1
Q
What are theories for allergy?
A
*rxns to parasite-like runs..when there is no parasites
-Genetic: no single gene
-Hygiene hypothesis: more allergic rxns if grow up too hygienic because body can’t swtich from Th2 bias to Th1bias
-Food: less fruits and veggies. Food preservatives affect gut flora.
(those with poor nutrition > immune compromised > less hypersensitvity)
-Occupational/urban lifestyle: more Th2 > mast cells, allergies
-Meds: ex - PPIs decrease acid > incomplete digestion > new rxn to food
2
Q
What are 3 types of immediate hypersensitivity?
A
- IgE mediated
- non IgE mediated
- Non-immunologic (no mast cells, no IgE)
3
Q
What is non-IgE immediate hypersensitivity rxns?
Ex?
A
- direct activation of mast cells without IgE
- no prior exposure needed
- clinically presents similar to the IgE mediated rxns
ex: drug rxns - relaxants, antibiotics, ASA, NSAIDS, radial contrast agents
4
Q
What is non-immunologic immediate hypersensivitiy?
A
- no mast cells, no IgE
- complement-mediated (C3a, C5a)
ex: rxns to blood products, dialysis membranes
5
Q
What is IgE mediated immediate hypersensitivity?
A
- prior exposure
- B cells activated by CD40 and IL4 by Thelper > isotype switch to IgE
- IgE binds mast cells via FCepsilonRI receptors (high affinity)
- IgE sticks around for months
- antigen again > crosslink IgE on mast cells > mast cell degranulation
- similar antigen proteiin can cross react
6
Q
What do mast cells secrete?
Effects? early vs late
A
Immediate: >sneezing, congestion, itchy nose, watery eyes
- histamine
- TNF-alpha
- proteases
- heparin
Minutes: >wheezing, bronchoconstrict
- prostaglandins
- leukotrienes
Hours: >mucus, eosinophils, inflammatory
-cytokines - IL4, IL13
7
Q
Effects of histamine?
A
-from mast cells
-nonlife-threatening
-increase vascular perm, vasodilation, edema, bronchoconstriction, secretions, hives, conjuntivitis, rhinitis
(thick skin, eye, nose, lung)
8
Q
Effects of Platelet Activating Factor?
A
- from mast cells
- life-threatening! > anaphylaxis (can be uni or biphasic. 1-72 hrs)
- hypotension, increase vasc perm, bronchospasm, coagulopathy, impaired heart contraction
- deficiency in PAF acetylhydrolase is seen in fatal peanut allergy
9
Q
Clinical presentation of immediate hypersensitivity?
A
- depends on route, dose, host
- systemic, wheel&flare, hay fever, bronchial asthma, GI for food allergies
10
Q
How do skin tests work?
A
- inject antigen
- look for wheal&flare (bump and red) indicative of IgE adn mast cell rxn.
11
Q
Type of hypersensitivity reactions?
A
I: immediate (ex: IgE mediated)
II: mediated by antibodies binding antigens on membrane, basement, ECM
III: antibodies-antigen complex
IV: delayed-type - mediated by T cells. no antibodies
12
Q
What is hypersensitivity?
A
immune-mediated tissue injury
-allergy + others
13
Q
6 causes for hypersensitivity?
A
- allergic rxn
- infection
- autoimmune disease
- transplant rejection
- super antigen
- chronic inflammation unknown etiolog
14
Q
Type II Hypersensitivity
ex?
A
Ex: autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, Goodpasture’s, acute rheumatic fever
- cytotoxic antibody interact with CELL MEMBRANE component > attact other cells, complements > acute inflammation
- organ specific
15
Q
Type III Hypersensitivity
ex?
A
Ex: animal serum sickness, vasculitis, SLE, Hep B persistent infection, farmer’s lung
- antibody-antigen immune complex > activate complements > inflammation
- systemic
16
Q
Type IV Hypersensitivity
ex?
A
cell-mediated, delayed, T cell!
- not antibodies
- collateral damage from T cell response to:
- underlying infection (TB, HepB)
- autoimmune response
- contact hypersensitivity/allergy (poison ivy)
- chronic inflammatory disease (crohn’s, IBD, sarcoidosis)
17
Q
What can happen with overproduction of TGF-beta?
