hypersensivity and allergy

Question 1

what hypersensitivity reaction is considered an allergy?

Answer 1

hypersensitivity 1

Question 2

outline the steps involved in a hypersensitivity 1 reaction.

Answer 2

• sensitisation - priming of the immune system
• mast cell granulation
• leading to systemic effects around the body

Question 3

explain the full process of hypersensitivity 1 reaction, including sensitisation and mast cell granulation.

Answer 3

sensitisation:
- allergen/antigen enters body
- it gets taken up and presented on the surface (MHC-II) of APC
- presented to naive T-cells skewing it to develop into Th2 cells
- the Th2 cells release IL-4 and IL-13
- this activates B-cells to make IgE specific to the antigen/allergen (the B cell will already be making some random antibodies so it will enter gene recombination to make IgE)
- IgE will bind to IgE receptors on basophils and mast cells (FceRI receptor)

mast cell degranulation
- IgE is now presented on the mast cells
- when the antigen/allergen binds to the IgE, it causes the IgE to crosslink
- this results in a chemical cascade within the mast cell/basophill
this causes the degranulation of the cell and the symphesis of new cytokines - Ca2+ and arachodonic acid is used in this
- the cytokines are released from the cell via vesicles
- this then leads to systemic differences in the body and organs

Question 4

what are the cytokines produced by the mast cells?

Answer 4

• histamines
• tryptase
• chymotrypsin
• carboxypeptidase A
• leukotrines
• prostoglandins
• interleukins
• PAF
  TNFa

Question 5

what are the systemic effects which the cytokines produced by mast cells in the hypersensitivity reaction?

Answer 5

• increased vasodilation - redness
• increased vessel leakiness - swelling / oedema
• stimulation of nerve endings - itching
• smooth muscle contraction in airway passage - wheezing
• bronchospasm
• diarrhoea

Question 6

is an allergy response normal?

Answer 6

no, they mistake normal, unharmful antigens for antigens of harmful and invading microbes, and overreact creating potentially fatal states, in responce to a harmless substance in attempts to prevent it from causing damage in the body

Question 7

what effects does histamine have on the body, and what symptoms can arise?

Answer 7

Itching: Activates nerve endings via H1 receptors.

Swelling and redness: Increases vascular permeability, allowing fluid and immune cells to enter tissues.

Nasal congestion and mucus production: Stimulates glands and inflames mucosal tissue.

skin itching: activation of nerve endings

wheezing: bronchoconstriction

Question 8

what cells store and release histamine?

Answer 8

basophills and mast cells
can have some others but these 2 predominantly

Question 9

where is tryptase produced and secreted and whats its structure?

Answer 9

• mast cells
• tetromer
• it is inactive within the cell but once it is released outside the cell, the difference in PH causes it to become activated

Question 10

what are the functions of tryptase in the body and how can this be used in clinic?

Answer 10

• breaks down extracellular matrix, making tissues more permeable
• same functions as histamine and stimulates the release of histamines
• levels spike during allergy - this can be used in clinic to detect anaphalaxis

Question 11

outline the basic structure of IgE.

Answer 11

• 2 light chains and 2 heavy chains help together by a disulphide bond
• has a variable region and a constant region
  variable region binds to antigen
  constant region binds to Fc3RI
• monomer
• consists of 4 constant regions

Question 12

what determines the function of the IgE?

Answer 12

• its function determines its class
• its class is determined by the structure of the heavy chain

Question 13

what makes IgE a more flexible confirmation when it binds to its receptor?

Answer 13

Ce2 domain replaces the hinge structure which is found in other structures

Question 14

what function does IgE have from being heavily glycolysated and why is it heavy?

Answer 14

• contains 7 N-linked glycolysations on the heavy chain
• for binding to the high affinity receptor
• because of this it is heavy at 190Dka

Question 15

what is the half life of IgE and how does it differ when its bound?

