Hypersensitivity Lecture Flashcards
What are hypersensitivity reactions?
Hypersensitivity reactions are immune responses that damage to tissue. When these reactions cause diseases, they are called hypersensitivity diseases or immune-mediated inflammatory diseases.
What causes hypersensitivity reactions
- Uncontrolled/abnormal responses to foreign antigens
- Autoimmine responses against self-antigens
How are hypersensitivvity reactions classified?
According to HOW they cause damage to tissue.
Type I (Immediate)
Type II
Type III
Type IV (delayed)
Type I hypersensistivity
Type I hypersensitivity is immediate and caused by mediaters released from mast cells when activated by [environmental antigens bound to IgE]
Type II hypersensitivity
Mediated by antibodies that bind tissue antigens, causing complement-dependent tissue injury and dz.
Type III Hypersensitivity
Caused by Abs that bind to circulating Ags–> [immune complexes]
Immune complexes then deposit in vessels and cause complement‐dependent injury in the vessel wall (vasculitis)
Type IV hypersensitivity
T-cell mediated tissue damage due to cytokines released from Th1 and Th17 cells or the killing of hosts by CTLs.
Type 1 Hypersensitvity
What is atopy?
Genenetic tendency to develop and allergic disease.
People with a strong propensity to develop allergic reactions are atoic.
Mast cell mediators are responsible for acute reactions and inflammation (Type I).
-Histamine
-Proteases
-Prostaglandins
-Leukotrienes
-Cytokines
HISTAMINE is a vasoactive amine that causes vasodilation and smooth muscle contraction
Proteases cause tissue damage
PGs cause vasodilation
LTs cause prolonged smooth muscle contraction
Cytokines induce local inflammation (late phase reaction)
Initial allergen encounter
When an allergen is encountered,
- Allergen binds to B-cells and activates TH2 cells, allowing maturation of the B cell –> plasma cells that secrete IgE.
- IgE goes into circulation and binds to Fc3RI on mast cells in the tissues.
Subsequent allergen encounter
Allergen binds IgE on the mast cell and crosslinking occurs.
This causes the mast cell to release mediators that cause immediate hypersensitivity and late phase-reaction.
What substances from the mast cell causes immediate hypersensitivity reaction, minutes after repeat exposure? What causes the late-phase reaction 6-24 hours after repeat exposure to the allergen?
Immediate: vasoactive amines, lipid mediators
Laterphase: cytokines
Immediate reaction is characterized by smooth muscle rxn, vasodilation, congestion and edema.
Late phase reaction is characterized by?
An inflammatory infiltrate rich in eosinophils. neutrophils, and T cells
Asthma is a reversible airway obstruction casued by inflammatory mediators from mast cells once encountered by allergens.
The mediators cause loosening of tight junctions in the BRONCHIOLE epithelium, increased capillary permeability and spasmatic contraction of smooth muscle around the bronchi, resulting in?
A deecrease in the size of the bronchial lumen, resulting in shortness of breath.
The lumen of bronchioles contain what?
Goblet cells that secrete mucus.
non‐immunologic stimuli such as cold, viral infections, and exercise, do what?
Stimulate the same airway inflammation and bronchospasms
How does anaphylaxis occur?
Allergins cause the RAPID release of vasoactive amines from mast cells, basophils and cytokines, causing smooth muscle (of vascular) to contract and vasodilation of the capillary endothelium.
As a result, BP decreases and vascular shock occurs. Mediators that are released cause the smooth muscle in bronchi and bronchioes to contract, also making breathing difficult.
Allergen testing
Test what kind of hypersensitivies?
How does it occur?
Allergen testing tests Type 1 hypersensitivites to allegens.
On the ventral arm, a grid is made allergens are injected into the dermis. If allergic, redness and swelling will occur 20-30 mins after
Allergen-specific immunotherapy (Allergen-SIT) is the only cure to allergic diseases. The aim of Allergen-SIT is to induce? (3)
Allergens are injected at increasing doses.
The aim is to.
- induce peripheral T cell tolerance
- Modulate the thresholds that mast cells and basophils are activated.
