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RespoLecoDecko3 Flashcards

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1
Q

Innate Immunity

Functions of ILCs? Ki

A

“sentinel cells at mucosal surfaces”

Similar effector functions to T cells but lacking a TCR

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2
Q

Innate Immunity
When does viral load peak in infection? When is viral load resolution?
Think of graph

A

3 days

Resolution by day 6 usually

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3
Q

Innate Immunity

When do IFN + NK cell levels rise and fall? Think of graph

A

Slight delay behind virus but similar shape on graph. LEARN TO DRAW GRAPH
Peak rough day 4
Both undetectable by day 7

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4
Q

Innate Immunity

When do T cells peak in viral infection?

A

Not until day 10/11 post acquisition

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5
Q

Innate Immunity

When does IgG peak post viral acquisition?

A

~14 days

Protects from re-infection

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6
Q

Innate Immunity
Anti-microbial Peptides:
What is the function of lysozyme?

A

Splits bacterial cell wall

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7
Q

Innate Immunity
Anti-microbial Peptides:
What is the function of lactoferrin? SECRETED BY NEUTROPHILS

A

Deprives bacteria of iron, works even better in anaerobic conditions.
- Also fungicidal/anti-viral by binding surface glycoproteins

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8
Q

Innate Immunity
Anti-microbial Peptides:
What is the function of a/b-defensins + SLPI?

A

Bactericidal, anti-viral

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9
Q

Innate Immunity
Anti-microbial Peptides:
What are the functions of Ficolins and collectins?

A

Binds bacteria - promotes phagocytosis

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10
Q

Innate Immunity

What are the four main groups of PRR?

A

TLRs
NOD-like / NLR receptors
RNA helicases
C-type lectins

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11
Q

Innate Immunity

What do TLRs recognise?

A

PAMPS

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12
Q

Innate Immunity

What do NODlike+NLR receptors recognise?

A

CpG, Peptidoglycan, dsRNA

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13
Q

Innate Immunity

What do RNA helicases recognise?

A

Intracellular viral dsRNA and ssRNA

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14
Q

Innate Immunity

What do C-type lectins recognise?

A

Carbohydrates

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15
Q

Innate Immunity

How many TLRs in humans?

A

13

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16
Q

Innate Immunity

Which TLRs are endosomal?

A

TLR3
TLR7,8
TLR9

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17
Q

Innate Immunity

Where are RNA helicases, MDA5 + RIG-I found?

A

Cytosolic

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18
Q

Innate Immunity

What motif is conserved in RNA helicases MDA5 + RIG-I?

A

DEAD box proteins

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19
Q

Innate Immunity

What domain do RNA helicases (RIG-I + MDA5) signal through?

A

Have CARD domain which allows caspase activation.

Require ATP

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20
Q

Innate Immunity

Most viruses are detected by…..

A

RIG-I>MDA5

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21
Q

Innate Immunity

Activation of RIG-I and MDA5 results in transcription of……

A

NFkB - pro infl (bacterial)

IRF3 - viral

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22
Q

Innate Immunity

What are the 3 signalling steps of PRR?

A
  1. PRR binds ligand in endosome/cytosol
    - Conformational change involving ATP
  2. Allows binding of a kinase adaptor complex
    - Phosphorylation of other signalling molecules
    - Cascade
  3. Kinase-adaptor complex phosphorylates TFs which migrate to the nucleus and bind promotors of affected genes
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23
Q

Innate Immunity

What are the two signalling proteins for interferon?

A

IKK
TBK-1
(TF = IRF-3)

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24
Q

Innate Immunity

How many types of interferon exist?