A
inhibitory cytokine -from chronic inflammation > fibrosis >leukocyte chemotaxis >angiogenesis in cancer: >early: growth inhibition >but late cancer: invasion, metastasis
18
Q
Other causes of hypersensitivity not in the 4 classifications?
ex:
A
*superantigens > dysregulated polyclonal activation of T cells > cytokine storm
ex: Toxic shock syndrome
*inherited autoinflammatory syndromes > excessive cytokine production
ex: Familial Mediterranean fever: pyrin gene mutation > IL1 production > suddent inflamm attacks
»inflammation!
19
Q
What are the immunologically privileged sites?
A
- eyes
- brain
- testes
- uterus
20
Q
Central vs peripheral tolerance?
A
Central:
T - negative and positive selection
B - negative selection
Peripheral:
- Regulatory cytokines: turn off cell (IL10, TGF beta)
- Immunoinhibitory molecules
- Treg
21
Q
Etiologies of autoimmunity? (8)
A
- molecular mimicry
- Treg failure (foxp3 mutation)
- polyclonal activationof B or T cells
- Mutations to AIRE/Foxp3
- Tissue damage > release hidden antigens
- vit D def maybe?
- drugs, toxins
- cancer
22
Q
Describe lupus.
cause, tx
A
- systemic autoimmune disease (type 3 hypersensitivity)
- anti-nuclear antibodies plus others
- immune complex deposition > skin rash, glomerulonephritis, arthritis, vasculitis, endocarditis..
Cause: drugs, early complement def
Tx: immunosuppressive drugs
23
Q
Which drugs can induce SLE?
A
hydralazine
procainamide
24
Q
What is IPEX syndrome?
A
-Foxp3 mutation > decrease Treg > autoimmunity
25
what is scleroderma?
-systemic autoimmune disease; (type 3 hypersensitivity)
-fibrosis of skin adn internal organs due to ANAs
>occlusive vascular disease, renal disease, Raynaud's
26
What is Rheumatoid Arthritis?
(type 3 hypersensitivity)
-inflammation of synovium, cartilage destruction
-RF = autoantibodies reactive to Fc of IgG
> joint deformities, vasculitis, lung issues
27
Describe how Type 1 DM is autoimmune?
-T cells recognize self peptides > kills beta cells of pancreas > no insulin
(mice models)
28
How is autoimmunity linked to cancer?
- anti-cancer immunity is often autoimmune to block inhibitory signals
- mutated tumour antigens > antigen mimicry > break tolerance
- tumours secrete mediators > changing tolerance
29
What is Paraneiplastic anti-NMDA receptor encephlitis?
- strange "exocist" symtoms associated
- ovarian teratoma > autoimmune attack on NMDA receptor > encephalitis
- young girls, early death
- removed tumour, pt is better
30
Therapy for autoimmune diseases?
SLE
Arthritis
MS
- not curative
- SLE: corticosteroids, immunosuppresive drugs; mono antibodies
- Arthritis: TNF-a IL6 blockade; monoantibodies
- MS: IVIG, immunomodulation
31
Factors affecting microbiome?
- No flow
- Skin, mucosal integrity: barrier, mucus, immune cells. opportunity for commensal bacteria to go inside.
- gravity, mobility: keeps bugs on right side of gut
- pH and chemicals (gastric acid, urinary chemicals, tears, saliva...)
32
Ex of altered flow problems > infection?
- tumour > penumonia
- prostatic hypertrophy > UTI
- lyphedema > cellulitis
33
What is a bedsore?
-prolonged pressure > damage > fibrosis > necrosis > opportunity for infecton
34
Describe cdiff:
-anaerobic, gram + bacillus
-antibiotic resistant
-in colon normally, antibiotic use eradicate protective bacteria > alter the normal flora > cdiff proliferate
>> diarrhea, colitis, death
-faecal-oral
35
Describe candida infection:
-yeasts
-normal flora : skin, GI, sputum, genitals
-antibiotic use > alter flora. yeast abnormally goes up.
>> genital yeasts, oral thrush, cadidoemia
36
What is biofilm?
