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Y1 TP2 Infection (topic 3 Onwards) > 3. Adaptive Immunity > Flashcards

3. Adaptive Immunity Flashcards

1
Q

S epsis

A

—> Sepsis is defined as lifethreatening organ dysfunction due to dysregulated host response to infection
It is part of the normal immune response that goes wrong – become disruptive

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2
Q

Organ dysfunction

A

is defined as an acute change in total SOFA score greater than 2 points secondary to the infection cause – higher score = worse
• Sofa – sequenctoial organ failure score

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3
Q

Sofa score

A
  • Sofa – sequenctoial organ failure score
    • Looking for markers that systems are failing respiratory = oxygen
    • Coagulation = platlet
    • Liver = bilirubin
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4
Q

Bacteraemia

A

bacteria in the blood

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5
Q

Septic shock

A
  • Can have bacteria in the blood that immune system is responding to
    • And can induce septic shock using endotoxins, not just bacteria
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6
Q

Normal immune response

A
  1. Infection in body
    1. activation of host defence mechanisms = macrophages swallowing cells
    2. influx of inflammatory cells
    3. release of inflammatory mediators – interleukines etc
    4. local vasodilation and increased endothelial permeability
    5. activation of coagulation pathway
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7
Q

Bacteria and sepsis

A

• Gram-positive and gram-negative bacteria induce a variety of proinflammatory mediators

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8
Q

Various bacterial cell-wall components that are known to release the cytokines

  • stimulate strong immune response in sepsis
A

– lipopolysaccharide (LPS; gram-negative bacteria),
– peptidoglycan (gram-positive and gram-negative bacteria),
– lipoteichoic acid (gram-positive bacteria).

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9
Q

Aetiology of septic shock

A
  • Started with gram positive bacteria
    • Antibiotics developed that wiped out gram positive bacteria
    • Now a ton of gram negative bacteria and some gram positive bacteria
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10
Q

Common causes of sepsis

A

= respiratory tract infections
• Abdominal infections
• Urinary tract infection
• Soft tissue infection

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11
Q

5 proposed mechanisms of injury - sepsis

A

Hypoxic hypoxia

Direct cytotoxicity (leading to histotoxic anoxia)

Coagulopathy

Immunosuppression - interfer with immune system

Apoptosis - interfer with programmed cell death

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12
Q

Hypoxic hypoxia

A

—> not enough oxygen getting to the cell
• CVD dysfunction and vascular redistribution
• Microvascular change; Thrombosis, endothelial dysfunction

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13
Q

Direct cytotoxicity (leading to histotoxic anoxia)

A

–> cell is so messed up it cannot use oxygen as normal
• Endotoxin, TNF-α, and NO
Effect mitochondria , can’t use oxygen to make energy

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14
Q

Coagulopathy

A

—> anything wrong with clotting system (too much or not enough or in the wrong place)
• Deficiencies of coagulation system proteins
• Cytokine effects

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15
Q

5 dysfunctions - organ failure

A
  • CNS
    • pulmonary
    • hepatorenal
    • cardiovascular
    • Gastrointestinal
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16
Q

Cardiovascular dysfunction

A

—> when septic = heart rate increases (tachycardia) - heart is trying to circulate nutrients, repair damage etc

Look for
• tachycarida
• hypertension

• Derangement in autoregulation of the circulatory system = release of Vasoactive mediators cause vasodilatation and increase the microvascular permeability at the site of infection.
• Changes in systemic vasodilatation = to create gaps so things can extrude and go to where it needs to go
• The microcirculation is the key target organ for injury in patients with sepsis - vasodilation
- hypotension

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17
Q

Hypotension

A

– Redistribution of intravascular fluid volume from reduced arterial vascular tone
– Diminished venous return from venous dilation
– Release of myocardial depressant substances