A

3 types
T1 = IFN a/b/delta etc…..
T2 = IFN gamma
T3 = Interferon lambda

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25
Innate Immunity | Name 4 ISGs = interferon stimulated genes
``` RNAse L 2,5-OAS PKR Viperin MxA ```
26
Innate Immunity | What does OAS, an ISG, do?
``` Binds dsRNA in cytoplasm. Removes 2 phosphate groups from dsRNA. This allows buildup of large chains called 2-5A. 2-5A activates RNAse L. RNAse L degrades viral RNA. Viral replication = blocked ```
27
Innate Immunity | What are the actions of IFN-B in the immune system? Think viral
``` Induction of ISGs Induction of "anti-viral" states of cells Dendritic cell activation and maturation Induction of other IFNs Enhanced expression of RNA helicases Induction of T cell chemokines Apoptosis ```
28
Innate Immunity What are the two types of DCs? How do they differ?
Both link innate+adaptive Plasmacytoid DCs - In circulation - Viral infections - Poor TH1 activators Conventional DCs - In tissue - activators of TH cells
29
Innate Immunity | What are the three functions of dendritic cells?
1. PRRs detect PAMPS 2. Respond to cytokines and GFs from infected cells 3. Ag presentation + cytokine production
30
Innate Immunity | What PRRs do DCs detect PAMPs with?
TLR 7/8/9 | NODs
31
Innate Immunity | What are the main cytokines that DCs produce?
IL12,15,18,23 | IFN required as an activator to produce these
32
Innate Immunity | How are riRNAs and iRNAs produced?
iRNAs stored in small vesicles and delivered to target cells OR Host cell DICER protein forms siRNAs from microRNAs (viral specific) DICER recognises hairpin structures
33
Innate Immunity | How do iRNAs work?
Complementary to Viral ssRNA - preventing reverse transcription. Binds ssRNA forming mRNA Viral mRNA is cleaved by RISC-AGO complex
34
Innate Immunity | How can viruses interact with the RNAi pathway?
Viral proteins that prevent DICER formation of viral specific siRNAs Viral microRNAs that manipulate host gene expression
35
Innate Immunity | What is unique about some siRNA Rxs? IE RSV siRNA V-Bikto et al
Prophylactic administration -> Mice RR/Lts in BALF remained close to normal Therapeutically = has effect even if given at day 4 (greater effect when earlier)
36
Innate Immunity IFNb/y is deficient in what disease? In the study they stimulated BECs with RhinoVirus What else was seen? WARK ET AL
Asthma Increased Viral titre of RhinoVirus WARK ET AL
37
``` Innate Immunity What is IRAK4 an adaptor for? What is the survival% of IRAK4 def? Why is this TREND seen after 5yrs life Ku et al ```
TLRs4,7,8,9..... These patients had reduced IFN production Survival 75% in 1st yr life Survival 55% after 5-10yrs. Mortality decreases as adaptive immune system develops Ku et al
38
Adaptive Immunity | Describe Innate LRT protection
``` Mucosal surfaces Lysozyme Sweeping Anti-microbial peptides eg B-defensins (made by epithelium) Alveolar macrophages ```
39
Adaptive Immunity | What are the four general responses?
Recognition of infection / damage - innate Recruitment of immune cells to site Elimination of pathogens Resolution and Repair
40
Adaptive Immunity | What happens day 1-3 of infection?
Innate recognition of infection PRRs engaged Early inflammatory mediators Leads to innate effectors -> neutrophils NK cells
41
Adaptive Immunity | What happens at day 4-7 post infection?
Dendritic cells and Macrophage APC | Present to The cells
42
Adaptive Immunity | What happens day 7+?
Activation of the adaptive immune system
43
Adaptive Immunity | Unique features of the adaptive immune system
``` Focuses response on a site of infection Specific to organism Memory Needs time to develop 1st exposure - takes days Subsequent exposures = faster and more pronounced ```
44
Adaptive Immunity | How does the body know what is foreign?
PRRs MHCs Central and peripheral tolerance to remove self-reactive cells
45
Adaptive Immunity | What is the MHC?
The protein complex that presents antigens to T cells Encoded by HLA genes in humans 6 different types of HLA -> infection/compatibility/donor matching
46
Adaptive Immunity | How does clonal selection work?
LOTS of T cells produced in thymus Each bares unique receptor (genetic re-assortment) Interaction between a receptor and foreign molecular = activation Self specific receptors deleted early in development Receptor activated cells -> undergoes clonal expansion once it sees antigen peripherally
47
Adaptive Immunity What is tolerance? What two facets of tolerance are there?
A state of functional unresponsiveness Central - self reactive T/B cells are destroyed before entering circulation Peripheral - Destroy / control any self reactive T/B cells which do enter circulation
48
Adaptive Immunity CD8+ T cells kill self cells. Overactivity of the adaptive immune system is damaging. What mechanisms are naive T cells stimulated by that prevent overactivity? 3 signals required
1 Must Bind specifically to the antigen / recognise VIA MHC 2 Antigen Co-stimulation - APC binds to TC via CD28 (B7 on APC) - The APC ONLY upregulates this when it presents - controls overactivity of T cells 3 Cytokine release - Shift T cells reponse
49
Adaptive Immunity | Broadly, how do T cells migrate from lymph to blood?
Downregulation of certain receptors which keep T cells in lymph (CCR7) Upregulation of receptors which allow movement to sites of infection (CCR5) + various adhesion molecules (selectins)
50
Adaptive Immunity | What is an antigen?
Proteins (99%) or molecules which induce an adaptive immune response
51
Adaptive Immunity | What is an epitope?
The region of an antigen which a receptor binds to
52
Adaptive Immunity | What sort of epitopes do T cells recognise?
The primary structure of the proteins. IE 10-15 amino acids in the peptide
53
Adaptive Immunity | What sort of epitopes do antibodies recognise?
Structural epitopes
54
Adaptive Immunity | What happens with DCs upon PRR activation?
Move to lymphoid tissue and present antigen via MHC
55
Adaptive Immunity What do MHCI molecules recognise? Where is the antigen processed? What do they present to?
Intracellular pathogens/antigens Processed in cytosol CD8+ T cells
56
Adaptive Immunity What to MHC2 recognise? Where are they processed? What are they presented to?
Extracellular pathogens/antigens Endosomes CD4+ cells
57
Adaptive Immunity | What is cross presentation?
Whereby antigens from MHC2->MHC1
58
Adaptive Immunity | What are the two families of TCR?
CD4+ helper | CD8+ killer
59
Adaptive Immunity | How do CD8+ cells kill targets?
Apoptosis Necrosis - Store perforin, granzymes, granulysin in cytotoxic granules Granules released after target recognising Perforin - forms pore -> allows secretion of granzymes into cells Granzymes induce caspase cascades OROROR Can bind directly by Fas + Fas ligands
60
Adaptive Immunity | How do CD4+ T cells influence the immune response?
TH cells produce diverse range of cytokines
61
Adaptive Immunity | What are the 5 subclasses of TH cells?
``` TH1 TH2 TFh TH17 Tregs ```
62
Adaptive Immunity | What are the functions of TH1 cells?
IFN production | Boost immune response
63
Adaptive Immunity | What are the functions of TH2 cells?
IL4,5,13 | Boost anti-multicellular organism response
64
Adaptive Immunity | What do TfH cells do?
Produce IL-21 + reside in Bed cell follicles | Essential for generation of iso-type switched antibodies
65
Adaptive Immunity | What are TH17 cell functions?
Secrete IL-17 (in autoimmune) | Important for bacterial control
66
Adaptive Immunity | What do Treg cells do?
Regulate activation of effector functions of other T cells There are natural + induced Tregs Necessary to maintain tolerance to self antigens
67
Adaptive Immunity | T helper cells are defined by the cytokines they produce and the TFs they use. What TFs do Each subset use?
``` TfH - Bcl-6 TH2 - GATA3 TH1 - T-bet TH17 - RORyt iTreg - Foxp3 ```
68
Adaptive Immunity | What are the phenotypes of Tregs?
CD4, High IL2R, FOXp3 TF
69
Adaptive Immunity | How do T regs exert an immunosuppressive effect?
Secretion of TGFb, IL10, IL35 | Inactivation of DCs and lymphocytes
70
Adaptive Immunity | What is the BCR?
The antibody that the B cell will produce will be kept on cell surface Triggering will lead to differentiation to plasma cells Antibody affinity improves over time
71
Adaptive Immunity | Are B cell responses T cell dependent?
YES OR NO YES: proteins NO: polysaccharides
72
Adaptive Immunity | What does the variable region of the BCR do?
Recognises antigen
73
Adaptive Immunity | What is the constant region of the BCR?
Important in intracellular signalling
74
Adaptive Immunity How many different BCRs can be made? What is the process that makes this many called?
10 ^ 10 | Recombination
75
Adaptive Immunity | How does recombination (BCR) work?
Germline DNA rearranged to form B cell DNA B cell DNA transcribed Forms primary RNA transcript Primary RNA transcript = spliced to form "mature RNA" Spliced mature messenger RNA = translated This occurs slightly randomly Light chains + heavy chains undergo this
76
Adaptive Immunity | What are the three fates of the B cell?
AB production - plasma cell Memory But cell - some sits in bone marrow for 2ndary response Or affinity maturation - point mutations allow altercations of BCR. B cell clonally expands, lots of mutations. The one with most affinity survives
77
Adaptive Immunity | How are B cells activated?
BCR recognises specific antigen BCR presents via MHCII (OCCURS WHILST DC recognises antigen -> lymph and activated TCs) In the lymph, T cells + B cells share the same antigen -> T cell licences B cell B cell forms plasma cell
78
Adaptive Immunity | How do cytokines influence B cells?
``` Influence the types of AB produced Activated B cell proliferates after exposure to IL2/4/5 IFNy -- IgG2a/3 TGFb - IgA or IgG2 IL4 - IgE or IgG1 IL-21/4/5 - IgM ```
79
Adaptive Immunity | What kind of Ig production is stimulated via IFN-y
IgG2a/G3
80
Adaptive Immunity | What kind of Ig is stimulated by TGFb?
IgA or IgG2b
81
Adaptive Immunity | What kind of Ig is stimulated by IL4 alone?
IgE or IgG1
82
Adaptive Immunity | What kind of Ig is stimulated by IL2/4/5?
IgM
83
Adaptive Immunity | Which cytokines cause B cell proliferation?
IL2/4/5
84
Adaptive Immunity | How are antibodies defined?
``` heavy chains G = y heavy chains A = a heavy chains E = e heavy chains D = Delta M = u heavy chains ```
85
Adaptive Immunity | What binds to antibody heavy chains?
FcRs
86
Adaptive Immunity | MoA of ABs
Neutralization Opsonization (promotes phagocytosis) Complement activation - enhances lysis and opsonization
87
Adaptive Immunity What is AID enzyme? How does it work?
The enzyme that induces point mutations. | C->U
88
Adaptive Immunity | What is T cell exhaustion?
