Immunity - the basics Flashcards
What part of the immune system are inflammasomes found?
Part of the innate immune system
Outline the immune mechanism associated with gout
- multiprotein complexes in the cytosol of cells
- respond to microbes or changes associated with cell injury
- lead to activation of IL-1b and IL-18
- use the sensor NLRP3 found on PCS (macrophages/neutrophils/keratinocytes) that is stimulated by URIC ACID
- urate crystals are recognised by inflammasomes and IL-1 beta production
What is the CD4+ T cell response that IFN-gamma is associated with?
Th1 responses > key cytokines - IFN-gamma + IL-2
Briefly outline the Th1 response
(a) functions
(b) cytokines
(c) clinical application examples
- key functions - production of opsonising antibodies, induction of cellular toxicity, macrophage activation (key feature)
- key cytokines: IL-2, IFN-gamma
- Clinical examples
> help in the eradication of intracellular micro-organisms such as mycobacteria
> promote cytotoxic T cell development + delayed type hypersensitivity reactions
Briefly describe the difference between classic and alternative macrophage activation
- Classically activated macrophages are known to have major roles in host defense against various microbial pathogens, including fungi
- alternatively activated macrophages are instrumental in immune-regulation and wound healing.
Briefly outline the Th2 response
(a) functions
(b) cytokines
(c) clinical application
- functions - Eosinophil + mast cell activation
- Key cytokines – IL-4, IL-5, IL-13
- Clinical applications - immune response against parasitic infections, role in development of allergy + asthma, role in collagen deposition
Dupilumab is used in the treatment of Asthma. What is it and list 2 other conditions it may be used for
- IL-4 receptor antagonist (monoclonal antibody)
- Indications
> asthma - mod-severe eosinophilic or oral glucocorticoid dependent
> atopic dermatitis
> rhinosinusitis, COPD refractory, eosiniphilic esophagitis
Briefly outline the Th17 response
(a) functions
(b) cytokines
(c) clinical application
Key functions: production of pro-inflammatory cytokines + chemokines + neutrophil recruitment
Many cytokines
Clinical application
- Early response to numerous extracellular pathogens (including bacteria + fungi)
- Important role in driving chronic inflammatory responses (e.g. chronic infection, allergy, autoimmunity) + neutrophil predominant asthma
What is the main chronic condition IL-17 antagonists are approved for
psoriasis
What is the broad role of TNF
- pro-inflammatory cytokine - many roles (induces fever, inflammation, cell death)
- thought to have dysregulation in conditions such as Alzeihmers disease, IBD, cancer
List one example of a TNF inhibitor and 3 conditions it can be used for
- etanercept (E), infliximab (I), adalimumab (A), certolizumab pegol (C), and golimumab (G), are biologic agents which are FDA-approved
- Clinical uses - Crohns disease/UC (IBD), Ankylosing spondylitis, psoriasis, uveitis
What are the principal targets of rejection in transplantation?
proteins encoded in the MHC
List the 3 types of transplant rejection
- hyperacute
- acute
- chronic
Briefly outline the features of hyperacute rejection and the mechansims associated with this
- onset: minutes to hours
- pre-existing antibodies of the RECIPIENT match foreign antigens of the donor (e.g. HLA antibodies, ABO isoaggutinnins)
- thrombosis of graft vessels + ischarmic necorosis (immune reaction activates the complement/clotting system) –> endothelial injury + thrombus formation
- Hypersensitivity Type II (completement/antibody mediated)
In a hyperacute rejection, the donors antibodies attack the graft vessels. What might be the source of how these antibodies were generated?
- previous blood transfusions (therefore importance of cross-matching)
- previous transplantations
- multiple pregnancies
*this is more a situation where there is pre-formed donor specific antibody attacking the graft tissue vs. acute rejection where there is acute cellular rejection (T-cell mediated)
Briefly outline the features of acute rejection + immune mechanism
- Type IV hypersensitivity response (T cell mediated, either CD4 or CD8 response)
- antibody mediated responses usually contribute to the vascular components of acute rejection
- classical pathway (complement activation)
***important target in immunosuppressive therapy
What are the signs of transplant rejection?
- fever
- increase SCr (serum creatinine)
- fever
- oliguria
- graft pain
List 2 drugs commonly used for transplants
- MMF
- corticosteroids
- Calcunerurin inhibitors
What is the mechanism of tacrolimus?