- prosthetic devices, intravascular devices
- introduce infection at time of insertion (usually old bacteria on skin)
- usually: coag -ve staphylococci, staph aureus
1. bacteria adhere to polymer material
2. proliferate > multilayer cell clusers + ECM
- hard to remove. need to take device out
37
What infection is late complement def associated with?
meningococcus
| -but later onset, lower mortality because not responding
38
Neutropaenia vs neutrophil dysfunction
| what are common infections at risk?
neutropaenia:
-low
-more common: inherited, acq, drug-induced, autoimmune, cancer
>>sepsis
dysfunc:
-problems with adhesion, chemotaxis, opsonization, killing
>>infection localized
*common infections with: staphylococci, gram -ve, Aspergillus fungi
39
What is febrile neutropaenia?
| what happens when pts recover from FNP?
- neutropeania syndrome
- most common cause of neutropaenia = chemotherapy
- FEVER. other symptoms subtle.
- causes: sick, lying around, use of antibiotics, lines, catheters > risk of infection from own flora
- granuloctyes decrease to 0.5x10^9/L
- when neutrophils come back > robust immune response risking pulmonary infiltrates and hepatosplenic candidiasis (fungal infections)
40
Pts hospitalized have increased risk of which infections?
| Why is this impt to know?
- cdiff
- UTIs
- bacteraemia (from venous catheters)
- MRSA
- VRE
- surgical site infections
* infection control is impt!
41
Asplenia at risk of what infection?
| infection precautions for these pts?
OPSI: overwhelming post-splenectomy infection
pathogens: s.pneumoniae, N.meningitidis, malaria, baesia
infection prev: vaccination, stay away from dogs, travel...
42
IgG def/dysfunction at risk of what infection?
>s.penumoniae
| >>sinopulmonary, GI, skin infections
43
Cell-mediated immunocompromise at risk of what infection?
ALL
| think HIV: viruses, mycobacteria, fungi, protozoa
44
Hypogammaglobulineamia vs dysgammaglobulinaemia?
-def in ALL Igs (hypo) is more common than def in some (dys)
45
What are common acquired causes of Ig def?
- nephrotic syndrome > renal loss
- GI malabsorption > loss
- CLLeukaemia > lack of production
46
Stem cell transplant: autologous vs allogenneic vs syngeneic?
1. own stem cell
2. matched donor
3. twin
47
What is Graft-vs-host-disease?
-donor lymphocyte attack host
-HLA not matched
-usually via GUT b/c conditioning meds damage gut>LPS of bacteria goes into tissue> inflammation > cells react like normal.
>dendritic cells take the antigen > lymph nodes > now DONOR cells react...to host
48
What is conditioning for transplant?
- meds to wipe immune system for transplant
- chemo w+/out radiation
- only in haematopoetic stem cell transplant
49
What are common viruses that reactive if immunocompromised?
- herpes
- polyoma: BK, JC
- HPV
50
Infection prevention for transplant pts?
1. Prophylaxis: vaccincation, handwash, low contact, meds
2. Pre-emption: early treatment even if no infection yet (ex: antibiotic for CMV)
* minimize exposure
51
What is transplant pt at risk of pre engraft and post engraftment? what is risk based on?
-1 month pre-engraft: like chemo induced NFP
-30-100 days post engraft: risk of viral reactivation, fungal infection.
Risk depends on graft-vs-host-disease
52
Difference bt HSCT and solid organ transplant?
| risk over time for solid organ transplant?
solid organ: no conditioning, no graft-vs-host-disease
-infection risks over time come from own flora, transplanted organ, from procedure/equipment > reactivation opportunitistic infections > community acquired
53
Public health and infection control where?
- overcrowding
- handwashing
- safe practices
- animals and humans
- food
- vaccination
- travel
54
What is anti-HLA antibodies? Why is this important?
-check recipient for presence of anti-HLA against donor
-caused by exposure to antigen: preg, blood transfusion, organ transplant OR cross-link from viral infection
>CROSSmatch test
55
Tolerance in transplantation
| -explain trial
-pt is immunologically competent but unresponsive to antigen of graft
-no T cell response, no donor-specific ab
-normal response to other antigens
TRIAL:
-get mix of donor and recipient lymphocytes in system
-immunosup before transplant > infuse donor bone marrow in addition to transplant > withdraw immunosup meds slowly post.
