration and scarring
What are the functions of the lymphatic system?
Fluid balance (homeostasis)
Tissue immunosurveillance - immune response
Fat homeostasis
What are the mechanisms for chronic oedema?
Veins are dumping more fluid than lymphatics can drain
Lymphatic failure - lymph build up
Long standing increased venous filtration
What is tuberculosis?
Contagious, debilitating bacterial disease spread by airborne droplet nucleii for an infected person
What is the infectious dose of TB?
Only 1-3 organisms - very transmissible
What happens following initial infection with TB?
5% will progress to active infection
90% will have latent infection
About 10% of those with latent will have reactivated disease
Latent vs active TB infection - symptoms, spread, skin test, x-ray
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Risk factors for reactivation
Malnutrition Poverty Immunosuppression Diabetes Old age Poor health HIV
What is a Ghon complex?
Ghon focus (lesion) + lymph node Sign of primary tuberculosis
What is miliary TB?
TB in another part of the body
Describe intestinal TB - causes
Can be secondary to pulmonary TB, swallowed from infected sputum
Primary cause is milk infected with M. bovis (now rare)
How does milliary TB cause damage around the body?
Chronic granulomatous tissue damage
Describe the immune response to TB - the good and the bad
Good - Innate immunity as macrophages try to kill ingested bacilli, adaptive response with CD8 and CD4 T cells, IFN-gamma
Bad - Excessive response leads to overproduction of TNF-alpha leading to damage of healthy tissues by macrophages
Overview of general pathogenesis of TB (active) - simple steps
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Outline Koch’s postulates
Working in anthrax, cattle
Criteria designed to establish causative relationship between microbe and disease
- Organism is in the lesions in ALL cases of disease
- Isolate organism and cultivate it outside host
- Produce the same disease if pure culture is injected into healthy subject
- Recover microbe from experimentally infected host
Does NOT work for many organisms - M.leprae, treponema pallidum (syphillus)
How do you diagnose TB?
Blood - Interferon-gamma blood test Chest x-ray PCR - GeneXpert looks at TB DNA and looks for Rifampcin resistance Sputum smear, culture Bronchoscopy Biopsy
Management of TB
Rifampicin, Isoniazid, Pyrazinamide, Ethambutol (initial 2 months)
Further 4 months with Rifampicin, Isoniazid
Treatment side effects - rifampicin
hepatitis rash GI upset intermittent Rx can give rise to flu like symptoms drug interactions - OCP/prednisolone
Treatment side effects - isoniazid
rash
peripheral neuropathy
hepatitis
Treatment side effects - Ethambutol
dose related optic neuropathy
Treatment side effects - Pyrazinamide
hepatitis facial flushing rash nausea & anorexia arthralgia high uric acid
Expectations with treatment
Non-infectious within 2 weeks (90% fall in number of viable organisms)
Temperature settled and feeling better
Gaining weight at 1mth with sputum smear negative
Sputum culture negative by 2mths
Considerations if patients are not improving
Compliance, AMR
Does TB have caesating or non-caesating granulomas?
Either, but more things cause non- so more tests / clarity needed
What are the roles of complement? (8)
induces inflammatory response promotes chemotaxis increases phagocytosis by opsonisation increases vascular permeability mast cell degranulation lysis of cell membranes activates macrophages (C3a) Removal of immune complexes
Complement system overview
IgM or IgG bind, complement unit bind, complement pathway activated which leads to MAC tunnel in microbe surface, creates hole/pore that causes lysis
Which complement factor is involved in opsinisation?
C3b opsonises bacteria, which tags it for killing
Roles of C3b (3)
Opsonises bacteria
Vasodilator
Activates phagocytes
How can bacteria stop the complement process?
Bacteria binds Factor H (regulator molecule) so that the complement system can’t act on the surface
What does protein A do?