- Decrease histamine release
The reason why induction of peripheral T cell tolerance and formation of regulatory T cells are important is becuase they (FOXP3+CD4+CD25+Treg) play a key role in?
successful allergen-SIT and helathy immune response to allergens
What is type II hypersensitivity?
- IgG and IgM antibodies bind to antigens located on the tissue, causing tissue injury and dz..
- IgM and IgG promote phagocytosis of antigens that they bind to and promote inflammation via complement- mediated (classical pathway) and Fc receptor–mediated leukocyte recruitment (neutrophils and macrophages)
- ROS and lysocomal enzymes then damage adjacent tissue.
What are important diseases that are associated with Type II hypersensistivity?
- Hemolytic anemia
- Graves disease (hyperthyroidism-TSH receptor)
3 .Myasthenia gravis (Ach receptor)
- Pemphigus vulgaris
- Pernicious anemia
- Rheumatic fever
- Good pasters syndrome
How does type II hypersensitibty work?
- IgG and IgM opsonize cells and activate compliment system, leading to phagocytosis through phagocyte receptors or CR1.
- C3a and C5a recruit leukocytes
- Ab may then cause an abonormal response: stimulates receptor without the legand or preventing the binding of a ligand.
Graves Dz and Type 2 hypercensitity
Antibody binds to TSH receptor, even when the hormone that causes hyperthyroidism is not there.
Myasthenia gravis and Type 2 hypersensitibty
Antibody prevents binding of Ach to AchR.
Type 3 hypersensitibity
Immune complexes deposit in the blood vessel, causing vascular inflammation and ischemic damage to tissues.
Injury is due to activation of the compliment system (classical pathway) and the Fc-receptor mediated recruitment of leukocytes–> inflammation.
Diseases of type 3 sensitivity are caused by
A buildup of immune complexes in the blood or in the tissues.
What are the 5 diseases of type 3 hypersensitivty?
- Lupus
- Polyarteris nodosa
- Post-streph glomerulonephritis
- Serum sickness
- Arthus reaction
How is injury caused in all Type III hypersenssitivities?
caused by complement-mediated and Fc receptor-mediated inflammation
What is the arthus reaction?
Arthus reaction is induced by subcutaenous injection of antigens to a previously immunized animal, forming immune reactions at the site of injection and local vasculitis.
- Lupus: Abs to DNA, nucleoproteins: Clincal Manes(CM)?
- Polyarteritis: abs to microbial antigens CM?
- Post streptococcal gomerulonephritis: ab specific to streptococcal wall ags, CM?
- Serum sickness: Abs to many proteins/ CM?
- Arthus reaction: Abs to many proteins/
- Nephritis, arthritis, vasculitis
- Vasculitis
- Nephritis
- Systemic vasculitis, nephritis, arthritis
- Cutaneous vasculitis
Systemic reactions of type 3 hypersensitivity
- Fc receptors on the endothelium will bind [antibody + the toxin].
- More complexes bind, forming a larger complex.
- of classical pathway of compliment is activated
- Anaphylotoxins, C5a, C4a and C3a are released, attracting MO and neutrophils
Local reaction/arthus reaction of Type III:
- AB and cells are transported to the site of antigen deposition
- Classical compliment cascade
- Anaphylatoxins C3a, C5a and C4a attract macrophages and neutrophils to the site of tissue damage.
Type IV hypersensivity are _______ mediated diseases
T-cell
Type IV: T cell mediated diseases:
- CD4 Tcells (cytokine-mediate inflammation)
- CD8 Tcells (T-cell mediated cytolysis)
- Activate macrophages and cytokine-mediated inflammation
- Cause lysis of target cell and cytokine mediated inflammation
What are the major triggers of type IV hypersensistivity reactions?
- Autoimmunity
- Exaggerated or persistent responses to environmental antigens
- Microbial antigens
What causes tissue injury in Type IV hypersensitiivty?
- macrophage activation
- Inflammation caused by cytokines made from Th1/Th17 cells
- Killing of host cell by CTL
Autoimmune diseases mediate by type IV hypersensitivity include?
