Hypersensitivities

Question 1

what are the 3 ways acute inflammation can manifest?

Answer 1

1) local
- characterized by swelling, redness, heat, pain
2) systemic
- characterized by fever, sleepiness, and production of acute phase proteins
3) hypersensitivity
- inappropriate specific immunological responses mediate by antibodies and t-cells
- immune response to an antigen poses little to no threat

Question 2

what is hypersensitivity?

Answer 2

an exaggerated or inappropriate immune response to an antigen that normally wouldn’t elicit such a reaction

Question 3

immediate vs. delayed-type hypersensitivity

Answer 3

immediate hypersensitivity:
- reactions that trigger immediately upon exposure to the antigen (i.e 30 secs)
- antibody mediated

delayed-type hypersensitivity:
- reactions that take 1-3 days to become evident (i.e could be exposed on weekend but not reacting till midweek)
- t-cell mediated

*delayed type is hard to diagnose due to the delayed response

Question 4

what are the 4 type of hypersensitivities?

Answer 4

• type 1
• type 2
• type 3
• type 4

Question 5

what is the mechanism of action for type 1 hypersensitivites?

Answer 5

• an allergen binds to IgE antibodies that are bound to the surface of mast cells and basophils.
• the mast cells or basophil are are activated and release inflammatory mediators (i.e histamine)

example: respiratory allergens and food allergens

Question 6

what is the mechanism of action for type 2 hypersensitivities?

Answer 6

IgG or IgM antibodies bind to the surface of the host cell leading to its destruction through:
1) antibody-dependent cellular cytotoxicity (ADCC)
2) complement activation

example: blood transfusion reactions, hemolytic anemia in newborns

Question 7

what is the mechanism of action for type 3 hypersensitivities?

Answer 7

• antigen-antibody complexes accumulate in the host cells or tissues triggering complement and granulocyte activation

example: stem cell transfusions (transfusions of serum containing non-self proteins)

Question 8

what is the mechanism of action for type 4 hypersensitivities?

Answer 8

• results from excessive and inapporopriate t-cell activation

example: poison ivy

Question 9

what is an allergic reaction?

Answer 9

an immunological reaction to an antigen that causes damage to the host instead of a protective response
–> instead of removing it, it shuts body down

Question 10

what is an allergen?

Answer 10

an antigen that triggers a hypersensitivity response

Question 11

allergy vs autoimmunity

Answer 11

• allergies occur when the immune system overreacts to a harmless, non-self substance (i.e pollen)
• in autoimmunity, the immune system attacks the bodies own cells as if they were foreign

Question 12

what triggers a type I hypersensitivity reaction?

Answer 12

• many allergens can trigger type I hypersensitivity (pollen, dust mites, foods, animal dander)
• allergens are commonly highly soluble proteins or glycoproteins containing multiple epitopes

Question 13

what are features common to allergens?

Answer 13

1) contain protease (enzymes the break down proteins) = can trigger immune responses
2) many allergens are PAMPS and bind PRRs = trigger innate immune responses
3) enter the host via mucosal surfaces (through mouth, eyes, nose) at low concentrations = trigger Th2 response and class switching to IgE (which binds to mast cells)

Question 14

what is the pathway of type I hypersensitivities?

Answer 14

1) an APC (macrophage) picks up an allergen from mucosal surface and presents to t-cells in lymph node
2) the allergen activates a CD4+ t-cell and is polarized int a Th2 helper t-cell
3) The Th2 cell interacts with a B-cell that has a matching BCR specific for the allergen = activates the b-cell with effector cytokines (t-cell dependent b-cell activation)
4) the activated b-cell undergoes class switching to produce IgE antibodies
5) IgE is released and binds to mast cells (in tissues) and basophils (in blood) through high affinity receptor
6) upon re-exposure to the same allergen, the allergen cross-links IgE to mast cells and basophils = trigger massive degranulation of histamine, heparin and proteases from the mast cell

Question 15

what is mast cell degranulation?

Answer 15

the process by which mast cells release inflammatory substances and proteases into the body, causing an allergic reaction

Question 16

how does the immune system respond during the first and second exposures to an allergen?

Answer 16

1) first exposure = sensitization
- the initiall exposure to an allergen triggers the production of IgE antibodies specific to the allergen
- these IgE antibodies bind to mast cells and basophils to sensitize them for future exposures
2) second exposure = allergic reaction
- upon re-exposure to the same allergen, the allergen binds to the IgE antibodies already bound to the mast-cell
- this causes mast-cell degranulation

Question 17

what is mast-cell degranulation?