Idea that over time if an infection is not cleared then the CD8+ t cell pool contracts (homeostatic to prevent excessive damage - cancer/HIV/CMV) It upregulates MORE AND MORE inhibitory surface molecules as the cell ages Less likely to be activated Eventually apoptosis occurs Surface molecules = PD1, LAG3, CD244
89
Adaptive Immunity | What is AIRE protein?
Protein that is responsible for allowing thymus to create and express all types of human proteins
90
Adaptive Immunity | What happens in AIRE deficiency?
T cells react to self BUT B cells able to (through maturation affinity) produce antibodies to cytokines released when a t cell reacts to self. B cells also have extremely good antibodies for disease. Levels of binding better than synthetic mABs. End-point antibodies are not related to DNA - it has matured so much.
91
Neonatal Immunology | List major respiratory viruses in young children? (4)
RSV B pertussis Strep Pneumoniae H Influenza
92
Neonatal Immunology | What is seen with regards to age and mean annual incidence of resp diseases?
``` MF = roughly similar Males higher in first 2 yrs Peak incidence = <1yo Decreases gradually Inc again in young adulthood ```
93
Neonatal Immunology | How many colds per yr, adults + pre-school children?
Pre = 6-10 | Adults 2-5
94
Neonatal Immunology | What amount of GP consultations are cold-related?
17%
95
Neonatal Immunology Colds Bacteria:virus
1:3
96
Neonatal Immunology | Most common cold virus + percentage
RV 60% Corona = 15% Flu = 10% RSV = 10%
97
Neonatal Immunology SS or DS DNA/RNA RSV?
ssRNA virus
98
Neonatal Immunology | Which two groups susceptible for RSV?
YOUNG MAINLY - worst in 1-6months | elderly
99
Neonatal Immunology | RSV reinfects through life (2-3 per yr). Are there any treatments? Who gets them?
NO VACCINES But prophylactic mAB possible Very pre-term babies born during summer
100
Neonatal Immunology | Why is it that neonates and elderly get more severe RSV?
``` Young = immature immune system Old = declining immune system ```
101
Neonatal Immunology | What did BORG et al discover with regards to RSV load?
RSV load sig higher in children vs adults with COPD BUT THE RANGE IN CHILDREN VARIES HUGELY - may be due to virus or immune response that causes pathology
102
Neonatal Immunology | What do we know about respiratory infections in children, with regards to severity/frequency/repercussions?
Enhanced susceptibility More severe Vectors of disease EARLY life events seem to influence respiratory health in the long term May result in asthma development / allergies
103
Neonatal Immunology | Why are neonatal immune responses different?
Fetus is allograft to mother Strong TH2 immune response + Treg bias to immune responses Tendency to initially manifest in newborns
104
Neonatal Immunology | What are the advantages of neonate TH2/Treg Bias?
Neonates need to establish tolerance/gain flora - avoids exuberant and harmful reactions Inflammatory responses can be inherently dangerous to postnatally developing tissues - EG LUNGS
105
Neonatal Immunology | List a few differences of immunity in early life (vs adult)
DCs = dec T1IFNs | Inc TH2 differentation/ TH17
106
Neonatal Immunology | What is the mouse model for neonatal immunology?
Murine model = <1 week | Human = usually use cord blood
107
Neonatal Immunology | Levy et al discovered what, with regards to TNF production from human neonatal cord blood (vs PBMCs)
TLR1/2 2/6 and 4 stimulation = Newborn cord monocytes releases sig less TNFa in comparison to adult PBMCs LEVY et al
108
Neonatal Immunology | Describe (roughly) age dependent changesin TLR induced immune reg functions.
Anti-inflammatory IL10 predominates preterm TH17 peaks at term Post term antiviral functions kick in. TH1 + TNF gradually increase
109
Neonatal Immunology | Describe neonatal dendritic cell functions/deficits in the neonate?
Weak signals = low numbers and poor responses to TLRs | STRONG signals = express IL12 + costimulatory molecules (to TH1/TH2)
110
Neonatal Immunology What did Goriely et al show with regards to IL12 production? How did this depict the "two sides of the dendritic coin"?
Showed that with LPS stimulation, human monocyte derived cells produce sig less IL12 than adult counterparts BUT With LPS and IFN-y stimulation IL12 production was non-sig between adults and neonates
111
Neonatal Immunology | Differences between neonatal T cells and adult?
Neonatal - Adult More innate - Cellular TFs related to haematopoiesis - TFs related to T cell functions
112
Neonatal Immunology Why is neonatal immunology so complicated AKA what is seen with T cell responses in Neonates (think DC). ADKINS et al
Pretty much the opposite of DC responses In neonates: High dose leukaemia virus - drives TH2 response with POOR CTL response. No disease protection Low dose virus - Drives adult like TH1 response with CTLs ADKINS et al
113
Neonatal Immunology | What did ADKINS study show RE Incomplete Freuds antigen and complete freuds antigen?
Giving IFA protocol immunisation = TH2 response | Giving CFA = TH1 response
114
Neonatal Immunology | What evidence is there that the ENVIRONMENT is the reason for defective T cell function? Qureshi 2001
Neonatal T cells able to resolve P.Carinii infection when transferred to adults
115
Neonatal Immunology What evidence is there that T cell defects re related to the cells themselves? Adkins et al White et al
T-cells still TH1 deficient in adults. Adkins et al IFN-y promotor is differentially methylated - suggesting different gene regulation in neonatal T cells
116
Neonatal Immunology | In what ways are neonatal T cells different to adult?
``` Less cytotoxic Less TCR signalling More cell cycle gene exp More antimicrobial peptides Produce ROs ```
117
Neonatal Immunology | In what ways do neonatal B cells differ from adult?
Reduced+delayed antibody secreting frequency Dec expression of costimulatory molecules -> DCs T+B Preferential differentiation to memory cells POOR affinity maturation Decreased survival signals and access to survival niches Germinal centres in spleen peak at a later date and lower level Neonates lack B cell follicles in spleen and bone marrow SECONDARY IMMUNISATION FAILS TO CORRECT THIS
118
Neonatal Immunology | What is the problem with neonatal vaccination?
Many commonly used vaccines = ineffective - Weak - Short lived - Inappropriate response - Require CFA - complete freud antigen Otherwise TH2 inflammation that does not combat disease
119
Neonatal Immunology | What immunisation may babies receive in their first week?
BCG
120
Neonatal Immunology What immunisations will babies receive at 8 weeks? (4)
Pneumococcal Rotavirus MenB 6 in 1 (diptheria, tetanus, pertussis, polio, H influenzaB, hep B)
121
``` Neonatal Immunology What immunisations (2) do babies receive at 1 year? ```
Meningococcal C | MMR
122
Neonatal Immunology | What can happen with maternal antibodies + vaccines?
Neutralisation (red dose needed) Binding to epitope specifically APC altered as complex pocessed
123
Neonatal Immunology | What is "maternal vaccination"?
AB transfer across placenta in 3rd trimester Breastmilk - Provides IgMAG + antimicrobial peptides Also provides GFs ies TGFb IgG taken up from gut via neonatal FcR
124
Neonatal Immunology | What does TGFb in breast milk do?
Appears to induce Tregs (mouse studies) | May be reason for allergy and wheeze
125
Neonatal Immunology | What effects the microbiome development in neonates?
``` Delivery routes Breast feeding Diet ABx Cleanliness of environment - Breast feeding and weaning most important ```
126
Neonatal Immunology What trend was seen with S.pneumoniae, H influenza or M Cayarrhalis colonisation in the neonatal lung? Bisgaard et al 2007
Inc risk of asthma | Bisgaard er al 2007
127
Neonatal Immunology What is seen in germ free mice, with allergic inflammation? What may be causing this?
More susceptible to developing allergic lung inflammation. | In ordinary microbiome Tregs are stimulated more
128
Neonatal Immunology | Infants born by C section have microbiome developing from.....
Skin microbiota
129
Neonatal Immunology | List allergens in HDM?
``` Fungal spores Chitin Immunogenic epitopes Fecal pellets LPS from bacteria ```
130
Neonatal Immunology What is the association between bronchiolitis, wheeze and asthma? Sigurs et al
Inc asthma and wheeze with bronchiolitis in childhood | Sigurs et al
131
Neonatal Immunology | What was seen in Pravilizumab prophylaxis on RSV?
Dec cumulative wheezing days by 40%
132
Neonatal Immunology | Leading cause of Asthma exacerbations
Human RV
133
Exacerbations of Asthma | How many exacerbations on average per year?
Typical mild-mod = 1-1.5x per yr
134
Exacerbations of Asthma | What are the needs for exacerbation red. therapies?
Major cause morbidity/mortality Cost associated with exac = 3.5x that stable asthma Also days off school/work Need for more specific/effective therapies
135
Exacerbations of Asthma GC + LABA fixed GC + LABA as needed % decrease in exacerbation?
Fixed = ~30-40% reduction in exacerbations As needed = ~50% Therefore need more Rxs
136
Exacerbations of Asthma | 2/3rd of viruses detected in exacerbations are.......
RVs
137
Exacerbations of Asthma | What viruses cause asthma exacerbations?
RV:RSV:Corona:Flu:Adeno:Other 62:11:9:5:2:11 %%%%%%%%
138
Exacerbations of Asthma | SS Picornavirus RNA genome 6-7kb
RV
139
Exacerbations of Asthma | What two receptors//classes are RV classed by?
Major group - use ICAM-1 Minor - LDL receptor Also classed by RV-A/B/C
140
Exacerbations of Asthma | Why is RV hard to develop vaccines for?
100+ serotypes High level of mutation / recombination events [High level of errors by RNA polymerase]
141
Exacerbations of Asthma What did NW johnston show with regards to children, asthma and september? What was seen with regards to inhaler use? Viruses were detected in what percentage of hospitalised?
Inc exacerbations every 1st 3 weeks september -> first back to school Those hospitalised were those less likely to have used inhalers. 62% (also hard to grow)
142
Exacerbations of Asthma What happened with CORNE et als study, comparing 74 atopic asthmatics vs spouses (non). Reg nasal sampling 2 weeks over 3 months. PCR
Incidence infection similar between both groups. LRT symptoms and PEF falls more severe in asthmatics. THEREFOREHOST RESPONSE DIFFERENCE
143
Exacerbations of Asthma | What did Peter Wark et al show in 2005, with regards to IFN, apoptosis, RV replication?
Deficient IFNa/b/y observed in asthmatic tissues (20 studies have confirmed). In HBECs, DCs, PBMCs Decreased apoptosis INCREASED RV replication Pro-inflammatory cytokines normal
144
Exacerbations of Asthma | What effect do TH2 cytokines have on T1/3 interferons?