Binds antibody wrong way round which makes it useless
defense mechanism of bacteria
Summary of antibacterial roles of antibodies
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Summary of types of immune response to bacteria (based on location)
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Pathogenesis and defence response of neisseria meningitidis
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Pathogenesis and defence response of mycobacterium tuberculosis
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Pathogenesis and defence response of staph aureus
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Overview of types of cells - macrophages, PMN, NK cells, dendritic cells, CD8, CD4, B cells
Macrophages and neutrophils (PMNs) - phagocytose free bacteria & present antigen
NK cells - kill infected cells showing antigen
Dendritic cells - present antigen at lymph nodes
Cytotoxic T cells CD8+ kill cells expressing antigen
CD4 helper cells - activate macrophages & stimulate B cells
B cells - antibodies
What is hypersensitivity?
Diseases caused by abnormal immune responses (excssive response to innocuous antigens) or response against self antigens (autoimmune)
Misdirected, excessive, poorly controlled
Leading to tissue damage
Outline the types of hypersensitivity reactions
Type 1: Immediate (IgE) / allergic
Type 2: Antibody mediated (IgM, IgG)
Type 3: Immune complex mediated
Type 4: T cell mediated
Describe type 1 hypersensitivity reaction
Allergic response
Fast immune reaction
Triggered by exposure to allergen, which binds to IgE on surface of mast cell
Most common
Healthy subjects would respond to igM/igG, atopic subjects produce IgE
Examples of type 1 hypersensitivity reaction (what can cause)
Hay fever, atopic dermatitis, allergic asthma, pollen, dust mites, animal dander, food (peanuts, eggs), chemicals (penicillin), insect venom
Asthma (kind of, also chronic)
What is the series of events in SENSITISATION in type 1 hypersensitivity reaction
SENSITISATION Antigen presenting cell brings antigen Th2 cell response Activation of B cells and IgE switch (from IgM) IgE production IgE binds to Fc receptors on mast cells
What is the series of events in SUBSEQUENT EXPOSURE TO ALLERGEN in type 1 hypersensitivity reaction
Allergen binds on IgE on mast cells
Activation of mast cells, release of mediators
Vascular and smooth muscle reactions within minutes
Late phase reaction (inflammation) (2-24 hours)
What happens during the activation of mast cells
Release of preformed mediators - histamine and enzymes
Production and secretion of lipid mediators
Production and release of cytokines
What happens with the late reaction of type 1 hypersensitivity reaction?
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What is anaphylaxis?
Systemic response all over body
Can happen with injection, insect bites, absorption through mucosa/skin
Activation and degranulation of mast cells
Clinical signs - Drop in blood pressure (shock), airway constriction, widespread oedema, vomiting, cramps, diarrhoea
What is a type 2 hypersensitivity reaction?
Antibodies to cell-bound antigens (self-antigen)
MECHANISMS
Opsonisation and phagocytosis
Complement and Fc receptor mediated inflammation
Antibody-mediated cellular dysfunction
Types of type 2 hypersensitivity reactions (conditions)
Autoimmune haemolytic anaemia Agranulocytosis Autoimmune thrombocytopenic purpura transfusion reactions haemolytic disease of newborn Organ transplant rejection
What occurs in antibody-mediated cellular dystunction in type 2 hypersensitivity reactions? (2 condition examples)
There is no inflammation, they just make particular antibodies more or less effective
EXAMPLES
Blocking antibodies - Myasthenia gravis
Stimulating antibodies - Graves disease
What is a type 3 hypersensitivity reaction?
Immune complex-mediated hypersensitivity reaction
Antibodies and antigens combine to form COMPLEX, get deposited in vessel wall which causes inflammation
Arthritis, vasculitis, glomerulonephritis, SLE
What is type 4 hypersensitivity reaction?
Mediated by CD4 T cells, delayed type
Th1, Th17 mediated autoimmune diseases - theumatoid arthritis, MS, IBD, psoriasis
OR Mediated by CD8 T cells
Type 1 diabetes, viral hepatitis, organ transplant rejection
System for assessing a chest x-ray
Adequacy - well centred, inspiration, exposure
A- airway
B - breathing, looking at zones not lobes
C - cardiomediastinal contour (and hila)
D - diaphragm
E - everything else - bones, soft tissues, and upper abdomen