Answer 17

the process by which mast cells release inflammatory substances and proteases into the body when activated

Question 18

effects of degranulation

Answer 18

active mediators in granule can trigger:
- inflammation (redness, swelling)
- acute, immediate changes to tissue function (i.e bronchodilation)
- long term changes to tissue structure and remodelling (i.e air way thickening)

Question 19

how does chronic allergen exposure impact how we interact with the environment?

Answer 19

continuous exposure to allergens = persistent inflammation in affected tissues = long-term health issues.
–> individuals may need to avoid or minimize exposure to allergen to manage symptoms (i.e staying inside during pollen season)

Question 20

what is local hypersensitivity?

Answer 20

an allergic reaction that is limited to a specific part of the body, often at epithelial surfaces (skin, mucosal membranes)

examples: hay fever, asthma, eczema, hives

• antihistamines can be an effective treatment for treating some localized hypersensitivities (i.e claritin, reactin)

Question 21

what is atopy?

Answer 21

the genetic tendency to develop allergic diseases
- affects more than 20% of the population and is increasing
- even without a first sensitization event, individuals with atopy can still develop allergic reactions

Question 22

what is systemic hypersensitivity?

Answer 22

• known as anaphylaxis, a potentially fatal allergic reaction that occurs when allergen enters the bloodstream or absorbed through the gut or skin
• leads to systemic immune response
• causes rapid and systemic degranulation of mast cells causing vasodilation and smooth muscle contraction = suffocation, pulmonary adema and loss of consciousness

–> epinephrine (epipen) counteracts granulocyte mediators = smooth muscle relax, prevent vascular collapse

Question 23

what is the hygiene hypothesis?

Answer 23

the idea increased frequency of infections contributes to a decrease in autoimmune and allergic diseases
- low exposure to microorganisms is associated with increased hypersensitivity
–> for example kids need to be exposed to germs in order to develop healthy immune systems

Question 24

how are allergies diagnosed?

Answer 24

1) skin test:
- the allergen is injected under the skin, stimulating local mast cell degranulation
- Wheal and flare reaction observed within 30 minutes indicates an allergic response.
2) blood test (ELISA)
- Detects specific IgE antibodies in the blood to identify allergies

Question 25

what treatment is available for allergies?

Answer 25

there is no real treatment to completely eliminate allergies

1) identify and avoid the allergen
2) immunotherapy = therapeutic anti-IgE antibody
3) antihistamines = bind to histamine receptor and block downstream effects
4) adrenalin = reverse systemic anaphylaxis
5) anti-inflammatory drugs

Question 26

how does an allergic reaction to peanuts develop?

Answer 26

the intial step towards an allergy is an allergen crossing an epithelial barrier, often through skin (i.e touch peanut butter)

1) sensitization (first exposure @ skin)
- the epithelial barrier loses integrity, allowing peanut allergens to enter.
- epithelial cells release cytokines: TSLP, IL-33, and IL-25.
- these cytokines activate dendritic cells (DCs), which take up the peanut allergens, process them, and present them on MHC Class II molecules.
- the dendritic cells migrate to secondary lymphoid tissue (e.g., lymph nodes), where they present peanut allergen peptides to CD4+ T cells.
- the dendritic cells also release polarizing cytokines to cause differentiation of CD4+ T cells into TH2 cells.
- TH2 cells then activate B cells with matching BCRs, leading to the production of IgE antibodies through class switching

2) second exposure (ingestion)
- intestinal epithelial cells response to allergen by producing TSLP, IL-25 and IL-33
- these cytokines activate dendritic cells, TH9 cells, and innate lymphoid cells (ILCs).
–> dendritic cells present the peanut allergen to TH2 and TH9 cells.
–> TH9 cells secrete IL-9, which helps support and activate mast cells.
–> ILC2 cells release IL-5 and IL-13, which recruit and activate basophils and eosinophils.
- TH2 cells activate B cells, making more plasma cells that produce IgE antibodies
- granulocytes release active mediators (i.e histamie) that causes food allergy symptoms

Question 27

why is early intervention key for allergies?

Answer 27

• early introduction of allergens (such as peanuts) can help establish immune tolerance, reducing the likelihood of developing allergies later in life.
• intervention is more effective when it occurs earlier in life rather than later, as it can help prevent the immune system from becoming sensitized to allergens in the first place.

