Hypersensitivity

2. What makes us sick?
“enemies” in the environment in the form of microbes and
chemicals are constantly attacking our bodies, disrupting
homeostasis
sometimes immune system homeostasis is disrupted on its
own

3. Gell and Coombs Classification
• P. G. H. Gell and R. R. A. Coombs classified hypersensitive reactions into four types.
Type I reactions
• involve immunoglobulin E (IgE)–mediated release of histamine and other mediators from
mast cells and basophils.
Type II reactions
• involve immunoglobulin G or immunoglobulin M antibodies bound to cell surface
antigens, with subsequent complement fixation.
Type III reactions
• involve antigen-antibody immune complexes that deposit in postcapillary venules, with
subsequent complement fixation.
Type IV reactions
• mediated byT cells rather than by antibodies.

4. Hypersensitivity reactions
• Aberrant or excessive immune response to foreign antigens
• Primary mediator is the adaptive immune system
T & B lymphocytes
• Damage is mediated by the same attack mechanisms that
mediate normal immune responses to pathogen

5. Type I: Immediate
hypersensitivity

6. • Rapidly developing immunogenic reaction occurring within
minutes after the combination of an antigen when antibody
bound to mast cells or basophils in individuals.
• may occur as a systemic or as a local reaction

7. Etiology
Allergic reactions
• Reactions can be elicited by various
aeroallergens ( pollen, animal dander),
drugs(penicillin, sulfonamides) or insect
stings(bee venom, wasp venom)
• Other possible causes are latex ,foreign
serum and food allergy.

8. Biological basis allergies

9. Allergens
• Allergens have intrinsic enzymatic activity- allergen extracts from dust mites as
well as from fungi and bacteria have high protease activity.
• Protease cause the disruption of epithelial cell junctions, allowing allergens to access
the underlying cells and molecules of the innate and adaptive immune systems.
• Cleave and activate complement components at the mucosal surface.
• Allergens contain potential pathogen associated molecular patterns(PAMPS).
• Interact with receptors of the innate immune system and initiating a cascade
of responses leading to an allergic response.

10. Mechanism of Allergic Response
• Repeated exposure to allergens initiates immune response that generate IgE .
• IgE antibodies alone are not destructive.
• They cause hypersensitivity by binding to Fc receptors specific for their constant
regions (FceRs).
• The FceRs are expressed by mast cells, basophils and eosinophils.
• The binding of IgE antibodies to FceRs activates signaling cascade that causes
cells to release intracellular granules into the blood, process called
degranulation.
• The contents of granules vary from cell to cell, include histamine, heparin, and
proteases.
• Along with granulocytes, leukotrienes, prostaglandins, chemokines, and
cytokines are synthesized ,act on surrounding tissues and other immune cells,
causing allergy symptoms.

11. • Exposure to an allergen activatesTH2 cells
that stimulate B cells to form IgE-secreting
plasma cells.
• The secreted IgE molecules bind to IgE-
specific Fc receptors (FceRI) on mast cells
and blood basophils.
• Exposure to the allergen leads to cross-
linking of the bound IgE, triggering the
release of pharmacologically active
mediators.
• The mediators cause smooth muscle
contraction, increased vascular
permeability and vasodilation.

12. Mechanisms of allergic response Fc e receptors (FceR)
• IgE binds two different receptors –
FceRI
• High affinity IgE receptors found on – mast
cells/basophils/activated eosinophils.
• Allergen binding to IgE attached to FceRI triggers
release of granules from cell.

13. Fce RII
• Low affinity IgE receptors found on-B cells
• Type II transmembrane protein, N-terminus
directed toward the cell interior and C-
terminus directed toward the extracellular
space.

14. Mechanisms of allergic response
Effector Stage of Hypersensitivity

15. Mediators of Type I Hypersensitivity
• Primary Mediators – produced before degranulation and are
stored in the granules.
• Secondary Mediators - synthesized after target-cell activation or
released by the breakdown of membrane phospholipids during the
degranulation process.

