Immuno 2 Flashcards
Allergic Disorder
immunological process that results in immediate and reproducible symptoms after exposure to an allergen
o Usually involves an IgE-mediated type 1 hypersensitivity reaction
Sensitisation
detection of specific IgE either by skin prick testing or in vivo blood tests
this shows risk of allergic disorder but does not define allergic disease
How does our immune system differ in detecting unicellular vs multicellular organisms?
We can recognise the structural features of unicellular organisms via their PAMPs by our TLRs etc. on the surface of Th1 and Th17 cells.
Multicellular organisms are more complex and don’t necessarily have the conserved structures that our immune system recognises. Instead they release inflammatory mediators that damage our endothelium and we recognise these instead (Th2 mediated response). [Damaged endothelium releases CKs e.g. TSLP and ILs and these act on Th2, Th9 and ILC2 cells.
What part do Th2, Th9 and ILC2 play in recognising and defending against multicellular organisms?
Multicellular organisms damage our endothelium. This releases CKs such as TSLP and ILs which activate Th2, Th9 and ILC2 cells AND Tfh2. Activated Th2, Th9 and ILC2 cells produce further interleukins which activate eosinophils and basophils which produce mucous and result in the organism’s expulsion.
Activated Tfh2 produces IL 4 and 21 to activate B cells which produces IgE and IgG4.
How do allergens trigger this pathway?
The sensor of the pathogen is the mast cell
The allergen will cause cross-linking of IgE on the mast cells and thus activating it to produce histamine, prostaglandins and leukotrienes
These mediates act on the endothelium causing increased permeability, the smooth muscle (contract) and neurones (to cause an itch)
This response will expel the parasite/allergen or it will be responsible for the symptoms of asthma, eczema and hayfever.
How does oral vs respiratory exposure to an allergen differ?
oral exposure promotes immune tolerance whereas skin and respiratory exposure induces IgE sensitisation
When an allergen is ingested through the oral route, Tregs derived from the GI mucosa will inhibit IgE synthesis to keep the immune system in balance
But skin dendritic cells (Langerhans cells and dermal dendritic cells) promote secretion of Th2 cytokines much more efficiently than other dendritic cell subtypes and suggests that it will prime the Th2 cell response
Age of onset of allergic diseases
Infants o Atopic dermatitis o Food allergy (milk, egg, nuts) Childhood o Asthma (house dustmite, pets) o Allergic rhinitis Adults o Drug allergy o Bee allergy o Oral allergy syndrome o Occupational allergy
Features of an IgE mediated response
- Occurs minutes-3 hours after exposure
- 2 organ systems involved
- Reproducible
- Allergic symptoms can be triggered by co-factors (e.g. exercise, alcohol)
Investigations of allergic disease
o Skin prick (more specific than blood test, discontinue anthistamin for 48 hrs beforehand and rapid.>3mmwheel.)
o Laboratory measurement of allergen-specific IgE concentration and affinity (good for people with eczema, dermatographism (allergen causes hives and itch), pts who can’t come off anthistamines))
The above two only demonstrate sensitisation and not clinical phenotype of allergy.
o Component-resolved diagnostics
(Detects IgE to a single protein component, not entire allergen. Good for crossreactivity testing e.g. peanut/pollen. Wouldn’t be the initial test!!)
o Basophil activation test
o Challenge test (supervised exposure to the antigen) (gold standard)
During Acute Episode
o Evidence of mast cell degranulation
• Serial mast cell tryptase - good for when pt is under anaesthetic and is hypotensive/rash
• Blood and/or urine histamine
Anaphylaxis definition
severe potentially systemic hypersensitivity reaction. Rapid onset, life-threatening airway, breathing and circulatory problems which is usually but not always associated with skin and mucosal changes
Skin is the most frequent organ involved (84%)
Cardiovascular (collapse, syncope, drop in BP)
Resp compromise - SOB, wheeze, stridor
Anaphylactic mimics
ACE inhibitors - Angiodemia, uticaria (can occur at any point in treatment)
CI inhibitor defciency - throat swelling
MI/PE
Carcinoid/Phaeocytochroma - CVS distress
Scromboid poisoning - after the ingestion of soiled fish - histamine poisoning
Systemic Mastocytosis
Anxiety/panic attack, FBO inhalation, severe asthma
IgE mediated food allergy syndromes
- Anaphylaxis (peanut, tree nut, shellfish etc.)