Question 28

is sensitization required for allergies?

Answer 28

Yes, sensitization is required for an individual to develop an allergy.

• sensitization occurs occurs when the immune system first encounters an allergen and produces IgE antibodies
• on subsequent exposures, these antibodies trigger an allergic reaction, causing symptoms like swelling, itching, or more severe responses.

Question 29

what is immunotherapy-induced desensitization?

Answer 29

A therapeutic protocol where an individual is repeatedly exposed to increasing amounts of allergen over time to build tolerance to the antigen
- can be administered via injections, skin application, sublingual tablets, or even oral ingestion.
- initially used for environmental allergies like pollen, dust, and mold.
- while injections were traditionally used, desensitization can now be done with pills or sublingual treatments for convenience and reduced side effects.

Question 30

what is oral immunotherapy (OIT)?

Answer 30

a new treatment approach specifically designed for food allergies, especially for children with anaphylactic reactions
- begins with very small doses of the allergen, typically in a hospital or doctor’s office for safety.
- doses are gradually increased over time.

–> in high-risk patients, omalizumab (a monoclonal antibody) can be added = blocks IgE binding to mast cell FcεRs, reducing the risk of anaphylaxis during treatment

Question 31

how does oral immunotherapy work?

Answer 31

in a normal allergic response:
- TH2 CD4+ T cells are activated and triggering class switching of B cells to produce plasma cells secreting IgE
- The IgE binds to mast cells, which causes degranulation and an allergic reaction

in OIT approach:
- Low doses of allergen in OIT shift the immune response towards a TH1 dominance
- TH1 CD4+ T cells support class switching to IgG4, which:
1) Binds to FcɣRIIB on mast cells, an inhibitory receptor that blocks mast cell degranulation.
2) competes with IgE for allergen binding
- regulatory T cells (Tregs) are also activated, to actively suppress TH2 responses at low doses.
- as doses increase, TH2 cells may undergo apoptosis (cell death) or become anergic (unresponsive).

–> There is a threshold where the immune system becomes more tolerant to the allergen, reducing the allergic response over time.

Question 32

what are some examples of type II hypersensitivities?

Answer 32

• blood transfusion reactions
• hemolytic anemias in newborns

Question 33

what is tolerance?

Answer 33

tolerance is what our body learns to ignore or not ignore
–> the ability of the immune system to differentiate between “self” and “non-self”
–> determines what the body ignores (self antigens) or attacks (foreign antigens form pathogen or mismatched blood types)

Question 34

how are blood types determined?

Answer 34

blood types are determined by the presence or absence of certain antigens (sugars) on the surface of red blood cells
- blood types are A, B, AB or O
–> everyone has H antigen
–> some also have A antigen or B antigen or BOTH
- different sugar conformations determine whether an A antigen, B antigen, or both are produced, driving blood type diversity.

different sugar conformations are what dictate if a A antigen is made versus a B antigen etc

Question 35

How does blood type impact immune tolerance

Answer 35

• many microbes in the environment also express sugar antigens (A, B, H) that resemble those found on human cells
• tolerance to certain pathogens is based on the antigens expressed on your cells
• the absence of certain antigens leads to the production of antibodies against those antigens.

tolerance mechanism:
- If you express A and H antigens, your B cells recognize A and H as “self” and become tolerant
–> you will produce anti-B antibodies = react to B
- If you express B and H antigens, your B cells recognize B and H as “self.”
–> you will produce anti-A antibodies = react to A blood
- if you express A, B, and H antigens, your B cells tolerate all three
–> you can accept blood from from anyone = no recation
- If you only have the H antigen, your B cells tolerate H but will respond to A and B antigen
–> you produce anti-A and anti-B antibodies = react to A and B
–> universal donor (everyone has H antigen)

*essentially, whatever antigen you DON’T have, you have antibodies against them so if you’re exposed to other antigen = reaction

Question 36

how do blood transfusion reactions occur?

Answer 36

• blood must be cross-matched prior to transfusion to avoid severe transfusion reactions
• you have to make sure that the recipient doesn’t have pre-existing antibodies agains the donors RBC antigens
• if you dont, the pre-existing antibodies will bind to the donor RBC = bad

Question 37

what is the mechanism of action during a blood transfusion reaction?