17. Systemic Anaphylaxis
• It is a shock like and occurs within minutes of exposure to an allergen.
• Initiated by an allergen introduced directly into the bloodstream or absorbed from
the gut or skin.
• Symptoms include labored respiration, drop in blood pressure leading to
anaphylactic shock ,contraction of smooth muscles leading to defecation,
urination, and bronchiolar constriction.
• Leads to anaphyxiation, which lead to death within 2 to 4 minutes of exposure to
the allergen.
• venom from bee, wasp, hornet, and ant stings; drugs such as penicillin, insulin,
and antitoxins; and foods such as seafood and nuts cause anaphylaxis.
• Epinephrine is used for treating anaphylaxis.
• It counteracts the effects of mediators such as histamine and the leukotrienes,
relaxing the smooth muscles of the airways and reducing vascular permeability.

18. Localized Hypersensitivity Reactions (Atopy)
• The pathology is limited to a specific target tissue or organ, and often occurs at the
epithelial surfaces first exposed to allergens.
• Atopic allergies include a wide range of IgE-mediated disorders, such as allergic
rhinitis (hay fever), asthma, atopic dermatitis (eczema), and food
allergies.
• Hay fever is the most common and results from the inhalation of common airborne
allergens (pollens, dust, viral antigens).
• Allergen react with IgE molecules bound to sensitized mast cells in the conjunctivae
and nasal mucosa.
• Cross-linking of IgE receptors induces the release of histamine and heparin from
mast cells, which then cause vasodilation, increased capillary permeability, and
production of exudates in the eyes .
• Tearing, runny nose, sneezing, and coughing are the main symptoms.

19. Atopic dermatitis ( allergic eczema)-
• Inflammatory disease of skin and observed in young children.
• The affected individual develops erythematous (red) skin eruptions that fill with pus if
there is an accompanying bacterial infection.
Food allergies
• The most common food allergens for children are cow’s milk, eggs, peanuts, tree
nuts, soy, wheat, fish, and shellfish.
• Food allergens are water-soluble glycoproteins that are relatively stable to heat,
acid, and proteases and, therefore, digest slowly.
• Some food allergens acting directly as an adjuvant and promoting a T H 2 response
and IgE production in susceptible individuals.

20. Diagnostic Tests and Treatments
• Type I hypersensitivity is commonly assessed by skin testing.
• Small amounts of potential allergens are introduced at specific skin sites (e.g.,
the forearm or back), by intradermal injection or by dropping onto a site of a
superficial scratch.

21. Hyposensitization –
• Immunotherapy with repeated injections of
increasing doses of allergens has been known for
some time to reduce the severity of type I
reactions.
• This cause a shift toward IgG production or
induceT-cell mediated suppression that turns
off the IgE response.
• The IgG antibody, called as blocking antibody
because it competes for the allergen and binds to
it, and forms a complex that can be removed by
phagocytosis.

23. Antibody-Mediated Cytotoxic (Type II)
Hypersensitivity

24. Antibody-Mediated Cytotoxic (Type II) Hypersensitivity
• Body makes special autoantibodies directed against self-cells
(antigens present on the surface of cells or tissue components)
Antigen:
• 1. may be intrinsic to the cell membrane
• 2. may take the form of an exogenous antigen adsorbed on the cell
surface.
• hypersensitivity results from the binding of antibodies to normal or
altered cell-surface antigens

25. • Antibody bound to a cell-surface antigen and induce death of the
antibody-bound cell by
• Activate the complement system, creating pores in the membrane
of a foreign cell.
• Antibodies can mediate cell destruction by antibody dependent
cell-mediated cytotoxicity (ADCC).
• Antibody bound to a foreign cell can serve as an opsonin.