-mixed results - rejection at different stages. some ok after 2-5 yrs. don't know if never rejection
56
What is HLA? Why is it impt in transplant?
- human leukocyte antigen is a MHC
- on all cells: MHC1
- gene on Chrom 6.
- many loci for it so check match between donor and host. Usually 16 alleles (8 loci)
- even if 0 mismatch, doesn't mean genetic identity b/c there are other HLA loci, and non HLA loci.
- aim for 0 mismatch >longer graft survival, less immunosup needed.
- but diff between 1 and 2..onward is not major.
57
What are Crossmatch Tests?
- detect presence of anti-HLA antibodies against donor in pt before transplanting. test for T and B cell.
1. Complement-Dependent Cytotoxicity (CDC) Test
- add pt serum to donor sample with dye
- if have antibodies: ab binds HLA antigen > fixes complements > MAC = holes, dye goes into cell > lights up = POSITIVE = bad!
2. Flow Cytometry
- more specific and sensitive
- fluorescent tagged ab binds anti-HLA antibody > binds HLA antigen - see fluorescence in Coulter counter
- no complements
- may be different than CDC test
3. Beads
- most specific and sensitive
- use comercial beads with HLA antigens, add host antibodies and check fluorescence through Coulter counter
58
What is Hyperacute Rejection?
-antibody mediated rejection
-anti-HLA class 1 donor-specific ab present at transplant
>endothelial damage, thrombus, necrossi
=immediate graft loss
59
What is antibody-mediated rejection?
- 7 days post transplant
- activation of memory cells > production of anti-HLA ab > complements > reaction
- measure C4d for presence of complement reaction
60
Why is crossmatch test impt?
| when is a neg CDC but positive antiHLA ab?
-positive CDC T cell = absolute NO for transplant
-neg CDC T cell but anti-HLA ab may still be present if:
positive CDC B cell;
positive flow T or B cell;
single antigen bead detect anti-HLA;
risk of immediate rejection is low but memory response still an issue
-not as impt for all organs (ex: liver)
61
What is Panel Reactive Antibody? What is used for?
- use flow cytometry with beads
- test host serum against multiple HLAs
- % indicate having ab against % of HLA antigens
- virtual cross-match
62
What are the 2 signal pathways for T cell activation?
1. donor antigen processed by APC > presented on MHC, binds TCR > signal pathway to make IL2 > #3
2. Costimulation CD receptors bind > IL2 >#3
3. IL2 and CD25 activates mTOR > cell replication
63
What is acute cellular rejection?
-no immediate reaction but a few days after transplant:
antigen present > T CELLs mount a response > killing of cells with HLA antigens
>fibrosis of tissue; lympho infiltrate!
*needs immunosuppressive drugs to avoid this
64
Cyclosporine?
```
calcineurin inhibitor (CnI)> block cytokine production > inhibit T cell activation
-immuno sup
```
65
Tacrolimus?
```
calcineurin inhibitor (CnI)> block cytokine production > inhibit T cell activation
-immuno sup
```
66
Abatacept/Belatacept?
block costimulation > inhibit T cell activation
- immunosup
- fusion protein: Fc of IgG and domain of CTLA4. binds B7 on APC so T cell CD28 cant bind.
67
Basiliximab?
bind IL2> inhibit T cell activation
- immunosup
- monoantibody
- use prophalytic not tx in transplant
68
Azathiprine, mycophenolic acid, sirolimus?
act on mTOR > inhibit proliferation
| -immunosup
69
What is acute humoral rejection?
- activation of B cells against donor HLA antigen > NEW anti-HLA ab post-transplant
- complement deposits in graft!
- can lead to graft rejection but can take yrs
- unsure of med use to treat
70
What are potential rejection issues with transplant?
- hyperacute
- antibody mediated
- acute cellular
- acute humoral
- chronic (B and T)
* rejection doesn't not mean graft loss!
* no acute rejection doesn't mean longer term outcomes
71
What is chronic graft rejection?