- MOA – blockage of protein phosphatase calcinerurin
- This enzyme is required to allow translocation of the transcription factor NFAT to the nucleus; blocking its activity inhibits the transcription of cytokine genes in the T cells
What is the mechanism of action of MMF?
What is the mechanism of corticoteroids in immunosupression with relevance to transplants?
Briefly describe the mechanism of chronic rejection
- develops over months to years
- characterised by gradual narrowing of blood vessels (graft aretriosclerosis), fibrosis of graft
- mechanism: T cells that react against graft alloantigens and secreter cytokines; A foreign (graft) MHC ‘looks like’ a self MHC with an antigen
What is graft vs host disease ?
Donor T cells proliferate and attack recipient tissue - most common in bone marrow transplant
In a few sentences, describe the mechanism of types of hypersensitivity
In terms of urticaria, what are the three main mechanisms?
- IgE mediated
- direct mast cell activation (without IgE)
- pseudoallergic/pharmacologic
List the types of causes of urticaria and the mechanism
- IgE mediated - many causes (e.g. infection, foods, transfusion medications)
- Non-IgE mediated - e.g. vancomyin, contrast, opioids
- NSAIDs - abnormalities in arachidonic metabolism (usually seen in NSAIDs that block COX1)
List two common medications that block COX-1
- iboprufen
- paracetamol (weak COX-1 inhibitor)
What is the mechanism of allergy associated abnormality in arachnoid acid metabolism?
- Cyclooxygenase inhibition blocks the conversion of
arachidonic acid to prostaglandins and
thromboxane resulting in a therapeutic
anti-inflammatory effect. - The resultant increase in free arachidonic acid can be
alternatively converted into cysteinyl
leukotrienes. - These leukotrienes may
result in clinical features of allergy such as
angioedema, urticaria and bronchospasm
What is the test used to distinguish immune vs. non-immune causes of haemolytic anaemia?
DAT test - the DAT is used to determine whether patient RBCs are coated with IgG, complement, or both.
What are the key Ix of haemolytic anaemia and would they be high or low?
- LDH (HIGH)
> because released from RBCs during the haemolytic process - bilirubin (unconj - HIGH)
> product of heme recycling *unconj form - haptoglobin (LOW)
> mops up free Hb - reticulocyte count (HIGH due to haemolysis)
Note LDH, haptoglobin, unconj bilirubin are all non-specific
Describe the pathogenesis of a type 1 hypersensitivity reaction
- two broad steps - sensitsation then effect (latter = response)
- activation of Th2 response –> IL4,5,13 00 –> B cells switch to IgE –> secrete as plasma cells –> antibodies bind to mast cells and cross link releasing substances
*the IgE testing tells you about a sensitisation, NOT an allergy
What are the two in vivo methods of allergy testing and which is better (in terms of sensitivity and specificity?
*these methods allow detetection of sensitisation
- skin prick - more specific and sensitive
- specific IgE testing (blood test) IS NOT diagnostic (only assesses sensitisation)
What is the difference between temporary and sustained tolerance?
- temporary - small doses until target dose achieved (temporary, requires regular use) –> common approach with medication
*given at 15 min intervals - sustained aka immunotherapy - give increasing doses –> evoke a sustained response
Why is serum tryptase used and what does it measure?
- can support diagnosis of anaphylaxis (sensitive but not specific)
- need to repeat to ensure return to baseline range
- marker of mast cell degranulation
What is the most common cause of food dependent, excercise induced anaphylaxis?
omega-5-gliadin
What is the difference between a type A and B adverse drug reaction?
- Type A - predictable and dose dependent
- Type B - unrpredictable, immune medicated
What is the difference between immediate vs. non-immediate drug allergies?
immediate - IgE mediated associated with urticaria, angiooedema, anaphylaxis
non-immediate - T cells, DELAYED, organ involvement, systemic features
Explain the different type of testing used for Type 1 vs Type 4 hypersensitivity reactions
type 1 - skin prick, intradermal testing
type 4 - IDT, patch tests
What is the likely mechanism of penicillin cross reactivity?
side chain mediated - usually patients will tolerate the medication (e.g. cephlasporin, when you have a penicillin allergy) because its a side chain (and therefore cross reactivity thought to be low)
