Core Immunology - Part 2 Flashcards
1
Q
What does immunocompromised mean
A
disruption of specific defence of an organ/system
2
Q
What disease do we worry about with burns
A
Pseudomonas and group A streptococcal infections
3
Q
What can alter defence to make us more immunocompromised
A
Extremes of age, malnutrition or pregnant
Markedly immune compromised in neonates at 20 weeks and towards the end of pregnancy
4
Q
What are the type of qualitative defects you can get in neutrophils
A
Reduced chemotaxis - rare, congenital - due to inadequate signalling/receptors and movement
Reduced killing power
5
Q
how is killing power reduced in neutrophils
A
Inherited Chronic Granulomatous Disease
Defecient in NADPH Oxidase - can’t make H2O2 - can’t kill bacteria
Can’t mount a phagocytic response
Susceptible to Staph. Aureus infections
6
Q
What is the quantitative defect in neutrophils
A
Neutropenic - especially severe if less than 0.5x10^9
7
Q
What can make you neutropenic
A
cancer treatment
bone marrow malignancy
aplastic anaemia
8
Q
What infections are you particularly susceptible in neutropenic patients
A
Pseudomonal - over 50% will die from these within 24 hours
9
Q
What bacteria are you susceptible if you are neutropenic
A
Gram -ve e.g. E. coli
Gram +ve e.g. Staph aurues
Coagulase negative staph - when you put a line in
10
Q
What fungal infections are you susceptible if you are neutropenic
A
Candida albicans and aspergillus
11
Q
How to prevent infection in neutropenic patients
A
Broad spectrum antibiotics - amino glycoside and antipseudomonal penicillin
2nd line is carbapenems and then antifungals
Also give GCSF (granulocyte colony stimulating factors) - try to get the immune system working
12
Q
Discuss types of T cell deficiencies
A
Congenital: Rare - T helper dysfunction +/- hypogammaglobulinaemias
Acquired: Drugs (cyclosporin after transplantation as decreases change of rejection)
Also through viruses
13
Q
What pathogens usually infect you in T cell deficiencies
A
Opportunistic pathogens that tend to be intracellular
14
Q
What bacteria are you susceptible to in T cell defeciency
A
Listeria (in cheese and pate so pregnant women should avoid)
TB
15
Q
What viral infections are you susceptible to in T cell deficiency
A
HSV, CMV, VZV
Receive appropriate aciclovir and ganciclovir treatment and prophylaxis
16
Q
What fungal infections are you susceptible to in T cell deficiencies
A
Candida albicans and cryptococcus
17
Q
What Protozoa and parasitic infections are you susceptible to in T cell deficiencies
A
1) Cryptosporidium parvum (sporozoa)
2) Toxoplasmos Gondii (sporozoa)
3) Strongyloides stercolis (nematode)
18
Q
Describe cryptosporidium infection
A
Often in T cell deficiencies Spread by faecal/oral route - can be spread in water Get severe diarrhoea - unto 3 weeks Immunocompromised may not recover Only symptomatic treatment
19
Q
Descrive Toxoplasma Gondii infection
A
Humans infected with cat faeces or transplanted heart or liver
May get lesion in brains or neurological signs
Most immunocompetent patients are asymptomatic - only get infected with T cell deficiencies
20
Q
Describe strongyloides stercolis infection
A
Nematode
Get when worm enters your bare feet in the tropics - can be asymptomatic for a long time until immunocompromised
Worm can move from gut to bloodstream - infects blood with GI flora get gram negative septicaemia
Normal patients asymptomatic or rash of larva currens
21
Q
Who do we suspect strongyloides stercolis infection
A
Patients from tropical countries or old prisoners of war
22
Q
What are hypogammaglobulinaemias
A
Antibody problems/deficiences
23
Q
Congenital causes of hypogammaglobulinaemias
A
X-linked agammaglobulinaemias
24
Q
Acquired causes of hypogammaglobulinaemias
