What is immunopathogenesis? Give some examples
Pathologies following infection caused by immune reactions rather than pathogen replication Viral bronchiolitis, Septic Shock
What is viral bronchiolitis?
Inflammation of the bronchioles following viral infection
What are the aetiological agents of viral bronchiolitis?
–Respiratory syncytial virus (Paramyxoviridae)
–Influenza virus (Orthomyxoviridae)
–Human metapneumovirus (Paramyxoviridae)
Describe RSV on an electronmicrograph
Who is at particular risk of severe disease as a result of RSV?
The frail elderly
– Prophylactic monoclondal antibody given to high risk infants (bronchopulmonary dysplasia; <32 weeks gestation; congenital heart disease)
What is the disease burden of RSV wordwide?
64million infections per year and 160, 000 deaths
No vaccine or specific therapeutic
What are the risk factors for severe disease (caused by RSV) in infants?
•Prematurity (born more than 4 weeks early)
•Chronic lung disease or congenital heart disease
•Low birth weight
•Child care or day care attendance
•School-age brothers and sisters at home
•Crowded living conditions
•Multiple births (twins, triplets)
•Family history of asthma
•Exposure to tobacco smoke or other environmental air pollutants
When is there a peak in RSV infections?
In WINTER - Nov, Dec, Jan
What are some RSV - induced diseases?
• Otitis media
B+P = 25-40% during first infection
What is the pathology of Bronchiolitis and pneumonia?
–Necrosis and sloughing of small airway epithelium
– Increased mucus secretion (Obstructs airflow in small airways)
In Bronchiolitis - the airway becomes obstructed due to swelling of the bronchiole walls
What are the clnical implications of Bronchiolitis and Pneumonia?
What is the pathogenesis of RSV?
Virus replication triggers immune response in lungs
- Cytokine/chemokine release
- Infiltration of
- Prevascular and peribronchiolar cuffing (blood vessel is surrounded by cells that are trying to get out into the lungs)
- Trapping of air in lower lungs (lung hyperinflation)
- Once the immune response is triggered, removal of the RSV will NOT stop the pathogenesis
Nb most of the damage is caused by the immune response
What are the principal infiltrates in an RSV infection?
(Disease is immune-mediated)
Describe the histology of a normal lung
Single layer of cells around alveoli
Describe the mechanism of RSV-induced airway inflammation
- Virus infected epithelium
- Cytokines and Chemokines
- Inflammatory cell recruitment
- Neural Activation
- Airway hyperresponsiveness
- Mucous hypersecretion
- Plasma Leakage
This viral replication triggers intracellular signaling pathways that lead to increased secretion of multiple cytokines (tumor necrosis factor-alpha, granulocyte colony-stimulating factor, and interferon-gamma [IFN-g]), and chemokines (interleukin-8 [IL-8] and RANTES), and also to increased expression of adhesion molecules
These chemokines and cytokines are increased in airway secretions during viral infections. Their actions are thought to involve recruitment and activation of the inflammatory cells (neutrophils, eosinophils, and activated T cells) that have been linked to asthma exacerbations. Neutrophils are the main cells found in nasal and lower airway secretions during acute viral infections, and increases in blood and nasal neutrophils correlate with cold and asthma symptom scores and cold-induced changes in airway hyperresponsiveness.
Outline the primary immune responses in terms of cell level to RSV infection
Intially: Cytokines/Chemokines - show a later peak which is indicitive of invading leucocytes releasing cyto/chemokines
Then: Viral Replication, NK cells, Th cells, CTL cells
Lastly: IgG, IgA (much less important role in primary infection than the innate immune system)
What are the primary immune responses to RSV infection over the first 9 days?
- Early inflammatory mediators (TNF, CCL5, CCL11, T1 IFNs)
- NK and DC and macrophages
- Cytokine Release (IFNgamma, IL-2, IL-4,5,9,12)
- Migration of DCs and antigen presentation to CD4+ cell
Acquired immune response - B cell
What is Sepsis?
The presence of SIRS associated with a confirmed infectious process.
What is SIRS?
Systemic inflammatory response syndrome
At least 2 of the following symptoms:
•Temperature >38ºC or <36ºC
•Heart rate >90 beats/min
•Respiratory rate >20 breaths/min or PaCO2 of <32 mmHg
•White blood cell count >12,000 cells/mm3, <4000 cells/mm3, or >10% immature forms
What is Severe Sepsis?
Sepsis with either hypotension or systemic manifestations of hypoperfusion
•Lactic acidosis, oliguria, altered mental status
What is Septic Shock?
Sepsis with hypotension despite adequate fluid resuscitation, associated with hypoperfusion abnormalities
What is the burden of Sepsis in the UK?
–2nd leading cause of death
What are the causes of septicaemia in a previously healthy adult?
Skin - Staphylococcus aureus and other Gram-positive cocci
Urinary Tract - Escherichia coli and other aerobic Gram-negative rods
Respiratory Tract - Streptococcus pneumoniae
Gall Bladder or Bowel - Enterococcus faecalis, E. coli and other Gram-negative rods,
Pelvic organs - Neisseria gonorrhoeae, anaerobes
In normal conditions these don't cause problems, only if they get into the bloodstream
What are the causes of septicaemia in hospitalized patients?
