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Flashcards in I4 - Immunopathogenesis Deck (35):
1

What is immunopathogenesis? Give some examples

Pathologies following infection caused by immune reactions rather than pathogen replication Viral bronchiolitis, Septic Shock

2

What is viral bronchiolitis?

Inflammation of the bronchioles following viral infection

3

What are the aetiological agents of viral bronchiolitis?

 

Respiratory syncytial virus (Paramyxoviridae)

–Rhinovirus (Picornaviridae)

–Influenza virus (Orthomyxoviridae)

–Human metapneumovirus (Paramyxoviridae)

4

Describe RSV on an electronmicrograph

Long filamentous 

Smaller

5

Who is at particular risk of severe disease as a result of RSV?

The frail elderly 

Infants

The immunocompromised 

 

– Prophylactic monoclondal antibody given to high risk infants (bronchopulmonary dysplasia; <32 weeks gestation; congenital heart disease)

 

6

What is the disease burden of RSV wordwide?

Why?

64million infections per year and 160, 000 deaths

No vaccine or specific therapeutic

 

7

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 

8

When is there a peak in RSV infections?

In WINTER - Nov, Dec, Jan

9

What are some RSV - induced diseases?

Descending infection

• Rhinitis

• Otitis media

• Tracheobronchitis

• Bronchiolitis

• Pneumonia

• Asthma

 

B+P = 25-40% during first infection

10

What is the pathology of Bronchiolitis and pneumonia?

Necrosis and sloughing of small airway epithelium

Oedema

Increased mucus secretion (Obstructs airflow in small airways)

Interstitial infiltration

Alveolar filling

In Bronchiolitis - the airway becomes obstructed due to swelling of the bronchiole walls

11

What are the clnical implications of Bronchiolitis and Pneumonia?

  • Hyperinflation
  • Atelectasis
  • Wheezing

12

What is the pathogenesis of RSV?

Virus replication triggers immune response in lungs

  • Cytokine/chemokine release
  • Infiltration of 
    • neutrophils
    • lymphocytes
    • eosinophils
  • 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 

13

What are the principal infiltrates in an RSV infection?

Neutrophils

Lymphocytes

Eosinophils

 

(Disease is immune-mediated)

14

Describe the histology of a normal lung

Single layer of cells around alveoli

15

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.

16

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)

17

What are the primary immune responses to RSV infection over the first 9 days?

Day 1-3

  • Early inflammatory mediators (TNF, CCL5, CCL11, T1 IFNs)
  • NK and DC and macrophages

Day 4-7

  • Cytokine Release (IFNgamma, IL-2, IL-4,5,9,12)
  • Migration of DCs and antigen presentation to CD4+ cell

Day 7-9

Acquired immune response - B cell

 

18

What is Sepsis?

The presence of SIRS associated with a confirmed infectious process.

19

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

20

What is Severe Sepsis?

Sepsis with either hypotension or systemic manifestations of hypoperfusion

•Lactic acidosis, oliguria, altered mental status

21

What is Septic Shock?

Sepsis with hypotension despite adequate fluid resuscitation, associated with hypoperfusion abnormalities

22

What is the burden of Sepsis in the UK?

–36,800 deaths/year

–2nd leading cause of death

23

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, 

    Bacteroides fragilis

  • Pelvic organs - Neisseria gonorrhoeae, anaerobes

In normal conditions these don't cause problems, only if they get into the bloodstream

24

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
  • Post Surgery
    • ​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

25

  1. What is the pathophysiology of septicaemia?
  2. What does it result in?

  1. 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)

–Vasodilation

–Diffuse endothelial permeability/dysfunction

–Activation of coagulation pathways

26

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

 

 

•Fever

•Vascular collapse (or shock)

 

Peptidoglycans

27

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

•TNF-alpha

The coagulation cascade

•The fibrinolytic system

•Catecholamines

•Glucocorticoids

•Prekallikrein

•Bradykinin

•Histamines

•Beta-endorphins

•Enkephalins

•Adrenocorticoid hormone

•Circulating myocardial depressant factor(s)

28

In septicaemia, what are the consequences of 

  1. The coagulation pathway
  2. dysfunction of capillary endothelium
  3. the general pathways and mediators stimulated?

  1. Capillary microthrombi, End-organ ischaemia
  2. Vasodilation and capillary leakage (Plasma leaves, less volume in bloodstream – hypotension, heart will start racing)
  3. Global tissue hypoxia and organ dysfunction and failure

29

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

30

Outline the activities of bacterial endotoxin

Microbial endotoxin activates the immune system inducing cytokines causing a variety of biologic effects

31

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

32

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; NF&#954;B, nuclear factor kappa B; I&#954;B 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.

33

  1. What will Toll-Like Receptor Anatagonists lead to
  2. What will Toll-Like Receptor Agonists lead to?

  1. Exaggerated response: Atherosclerosis, Sepsis, Autoimmunity
  2. 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

 

 

34

  1. How can TNFa be beneficial?
  2. How can it be bad?

  1. essential step in endothelial cell activation
  2. 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

35

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