A
Multiple myeloma
Chronic lymphocytic leukaemia
Burns
25
What disease are you susceptible to in hypogammaglobulinaemias
Usually encapsulated bacteria in the respiratory tract (pneumoniae)
Or Giardia lamblia/cryptosporidium in the GIT
26
Why are you susceptible to parasites in hypogammaglobulinaemias
No IgA
27
How do we treat hypogammaglobulinaemias
Replace immunoglobulins
28
What are we at risk of in complement deficiencies
Encapsulated bacteria - we need complement activation to kill these organisms
The earlier the defect in the system the more susceptible we are
Also frequent S.pneumoniae infections due to poor opsonisation
29
What are we at risk of with C5-C8 deficiency
Neisseria meningitidis - MAC not formed so no lysis of bacteria
30
What does the spleen do
Source of complement and antibody producing B cells
| Also removal of opsonised bacteria from blood
31
Why might we have a splenectomy
Trauma
Surgery
Functional e.g. sickle cell anaemia
32
What are we susceptible to in splenectomies
Strep pneumoniea, haemophilius influenza type B, neisseiria meningitidis, malaria
33
How to treat people with splectomies
Education
Vaccination
Prophylactic penicillin
34
What are biologics
Antibodies or other peptides that inhibit inflammatory cytokine signals
e.g. TNF inhibiting T cell activation or depleting B cells
35
What are you at risk of rheumatoid arthritis
TB, HZV, Legionalla Listeria etc. Due to biolgics Same as T cell deficiencies
36
What do we have liver transplants for
Hep C
| Paracetamol overdose
37
What are the opportunistic infections after transplantation
CMV and aspergillus in the first 3 months
38
What are the later infections after transplantation
More T cell deficiency problems
| E.g. listeria, VZV, candida
39
How do we prevent infection in immunocompromised infections
Hand washing
Aseptic techniques
Protectice isolation
Vaccinated patients - avoid live vaccines in T cell deficieincies
HEPA Air filtration removes aspergillus spores
Prophylaxis
Special diets e.g. avoid soft cheeses and pate
40
Who do we not give live vaccines to?
T cell deficient patients!
41
What do cytotoxic T cells do
Bind to infected cell
Perforin makes a hole in the membrane
Injects enzyme to cause apoptosis
42
How do Helper T cells work
Secrete cytokines to control immune response and help B and T lymphocytes
43
What is the target of HIV
Helper T cells
44
What do suppressor T cells do
Dampen down the immune response
45
How do antibodies promote phagocytosis
Neutrolization (blocks viral binding sites and coats bacteria)
Agglutination of microbes
Precipitation of dissolved antigens
46
What do antibodies activate
The complement system leading to cell lyiss
47
How does the innate system activate adaptive
They engulf micro-organisms and present them to cells
48
What are there common causes of immunodeficiency
Some are primary due to genetic defects - rare and often diagnosed early in childhood due to recurrent infection
Secondary - due to external factors e.g. stress, trauma, malnutrition, cancer, immunosuppressants, TB, HIV, AIDS, irradiation
49
What does IRAK do
It is a protein that causes the Nf-kb transcription factors to be produced
50
What is Nf-kb pathway essential for
Essential for the cell to produce inflammatory cytokines and cheekiness!
51
What happens in IRAK deficiency
Normally Toll Like Receptors (TLRs) recognise components of the cell wall and feed to the IRAK protein to activate the Nf-KB pathway
In deficiency have normal levels of WBC's but much lower CRP in pneuomoccal pneumonia.
Would expect much larger response but no cytokines due to IRAK protein problems
52
What is chronic granulomatous disease
Mutation in NADPH Oxidase (gp91 most common and it is X-linked!!)