Answer 37

mechanism of reaction:
- the recipient’s immune system may have IgM antibodies targeting donor RBC antigens (e.g., anti-A or anti-B antibodies).
- these antibodies bind to antigens on donor RBCs.
- the classical complement pathway is triggered leading to the formation of the Membrane Attack Complex (MAC).
- RBCs are lysed by the MAC, releasing hemoglobin into the bloodstream.
- released hemoglobin is filtered by the kidneys, which can lead to kidney damage.
- hemoglobin is degraded into bilirubin, a by-product that, in high amounts, can be toxic and result in jaundice (yellowing of the skin and eyes).

Question 38

what blood types are the universal donor and universal accepter?

Answer 38

• Type O blood is the universal donor, as it lacks A and B antigens, minimizing the likelihood of a reaction.
• Type AB blood is the universal acceptor, as individuals with this blood type have no isohemagglutinins, making them tolerant to A and B antigens.

Question 39

what is hemolytic disease of a newborn?

Answer 39

• a condition where IgG antibodies from the mother cross the placenta, targeting fetal red blood cells (RBCs) and leading to their destruction (hemolysis).
• it occurs when there is incompatibility between the mother’s and fetus’s Rhesus (Rh) blood group.
• the mother would be Rh- and the fetus is Rh+ (inherited from the father)

this only matters if theres a MISMATCH of Rh- and Rh+ between fetus/mother

Question 40

how does hemolytic disease of a newborn occur?

Answer 40

1) first pregnancy = sensitization phase
- normally, the maternal and fetal blood are separated by the placenta (no direct blood flo)
- small amounts of fetal RBC crossing the placenta do not trigger an immune response initially because are mothers naive b-cells are not activated at threshold
- during delivery, the placenta detaches from the uterine wall, causing fetal umbilical blood (Rh+) to enter the mothers blood circulation
- the mothers immune system recognizes Rh+ blood as non-self and mounts an immune response
- the mother produces IgM antibodies that destroy fetal RBC (do not cross placenta)
- memory B-cells are created and class-switch to produce IgG antibodies for future responses

2) second pregnancy = immune response
- small of amounts of fetal RBC cross the placeneta during a subsequent pregnancy, which is enough to activate the mothers memory b-cells from the past pregnancy
- memory b-cells rapidly produce IgG antibodies which are small enough to cross placental barrier and attack fetal RBCs in the fetus (Rh+)
- this causes anemia, and hemoglobin to breakdown = bilirubin accumulating = jaundice

Question 41

what is the treatment for hemolytic disease of a newborn?

Answer 41

the main treatment is to administer anti-Rh antibodies to the mother to prevent the initial sensitization event in first pregnancy
- RhoGAM binds to fetal Rh+ RBCs that have entered the mother’s circulation.
- coated fetal RBCs are cleared by the maternal immune system before they can be recognized by B cells.
- this prevents the mother’s immune system from mounting a response or producing memory B cells, ensuring subsequent pregnancies are safe.

mothers are routinely tested for Rh compatibility and rising levels of maternal anti-Rh antibodies = indicated immune reaction against fetus RBCs

Question 42

what is type 4 hypersensitivity?

Answer 42

it is also called delayed type hypersensitivity (DTH)
- the only hypersensitivity reaction mediated by T cells rather than antibodies.
- it involves a delayed response (1-2 days) as T cells recruit and activate macrophages
- t-cells trigger excessive macrophage activation leading to tissue damage
- typically caused by intracellular pathogens and contact antigens (skin exposure)

Question 43

what is the mechanism of action for type 4 hypersensitivities?

Answer 43

delayed type hypersensitivity requires an initial sensitization event by an antigen

1) first event:
- APCs (dendritic, macrophages) present antigens (i.e poison ivy) that activate CD4+ TH1 cells and others
2) second event:
- upon re-exposure, sensitized T cells release cytokines and chemokines.
- this recruits and activates macrophages to the site of exposure.
- the peak response takes 48-72 hours, allowing time for the Th1 cells to activate and recruit macrophages, resulting in a slow building concentration gradient at the exposure site.

Question 44

what is tuberculin (TB) skin testing?

Answer 44

a test to see if a person has been infected with tuberculosis or has had the vaccine
- PPD from tuberculosis is injected into the skin
- 2-3 days later, redness and swelling are check for at the injection site
- if present, it indicates that memory T cells are recruiting macrophages, causing inflammation, and confirming a previous exposure to M. tuberculosis
- if not present, it suggests that the person has not been previously been exposed to tuberculosis