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18
Q

3 phases of pulmonary dysfunction

A

3 phases
– Exudative phase (oedema and hemorrhage) = cells push out into lungs
– Proliferative phase (organization and repair) = repair cells start to damage lung tissues
– Fibrotic phase (end-stage fibrosis) = scars – worse breathing

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19
Q

Direct/ indirect injury to cells of lung

A

• Direct/indirect injury to the endothelial and epithelial cells of the lung
– increases alveolar capillary permeability, causing ensuing alveolar oedema

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20
Q

Surfactant problems

A

• Surfactant problems enhance the surface tension producing diffuse microatelectasis
– Damage to pneumocytes = that secretes surfactant preventing alveoli from being pulled close
– Plasma proteins in alveolar fluid inactivate surfactant

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21
Q

Gatrointestinal dysfunction

Barrier function

A
  • Barrier function may be affected,
    • allowing translocation of bacteria and endotoxin into the systemic circulation
    • As bowel is full of faeces with bacteria that can go into systemic circulation so all bad stuff is pumped around body
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22
Q

Gatrointestinal dysfunction

• Interference with nutritional intake.

A
  • Interference with nutritional intake.
    • Septic shock usually causes ileus, (stops gi tract from flusing faeces and the use of narcotics and sedatives delays the institution of enteral feeding
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23
Q

Hepatic and renal dysfunction

A
  • The hepatic reticuloendothelial system acts as a first line of defense in clearing bacteria and their products; liver dysfunction leads to a spillover of these products into the systemic circulation.
    • Kidney and liver act as filters

Acute kidney injury (AKI)

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24
Q

Acute kidney injury (AKI)

A

– associated with systemic hypotension
– cytokines (eg, TNF)
– activation of inflammatory cells, which indirectly and directly contribute to renal tubular injury
Lack of function of kidney

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25
Q

CNS dysfunction

A 
Systemic inflammation 
• Hypoxemia 
• Hypotension 
• Haemorrhage 
• Medications such as sedatives and analgesics
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26
Q

Clinical assessment - what to look for

A

– possible source of infection
– factors that increase risk of sepsis = same factors for everything other disorders and infections
– any indications of clinical concern, such as new onset abnormalities of behaviour, circulation or respiration

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27
Q

Sepsis risk groups

A

Extremes of age
• Impaired immune systems because of illness or drugs, including people being treated for cancer with chemotherapy (suspect neutropenic sepsis)
• Recent surgery, or other invasive procedures
• Breach of skin integrity (e.g. cuts, burns, blisters or skin infections)
• IVDU
• Indwelling lines or catheters.
• Women who are pregnant, have given birth or had a termination of pregnancy or miscarriage in the last 6 weeks,
• Neonates

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28
Q

Clinical assessment - abcde

A 
• Assess 
– Temperature 
– Heart rate 
– Respiratory rate 
– Blood pressure 
– Level of consciousness 
– Oxygen saturation
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29
Q

NEWS national early warning scoring system

A
  • Score all assessments listed above from 0 –3
    • Higher score = worse case of sepsis

—> body goes to overcompensate that’s why most levels of bp, pulse, heart rate go higher but then body can’t do enough so it decompensates and goes lower = big problem
• Focus on the simple things – look at the patient, check their general levels, observe them

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30
Q

What to do when patient has Red flag sepsis

A 
• Immediate action required 
		○ Quick action of antibiotics and oxygen into patient – increase succces
		○ Early identification and treatment 
• Inform senior doctor for review 
• Send urgent investigations 
• Complete Sepsis Six Bundle
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31
Q

Sepsis six bundle

A

Titrate oxygen to a saturation target of 94% = Airways
• Take blood cultures. = circulation
• Administer empiric intravenous antibiotics.
• Measure serum lactate and send full blood count. = platelets
• Start intravenous fluid resuscitation.
• Commence accurate urine output measurement.