53
How does NADPH-oxidase mutation cause disease
Normally it transfers H+ across the membrane to produce free radicals and HOCL - makes the phagosome for more acidic to activate the proteolytic enzymes and kill bacteria
If theres a problem can't transfer the protein
Cant acidify the phagosome
Cant kill the bacteria
54
Disease in chronic granulomatosus
```
Osteromyelitis
Pneumonia
Swollen lymph nodes
Gingivitis
Non-malignant granulomas
IBD
```
55
How would we diagnose chronic granulomatosus
Nitroblue tetrazolium test (NBT)
Incubate neutrophils with NBT - they take in the dye
If NADPH-oxidase is working they make the blue dye a very dark colour --> in chronic granulomatous this doesn't happen
56
Absent terminal complement pathway activity (C5-8) makes you susceptible to what
Meningococcal infections
| But you would still have normal levels of immune molecules
57
How would we measure terminal complement pathway activity
Incubate sheep RBC with antibody to sheep RBC
| Complement system should activate in this and should be lysis of the RBC
58
Presentation of absent terminal complement activity
Previous episodes of meningitis
No family history
Normal immune levels
59
Presentation of X-linked agammaglobulinaemias
history of recurrent sino-pulmonary infections
Maternal uncle/grandad has history of recurrent chest infections
Undetectable/low antibodies
Absent peripheral B cells, normal T cells
Bronchial dilation evident
60
What is X-linked agammaglobulinaemia
Defects in B cells - loss of antibody secretion, get recurrent bacteria infections
Usually only diagnosed at 1/2 years as mothers antibodies protect you until then
61
What is SCID
Severe combined immunodeficiency syndromes
| When you have defects in T and B cells
62
How to cure SCID
bone marrow transplant
| Gene therapy
63
Why are defects in T cells more dramatic
B cells need T cells help
| Recurrent infection with opportunistic bacteria, viruses, fungi and protozoa
64
Presentation of SCID
Severe herpes zoster infection and extensive oro-pharyngeal candida
Parents might be first cousing
Normal IgG but no IgA and reduced IgM
65
Primary B-cell deficiencies
```
agammaglobulinaemias
IgA deficieincy
Autosomal recessive hyper IgM syndrome
IgA deficiency
Transient hypogammaglobulinaemia of infacncy
```
66
Primary T- cel deficiency
```
SCID
Adenosine deaminate deficiency
Purine nucleoside phosphorylase deficiency
MHC Class II deficiency
Wiskott-Aldrich syndrome
```
67
Deficiency of PRR's makes you susceptible to?
HSV, Pneumococcus
68
Deficiency of macrophages and neutrophils makes you susceptible to?
CGD, staphylococus, aspergillus
69
Deficiency of T cell receptors makes you susceptible to?
SCID, opportunistic infections
70
Deficiency of complement proteins makes you susceptible to?
Meningococcus
71
Deficiency of cytokines makes you susceptible to?
Mycobacterium
72
Deficiency of B cell makes you susceptible to?
Recurrent sino-pulmonary infections
73
What is immunomodulation
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response
74
What are immunomodulators
Mechanical products produced using molecular biology techniques including recombinant DNA technology
75
What are the main classes of immunomodulators
Substances nearly identical to body own signalling
Monoclonal antibodies
Fusion proteins
76
What is etranercept
Fusion protein between Fc-TNF receptor
77
What is adalimumamb
Human IgG1 monoclonal antibody
78
What is infliximab
Chimer human-mouse IgG1 monoclonal antibody
| These antibodies detect TNF
79
What is cetrolizuman
Humanised monovalent Fab-PEG
| PEG (Polyethylene glycol) --> makes them more stable
80
Problems with immunomodulator drugs
We create an immune response to them each time we inject them - they get less effective
81
What is immunopotentiation
Essentially vaccination
82
2 forms of immunopotentiation
Active and passive
83
What is active immunopotentiation
Stimulates development of a protective immune response and immunological memory
84
What material is used in active immunopotentiation
Weakened form of pathogens
Inactivated pathogens
Purified materials (proteins DNA)
Adjuvant - most work via TLR's and PRR's
85
What are adjuvants
Work via TLR's and PRR's
| They stimulate different receptors to create the required response
86
Problems with active immunopotentation
Allergies
Limited usefulness in immunocompromised
Delay in achieving protection
87
What is passive immunopotentation
Transfer of specific high titre antibodies from nor to recipient
Provide immediate but transient protection
88
Problems with passive immunopotentation
Risk of virus transmission
transient protection
Can cause serum sickness - IgG can be pro-inflammatory
89
What are the uses of passive immunopotentation
Hep B - prophylaxis and treatment
| Botulism, VZV (in pregnancy), diphtheria and snake bites
90
What can we use for passive immunopotentiation
```
Pooled human immunoglobulins
Animal sera (antitoxins and antivenins)
```
91
What does GCSF do
Acts on the bone marrow to increase the production of mature neutrophils
92
What does Il-2 do?