Urinary catheter - Escherichia coli, Klebsiella spp., Proteus spp., Serratia spp., Pseudomonas spp.
Intravenous Catheter - Staphylococcus aureus, Staph. epidermidis, Klebsiella spp., Pseudomonas spp., Candida albicans
- Peritoneal Catheter - Staph. epidermidis
Wound Infection - Staph. aureus, E. coli, anaerobes(depending on site)
Deep Infections - Depends on anatomical location
Burns - Gram-positive cocci, Pseudomonas spp., Candida albicans
Immunocompromised Patients - any of the above
- Wound Infection - Staph. aureus, E. coli, anaerobes(depending on site)
- Deep Infections - Depends on anatomical location
- Burns - Gram-positive cocci, Pseudomonas spp., Candida albicans
- Immunocompromised Patients - any of the above
- What is the pathophysiology of septicaemia?
- What does it result in?
- Activation of host defence mechanisms by
- Endotoxins, e.g., lipopolysaccharide (LPS) (gram –ve bacteria)
- Exotoxins, cell wall components or super antigens (gram +ve bacteria)
2. Activation of neutrophils and monocytes
–Release of inflammatory mediators (TNFα, IL-1, IL-6)
–Diffuse endothelial permeability/dysfunction
–Activation of coagulation pathways
In septicaemia, most bacterial endotoxins are lipopolysaccharides (LPS), how do they exert their main effects?
Clinically, what are the most important effects?
What other bacterial components are also important?
By stimulating cytokine release
•Vascular collapse (or shock)
Give examples of of some systems and mediators stimulated in septic shock
•Arachidonic acid metabolites (eg, leukotrienes, prostaglandins, thromboxanes)
•The complement system
•IL-1 and IL-6
•The coagulation cascade
•The fibrinolytic system
•Circulating myocardial depressant factor(s)
In septicaemia, what are the consequences of
- The coagulation pathway
- dysfunction of capillary endothelium
- the general pathways and mediators stimulated?
- Capillary microthrombi, End-organ ischaemia
- Vasodilation and capillary leakage (Plasma leaves, less volume in bloodstream – hypotension, heart will start racing)
- Global tissue hypoxia and organ dysfunction and failure
What are the symptoms of septic shock and how do they arise?
Severe hypotension - Decreased CO
Cold, clammy skin - Hypoperfusion of tissue
Edema - Thrombosis
Somnolence, Coma - Shock
Oliguria - Renal Failure
Dyspnea - Lung Failure (ARDS)
GI Bleeding, Paralytic Ileus - GI Lesions
Can lead to death due to Cardiorespiratory failure
Outline the activities of bacterial endotoxin
Microbial endotoxin activates the immune system inducing cytokines causing a variety of biologic effects
Outline LPS and TLR4 Interaction
Lipopolysaccharide (LPS) monomers are extracted from bacterial membranes by the serum protein LPS-binding protein (LBP) which transfers the LPS monomer to a lipid-binding site on CD14 in the membrane of phagocytes.
CD14 promotes the binding of LPS to the TLR4–MD-2 complex, which signals to the cell interior. In the absence of CD14, TLR4–MD-2 can still function with some forms of LPS or with much higher LPS concentrations
What are the innate immune responses to LPS?
Induction of the innate immune response by the lipopolysaccharide-lipopolysaccharide-binding protein (LPS-LBP) complex
IL-1, IL-6, TNFa produced which mediate inflammation and metabolic response
Reactive oxygen and nitrogen species are produced from the macrophage and bacterial killing occurs
LPS, lipopolysaccharide; LBP, lipopolysaccharide binding protein; LTA, lipoteichoic acid; NFκB, nuclear factor kappa B; IκB inhibitory factor kappa B; PEPG, peptidoglycan-N; TLR, toll-like receptors; MSR, macrophage scavenger receptor; MYD88, myeloid differentiation factor 88; TIR, toll-interleukin receptor; TIRAP, toll-interleukin 1 receptor adaptor protein; MD2 is a secreted protein involved in binding liposaccharide with TLR4; TIRAP/Mal, an adaptor protein for TLR2 and TLR4.
- What will Toll-Like Receptor Anatagonists lead to
- What will Toll-Like Receptor Agonists lead to?
Exaggerated response: Atherosclerosis, Sepsis, Autoimmunity
Appropriate Response: Vaccine = Th1 adjuvant, Allergen = decreased IgE and eosinophils, Anti-allergen, Tumor and Pathogen = IFNS, IL-12, NO, chemokines, NK activity, phagocytosis, anti-infection and anti-cancer
- How can TNFa be beneficial?
- How can it be bad?
- essential step in endothelial cell activation
- Role in septic shock
Illustrates the confusing role that cytokines play in infections of all kinds
‘enough is enough’ but ‘too much is dangerous’
Depends on Levels and location
Outline Bacterial Septic Shock
(cytokine related disease)
–Blood pressure drops, clots form, hypoglycemia ensues, patient dies
–LPS trigger results in TNF release
–TNF induces IL-1 which induces IL-6 and IL-8