26. Type II examples
1.Transfusion reactions
• cells from an incompatible donor react to the host’s antibody
2. Erythroblastosis fetalis
• there is an antigenic difference between the mother & the fetus,
and antibodies (IgG) cross the placenta & cause destruction of fetal
red cells.
3. Autoimmune hemolytic anemia, agranulocytosis,
thrombocytopenia
• individuals produce antibodies to their own blood cells and are
then destroyed.
4. Drug reactions
• antibodies are produced that react to the drug

27. RH INCOMPATIBILITY
• Rh incompatibility occurs when the mother's
blood type is Rh negative and her fetus'
blood type is Rh positive.

28. • If some of the fetus' blood passes into the
mother's blood stream, her body will produce
antibodies in response
• these antibodies could pass back through
the placenta and harm the fetus' red blood
cells, causing mild to serious anemia in the
fetus

29. Symptoms
• Rh incompatibility can cause symptoms ranging from very mild to
deadly.
• In its mildest form, Rh incompatibility causes the destruction of red
blood cells.
• After birth, the infant may have :
• Yellowing of the skin and whites of the eyes (jaundice)
• Low muscle tone (hypotonia)

30. Complications
• Possible complications include:
• Brain damage due to high levels of bilirubin
• Fluid buildup and swelling in the baby (hydrops fetalis)
• Problems with mental function, movement, hearing, speech, and
seizures

31. Signs and tests
•polyhydramnios (excess of amniotic fluid in the amniotic sac)
• A positive direct Coombs test result
• Higher-than-normal levels of bilirubin in the baby's umbilical cord
blood
• Signs of red blood cell destruction in the infant's blood

32. Prevention
• Rh incompatibility is almost completely preventable.
• Special immune globulins, called RhoGAM, are now used to prevent
RH incompatibility in mothers who are Rh-negative.
• If the father of the infant is Rh-positive or if his blood type cannot be
confirmed, the mother is given an injection of RhoGAM during the
second trimester.
• If the baby is Rh-positive, the mother will get a second injection
within a few days after delivery.

33. ABO INCOMPATIBILITY
• ABO incompatibility is reaction of the
immune system if two different
and not two compatibles blood
types are mixed together.

35. Symptoms
• The following are symptoms of ABO incompatible transfusion
reactions:
• Back pain
• Hematuria
• Fever
• jaundice

36. Treatment
• Treatment may include:
• Antihistamines
• Steroids
• Vasopressors

37. Immune Complex–Mediated (Type III)
Hypersensitivity

38. Immune Complex–Mediated (Type III) Hypersensitivity
Immune Complex Disease
• Involve reaction against soluble antigens circulating in the serum.
• Involve IgM ,IgG antibodies.
• Every time an antibody binds to antigen, an immune complex is formed .
• Under normal conditions complexes are bound by complement to RBCs
and then eliminated by phagocytes.
• InType III hypersensitivity, immune complexes are not cleared out and
they become deposited in tissues.

39. • InType III hypersensitivity, the antibody involved is primarily IgG
• The immune complexes activates complement (C3a, C4a and C5a ),
leading to degranulation of mast cells.
• The products of mast cell degranulation cause blood vessels to
become more permeable.
• This allows immune complexes to be deposited in the walls of
blood vessels.
• The neutrophils release lysosomal enzymes into the area, causing
further damage to the vessel wall

40. Immune complex formation and deposition

41. LOCATION
• The immune complexes are formed in the circulation & are deposited in many organ .
• kidney (glomerulonephritis), joints (arthritis), small blood vessels of the skin if the
complexes are formed and deposited locally (local Arthus reaction)
Arthus reaction
• If an animal or human is injected intradermally with an antigen to which large
amounts of circulating antibodies exist( intravenous injections).
• Antigen will diffuse into the walls of local blood vessels and large immune
complexes will precipitate close to the injection site.
• This initiates an inflammatory reaction that peaks approximately 4 to 10 hours post
injection and is known as anArthus reaction.
• Inflammation at the site of an Arthus reaction is characterized by swelling and
localized bleeding, followed by fibrin deposition