Appear to antagonise IFNs
145
Exacerbations of Asthma | Viruses promote airway damage, inflammation, and induce pro-angiogenic factors. T/F?
True
146
Exacerbations of Asthma | List some pro-inflammatory cytokines stimulated by viral lung infection?
``` Chemos: CXCL8 CXCL5 (ENA-78) CXCL1 (GROa) GM-CSF G-CSF IL1b TNFa RANTES - CCL5 ```
147
Exacerbations of Asthma | What proangiogenic/matrix factors are released during viral infection?
FGF2 VEGf Collagen TFGb
148
Exacerbations of Asthma | What pro-TH2 cytokines do viruses stimulate release of?
Eotaxin TSLP IL25/33 CCL17/22 TARC/MDC
149
Exacerbations of Asthma | What results were seen in the NHLI study whereby asthmatic patients were infected with HRV?
Dec chest score Dec morning PEF Inc BAL lymph/eosino/neutrophils
150
Exacerbations of Asthma Qui et al discovered what with regards to NE in asthma? Thorax 2007 Qui
INC neutrophil elastase seen in lung DURING viral induced exacerbation. No additional NE found during stable asthma. Qui et al 2007
151
Exacerbations of Asthma | What did Psarras et al find with regards to VEGF in asthma?
Increased production of VEGF during exacerbation.
152
Exacerbations of Asthma | What did Kuo et al discover with regards to matrix proteins in asthma exacerbations?
Sig increase during exacerbation | Kuo et al
153
Exacerbations of Asthma What is the link between RV infection / sensitisation / exposure to allergen and ODDS RATIO of exacerbation? MURRAY: children trial GREEN: Adult trial
Combination of all three = 20x risk of exacerbation in children Combination of all three = 8x risk of exacerbation in adults Sensitisation + exposure combination = 2x risk exacerbation in adults MURRAY: children trial GREEN: Adult trial
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Exacerbations of Asthma Actions of TSLP? Acts via TSLPR/IL7R
Acts on DCs -> TH2 cytokine production | Stimulates TH2 differentation
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Exacerbations of Asthma | Actions of IL25? (AKA IL17E)
Activated NFkB TH2 cytokine induction Can act on epithelial cells + fibroblasts -> produce MDC+TARC = TH2 chemokines
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Exacerbations of Asthma | What do MDC and TARC do?
TH2 chemokines
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Exacerbations of Asthma Actions of IL33? Acts via ST2 receptor.
Danger signal/alarmin Activated NFkB Chemokine for TH2 Activates DCs/mast cells/basophils/eosinophils IL-33 + ST2 = GWAS hits for asthma
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Exacerbations of Asthma | What correlations have been seen with IL33?
Correlated with: IL4/13 release Total respiratory symptom score (both nasal and bronchial IL33) Peak viral load
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Exacerbations of Asthma | What is the model of asthma exacerbation?
``` Mouse Day 1 = OVA/alum i.p. Repeat challenge on days 11/12/13 Infection on day 13 4 groups: RV-OVA UV-OVA RV-PBS UV-PBS ```
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Exacerbations of Asthma | What fold improvement in AE was seen in Lebrikizumab? 13 Lebanons IL-13
>3 fold improvement but p=0.08
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Exacerbations of Asthma | What fold improvement in AE was seen with mepoluzimab? MePoscode is 5
>5 fold improvement in AEs p=0.008
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Exacerbations of Asthma What evidence is there that the -ve stimulation of IFN responses is DOWNREGULATED by mABs? Gill et al Teach et al What other info was gleaned, after a cheeky bit of stratifying?
Gill et al Teach et al IgE crosslinking inhibited IFN production Then randomised to Omaluzimab Rx Used PBMCs (sampled pre+post anti-IgE theraoy) to assess crosslinking. Giving Omaluzimab NOT ONLY decreased exacerbations by 30%, but also increased IFNa production even in "cross linked" group If Pts recieving omaluzimab were stratified by IFNa increase, those who had >median increase had: 4% exacerbations Those who had
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Fungal Allergy | Where are most fungi encountered?
Epithelial/mucosal sites
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Fungal Allergy | What is the overview of immunity to fungi?
``` Opsonisation by mannose-binding lectin + pentraxin 3. Phagocytosis NK cells release IFNy Failure of innate immunity -> adaptive DC -> present to T cells TH1 = stimulated by IL12 TH2 = stimulated by IL4 Tregs= stimulated by IL10 B cells produce some antibodies HYPHA = TH2 (multicellular) Single cellular = TH1 responses ```
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Fungal Allergy | In what morphologies can fungi exist in?
``` Budding yeast Pseudohypha Hypha Can form capsules to evade immune system Conidia = what yea inhale -> small bits off spores ```
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Fungal Allergy | What is seen with fungal infections and mortality with severity of immune response?
Increased mortality if: Immune response too severe Not severe enough ie immunosuppressed
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Fungal Allergy | What percentage of allergens do fungi make up?
16%
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Fungal Allergy Fungal: Rhinitis, asthma, ABPA are what type of hypersensitivity reaction?
1
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Fungal Allergy | Fungal ABPA and hypersensitivity pneumo are what type hypersensitivity reaction?
4 | NB aspergilloma + HP = T3 also
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Fungal Allergy | Chronology / timeline of fungal infection?
Many fungal spores inhaled daily -> abnormal host response -> allergic/invasive fungal disease -> hypersensitivity reactions Aspergillus = primary driver
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Fungal Allergy | What is the criteria for ABPA diagnosis?
``` Predisp - asthma / CF Obligatory criteria: iGE >1000IU/ml +ve hypersensitivity test Supportive: Eosinophillia > 500 cells/ul Radiographic abormalities Serum precipitating IgG Abs to asp fum ```
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Fungal Allergy | What are radiographic features of ABPA?
``` Dilated bronchi + walls Ring/linear opacities Upper/central predilection Promixam bronchiectasis Lobar collapse Fibrotic scarring ```
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Fungal Allergy | What is the management of ABPA?
Corticosteroids Itraconazole (indicated with no response to steroids) Omalizumab possible
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Fungal Allergy | Briefly what is ABPM?
ABPA caused by other mycoses
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Fungal Allergy | Neutrophil responses are dependent on what (in fungal allergy)?
IL17 + TNFa
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The Human Microbiome | Ratio of bacteria : human cells in body
1.6:1 until you poop | Unless you discount RBCs then ~10:1
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The Human Microbiome | Define microbiome + microbota
``` Microbiome = all microorganisms in an environment + their interactions with the environment Micropbiota = all the organisms in an environment ``` Majority of life = microbial
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The Human Microbiome | Where does the microbiome come from?
``` Birth canal: Skin bacteria = C section Vaginial = Vaginial Although this has recently been challenged Environment - food/air/other people/water - Lungs = microaspiration ```
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The Human Microbiome | What are the major sources of bacteria at headheight in major US cities? Summer/winter
``` Summer = plants Winter = dog poo ```
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The Human Microbiome | What is the "great plate count anomaly"?
Idea that only ~5% of microorganisms are culturable depending on sample/environment/effort ie only 60% of bugs from oral cavity can be cultured
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The Human Microbiome Why is it hard to culture all bacteria in a sample? What new technique may enhance detection?
- very dependent upon nutrients/temperature/salinity/ph | - DNA based techniques
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The Human Microbiome | What is the DNA sampling method (roughly)?
Take sample Freeze (or as environment selects, the microbiota combinaton will change) PCR - ribosome gene (16S) selected for - Each bacteria has one - Highly conserved but many variable regions - Therefore primers can be made to conserved regions - Illumina used
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The Human Microbiome | What is "alpha diversity"?
The diversity of organisms within a sample
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The Human Microbiome | What is "beta diversity"?
Comparing diversities between samples
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The Human Microbiome | What are Koch's postulates and why is he wrong?
1. Must find organism in diseased individuals, not healthy - Vibro cholerae may not always cause disease 2. Must be isolated and grown in pure culture - Hard to do 3. Isolate must cause disease in healthy individuals/animals - Animals not susceptible to leprosy 4. Must isolate again (should be same organism) - Same as 2
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The Human Microbiome | List 2 commensals which can cause disease?
Candida - immunocompromised | C.dif - systemic ABx causes pathogenesis
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The Human Microbiome | List a few beneficial bacteria?
Metabolites =- Vit K, folic acid, B12 Competitive exclusion = C.dif, phage, mucins Short chain fatty acids - can stimulate immune responses Drug metabolism - oestrogen processing
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The Human Microbiome | What is interesting about the effects of ABx on the microbiome//pathogen?
Doesn't seem to impact relative amount of pathogen in the microbiome but does alter amounts of commensals. Seems to "occupy" pathogen // switch its phenotype Commensals recover post Rx
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The Human Microbiome | ABx
- Produced by bacteria and used in LOW levels. We use them in vastly greater quantities - Resistance mechanisms exist for every ABx - Growth promotion for animals/inappropriate prescriptions/adherence XDR TB, MRSA, VRE
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The Human Microbiome | What are two alternatives to ABx?
Phage therapy | Vaccination (hard to design for bacteria though)
