Failures of the immune system

Question 1

What are the main primary immunodeficiencies?

Answer 1

Severe combined immunodeficiency (SCID), X-linked agammaglobulinemia and DiGeorge syndrome

Question 2

What are the two main types of SCID and what is the difference between them?

Answer 2

 X-linked SCID-have a loss of function or absence of T cells, which means that the T cells can’t help the B cells
 RAG-type SCID can also result in kids being born with no B cells or T cells

Question 3

Why does RAG-type SCID occur?

Answer 3

• This happens when there is a defect in the VDJ rearrangement genes(such as RAG1 or RAG2 or a gene called artemis)
  o This is already a process designed to be filled with errors and base insertions/deletions

Question 4

What happens in X-linked agammaglobulinemia and why?

Answer 4

o In X-linked agammaglobulinemia (XLA), the development of B cells is impaired
 BTK is an X linked gene so they can’t make B cells when they lack this BTK gene-> can’t make any antibodies
 Pre-B receptor is assembled by a successful cell (Checkpoint)-> this receptor is a structure created to identify successful cells that have made good rearrangements and allows them to expand. Pre-B receptor has heavy chains and surrogate light chains
* This expansion requires signalling through an enzyme called Bruton’s tyrosine kinase (BTK)

Question 5

What is DiGeorge syndrome?

Answer 5

• DiGeorge syndrome- epithelial defect where the thymus and a few other structures do not develop, then the person is born with no T cells

Question 6

What does IL-7 do during T cell development?

Answer 6

• T cell development from the lymphoid progenitor requires the cytokine IL-7 within the thymus to signal through the IL-7 receptor on the surface of a developing progenitor-> this signalling is what drives differentiation into T cells

Question 7

How is B cell and T cell receptor diversity generated?

Answer 7

B cell and T cell receptor diversity is generated by V(D)J recombination.
o The diversity derives from different combinations of V, D, and J gene segments, as well as variable intervening nucleotides that join the gene segments.
* There are two chains of the T cell receptor (α and β chains), just as there are two chains of the B cell receptor (heavy chain and light chain). This also contributes to receptor diversity.

Question 8

What are the 3 major mechanisms of immunological tolerance? Describe

Answer 8

o T cell tolerance is mediated by clonal deletion of self-reactive cells
 The cells that are self-reactive are tested and a signal is given to self-reactive cells so that they die by apoptosis
 This is in the thymus
o T and B cell peripheral tolerance is mediated in part by regulatory T cells that suppress self-reactive cells
o B cell central tolerance is mediated mainly by receptor editing
 This occurs in the bone marrow

Question 9

What are the two main mechanisms of autoimmune diseases?

Answer 9

o Defects caused by antibodies that block the normal function of a host protein or form immune complexes that impair organ function
o Defects caused by T cells that contribute to autoimmune disease by recognizing self antigens

Question 10

What is myasthenia gravis and how does it work? Include symptoms

Answer 10

o Antibodies block the normal function of a host protein, as in myasthenia gravis
 Myasthenia gravis is characterised by drooping eyelids
* Normally, acetylcholine produced by the neuron binds to the ACh receptor on the muscle cell
* Myasthenia gravis makes an autoimmune antibody that blocks the ACh receptor-> therefore no signal to the muscles

Question 11

What is lupus and how does it work? Include symptoms

Answer 11

o Antibodies form immune complexes that impair organ function, as in lupus
 Lupus can manifest into kidney disease because of an inflamed glomerulus
* The inflammation happens because the patient has made auto antibodies against DNA and chromatin components-> this forms immune complexes which also contain complement proteins-> they deposit into small blood vessels
o In skin they cause a rash, in joints arthritis and in the kidney they cause glomerular nephritis
 Patients get a rash called malar erythema over the cheeks

Question 12

What is type 1 diabetes and what is it caused by

Answer 12

• T cells contribute to autoimmune disease by recognizing self antigens, migrating into organs and tissues and causing inflammation
  o Type 1 diabetes (T1D) is caused by T cells that attack cells in the pancreas
   Inflammation in the pancreas-> inflammation prevents normal function of beta cells in the islets which results in reduced insulin production
• This is because immune cells damage beta cells

Question 13

What common immune agents do all allergies involve?

Answer 13

o IgE, mast cells, eosinophils and allergens (common environmental antigens)

Question 14

What are common allergens?

Answer 14

o Pollen
o Nuts
o Dairy products
o Shellfish
o Cats/dogs/animals
o Insect venom (bee sting venoms)
o Drugs

Question 15

What are the steps to allergies?