- fibrosis!
| - no treatment effective
72
If we block B and T cell, are we safe from rejection?
NO: Monocyte mediated rejection!
73
complications of transplant?
- acute rejection
- chronic loss of fnc
- infection
- recurrence of original disease
- malignancy (bc of disease, immunosuppression)
- htn, hyperlipid, DM > CVD
- weight gain
- acute renal failure
- osteopenia, osteoporosis
- teratogenic toxicity from drugs?
74
What organs are transplanted?
heart, liver, lungs, kidneys, pancreas, bone marrow
QoL: s.intestine, keratolimbal stem cell, abdo wall, arms, hands, larynx, face
75
What are some indications for heart transplant?
- adv failure
| - cardiomyopathy
76
What are some indications for lung transplant?
COPD
pulmonary fibrosis
CF
1ry pulmonary hypertension
77
What are some indications for kidney transplant?
end stage renal disease
78
What are some indications for liver transplant?
decomp cirrhosis
fulminant hepaptic failure
heptocellular carcinoma
79
What are some indications for pancreas transplant?
DM1
80
What are some ex of contraindications for transplant?
- infection
- psychososial - psych, compliance with treatment
- comorbities:
- cancer - depends
- adv heart disease in liver t
- cirrhosis in lung t
- renal in pancreas t
- DM in heart t
* age is not absolute contraindication
81
What is pretransplant eval?
1. pt meet criteria?
2. assess short term risks
3. assess immunologic risk of infection
4. assess long term complications
- assess psychosocial
- screen for cancer
82
What is living donation?
- liver donor
- ex: kidney, partial liver, rarely: pancreas, 1 lung, intestinal
- no wait list
- good health, normal fnc, no med hx
- consent
83
What are criteria for deceased donation?
- after brain death determination
- sometimes after cardiac death
- time is impt!
- cold flush the organ to slow down
84
heterotopic vs orthotopic surgery?
- h: kidney and pancreas put into new location. leave old one in body.
- o: remove old, transplant new.
85
Induction vs maintenance therapy? - drug class?
- Induction: monoclonal/polyclonal antibody. use higher dose
| - maintenance therapy: Calcineurin inhibitor; antiproliferative agent; steroid
86
Monitoring graft post-transplant?
- immunosup drugs
- tests of fnc: creatinine, pft, liver enzymes, amylase
- imaging: ultrasound, echocardio
- biopsy if unsure
87
What is chronic allograft disease?
| what are causes?
-no acute rejection
-gradual fibrosis
-paraenchymal atrophy; obliterative arteriopathy
-3-6 months post transplant
Causes:
-quality of organ
-cold/warm ischemia duration
-antibody-mediated response
-infection
-htn, hlipid
-primary disease
-toxicity: alcohol, smoking, meds
88
Cancer and transplant?
immunosuppression increases risk of cancer
- (esp thymoglobulin)
- greatest risk in viral-mediated cancers: cervix, lympho, kaposi's sarcoma, non-melanoma skin
- more aggressive cancer
- Tx as per standard
- SCREEN as per general population
89
Why acute renal failure post transplant?
- intra-operative hypotension
- sepsis
- meds are nephrotoxic: esp calcineurin inhibitors
- volume loss
- risk of chronic failure and death
90
Why transplant?
- curative treatment option
- no other treatment available
- improve survival
- improve QoL
91
Why use immunosuppressive drugs?
- autoimmune
- transplant
- cancer
92
Corticosteroids for immunosup?
| ex?
-systemic immunosup and anti-inflamm
-bind glucocorticoid receptor and NKkappaB transcription factor
-wide effects on different immune cells
-cheap
-don't use for long term
-side effects: infection, htn, hyperlipid, diabetes, wt gain, skin change, osteopenia, muscle weakness, cataracts poor wound healing, mood changes
ex: prednisone (oral), methylprednisolone (iv)
dexamethasone, hydrocortisone
93
Antiproliferative agents for immunosupp?
| ex?
ex: cyclophosphamide, azathiprine, mycophenolic acid, methotrexate
- purine analougues, block purine synthesis, block pyrimidine syn, block folic acid
- prevent DNA synthesis/proliferation of lymphocytes
- side effect: bone marrow suppression, neutropaenia, toxic to liver, GI, pancreas
94
What are monoclonal antibodies?