Stimulates T cell activation
93
What does alpha interferon treat?
Treats hepatitis C
94
What does beta interferon treat?
Multiple sclerosis
95
What does gamma interferon treat?
Intracellular infections e.g. atypical mycobacteria
Chronic granulomatous disease
IL-12 deficiency
96
What do interferons do?
cause protein synthesis in cells to make the cell less susceptible to viral infection
97
Problems with interferons
Makes you feel awful
98
What are DMARD's
Type of immunosuppressant
| Disease modifying anti rheumatic drugs - contain gold!
99
How do corticosteroids work
```
Decrease neutrophil margination
Reduces proliferation of inflammatory cytokines - as they INHIBIT PHOSPHOLIPASE A2 (this reduces arachidonic acid metabolites production)
Lymphonpenia
Reduced T cell proliferation
Reduced immunoglobulin production
```
100
Side of effects of corticosteroids
Carbohydrate and lipid metabolism affected - can cause diabetes and hyperlipidaemia
Reduced protein synthesis - poor wound healing
Osteoporosis
Glaucoma and cataracts
Psychiatric complications
101
Use of corticosteroids
Autoimmune diseases e.g. vasculitis and RA
Crohns, sarcoid, GCA, lymphoma, allograft rejection (initially)
BUT we don not want people on steroids long term - usually just give as part of an induction therapy
102
How are T cells activated
Interaction with an APC
| The T cell then produces IL-2 to increase transcription factors
103
What does IL-2 stimulate
Other signals such as m-Tor which allows the cell to go into proliferation
104
What do antimetabolites stop
```
Inhibit nucleoside (purine) synthesis
Stops the proliferation of T & B cells
```
Stops DNA synthesis
105
Examples of antimetabolites
```
azathioprine
mycophenolate mofetil (MMF)
```
106
What do Calcineurin inhibitor do
Inhibit initial T cell activation
107
Examples of calcineurin inhibitors
Ciclosprorin A
| Tacrolimus
108
What do M-tor inhibitor do?
Interfere with T cell proliferation
109
Examples of M-tor inhibitors?
Sirolimus
110
What do IL-2 Receptor Monoclonal antibodies do?
Block Il-2 binding as iL-2 stimulates other signals such as m-Tor which causes the T cell to proliferate
111
Examples of IL-2 Receptor Monoclonal antibodies
Basiliximab
| Daclizumab
112
What does ciclosporin A bind to?
Intracellular protein cyclophilin
| Prevent NFAT activation
113
What does tacrolimus bind to?
Intracellular protein FKBP-12
| Prevents NFAT activation
114
How do Calcineurin inhibitors prevent T cell activation?
Prevents NFAT activation
| NFAT normally stimulates cytokines (IL-2 and INF) and gene transcription
115
Is calcineurin reversible or irreversinle
Reversible
Have more of a targeted effect than steroids
Initially used for organ transplatation
116
What is siromilus
A macrolide antibiotic that inhibits T cell proliferation
117
How does sirolmilus (rapamycin) work?
Binds to FKBP-12
Inhibits mammalian target of rapamycin (mTOR)
Inhibits the response to IL-2
Cell cycle arrests at the G1-S phase hence stops proliferation
118
Is sirolmillus reversible?
Yes
119
Where does siromilus stop the T cell cycle?