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The Human Microbiome | What is the only strain used in probiotics that has actually shown an effect?
Lactobacillus Casei subspec Rhamnosus strain - Lecturer Mike Cox used to isolate strains from probiotics - Invariably different or dead. NONE WORK - Lactobacillus rarely survives small intestine too WOULD HAVE TO BE A FREEZE DRIED CAPSULE
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The Human Microbiome | What recurrent disease benefits extremely from faecal transplants? 94% cure in clinical trial - had to be stopped early
Recurrent C Dif
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``` The Human Microbiome What drug (CF) also modified the environement and microbiota? ```
Ivacaftor | Inc water in mucus ->alters environment
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Gene-environment Interactions + Asthma Why have genome wide projects "failed" in asthma to date? What about environmental studies?
``` Have not: - enabled us to diagnose better - Changed Rxs - Helped predict course of disease - Helped with primary prevention EXACTLY THE SAME - Such conflicting evidence ie good/bad/doesnt matter for asthma with Cats/breast feeding ```
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Gene-environment Interactions + Asthma Is high level endotoxin good or bad for atopy? What was seen with LPS in alpine regions of Europe? In estonia? Southern europe? What was seen with CD14 genotype variants (detects LPS)? What was the effect of this on IgE levels? What was seen when this was tested in Germany, Huturites (consanguinous),
Alpine europe: endotoxin good for prevention No effect in Estonia on atopy. In Arizona = increased endotoxin = increased atopy Differing levels of production CD14 expression Increased IgE in LOW expression CD14 ``` Germany = no association with atopy Huturites = Strong association with atopy Arizona = appeared to be protective against ``` THINK OF HOW THIS WAS ALL QUANTIFIED......TT homo = lots of CD14 CC = less
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Gene-environment Interactions + Asthma When children were split by TT/CT/CC combinations, what was seen with regards to endotoxin load and the predicted probability of sensitisation?
``` TT = probability remained roughly the same with low/high CT = hint (p=0.2) that increased endotoxin reduces senstisation CC = if you have this variant and high endotoxin - almost guaranteed not to have atopy, BUT almost guaranteed to have atopy with LOW endotoxin ```
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Gene-environment Interactions + Asthma What was seen with A allele homozygotes in TLR2-16934 with regards to ALEX study? [Rare allele] [A+T alleles] What was seen when this was replicated in nurseries by Custovic et al?
ACTUALLY at considerably greater risk of atopy/asthma than non-farmer children. AA homozygotes at risk = same as farming
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Gene-environment Interactions + Asthma What was seen with Glutathione S transferase alleles and wheeze resulting from smoking, BASED on the time of the exposure?
Susceptible and expose early = effect is much higher than late exposure
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Gene-environment Interactions + Asthma | What did Li discover with regards to grandmother smoking during mothers foetal period?
Increases risk of asthma Appears to be transgenerational effects of environmental exposures - Mice studies show this can occur in up to 5 generations
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Gene-environment Interactions + Asthma | What is epigenetics?
Heritable changes in genome function that occur without alterations to the DNA sequence - Histone modifications - DNA methylation
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Gene-environment Interactions + Asthma | What was seen with increasing methylation at IL2 CPG site?
Increased methylation = asthma
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Gene-environment Interactions + Asthma | Key message = what may appear to be an environmental exposure may be an indicator of their genetic predisposition
Gene-environment Interactions + Asthma | Key message = what may appear to be an environmental exposure may be an indicator of their genetic predisposition
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Gene-environment Interactions + Asthma | What was seen with ABx use in children?
- Studies appeared to show that ABx associated with increased risk asthma BUT was not associated with atopy? IT was shown children who took ABx early had impaired viral immunity Was shown that genetic variants - on 17q21 (associated with asthma) were associated with MORE ABx prescription (and impaired viral). Complex web - Always the possibility that an exposure may actually be an indicator of gene variants
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Treatment Strategies for allergic disease Allergen Exposure -> sensitisation -> re-exposure -> What factors affect sensitisation?
``` Allergic inflammation TIMING ROUTE (ie oral) COFACTORS Other RFs: Smoking, maternal diet, ABx, Pollution, ```
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Treatment Strategies for allergic disease Define atopy? Define allergy?
Tendency to produce an exaggerated IgE response as reflected by a positive skin prick test he clinical expression of allergic symptoms
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Treatment Strategies for allergic disease | What is used as a positive control in skin prick testing?
Histamine - Checks anti-histamine - Positive result = >3mm more than control Rhinoscopy (exposed), can do in vitro IgE testing
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Treatment Strategies for allergic disease | In what ways can allergen sensitisation be removed?
Eaarly introduction Peanuts LEAP STUDY Maternal smoking prevention/Paracetamol use
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Treatment Strategies for allergic disease | What did the LEAP study by Du Toit show?
Randomised Peanut eating BEFORE 5 to both skin-positive test and normal babies. BOTH groups who did receive them = reduced peanut allergy
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Treatment Strategies for allergic disease | Can allergens be avoided?
Yes eg no hay fever in december Dust mite = improves at altitude Sheikh - Syst review showed mono-intervention did not work Morgan - multi-intervention = effective (34 less wheezy days per yr), improved symptoms
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Treatment Strategies for allergic disease | What did the study by Sheikh et al show?
Sheikh - Syst review showed mono-intervention did not work
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Treatment Strategies for allergic disease | What did the study by morgan et al show?
Morgan - multi-intervention = effective (34 less wheezy days per yr), improved symptoms $1000 PER child -> Cheaper than MABS!
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Treatment Strategies for allergic disease | What pharmacological Rxs exist for allergic disease?
Anti-Histamine Leukotreine receptor antagonists / 5-LO (less effective than AHs) Mast cell stabilsers - chromoglycates (short duration of action) Adrenaline - inhibits mast cell degranulation 1 in 1000 (0.5mg) = anaphylaxis IM dose Salbutamol (also inhibits Mast cell degran) Corticosteroids Anti IgE (Busse et al) // IL5 (mepo) // Dupilimab TREAT RHINITIS IN ASTHMA - DECREASES EXACERB - Corren et al (some studies contend this)
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Treatment Strategies for allergic disease | What is the dose for IM adrenaline?
0.5mg | 1 in 1000
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Treatment Strategies for allergic disease | What did JM weiner systematic review show regarding corticosteroids vs Histamine for allergic rhinitis?
Corticosteroids much more effective
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Treatment Strategies for allergic disease | What percentage of asthmatics have AllRhin?
80% | Treating AR reduces exacerbation rate (some studies contradict this)
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Immunotherapy - Clinical Aspects | What percentage of wasp venom sensitised patients are cured by immunotherapy?!
95%
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Immunotherapy - Clinical Aspects | How does immunotherapy work?
Titrated dose for 16 weeks Increased to HUGE doses -> given over 3 yrs Favours TH1 responses. Works for rhinitis/wasp venom NOT asthma yet. Trained observation area, vaccine storage, resus facilities, auto-adrenaline GIVEN SLIT (daily), SCIT (weekly)
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Immunotherapy - Clinical Aspects | What is on an immunotherapy record card?
Date, Peak flow PRE, CONC, volume, arm, time, Registration of swelling/systemic reaction/peak flow after an HOUR
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Immunotherapy - Clinical Aspects | Contraindications IT
MOD/SEVERE asthma | A/I, Preg, malignancy, poor understanding/adherence, multiple allergies
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Immunotherapy - Clinical Aspects | Indications IT
No response to pharm therapy Intolerable SEs Disease/symptoms on exposure and IgE sensitisation
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Immunotherapy - Clinical Aspects | Study names for IT efficacy
COCHRANE = CALDERON ET AL Frew et al Creticos et al
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Immunotherapy - Clinical Aspects | What did Cochrane analysis by Calderon et al show?
SCIT>SLIT | SLIT = easier -> patient able to take on their own after monitoring 1st high dose
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Immunotherapy - Clinical Aspects | How safe is IT? Durham et al
Less than 5% withdrawals due to AEs across studies | Durham et al
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Immunotherapy - Clinical Aspects | What length Rx required for IT?
Durham et al - effects still exist 2 yrs post Rx (3yr Rx) | Scadding - Symptoms return with only 2 yrs GRASS TRIAL
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Immunotherapy - Clinical Aspects | What do studies by Abramson et al and Mosbech et al show with regards to asthma IT?
Improve asthma symptoms Decrease ICS (respectively) NO EFFECT ON FEV1 BOTH
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Immunotherapy - Clinical Aspects | What did the Mitra study show with regards to SLIT on asthma exacerbations?
34% reduction
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Biomarkers of Immunotherapy | What ways can AIT be monitored?