- Food, exercise-induced anaphylaxis (eat wheat/shellfish/celery and if exercise within 4-6 hrs … )
- Delayed food anaphylaxis to beef, lamb, pork (red meat and gelatin. also can be induced by tick bite)
- Oral allergy syndrome (sensitisation to inhalant -> IgE cross reactivity -> stone fruits, nuts and vegetables. NB cooked fruit/nut etc do not cause symptoms. Can be recognised by component testing.
Non Ige mediated?
Mixed IgE and cell mediated - atopic dermatitis
Cell mediated - contact dermatitis
Non-IgE - coealiac
Inflammasome complex
- The pathway is activated by toxins, pathogens and urate crystals
- These act via cryopyrin and ASC to activate procaspase 1
- The activation of procaspase 1 leads to production of IL1 and NFB (which is a transcription factor that regulates the expression of genes including TNF-)
- Pyrin-Marenostrin is a negative regulator of this pathway
FMF
• Autosomal RECESSIVE , Mutation in MEFV gene, which encodes Pyrin-Marenostrin (mainly expressed by neutrophils)
• Defective gene leads to failure to regulate cryopyrin driven activation of neutrophils
PC:
o Periodic fevers lasting 48-96 hours associated with:
• Abdominal pain due to peritonitis
• Chest pain due to pleurisy/pericarditis
• Arthritis
• Rash
Cx: Associated with long-term risk of AA Amyloidosis
• The liver produces serum amyloid A as an acute phase protein
• Serum amyloid A then deposits in the kidneys, liver and spleen
• Deposition in the kidneys is most problematic because it can lead to nephrotic syndrome and renal failure
Mx:
o Colchicine 500 mg BD
• Binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
o If this doesn’t work, then you should try and block the cytokines that are mediating this inflammatory response
• Anakinra - IL1 receptor antagonist
• Etanercept - TNF-alpha inhibitor
APECED
• Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy Syndrome
• Autosomal RECESSIVE
• Defect in autoimmune regulator (AIRE)
o This is a transcription factor that is vital in the development of T cell tolerance in the thymus
o It upregulates the expression of self-antigens by thymic cells which T cells are selected against
o It promotes the apoptosis of auto-reactive T cells
• Defect in AIRE leads to failure of central tolerance and the release of auto-reactive T cells
• This disease can cause multiple autoimmune conditions:
o Hypoparathyroidism
o Addison’s disease
o Hypothyrodism
o Diabetes mellitus
o Vitiligo
o Enteropathy
o NOTE: top two are the most common
• These patients are also predisposed to candidiasis
• This is because they produce antibodies against cytokines (IL17 and IL22) which increases their risk of candidiasis infection
IPEX
• Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome
• Caused by mutations in Foxp3 (Forkhead box p3)
• This is required for the development of Treg cells
• The lack of Treg cells means that these patients fail to negatively regulate T cell responses, leading to autoantibody formation
• These patients end up developing autoimmune diseases:
o Enteropathy
o Diabetes mellitus
o Hypothyroidism
o Dermatitis
ALPS
• Autoimmune lymphoproliferative syndrome
• Due to mutations in the FAS pathway
o E.g. mutations in TNFRSF6 which encodes FAS
o Disease is heterogenous depending on the mutation
• This leads to a defect in apoptosis of lymphocytes
• In turn, this will cause a failure of tolerance (as autoreactive lymphocytes do not die by apoptosis) and there is a failure of lymphocyte homeostasis (you keep producing more and more lymphocytes)
• Clinical Phenotype
o High lymphocyte count
o Large spleen and large lymph nodes
o Autoimmune diseases
• Commonly autoimmune cytopaenias
o Lymphoma