Answer 15

• unbound - 2 days
• bound to FceRI (receptor on mast cell) its 9-12 days

Question 16

why does IgE not play a role in defence against bacterial infections?

Answer 16

• it doesnt activate the compliment cascade
• doesnt act as an opopsin

Question 17

what is class switch recombination?

Answer 17

• process by which proliferating B cells rearrange the constant region genes in the Ig heavy chain to express one type of Ig to another eg IgM to IgE
• this produces an antibody with different effector properties without altering antigen specificity

Question 18

what are the symptoms of an allergic reaction?

Answer 18

• trouble breathing
• itching
• sneezing
• runny nose
• headache
• red / watery eyes
• hives / rash

can have a systemic overwhelm to the allergy called anaphalaxis

Question 19

what is the late phase response to allergy?

Answer 19

• there are 2 peak in allergen responce
• the first is after the mast cells release a cytokine storm
• the second is because immune cells are recruited and release inflammatory mediators by releasing prostoglandins and cytokines

Question 20

thinking of a triangle, what are the conditions which must be elict for a type.1 hypersensitivity reaction?

Answer 20

• host
• environemental
• allergen

Question 21

why are certain proteins allergenic? (molecular level)

Answer 21

while there are no proven conclusions, certain theorys state:
- high protease activity (Der P1)
- surface features on the protein (Ves V 5)
- glycolysation pattern of protein (Ara h1)

Question 22

describe how it is thought that Der P1 leads to an allergic response of specific antigens.

Answer 22

• main protein in house dust mite
• it can escape protein blockages eg surfacant
• breaks down tight junctions between epithelial cells to fascilitate its entry deep into tissues
• reduces interaction between the APC and the naive T cell so IL-12 isnt produced
• this causes for less Th1 to be produced and more Th2
• Th2 is the T-cell used in allergy, meaning the allergic response is further supported
  Th2 cells also release more IL-4 and less IFgamma
• this disrupts the negative feedback of IgE synthesis so more and more are made
• also induces IgE-independant granulation

Question 23

explain how it is thought that the protein structure of the antigen causes an allergy response.

Answer 23

• no clear abnormaility however it is thought that:
• seem to have more hydrophobic areas
• alpha-beta motifs in tertiary structure
  specific glycosylation patterns could mimic parasites

Question 24

what are the host factors of allergy responces?

Answer 24

• if parents have an allergy
• gene mutations can cause a predisposition to the Th2 skew

Question 25

name the 2 theories of why as a generation we have developed allergies to unharmful proteins.

Answer 25

- hygeine hypothesis - immune regulation theory

Question 26

explain the hygiene hypothesis of hypersensitivity 1 reactions.

Answer 26

- when newborns are born, they are born with it skewed towards Th2 and when they are released to bacteria and infections, the skew balances - because our environemnt is cleaner and cleaner, we are exposed to less bacteria, therefore meaning the skew never balances

Question 27

explain the immune regulation theory of hypersensitivity 1 reactions

Answer 27

- regulatory T cells dampen inflammatory responses after they have been amplified during an invade - when regulatory T cells are broken, they fail to dampen the responce

Question 28

what is the point of hypersensitivity 1 reactions?

Answer 28

- initiate responses to physically eject the antigen from the body - eg sneezing

Question 29

outline what a pseudo-type 1 reaction is and what it can be caused by.

Answer 29

a mimicked allergic responce where granulocytes are released without the presence of IgE causes: - drugs such as opioids - psychological stress - nutritional status - auto-immune disease - concurrent infection - physical stress

Question 30

what are some treatment options for allergy?

Answer 30

- adrenaline / epinephrine - antihistamines - corticosteroids - fluid resuscitation - Allergen avoidance - Topical corticosteroids - Antihistamines - desensitisation / allergen-specific immunotherapy - omalizumb

Question 31

outline what is desensitisation / allergen-specific immunotherapy?