Answer 15

• For allergens:
  o There is a first step of sensitization characterised by antibodies class switching to IgEl these antibodies then bind to mast cells
  o In the second step, re-exposure to allergen leads to mast cell activation. Mast cell degranulation can cause rashes, airway obstruction, GI symptoms and severe systemic symptoms

Question 16

Describe what the first step of allergies involves and where it happens

Answer 16

o There is a first step of sensitization characterised by antibodies class switching to IgEl these antibodies then bind to mast cells
 Involves first exposure to allergen protein
 Happens in the secondary lymphoid organs such as lymph node
 Both B cell and T cell component
* In the B cell component, helper T cell instructs the B cell to change its antibody to the IgE isotype-> leads to plasma and memory B cells make IgE
o IgE made binds to mast cells in the body with high affinity-> mast cell is sensitized
* Production of Th2 cells that make IL-4 and IL-5
o IL-5 cause growth and activation of eosinophils

Question 17

Describe the second step of allergies

Answer 17

o In the second step, re-exposure to allergen leads to mast cell activation. Mast cell degranulation can cause rashes, airway obstruction, GI symptoms and severe systemic symptoms
 Allergen binds to IgE-> causes movement of Fc receptors in the mast cell membrane called cross-linking which generates signals in mast cells that cause it to release granules and lipid-inflammatory mediators and cytokines
 Eosenophil releases its granules which include proteases that can be very destructive to tissue -> immediate sensitivity reaction
* Leads to hives, congestion/difficulty breathing, gastrointestinal symptoms such as diarrhoea, abdominal pain, nausea and vomiting, or bronchoconstriction, or anaphylaxis

Question 18

What is the role of mast cell granules in allergy?

Answer 18

• Granules contain amines such as histamines which bind to the blood vessels and increase their leakiness-> causes swelling of tissue

Question 19

What are examples of lipid-inflammatory mediators in allergy?

Answer 19

• Lipid-inflammatory mediators include prostaglandins and leukotrienes

Question 20

How do cytokines contribute to allergy?

Answer 20

• Cytokines include TNF
  o Binds to blood vessel and also increases leakiness in blood vessel-> causes swelling of tissue
• Vascular leak also promotes neutrophils coming out into the tissue

Question 21

What is involved in allergy testing?

Answer 21

• Allergy testing:
  o Put allergens on skin for few minutes to contact mast cells-> if mast cells are sensitive, they’ll release histamines which will fade in a few hours
   Don’t penetrate the skin deeply
   Histamine is put on as a positive response and saline as a negative response
   Will see results in 20 minutes
  o Reaction is usually tingles

Question 22

What are asthma symptoms?

Answer 22

o Asthma symptoms:
 Chronic cough
 Runny nose-hayfever
 Inflammation of lungs/constricted airways-difficulty in breathing
 Wheezing
 Chest tightness
 Triggered by dust and pollens and animals

Question 23

What is involved in a allergy physical exam?

Answer 23

• Physical exam:
  o Post-nasal drip
  o Nose- looks for evidence of swelling and blueish discoloration
  o Look for inflammation of ears, eyelids and throats
  o Looks for lumps/bumps in neck and groin
  o Sleep: ask if there’s coughing/shortness of breath that wakes them up
  o Checks for lung function and heart function

Question 24

What is the hygiene hypothesis for allergies?

Answer 24

o Hygiene hypothesis-
 When the immune system is tuned to presence of microorganisms of bacteria etc. in the environment it can sort out what is foreign AND dangerous or what is foreign but not dangerous
 Why allergies are on the rise in first country nations
 Early avoidance is a set up of developing allergies

Question 25

What is the mechanisms of allergy and what symptoms can it cause?

Answer 25

• Mechanisms of allergy
  o Allergies arise because the immune system is inappropriately responding with an inflammatory response to an otherwise harmless antigen
  o Basic mechanism-> B cells produce IgE-> IgE docks on surface of mast cell-> when antigen re-enters the body, it cross links to IgE on the mast cell-> induces mast cell activation and brings about symptom of allergic reaction
  o Activation of mast cells in skin can cause atopic dermatitis and cause hives
  o In respiratory systems it can cause allergies in lower and upper airways
  o Mast cells in gut mucosa can bring about food allergies

Question 26

How does allergy tolerance work?

Answer 26

• Mechanisms of tolerance
  o Chronic exposure can cause tolerance
  o Has to do with competing antibody production of IgG4 against the allergen-> antibody will bind to surface of mast cell and inhibit the mast cell: competes with IgE

Question 27

What are common allergy treatments?

Answer 27

• Treatments:
  o Staying away from the allergen-> environmental measures
  o Blocking mediators-> pharmacological agents such as antihistamines
  o Immunotherapy-> blocking mast cell activation