-ab against 1 molecule (ex: receptors, cytokines...)
```
side effects: infection, cancer
ex: basiliximab
infliximab
adalimumab
alemtuzumab
rituximab
eculizumab
natalizumab
```
95
Infliximab?
- monoclonal antibody against TNF-alpha
- induce apoptosis of TNFalpha expressing cells
- $
- used in: IBD, spondylitis
96
Thymoglobulin?
- polyclonal antibody (against 40+ antigens)
- depletes T cell
- can act on B cell, dendritic cells
- use: post transplant
- side effect: prolonged lymphopenia
97
IVIG?
intravenous Ig
- inhibit ab, complements, B cells, adhesion molecules
- use: autoimmune disease, transplantation to treat rejection
- pooled Ig from blood donors
- adv: well tolerated, no increase risk of infection/cancer, $
- not evidence based
98
What is a fusion protein?
| ex?
- receptor of target molecule bind to Fc of ab
- competes with molecule from binding receptor
- Fc part allows protein to stay in circulation instead of being metabolized
- "-cept"
- ex: Etanercept
99
Etanercept?
TNFalpha blocker
- fusion protein
use: IBD
100
What are sulfa drugs?
| ex?
ex: Sulfasalazine/5-aminosalicylic acid
- mech of action unknown
- use: IBD
- side effects rare: hepatitis, nephritis, agranulocytosis
101
hydroxychloroquine?
- originally used for malaria, now for lupus, rheumatoid arthritis, Sjogren's syndrome
- unknown mech - maybe impair stimulation of CD4 T cells by MHC
- side effect: macular (eyes) toxicity
102
Which blood type is the universal donor?
what blood can they get? why?
what about plasma transfusion?
- O = universal donor (no antigens)
- only get O because have antibodies against A and B.
- plasma transfusion is opposite = universal recipient
103
Which blood type is the university recipient?
what blood can they get? why?
what about plasma transfusion?
- AB = universal recipient (has A and B antigen) b/c no antibodies against anything
- plasma transfusion is opposite - have no antibodies = universal donor
104
Describe major blood groups - why A?B?
-antigen determined by glycosyltransferase enzyme adding sugars to RBC surface
A: N-acetyl-D-galactosamine
B: D-galactose
105
why is ABO antigen impt to look at during blood transfusion?
| -what do we see on slides?
attack > cytokines > inflammation > hemolysis
| -IgM mediated > agglutination
106
What are non ABO antibodies? why impt
| ex:
- more dangerous than ABO antibodies because less activators > more likely extravascular hemolysis
- first exposure > ab formation. delayed response
- IgG mediated - doesn't agglutinate
- misdiagnosed
- tires fall over time
- relevant in foreign blood exposure: transfusion, preg, transplant, needlestick
ex: *RhD - test babies and mothers
RhC, Kell, Duffy, Kidd - only test matching if high risk
107
What is the Coomb's Test?
| DAT vs IAT?
antiglobulin test
-give ab to antibodies on RBCs
>agglutination = positive
Direct AT: antiIg mixed with RBC > positive = RBC had Ab
Indirect AT: plasma mixed with RBC > positive = plasma had Ab against RBC
108
What is the compatibility testing?
- Check for blood group: ABO, Rh, and antibodies in serum
- screen for alloantibodies against minor blood group antigens by mixing pt plasma with panel RBCs and antiIg
- crossmatch with donor blood sample
109
If we don't have time to check blood, what do we give under emergency?
Give O-RhD-ve RBCs
110
Blood bank solution to
1. clotting
2. spoilage
3. contamination
4. supply
1. small citrate to bind calcium in blood > coaugulation pathway inhibited
2. additives to preserve RBC: glucose, adenine, phosphate
3. aseptic collection, refridgerate
4. good question!
111
What are blood products?
- whole blood
- RBC
- plasma - coag factors in cryoprepitate, Ig, albumin
- platelets - don't need to be ABO compatible
112
What is apheresis?
- collecting specific component of blood
| - run donor blood through device, centrifuge, take adn return remaining into donor
MMMD 1 - QH
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