Answer 31

Desensitisation or allergen-specific immunotherapy A process whereby the immune system is exposed to gradually increasing doses of allergen in order to develop tolerance Administered via subcutaneous or sublingual route Used in allergic rhinitis, venom allergy and drug allergies predominantly

Question 32

outline what is omalizumab.

Answer 32

Omalizumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to human immunoglobulin E (IgE) and inhibits its binding to the high-affinity IgE receptor (FcεRI) - this is however a long process - 3 years - there is a risk of anaphalaxis

Question 33

describe common diseases associated with allergy and how allergy affects health

Answer 33

allergic rhinitis (hay fever): - allergy to airborne allergens like dust mites, pollen, mold impact on health: - quality of life - sleep, work - sleep disturbances - risk factor for developing asthma asthma: - triggered by allergens like pollen, dust mites, dung, leading to airway inflammation and constriction impact on health: - wheezing, shortness of breath, coughing, chest tightness, can stop breathing - physical limitations - exersize eczema: - results from allergens like food, dust mites or pet danger impact on health: - itching and discomfort - infection risk - social impact food allergies: impact on health: - anaphalactic shock - dietary limitations - may lead to nutrient imbalance - psychological impact - fear and stress hives: - skin reacts to allergens, medications, or physical stress affect on health: - itching and discomfort - chronic hives - social embarrassment

Question 34

outline and contrast all the hypersensitivity types and examples of each.

Answer 34

hypersensitivity 1: - IgE - allergy - allergen specific IgE bind to mast cells, causing degranulation and cytokine release - anaphalaxis, food allergy, dust mites hypersensitivity 2: - IgG IgM mistakenly target antigens on the bodys own cells leading to damage through complement activation and MAC lysis, oponization and phagocytosis - red blood cell destruction after incorrect blood type transfusion hypersensitivity type 3: - antigen-antibody (IgG or IgM) complexes that depsit in tissues, leading to inflammation and tissue damage - this activates the complimentary system which attracts inflammatory cells which release enzymes and reactive oxygen that damages surrounding tissue - serum sickness and arthiritis type 4: - APCs activate Th1 - cytotoxic T-cells which recruit macrophages and cytokines which attracts immune cells such as macrophages which leads to localised tissue injury - type 1 diabetes - CD8 cells destroy beta cells in pancreas - arthiritis, Th17 cells drive chronic inflammation and joint destruction

Question 35

outline the differences between Th1 Th2 CD4+ and CD8+ cells.

Answer 35

- Th1 and Th2 are subsets of CD4+ cells - CD4+ = T helper - CD8+ = cytoxic T - Th1 - cell mediated immunity - Th2 - humoral immunity

Question 36

name the treatment and ADRs for each hypersensitivity reaction.

Answer 36

1: Treatment: Includes adrenaline (epinephrine) for anaphylaxis, antihistamines (e.g., cetirizine), and corticosteroids to reduce inflammation. ADRs: Drugs that can cause Type I hypersensitivity include antibiotics (e.g., penicillins, sulfonamides) and contrast agents. 2: Treatment: Discontinuation of the offending drug, use of immunosuppressants (e.g., corticosteroids), and sometimes plasmapheresis. ADRs: Drugs like penicillin, cephalosporins, and methyldopa can cause Type II hypersensitivity by binding to cell surfaces and eliciting an immune response. 3: Treatment: Corticosteroids to control inflammation, and avoiding further exposure to the antigen. ADRs: Drugs like antitoxins, vaccines, and some monoclonal antibodies (e.g., infliximab) may cause immune complex formation and Type III hypersensitivity. 4: Treatment: Topical or systemic corticosteroids (e.g., hydrocortisone or prednisolone) to suppress the immune response. ADRs: Drugs like sulfonamides and anticonvulsants (e.g., carbamazepine) can cause delayed hypersensitivity reactions, including severe conditions like Stevens-Johnson syndrome.