MS
T cells are specific to myelin proteins
rheumatoid arthritis
T cells are specific to unknown antigens in joint
type 1 diabetes
T cells are specific to pancreatic islet antigens
What inflammatory disease has both autoimmunity component and is likely caused by the aberrant reactions to intestine microflora?
Crohns
Type IV hypersensivity are T-cell mediated inflammatory reactions. They are also called what? and why
Delayed-type hypersensitivity reactions that develop 24-48 hours after antigen binds.
Inflammation is due to cytokines secreted from CD4+ Th1 and Th17, which recruit and activate leukocytes.
What causes tissue injury in type 4 hypersensitivty reactions?
Products of the activated neutrophils and macrophages, such as lysosomal enzymes, ROS, NO and proinflammatory cytokines.
Inflammation in T-cell mediated diseases are ______
chronic
How can humans be sensitized to DTH reactions?
- Microbial infection (TB)
- Contact sensitization (poison ivy)
- Immunization (dip toxin, tetanus toxin)
Purified protein derivative (PPD), a protein antigen of Mycobacterium tuberculosis causes what?
A DTH reaction called a tuberbulin reaction.
Poison Ivy releases pentadecacatechol molecules which come in contact with the skin protein and combine.
During primary contact (T cell sensitization) and T memory cells are made **no dermatitis occurs
During secondary contact what occurs?
T memory cells respond to the pentdecacatechol and activate many T cells leading to dermatitis.
Allergic contact dermatitis (ACD)–> caused by environmental exposure to external agens that come in contact with the skin and cause inflammation. This results from DTH reactions.
Metals are the most common contact allergens. Sensitization occurs at any age, costume jewelery is linked to increased sensitation to Nickel and Cobalt. Whats the most common source of sensitization to chromium?
Leather
TB granulomas, contains what?
Theyre giant
- activated Mø
- Many nuclei
- lymphocytes (primarily T cells).
In some granulomas, there may be cenral areas of necrosis.
CD4Th1 cells release TNF and IFNy which does?
Recruits mø and leukocytes.
Prolonged reactions of this type lead to formation of granulomas
How are mature granulomas formed?
- Hours after antigen exposure, activated Th1 home to the tissue. If antigens are not taken care of, inflammation persists.
- CD4+ Th1 cells and macrophages activated by IFN-y release TNF.
- IFN-y and TNF further stimulate MO
- After several days-weeks–> mature granuloma is formed.
Systemic Lupus erythematosus (SLE) is prototypic immune complex mediated disease: Type III hypersensitivity.
Manifests as rashes, arthritis and gomerulonephritis.
Mainly consist of anti-DNA abs (auto-abs).
Immune complexes formed from these auto-abs and specific Ags are responsible for the side affects. What is the principle diagnostic test?
The presence of anti-nuclear IgG abs (DNA)
RA is an inflammatory disease involving small and large joints. Inflammation here is associated with destruction of the joint cartilage and bone.
Mediated by Type II/III hypersensistivities.
Cells involved?
Th1
Th17
Activated B cells
Plasma cells
Macrophages
RA patients frequently have circulating what?
Auto-antibodies called rheumatoid factors: IgM or IgG that react with Fc of own IgG.
If these are present, you can diagnose w RA
MS pathogenisis- TYPE IV 1. Activated T cell by APC is released into blood, uses rolling adhession to move into brain tissue. 2. T cell reactivated by APC-microglialcell/astrocyte 3. T cell activates mø in brain tissue by releasing IFNy/IL2, Mø releases IL1/IL12 and chemokines to attract more T cells to the site 4. Mø releases TNFA/ROS/NO which degrades axon 5. B cells come to the brain tissue and do what???
- B cells make autoantibodies to complmenet on axons and degrade the axons
IBD what is wtype of hypersensitivty?
4
Immunotherapy: CTLA4-iG blocks costimulation
Anti-TNF, Anti-IL1,Anti-IL6R Anti-IL17: block inflammation
Anti-integrins (Anti CD40L) block adhesion
Anti-p40=?
Antip40 blocks Th1 Th17 response by inhibiting IL12/IL23