Investigations
• Lactate – hypoxic injuries = more lactate , anaerobic respiration
• Full blood count - platelets

32
Q

Venous blood test for

A 
• carry out a venous blood test for the following: 
– blood gas including glucose and lactate measurement 
– blood culture 
– full blood count 
– C-reactive protein 
– urea and electrolytes 
– creatinine 
– clotting screen
33
Q

For a person> 12 with high rish criteria

A

—> start treatment whilst monitoring – give the best guess of what the causative thing is
• give a broad-spectrum antimicrobial at the maximum recommended dose without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting)

• Monitor people physiological parameters

34
Q

Antibiotics - how to give and examples

A

Ensure mechanisms are in place to deliver antibiotics fast

• Take microbiological samples before prescribing an antimicrobial (where possible)
• If meningococcal disease is specifically suspected (fever and purpuric rash)
– parenteral benzyl penicillin in community settings
– intravenous ceftriaxone in hospital settings.

35
Q

Oxygen

A

Oxygen keep it > 94%
• Give oxygen to target saturation of 94–98%
○ Sigmoidal curve levels off at 94% - oxygen dissociation
• 88–92% for those at risk of hypercapnic respiratory failure

36
Q

Examination

A
  • Rash – non blanching (do not disapear under pressure)

* Peripheral sinosis, ischaemia

37
Q

Adaptive immunity definition

A

—> Adaptive immunity is the process by which a specific immune response is elicited
Adaptive immune system gives innate immune system focus

38
Q

Cells in the Innate immune system

A
  • Neutrophil
    • Macrophage
    • Eiosinophil
    • Dendritic cell
    • Natural killer cell
    • Mast cell

Innate immune system –> myeloid cells, mature systemically in tissues

39
Q

Cells in the Adaptive immune systetm

A
  • Helper T cell
    • Cytotoxic T cell
    • B cell – antibody producing cells
    • Natural killer cell

Adapative immune system –> lymp, lymphoid system

40
Q

T cells

A

—> primary cells

* Mature in the Thymus – hence T cells  
* Originate as haematopoietic stem cells (HSCs) in the bone marrow. 
* In the thymus they are screened for their ability to recognise ‘self’ antigens. Those that do are directed towards apoptosis.
41
Q

T cells and cd3 receptors

A

○ Every T cell has a T cell receptor = CD3 on surface of every T cell but every CD3 receptor is different as they all recognise different potential antigens
○ Each T cell has its own CD3 receptor

• Self tolerance – CD3 receptors should never revognise self
42
Q

What are Major histocompatibility complexes

A
  • Differentiate between what is self and not self
    • It uses signposts on each cell. These are known as MHC I and MHC II.
    • MHC complexes are tissue antigens which display proteins which are being made within that cell.
    ○ This allows the immune system to determine if it’s observing “self” or “non-self”.
    ○ This is critical for T cell tolerance.
43
Q

• MHC I

A

• MHC I interacts with CD8 on cytotoxic T cells. - self antigens made within host cell
○ This can be important for cancer cell detection and clearance as well as virally infected cells.- self cells are hijacked by virus to produce things that are not self – Present on all nucleated cells. (not red blood cells as there is no nucleus)

44
Q

• MHC II

A

• MHC II interacts with CD4 on helper T cells.
- foreign antigens from phagocyte on antigen presenting cells
○ This displays antigens which have been processed by antigen presenting cells and leads to an antibody response.

45
Q

Other things in T cells

A 
CD25 = receptor for an interleukine 
IL2 = growth factor for T cells
46
Q

Thymus

A

• cortical region at top (cortex) = where t cells differentiate into either CD4 or CD8
○ CD4 interacts with MHCII
○ CD8 interacts with MHC1
• Medulla region – medullary epithelial cells, if the cd8 or CD4 interacts with self cells on MHC1/2 they are targeted for apotosis as they will target self cells which is damaging