``` Red Mast cells and Eos Reduced ILC2 and IL13+ve ILC2 Deviation of TH2->1 Reg T cell Induction IgG4 antibodies IL10+ reg B cells IL35+ve T reg cells ```
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Biomarkers of Immunotherapy | What is seen with Mast cell + Eo numbers with AIT?
Reduced
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Biomarkers of Immunotherapy | What do ILC1 produce and respond to?
Produce IFNy | Respond to IL 12/15/18
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Biomarkers of Immunotherapy | What are the functions of ILC1?
Cytotoxicity Macrophage activation O2 radicals
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Biomarkers of Immunotherapy | What do ILC2 produce and respond to?
Produce IL4,5,13 | Respond to 25/33/TSLP
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Biomarkers of Immunotherapy | What are the main functions of ILC2?
Effector: mucus, vasodilation, tissue repair
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Biomarkers of Immunotherapy | What do ILC3 produce and repsond to?
Produce - IL17,22,IFNy Respond to IL23, IL1B (phagocytic)
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Biomarkers of Immunotherapy | What is the effect of AIT on ILC2?
Reduces ILC2
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Biomarkers of Immunotherapy | Dendritic release of IL27 does what?
Reduces proliferation of TH2 cells (dependent on PDL1)
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Biomarkers of Immunotherapy | What is seen with IL27+ve DCs with AIT?
Increase - Shamji et al
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Biomarkers of Immunotherapy | WHat is seen with Foxp3+ve Regs with AIT?
Increased - Durham
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Biomarkers of Immunotherapy What is seen with increased IL35 with AIT? What are the functions of IL35?
Increased production, Increased IL-35 +ve Tregs Suppresses TH2 proliferation and cytokine responses Decreases TH17 Increases TH1+Treg1
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Biomarkers of Immunotherapy | What is seen with IgG4 production?
Sig increased
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Biomarkers of Immunotherapy | Where should IgG4 be measured?
Nasal Fluid
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Biomarkers of Immunotherapy | What is seen with Bregs?
Increased
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Influenza | What percentage of adults are affected by influenza each year? Children?
5-10% | 20-30%
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Influenza | Which affects more lives, and has a greater mortality, seasonal or pandemic flu?
Seasonal much more 8k deaths Seasonal flus are pandemics that have survived and matured
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Influenza | What is the economic burden of flu?
400k GP consultations Elderly resp hosp admissions = NHS £22m 6 million working days lost each year
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Influenza | Why more flu in winter?
Winter in northern hemisphere = dry and cold. Aerosols stay in air longer when dry -> humid they will fall to floor as water droplets Indoor existence too
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Influenza | Is flu season this year worse than last? 3 methods
Data from public health england suggests so Flu survey by LSof hygeine and tropical medicine suggests so RCGPs (royal college) also shows much more consultations (lab confirmed by isolation and PCR)
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Influenza | What strains are there?
Influenza A = H1N1 (seasonal), pH1N1, H3N2 [subtypes] Influenza B = B Yamagata, B Victoria [Lineages] Ideal vaccine would be quantravalent
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Influenza | Why is this year different to other (even worse) flu seasons?
ALL 4 subtypes appear to be increased rather than ONE
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Influenza | Where do influenza pandemics arise from?
Zooinosis of INFLUENZA A | Often from birds
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Influenza | Why are influenza pandemics so severe?
No immunity in the community as nobody has been previously exposed. No antibodies that can cross-react
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Influenza | Why did the spanish flu [1918] outbreak cause 50million deaths (eg swine flu 2009 only 200k deaths)?
Antibiotics were not discovered | Influenza predisposes to secondary bacterial infection, ie strep pneumoniae
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Influenza | Why were there two waves of swine flu?
In july when school children roke up the incidence went down (as did number of hospitalisations)
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Influenza | What is the difference between those affected by flu, between seasonal and pandemic?
``` Seasonal = elderly Pandemic = tends to be 16-64yos ```
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Influenza | What were newly discovered RFs for pandemic flu?
FAT Preg ImmunoCompromised
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Influenza Which genomic variant was associated with increased susceptibility? What is a theory of the origin of flu pandemics? DONG et al
IFITM3 CC homozygosity increases risk 44% of japanese and 26% of chinese have these alleles Thought that pandemics arise from ASIA
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Influenza | Increased CD8 associated with
Reduced infection
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Influenza | Describe the structure of influenza?
``` -ve sense single stranded virus 8 RNA segments Protein shell and lipid envelope Ha [haemaglutinase] and Na [neuraminidase) antigenic proteins M2 ion channel ```
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Influenza | Life cycle of flu virus
``` Fuses with membrane Endocytosed Releases genome mRNA synthesis from genome in nucleus Host produces viral proteins Virus assembles on lipid membrane -> buds off ```
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Influenza | How do the two pharmacological treatments for flu work?
Adamantanes block release of genome from endosome (ion channel M2) - All viruses are resistant to adamantanes Neuraminidase inhibitors (one of the spike proteins on the surface of flu) - Neuraminidase cleaves sialic acid (virus requires to LEAVE infected cell) [Relenza and Tamiflu]
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Influenza The UK government stockpiled 500ml of tamiflu. Why was this met with harsh criticism by some? What evidence is there for it?
Against - alltrials BMJ and Ben Goldacre - Cochrane review 2014 stated only shortened illness length by 21 hrs KrumHolz et al For - Early administration vs late with SEVERE reduced mortality - Retrospective trials have shown benefits eg Lancet
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Influenza | What effect does time-to-treat have on survival?
Delayed = increased mortality
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Influenza | What are some problems with neuraminidase Rxs?
Aministration, compliance and SEs (3% NV) Drug resistance (neuraminidase itself ungoes rapid antigenic shift) Lack of rapid diagnostics / kinetics of viral infection
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Influenza | What are the kinetics of viral infection?
Often symptoms peak as virus is shedding anyway + immune system has under control
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Influenza | Olseltamivir resistence occurred when? Why?
After 2007/08 flu season -> could no longer bind in 08/09 season
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Influenza | Which individuals contribute to viral resistance?
Immunocompromised Often multi-infected. Giving drug alone will cause resistance -> only one nucleotide needs to change for drug to be unable to bind
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Influenza | Who gets the annual trivalent/quad INACTIVATED flu vaccine? What is the immunity like?
Elderly and severe risk | Short term specific immunity mediated by antibody to HA head
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Influenza | Who gets the quadravalent live attenuated flu vaccine? (cold adapted virus, can only replicate in nose) [NASAL SPRAY]
Children | More broad, cross reactive immunity
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Influenza | Why was swine flu hard to develop a live attnuated vaccine for?
Unable to transfer across acidic nose -> releases genome in acidic conditions
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Influenza | Could there be a single flu vaccine?
Theoretically if targetting the highly conserved stem of the viral spike
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Vaccines | What are the aim of vaccines?
Mimick aspects of infection to stimuate long lasting immunological protection
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Vaccines | What are the requirements of vaccines?
``` MUST Must not cause disease - simian virus in polio vaccine Stop viral spread (08-85%herd) Long lastimng Cheap Genetically stable / storage / delivery ```
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Vaccines | What vaccine types exist?
Live attenuated Inactivated Subunit/fractional Clining -> viral vector/DNA vaccine/Viral proteins
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Vaccines | Attenuated vaccine
MMR/BCG
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Vaccines | Fractionated vaccine example
HepB
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Vaccines | Inactivated vaccine example
Salk
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Vaccines | What is seen with RSV vaccination? Why?
``` Increased RSV infection 83vs29% (lung disease) Formalin inactivation (FI) drove TH2 responses in mice due to carbonyl groups on certain amino acidsm (as a resuult of FI) ```
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Vaccines | Why is flu hard to develop vaccines for?
Antigenic DRFIT = copy errors during replication and through immune pressure Antigenic SHIFT = diversity through recombination - reassortment of gene segments creates new strain progeny virus
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Vaccines | Spanish flu strain?
H1N1
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Vaccines | Asian flu strain?
H2N2
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Vaccines | Hong Kong flu strain?
H3N2
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Vaccines | Russian flu strain?
H1N1