43. Diseases

44. SERUM SICKNESS
• A condition may develop when a patient is injected with a large
amount of antitoxin that was produced in an animal . Like horse
antitetanus or antdiphtheria serum.
• After about 10 days ,the immune system produces antibodies,
combine with these proteins to form immune complexes.
• The immune complex precipitate and enter the walls of blood vessels
and activate complement cascade ,initiating inflammatory response .
• These symptoms include fever, weakness, generalized vasculitis
(rashes) with edema and erythema, arthritis and sometimes
glomerulonephritis

45. Type IV: Delayed
Hypersensitivity

46. Type IV: Delayed Hypersensitivity
• The only type that is not antibody-mediated.
• contact hypersensitivity (poison ivy, poison oak and reactions to metals
in jewelry);
• tuberculin-type hypersensitivity (the tuberculosis skin test);
• granulomatous hypersensitivity (leprosy, tuberculosis, schistosomiasis
and Crohn’s disease).
• It is called delayed because its onset may vary;
• Occurs hours to days
• The length of the delay varies from 72 hours in contact hypersensitivity
and 21-28 days in granulomatous hypersensitivity.

47. Th1 cells and macrophages
• In sensitization phase
• The dendritic cells pick up antigen
and present the antigen toT cells.
• TheT cells proliferate and
differentiate intoTH1 cells.
• These Th1 cells can activate
macrophages and trigger
inflammatory response.

48. • In the effector phase ,exposure of sensitizedTH1
cells to antigen.
• TH1 cells secrete a variety of cytokines and
chemokines.
• IFN-g, TNF-a, and TNF-b - cause tissue
destruction, inflammation.
• IL-2 - activates T cells and CTLs.
• Chemokines - for macrophage recruitment.
• IL-3, GM-CSF -increased monocyte/macrophage
• Inflamed area becomes red and fluid filled can
form lesion.
• Tissue damage there is activation of clotting
cascades and tissue repair.

49. Contact dermatitis
• The response to poison oak is a classic
Type IV.
• Small molecules act as haptens and
complex with skin proteins to be taken
up by APCs and presented toTh1 cells
to get sensitization.
• During secondary exposureTh1
memory cells become activated to
cause DTH.

50. Tuberculosis skin test
• a small amount of soluble antigen (tuberculin) is
injected into the skin
• TheT cells that are activated by the antigen secrete
cytokines that draw other cells to the site.
• Within four hours, neutrophils have arrived,
followed by an influx of monocytes andT cells at
about 12 hours.
• The peak of activity is at about 48-72 hours, at which
point the area has become red and swollen.

51. Granuloma Formation from DTH Mediated by Chronic Inflammation
• In some cases, the antigen is not easily cleared.
• A prolonged DTH response can develop, which
becomes destructive to the host, causing a visible
granulomatous reaction.
• Continuous activation of macrophages induces them
to adhere closely to one another and form
granulomas.
• Macrophages assume an epithelioid shape and
sometimes fuse to form multinucleated giant cells.
• Giant cells displace the normal tissue cells, forming
palpable nodules, and releasing high concentrations of
lytic enzymes, which destroy surrounding tissue.
• The granulomatous response can damage blood
vessels and lead to extensive tissue necrosis.

52. Patch Testing
• Used to identify the allergen
• Skin contact with substances to which the client
is potentially allergic
• Contact with a specific allergen results in a
delayed reaction that develops in 48-96 hours
• Substances applied under occlusive tapes
• Localized erythema, blister, swelling

53. References
• "Kuby Immunology." Google Books. N.p., n.d.Web. 13 Oct. 2016.
• Bloom, B. R., & Bennett, B. (1966). Mechanism of a reaction in vitro associated with
delayed-type hypersensitivity. Science, 153(3731), 80-82.
• Sampson, H. A., & Scanlon, S. M. (1989). Natural history of food hypersensitivity in
children with atopic dermatitis. TheJournal of pediatrics,115(1), 23-27.
• Venter, C., Patil,V., Grundy, J., Glasbey, G.,Twiselton, R., Arshad, S. H., & Dean,T. (2016).
Prevalence and cumulative incidence of food hypersensitivity in the first 10 years of
life. Pediatric Allergy and Immunology.