47
Q

Development of T cells - steps

A
  1. Lymphoid progenitor cell enters the outer cortex of the thymus.
  2. T cell which don’t express CD4 or CD8 (double negative; DN) go migrate through the thymus.
  3. Expression of CD4 and CD8 leads to a double positive (DP) cell.
  4. DP cell interacts with cortical epithelial cell where it recognises either MHC I or MHC II.
  5. Lack of interaction leads to cell death by neglect.
  6. Depending on MHC class interaction, cells will become committed to the CD4 or CD8 lineage.
  7. CD4 and CD8 cells pass into the medulla. Here, they interact with dendritic cells displaying “self” antigen. Recognition leads to cell death.
48
Q

What is antigen presentation - cd4 cells

A

Antigen presentation is a two-step process which occurs in the lymph node*
CD4 cells:
• APC finds T cell with complementary receptor
• If complementary receptor is found, cell and T cell form together with CD4 and MHCII
• Activates T cell
—> make sure T cell receptor is completely complimentary to MHCII by using secondary signal
• If it is not complementary it would activate wrong b cell and produce wrong antibodies

49
Q

2 step antigen presentation process

A
  1. Presentation of the antigen by an antigen presenting cell (macrophage, dendritic cell, professional antigen presenting cells) to T cells.
  2. Helper T cells activate B cells expressing a specific B cell receptor (Ig) for the antigen.
50
Q

MHCII - antigen processing pathway

A
  • exogenous
    1. APC picks up an antigen
    2. Activate MHCII
    3. Present receptor of pathogen on MHCII receptor
51
Q

MHCI - antigen processing pathway

A

– endogenous

1. Normal somatic cell produces proteins
2. Puts them onto MHCI
3. Only recognised by CD8 t cells when the proteins on self cells aren't familiar (virus or mutation in cell that alters proteins)
52
Q

T cell specificity

A

T cells have specific receptors on their surface – one T cell recognises one antigen (lock and key cell)

53
Q

VDJ recombination

A

’—> Process of gene rearrangement whereby variable, diverse and joining regions are rearranged in different combination to produce a vast range of unique receptors.
• Recombination of 3 gene elements to give a huge array of protein outputs

54
Q

Process of VDJ recombination

A
  • Germline seqments , V, D , J anc constant regions at end = give antigen recognition
    • D and J recombination – splice some diverse and joining regions, reorganise
    • V to DJ recombination
    • Recombine all regions to give more simple focused, spliced transcript

Mediated by VDJ recombinase – which does splicing and joining together to give transcript

55
Q

T cell/ B cell interaction

A

• B cells, like T cells, have receptors which are specific to a single antigen.
• B cell receptor is essentially an immunoglobulin = sereted to vecome soluble effector
• B cells will encounter the antigen on their own, but this isn’t sufficient to activate the B cell.
○ Instead, the B cell internalises the antigen and then presents it on MHC II.
• Primed (activated) T cells secrete more IL2 (T cell growth factor… remember CD25 It’s the IL2 receptor!)
• IL2 growth factor causing expansion of the population of T cells which recognised the antigen.

• Primed T cells then encounter B cells. If they come across a B cell displaying the antigen that theyrecognise, they bind to it causing activation of B cell

56
Q

B cells

A 
• Progenitor lymphoid cell
	• Differentiates into progenitor b cell
	Somatic recombination (VDJ) recombination
	• Differentiate into immature b cell with receptor to recognise one specific antigen
	• Leave bone marrow to become = naïve b cell (that hasn't met an antigen yet from T cell)
57
Q

Lymph node – germinal centre

2 zones

A
  • Dark zone

* Light zone

58
Q

Clonal expansion

A

• Clonal expansion – rapid expansion of b cells in dark zone

59
Q

—-> T cells finding complimentary B cell

A

T Cells carry bacteria migrate to lymph, leave captured antigens for b cells to pick up and recognise with b cell receptor (mature b cell)
• Enter dark zone and activate b cells
• Clonal expansion – rapid expansion of b cells in dark zone
• B cells internalise antigen
• In light zone B cells are screened to make sure that they don’t recognise self antigens
• If b cells don’t recognise self antigens – they are released as plasma cells

60
Q

Plasma cells

A

Plasma cells – secrete immunoglobulins into plasma (systenic release of antibody)
• Plasma cells produce antibodies
• They are effector cells

61
Q

3 immunoglobulins.