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Vaccines How is the inactivated flu vaccine made? What is its effectiveness?
Grown in eggs then formalin inactivated 60-90% effective Virus mutates and rearranges surface antigens In jan = determine strains circulating from asia and subcontinent
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Vaccines | How could plants be used?
GM plants could grow virus like-particles
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Vaccines | Why is RV a challenge to develop vaccines for?
160+ strains identified | Poor cross serotype protection BUT a conserved RV capsid protein target found
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Bacterial Infection | How many deaths WW from LRT infections?
3.46ml
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Bacterial Infection | Which age groups are affected most by LRT infections?
Increasing incidence with age Relatively low in young >90 = biggest age group Increasing mortality with age too
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Bacterial Infection | Which sex is affected by LRTI more?
M
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Bacterial Infection | Rfs pneumonia`
``` Age Social Comorbidities Smoking Drugs etc...... ```
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Bacterial Infection | Most frequent causative organisms of CAP?
50% UNIDENTIFIED S.Pneumo. H influenza, (Legionella, M pneumonia, Chalmidya) Atypical = low neutrophils / SIADH Do LFT (legionella)
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Bacterial Infection | When do you do blood cultures/sputum cultures
Only if mod-severe severity Able to expectorate Not recieved ABx in community Urinary pneumococall antigen/legionella antigen important
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Bacterial Infection | What is CURB score?
``` Confusion Urea > 7mmol RR >30 BP <70 S or 60 diastolic 65 YOs 2 points = hospitalisation 1-0 = reduced risk -> home ``` 30 day mortality predictor
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Bacterial Infection | Strengths and weaknesses of CURB 65
Robeust Validated Identifies low risk patients Simple and easy to use ``` BUT Weighted by age Underestimates mortality in young patients Doesn't predict ventilation Doesn't include oxygenation ```
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Bacterial Infection | What are contraindications for outpatient pneumonia care?
Hypoxaemia Failure of outpatient oral therapy Comorbidities Unmet social needs
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Bacterial Infection | What is the initial ABx choice?
Empirical | 3-5 = IV Rx
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Bacterial Infection | What factors influence ABx choice?
``` Culture Allergy Hx If anaphylaxis -> no cephalosporin/penicillin - fluroquinolones / macrolide (covers atypical too) Previous pathogens Local epidemiology Severity of disease Comorbidities ```
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Bacterial Infection | How does one avoid sepsis complications in pneumonia?
BroadS in 2 hrs | Every hour ABx delayed in a pt with septic shock = 8% increase risk of death
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Bacterial Infection | What pneumonia vaccines exist?
Purified polysaccharide capsular extract from 23 common serotypes Ineffective in children below 2 Aspenia = dose needs to be repeated every yr 13-valent form for children <5
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Bacterial Infection | RFs for HAP?
Post surgical/sedation Head injury NeuroEvent Bed ridden
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Bacterial Infection | Causes of pneumonia Rx failure?
Resistance Incorrect diagnosis Unrealistic expectations -> Rx longer
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Bacterial Infection | Pulmonary abscess
Klebs | TB
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Bacterial Infection | AVOID WHICH DRUGS IN THE ELDERLY for Cdif prevention
Cephalosporin Clindamycin Quinlones
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Microbiology and Immunology of TB infection | MTB genome size?
4000 genes | 250 for fatty acid metabolism
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Microbiology and Immunology of TB infection | What is the region of difference 1 area on the Mtb chromosome?
Essential region on genome - codes for virulence factors - RD1 EG ESX-1 secretion system - Secretes ESAT-6 and CFP-10 proteins
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Microbiology and Immunology of TB infection | What is MTB cell wall made from?
``` Peptidoglycan Arabinogalactan LAM Mycolic acids Capsule ``` Overall 60% lipid. Confers resistance and virulence
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Microbiology and Immunology of TB infection When does MTB enter a dormant state? What receptor mediates this? What happens in its dormant state?
In response to depletion of oxygen Mediated by DosR regulon Low metabolic activity/upregulation of lipid metabolism Reduced susceptibility to ABx Do not form spores
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Microbiology and Immunology of TB infection | Name a few things that can result in reacivation of TB?
CD4+ depletion eg HIV TNF blockade - GC therapy Altered antigen expression? Altered cell trafficking?
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Microbiology and Immunology of TB infection | What innate receptors recognise TB?
``` Completement C type lectins - mannose receptor TLR2 INTRACELLULAR NOD2 TLR 9 NLRP3 ```
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Microbiology and Immunology of TB infection Where does MTbB often survive? How does it survive? What process does it rely on to spread?
Macrophages ``` Able to tolerate low pH Avoids lysosome fusion to phagosome ESX1/ESAT-6 allows rupture of phagosome LAM protein neutralises ROS Also inhibits apoptosis of infected cells ``` Requires necrosis. More macrophages come to try to clear necrotic macrophages -> leads to increased spread. Eventually a granuloma will form STUDIES SHOW removal of RD1 domain results in apoptosis and termination of infection
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Microbiology and Immunology of TB infection | What effect does TB infection have on DC migration?
Inhibits this Reduced expression of MHC2 on macrophages and DCs Adaptive immune response still detectable 3-8 weeks post exposure
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Microbiology and Immunology of TB infection | What is a granuloma?
Collection of macrophages and other immune cells Contain mature macrophages Require persistent stimulus Apoptotic macrophages, epithelial like macrophages Can be necrotic in TB
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Microbiology and Immunology of TB infection | Which cells are crucial in the immune response?
TH1 cells -> activate macrophages via IFNy -> kill TB CD8+ cells can kill via perforin/granulysin BUT adaptive immune responses often fail USUALLY equilibrium is reached -> latent TB Microbiology and Immunology of TB infection
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Microbiology and Immunology of TB infection | What is seen with severe inflammation in TB?
T1 interferon response in active disease | DETRIMENTAL neutrophil overactivation which increases tissue pathology
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Microbiology and Immunology of TB infection | Unanswered TB questions
What leads to complete clearance of MTB in vaccine induced, natural transmission. What causes latent->active Complete vaccine? Promotion of protective immune responses in infected
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Microbiology and Immunology of TB infection | How is TB transmitted?
Droplet Close contact ~6myco per droplet infection ~5-200 required to establish infection = 6hr in same room
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Microbiology and Immunology of TB infection What is a Ghon complex? What is a ghon focus?
Sub-pleural patch of parenchymal infection with enlarged LNs Successful containment with scarring and calcification
316
Microbiology and Immunology of TB infection | Clin symptoms active TB?
``` Coiugh >3 weeks Fever Haemoptysis WL Atelectasis Bronchiecrasis Plueral Eff ``` ``` Max burden = in reinfection/activation - typically apical SUBSTANTIAL tissue damage 60% mortality Fibrocavitatory + millary = inflammatory nodules ```
317
Microbiology and Immunology of TB infection What are the complications of post primary TB? Think Pulmonary/pleural/extrapulmonary
``` Fibrosis Mediastinal displacement Resp failure Bronchiectasis Rasmussens aneurysm Aspergilloma ``` Pneumothorax Pleural effusions Empyema ``` Extrapulmonary Pericarditis Spinal TB Poncets arthropathy TB meningitis 1% LN TB (90% cervical) ```
318
Microbiology and Immunology of TB infection | Diagnosis TB
Bloods - ESR/CRP ACD Micro - sputum 3x days in a row (take in morning), BAL, Early morning urine, Biopsy Nucleic acid amplification tests = new (88% sensitivity) Mantoux (TST) IGRAs
319
Microbiology and Immunology of TB infection | What stains are used in microscopy fo TB?
Ziehl Neelsen Auramine-O or Rhodamine NOT ALL AFBs MTB - Gold standard = culture
320
Microbiology and Immunology of TB infection | Caveats of TB culturing
Not always effective Takes weeks (14 days if liquid culture) Able to test drug sensitivities
321
Microbiology and Immunology of TB infection | How does one perform TST?
Injection of tuburculin PPD ID 48-72 hr wait Measure swelling 5mm or larger = TB exposed Poor spec - cross reacts with BCG vaccine
322
Microbiology and Immunology of TB infection | How does one perform IGRA?
Detects T cell IFN release Elisa = labelled AB to AB that binds IFN BETTER specificity as it doesnt cross react with BCG (does not have RD1) Still doesn't CONFIRM tb though
323
Microbiology and Immunology of TB infection | What is an FDG pet scan?
Looks for areas of high FDG uptake | - Low specificity but still useful for Rx followup
324
Microbiology and Immunology of TB infection | What is the Rx for infection?
``` Group 1 = Rifampicin, isoniazid, pyrazinimide, ethambutol RIPE Must give cocktail of drugs MUST MONITOR LFTS Always give pyridoxine with rifampicin to prevent nerve damage 6 month Rx - 4 months ALL, 2 months RI__ CNS infection = 12 months 2 months RIPE 10 months RI__ Dex/pred too ``` RIFAMPICIN is a cyt inducer
325
Microbiology and Immunology of TB infection | What is contact tracing?
If an individual is diagnosed -> must test close relatives/contacts IGRA//TST Can offer latent treatment Latent Rx = Rifampicin + pyridoxine 3/6 months