G1-S phase
120
Side effects of calcineurin and mTOR inhibits?
```
Hypertension
Nephrotxocitiy
Hepatoxicity
Lymphones
Hirsutism
Opportunistic infections
Neurotoxicity
Drug interactions
```
121
What was a main problem of ciclosproin
Nephrotoxicity as commonly used in kidney transplantatinos
122
What Azathioprine (AZA)
Anti-metabolite
Guanine anti-metabolite
Rapidly coverted to 6-mercarptopurine
Inhibits nucleotide (purine) synthesis
123
What is mycophenolate mofetil (MMF)
Anti-metabolite
Non-competitive inhibitor of IMPDH
Prevents production of guanosine triphosphate
124
What is the only T cell targeted immunosuppression that targets B & T cells
Anti-metabolites
As causes impaired DNA production
Prevents early stages of active cell proliferation
But can target any rapidly dividing cell
125
What is methotrexate
Anti-metabolite
| Folate antagonist
126
What is cyclophopsphamide
Cross-links DNA (CYTOTOXIC DRUG)
127
Side effects of T cell suppression deugs
Gastric upset
Bone marrow suppression
Heptatitis
Susceptibility to infection
128
Specific side effect of cyclophosphamide
Cystitis
129
Uses of AZA and MMF
Both antimetabolites
Used for autoimmune diseases and allograft rejection
(Vasculitis, SLE, IBD)
130
Methotrexate uses
Rheumatoid arthritis Vasculitis, GvHD, Polymyositis, PsA
131
Cyclophosphagmide use
Vasculitis (Wegeners, CSS) SLE
132
What are biologic DMARDS
```
Can target specific cell types
E.g. Anti-cytokines
Anti-B cell
Anti -T cell activation
Anti-adhesion molecules
Complement Inhibitiors
```
133
Treatment of Rheumatoid Arthritis
Anti-TNF
Anti-IL-6 (Tocilizumab)
Anti IL-1 (Anakinara, rilonacept, canakinumab)
Rituximab
134
What is Anti-TNF
TNF important for macrophage activation
Use anti-TNF to prevent full activation and treat rheumatoid arthritis
Can also be used in Crohns, psoriasis and ankylosing spondylitis
BUT Susceptible to TB as macrophages not fully primed
135
What does anti IL-6 (toclizumab) do?
Blocks IL-6 receptor
Treats rheumatoid arthritis and AOSD
But may cause problems with control of serum lipids
136
What does anti-IL-1 treat?
AOSD and auth inflammatory responses
137
What is rituximab
A chimeric monoclonal antibody to CD-20 on B cell surface
Only cells in blood express CD-20 not the ones in the bone marrow hence rituximab can target these cells
138
What does rituximab treat?
```
Chemo resistant DLCL
Lymphomas
Leukaemias
Transplant rejections
Autoimmune disorders
```
139
What is adoptive immunotherapy
Bone marrow transplant and stem cell transplant
140
what is adoptive immunotherapy used for
```
Immunodeficiency (SCID)
Lymphomas
Leuaemias
Inherited metabolic disorders (osteoporosis)
Autoimmune diseases
```
141
What is allergen specific immunotherapy
Take something you are allergic to in a controlled manner
Start small and build up dose
Develop a tolerance
142
How does allergen specific immunotherapy work?
Switches immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T regulator cells and tolerance
143
What is omalizumab
Monoclonal antibody against IgE
Treats asthma, urticarial and angiodema
BUT may cause sever systemic anaphylaxis
144
What is mepolizumab
Monoclonal antibody against IL-5
Prevents eosinophil recruitment and activaton
Limited effect on asthma
No clinical efficay in hypereosinophil syndrome
145
What does IL-5 do?
Eosinophilic recruitment and activation
146
What do allergy immunomodulators target
Can use immunosuppressants e.g. steroids but not good for long term use
Allergen specific immunotherapy
Anti-IgE therapy (omalizumab)
Anti IL-5 Monoclonal treatment (mepolizumab)