A

IgD

IgM

IgG

62
Q

IgD

A

IgD = b cell receptor, membrane bound, sits on membrane

63
Q

IgM

A

IgmM= mainly produced by infanats/ children
• Very sticky but only some specificty to target antigen – off tagret effects may stick to something it is not supposed to
• Produced in first days of immune response in adults

64
Q

IgG

A

IgG = most common effective form of antibody
• Very highly specific, very sticky
• Only produced in any large quanity aboove age 6
• Vaccines in children – used to kick start igG production

65
Q

Class switching

A

Class switching = must occur for appropriate antiboidy production
• B cells first produce igm
• Switch to produce igG

66
Q

Antibody formation

A
  • Each antibody can capture 2 antigens – fragment antigen binding region at top of antigen
    • Fragment crystallisation region on bottom
67
Q

Opsonisation

A

—>• An opsonin is a molecule which can attach to an antigen on the surface of a bacteria (or virally infected cell).
It acts as a beacon for phagocytes which will come in and ‘eat’ the pathogen.

• Binding of opsonin allows neutrophil to internalsie antibody antigen complex
68
Q

Excumples of opsonins

A

– Complement proteins (innate immunity)

– Antibodies (immunoglobulins, Ig; adaptive immunity)

69
Q

IgG and complement

A

IgG can further activate compliment when bound to antigen

70
Q

Clearance of opsonised pathogen

A

• C3 opsonising complement protein

* This leads to internalisation of the pathogen which has been coated in antibody.
* The macrophage produces reactive oxygen species to destroy the pathogen
71
Q

Complement

A

—-> Complement can “punch holes” in the cell membrane of the pathogen leading to death.

• Phagocytes such as macrophages and neutrophils have Fc receptors on their surface which bind to the Fc region of an antibody which has formed a complex with an antigen.

72
Q

Immunological memory

A

• Once T and B cells have encountered an antigen for the first time and are prompted to proliferate,- clonal expansion - some will be become effector cells which combat the infection.
○ Others don’t proliferate and reside predominantly in the spleen (45% of memory B cells) and some in the circulation awaiting a second encounter with their specific antigen. - some wait in the lymph as memory population
○ A second challenge from the same pathogen with unaltered antigens elicits a much swifter immune response as mature effector memory cells are already present.
○ These just need to be instructed to proliferate and migrate out of the lymph node

73
Q

Immunological memory and vaccines

A

Immunological memory is the foundation principle of immunity which allows vaccination to work

Vaccines

Information in the grid
—> therapeutic way of manipulating function of immunological memory

74
Q

Natural killer cells – Fas / Fas ligand

A
  • Bind to things that are abnormal on cells

* Secret enzymes liker perforin (perforate cell) and granzymes (effect capsins which lead to apoptosis)

75
Q

Cytotocxic t cells – CD8

A

These cells directly have an effect on thwat they are are targeting
• Recognise cells infected by virus – that are producing viral proteins that are put on MHC1
• There is now a not self protein on MHCI as it is a viral protein
• CD8 binds to and anchors cytotoxic t cell to MCHi
• Complementary to antigen – 2 step verification system
○ The still have a two-step verification system in place and won’t induce apoptosis without interaction of Fas ligand (FasL) on the T cell surface with Fas on the surface of the infected cell
• Cytotoxic t cell marks cells for apoptosis – cell death

76
Q

Sepsis six - way to remember

A

3 things in: antibiotics, oxygen fluids

3 things out: lactate, urine output blood culture.,.

Y1 TP2 Infection (topic 3 Onwards) (9 decks)

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