326
Microbiology and Immunology of TB infection | BCG effectiveness?
0-80% Very good at protecting against meningitis TB Live attenuated vaccine, ID left upper arm
327
Microbiology and Immunology of TB infection | Who is vaccinated with BCG now?
``` Used to be schools programme Nice indicated only High risk groups Neonates in high incidence areas New entrance from high risk countries Healthcare workers Contacts of people with TB Prison staff/vets care homes ```
328
Microbiology and Immunology of TB infection | What is the MDR TB Rx?
Multi = HR + second line drugs XDR = Extensively drug resistant - MDR Rx plus 1-3 injectable second line drugs eg kanamycin % of TB in UK Result of poor compliance and inadequate drug supplies
329
Microbiology and Immunology of TB infection | Risk of TB in HIV?
30x more likely to get TB Reinfection more common that reactivation -> less inflammation, less cavitation, mimics primary infection Smear negativity -> no sputum
330
Microbiology and Immunology of TB infection | What test is used to detect TB in HIV patients?
Xpert = NAAT
331
Microbiology and Immunology of TB infection What is the process called whereby HIV patients on HIV Rx have restoration of cellular immunity and a sudden heightened response to MTB?
Immune reconstitution syndrome IRIS (TB may be unmasked or known)
332
TB Epidemiology | What trend has been seen with TB mortality since the 1860s
``` Been steadily decreasing from 300per100k -> ~10per100k EVEN before TB bacillus identified + long before TB antibiotics developed Slight peaks in WW1/2 Living conditions ```
333
TB Epidemiology | What factors determine the risk of exposure to TB?
Prevalence in area Duration off infectiousness (ie to Rx) Number and nature of interactions with infected
334
TB Epidemiology | What are the RFs for becoming infected once exposure has occurred?
Airborne transmission through infectious droplet - MUST be smallness to reach an alveolus in the periphery of the lung and remain suspended in the air for several hours Characteristics of infected patient - number of bacilli sputum specimens correlated with infectiousness Air ventilation Host immune response
335
TB Epidemiology | What are the RFs for disease if infection occurs?
HIV | Time elapsed -> reinfection more likely to occur in 1st yr
336
TB Epidemiology | RFs for dying from TB?
Timeliness of diagnosis Type eg LN not bad, TB meningitis = bad Sputum positive pulmonary TB = worst
337
TB Epidemiology | Incidence of TB WW?
10ml per yr | Indonesia, China, Nigeria, Pakistan, SA = account for 60% of cases
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TB Epidemiology | Incidence of MDR TB?
500k per yr
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TB Epidemiology | Mortality of TB?
1.5ml per yr | 5th most common cause of death
340
TB Epidemiology | Where is TB increasing in prevalence
Congo | North Korea
341
TB Epidemiology | Where is MDR TB highest?
Russia | Also indian subcontinent
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TB Epidemiology | Where in UK is TB worst?
London - some parts red. 40% of UK TB 73% of cases occurred among people born OUTSIDE UK Most cases thought to be reactivation
343
TB Epidemiology | Prevalence of TB in UK trend?
Increased to 2009 Decreasing since then Due to systematically implimenting new entrant latent TB screening from high risk countries. Must prove TB screening when applying for VISA
344
TB Epidemiology | What factors impair host defense to TB and increase likelihood of infection?
Age, sex, genetic factors, HIV, malnutrition, diabetes, alcoholism, tobacco, smoke, air pollution
345
Bacteria in Asthma and COPD | What are the impaired host defenses in COPD?
Reduced CBF + Numbers Squamous metaplasia = reduced ciliated cells Increased Goblet cells + Submucosal glands Damaged epithelial junctions -> inc permeability Impaired macrophage phagocytosis Reduced IgA
346
Bacteria in Asthma and COPD | Are there more bacteria in COPD pts?
Yes - detectable in 30% of COPD patients SETHI et al - Increased with severe disease - Bacteria present in 30-50% of sputum samples PATEL et al
347
Bacteria in Asthma and COPD | Most common bacteria found in COPD?
H influenza S pnuemonia M catarrhalis DOES VARY with severity -> ie P.Aeruginosa found in severe airflow obstruction NOT STATIC -> appears to alter in terms of types MARIN ET AL
348
Bacteria in Asthma and COPD | What is the result of increased bacterial in COPD?
``` More symptoms Poorer health status More exacerbations Airway inflammation SETHI ET AL ```
349
Bacteria in Asthma and COPD | What are the benefits of PCR // Sputum
Sputum Cheap, easy, 3 days, LIVE ONLY, sensitivity testing, <30% bacteria can be cultured PCR Easy/automated, LIVE AND DEAD, hours, no sensitivity testing, only specified bacteria, TOO SENSITIVE? Sequencing, Expertise, expensive, slowm, LIVE AND DEAD, all bacteria detected
350
Bacteria in Asthma and COPD What does some evidence show with regards to a bacterial switch in strain (ie same bacteria type but new strain version of that type)?
Some studies have suggested that it is the change in strain that may cause infection and exacerbation SETHI + MURPHY et al
351
Bacteria in Asthma and COPD | Describe the microbiome in health?
Proteobacter + Bacteriodetes + Firmicutes No / low frequency of pathogenic microorganisms Microbiome of bronchial tree = similar to microbiome of the oropharynx
352
Bacteria in Asthma and COPD | How does the microbiome alter in COPD?
More heterogenous ie alters by lobe/vs large small ariweays More advanced COPD = decline in bacterial diversity Overrepresentation of Proteobacter Phylum is seen Each individual patient is very different too
353
Bacteria in Asthma and COPD | What factors influence the microbiome in COPD?
Contoli et al - ICS Rx alters microbiome | Molyneaux et al - RV infection also alters microbiome (NOT IN HEALTHY CONTROLS, BUT INCREASED H INFLUENZA IN COPD)
354
Bacteria in Asthma and COPD | What is seen with bacteria in asthma?
Present in 15% of asthmatics - increaes with severity (52%) BUT in general less than COPD. Correlates with increased freq + duration exacerbations BUT FEW STUDIES Some evidence to suggest that atypical bacteria eg M.pneumonaie are important
355
Bacteria in Asthma and COPD | Should you give ABx to an asthmatic during an exacerbation?
Viral infections more common Routine prescription NOT indicated 57% of AEs Rx with ABx Johnston et al = trial of azithromycin for AE = negative. Underpowered though
356
Bacteria in Asthma and COPD | Do you see atypical bacterial in asthmatics?
Not relleh. Chlamidya bit more common in children
357
Bacteria in Asthma and COPD | What is seen in the microbiome of asthma?
Similar to COPD Increased proteobacter - H influenza HILTY ET AL Even in mild asthma
358
Bacteria in Asthma and COPD | What is the microbiome like in SEVERE asthma Rx resistant?
M.catarrhalis Haemophillus or Strep Genera = the more prominent species Such colonisation is associated with longer disease duration Worse FEV1 Inc neutrophil count sputum Inc IL8 sputum Cause or effect though? Longitudinal needed
359
Why AIT Fails | Give reasons why AIT fails?
Wrong: | Set up, dose, patient, allergen, duration
360
Why AIT Fails | What is required for immunuotherapy to succeed with regards to the clinic itself?
Leadership/organisation Staff competancies Clinical facilities - storage, equipemnt, rescue equipment Protocols
361
Why AIT Fails | What staff competencies are specifically required?
``` Evaluation of condition ENTERING THE IMMUNOTHERAPY RECORD FORM Injection technique Dose modification Active observation Early recognition of anaphylaxis Scheduled assessments Factors determining whether or not to stop ```
362
Why AIT Fails | What are the "right patient" characteristics?
Symptoms induced by allergen Atopy IgE to relevant allergen (SPT, ImmunoCAP, Nasal challenge) No contra-indications - severe asthma, multiple allergies, inability to comply, nonadherence
363
Why AIT Fails | What qualities with regards to the allergen, dictate success of AIT?
IN HOUSE REFERENCE STANDARDS - often given different ways by manufacturers Recombinant allergens Major allergen content FROM TRIALS: Documented efficacy/safety/long term effects
364
Why AIT Fails | When do you initiate AIT [with regards to pollen season]?
Meta-analysis by Calderon et al suggests that Rx effect (on symptoms + Medications) can be doubled by beginning >8 (~16) weeks before vs <8
365
Novel AIT | What is the adherence of SCIT vs SLIT?
``` SCIT = 25% non SLIT = 12% ```
366
Novel AIT | WHAT IS THE IDEA OF CHEMICAL MODIFICATION?
Whereby you give a linear epitope -> cannot be bound by IgE [not conformational]
367
Novel AIT | What other routes could AIT be given in?
Bronchial? Epi? Nasal? Oral? Sublingual
368
Novel AIT | What have studies shown with combination of omalizumab + AIT?
Pts randomised to anti-IgE or placebo Grass pollen + Birch pollen allergy arms Enhanced response with IgE co administration Shorter administration
369
Novel AIT | What happened with AIT administration PLUS TLR 9 agonist (induces TH1 + IL10 [IgG4 stimulant])
Decreased SS Decreased Visual analogue scale Shorter administration
370
Novel AIT What occurred with ASIT biotech highly purified linear eptides (made by hydrolysis of purified allergen extract). Have less capacity to activate basophils, TH2 responses and IgE
Reduced TH2 responses (T cell proliferation) Reduced basophil activation Still Dose-response Did induce T cell proliferation in non-atopics, (BUT THIS IS TH1) BUT FAR less in peptide group + IL5 production was reduced
371
Novel AIT | What was the set-up of the phase 2a study on ASIT biotech purified peptide immunotherapy? What was the result?
Open prospective dose escalation study 8 visits with incremental dose increase n=65 Measured IgG4 throughout Did conjunctival provocation testing b4 and after Mean wheel diameter less than 5cm No increase seen with increasing dose No increase in late phase reactions No significant AEs [No grade 3/4 systemic effects] Increasing IgE and IgG4 Reduction in IgE:IgG4 ratio Decreased allergen IgE binding Decreased Conjunctival provocation testing scores
372
Novel AIT | What was the result of the placebo controlled trial of Lolium Perenne peptides (highly purified)
Decreased conjunctival provocation test scores. Decreased IgE FAB Increased IgG4
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Novel AIT | What are the benefits of L perenne purified peptides? LINEAR PEPTIDE allergic rx?
SHORTER COURSE OF SCIT 3 visits over 4 weeks Higher pt compliance? Could get cover just for grass pollen season

Sdpeh (50 decks)

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