1. Hypersensitivity Reactions
Hypersensitity = Allergy
In Greek: allo 􀃆 different
ergo = activity

2. Hypersensitivity
Refers to undesirable (damaging, discomfort producing and sometimes fatal) reactions produced by the normal immune system
Hypersensitivity reactions require a pre-sensitized (immune) state
of the host.
Atopy
Hereditary predisposition to the development of immediate hypersensitivity reactions against common environmental antigens.

3. Immediate hypersensitivity
Because the symptoms are manifest within minutes or hours after a sensitized recipient encounters antigen.
Delayed-type hypersensitivity (DTH):
Is so named in recognition of the delay of symptoms until days after exposure

4. Classification of hypersensitivity reactions

5. Type 1 hypersensitivity reaction (Immediate,IgE-mediated,Anaphylactic
Occurs within minutes of exposure to antigen
􀁠 IgE-Mediated :
◦ Allergen activates B cells to form IgE secreting plasma cells
◦ Secreted IgE molecules bind to high affinity FcεR1 on mast
cells
◦ A subsequent exposure to the allergen results in crosslinking
of the bound IgE
◦ Cross-linking of IgE molecules results in the degranulation of mast cells
◦ Degranulation results in the release mediators (histamine,
prostaglandin, leukotropine, ..etc), which mediate the
hypersensitivity reaction

6. Allergens
Allergen : Refers specifically to non parasitic antigens capable of stimulating type I hypersensitive responses in allergic individuals

7. Components of Type I :

8. What distinguishes a type I hypersensitive response from a normal humoral response?
Plasma cells secrete IgE. This class of antibody binds with high affinity to Fc receptors on the surface of tissue.
Mast cells and basophils coated by IgE are said to be sensitized.
A later exposure to the same allergen cross-links the membrane-bound IgE on sensitized mast cells and basophils, causing degranulation of these cells

9. Properties of mast cells ,Basophils and Eosinophils
Sequence of events in immediate hypersensitivity reactions
Properties of mast cells ,Basophils and Eosinophils

11. Toxic granule proteins and inflammatory substances released upon activation of eosinophils

12. Toxic granule proteins and inflammatory substances released upon activation of eosinophils

13. Biological effects of mediators of type I

14. Regulatory factors
The following factors influence IgE response to allergens:
Level of Ag dose
Mode of antigen presentation
Relative presence of TH1 and TH2 titres
TH2’s release IL-3,4,5, and 10
TH1’s release IFN-γ
Atopic vs non-atopic individuals express qualitatively different Type I responses to allergens…
Atopic responses involve TH2  production of IgE from B cells
Non-atopic responses involve TH1  production of IgM or IgG

15. Diagnosis Skin tests- injections or scratchings -Stim local Mast cells
-Produces P-K rxn (wheal and flare)
-Inexpensive and quick
-May sensitize one to new Ag’s
-May stim late-phase rxn in some
Immunoassays for serum IgE
-Radioimmunosorbent test (RIST)
-Radioallergosorbent test (RAST)

16. Treatment approaches for IgE-mediated Allergy

17. Antibody-Mediated Cytotoxic (Type II) Hypersensitivity
Type II hypersensitive reactions involve antibody-mediated destruction of cells
􀁠 Antibody can activate the complement system, creating pores in the membrane of a foreign cell
􀁠 Or it can mediate cell destruction by antibody dependent cell-mediated cytotoxicity (ADCC)
􀁠 In this process, cytotoxic cells with Fc receptors bind to the Fc region of antibodies on target cells and promote killing of the cells
􀁠 Antibody bound to a foreign cell also can serve as an opsonin, enabling phagocytic cells with Fc or C3b receptors to bind and phagocytose the antibody-coated cell

18. Types of antibodies mediated diseases

19. Transfusion Reactions Are Type II Reactions
Antibodies to the A, B, and O antigens, called isohemagglutinins,
are usually of the IgM class.
Hemolytic disease of the newborn :
Caused by Rh incompatibility in a subsequent pregnancy can be almost entirely prevented by administering antibodies against the Rh antigen to the mother within 24–48 h after the first delivery. These antibodies, called Rhogam, bind to any fetal red blood cells that enter the mother’s circulation at the time of delivery and facilitate their clearance before B-cell activation and ensuing memory-cell production can take place

21. Drug-Induced Hemolytic Anemia
This is where certain antibiotics can absorb nonspecifically to the proteins on RBC membranes
Examples: penicillin, streptomycin
Sometimes antibodies form inducing complement-mediated lysis and thus progressive anemia
When drug is withdrawn the hemolytic anemia disappears

22. Immune Complex–Mediated (Type III) Hypersensitivity
Normally, the reaction of antibody with antigen generates immune complexes, which facilitate the clearance of antigen by phagocytic cells.
􀁠 In some cases, large amounts of immune complexes are deposited in tissue, which can lead to tissue-damaging type III hypersensitive reactions.
􀁠 In particular, complex deposition is frequently observed on blood vessel
walls, in the synovial membrane of joints, on the glomerular basement membrane of the kidney, and on the choroid plexus of the brain.
􀁠 The deposition of these complexes initiates a reaction that results in the movement of neutrophils to the site.
The tissue there is injured as a consequence of granular release from the neutrophil

23. Type III mechanisms of occurance
Immune complexes deposited in the tissues (mostly blood vessels
basement membranes) activate the complement system by the classical pathway
􀁠 C3a, C4a, and C5a complement split products are anaphylatoxins causing localized mast-cell degranulation and consequent increase in local vascular permeability.
􀁠 C3a, C5a, and C5b67 are also chemotactic factors for neutrophils, which can accumulate in large numbers at the site of immune-complex deposition and release lytic enzymes as they attempt to phagocytose immune complexes

24. Further activation of the membrane-attack mechanism of the complement system can also contribute to the destruction of tissue
􀁠 In addition, the activation of complement can induce aggregation of platelets, and the resulting release of clotting factors can lead to formation of microthrombi
􀁠 This total process leads to the condition recognized histologically as vasculitis
􀁠 When it occurs locally (in the skin) it is known as an Arthus reaction, when it occurs systemically as a result of circulating immune complexes it is know as serum sickness

25. Immune Complex mediated local inflammation such as in Arthus Reaction
Immune Complex mediated local inflammation such as in Arthus Reaction

27. Formation of circulating immune complexes contributes to the pathogenesis of a number of conditions other than serum sickness. These include the following:
Autoimmune Diseases
Systemic lupus erythematosus
Rheumatoid arthritis
Goodpasture’s syndrome
Drug Reactions
Allergies to penicillin and sulfonamides
nfectious Diseases
Poststreptococcal glomerulonephritis
Meningitis & Hepatitis
Mononucleosis
Malaria& Trypanosomiasis

28. Type IV or Delayed-Type Hypersensitivity (DTH)
􀁠 The hallmarks of a type IV reaction are the delay in time required for the
reaction to develop and the recruitment of macrophages (as opposed to
neutrophils, as found in a type III reaction)
􀁠 DTH results from reactions involving T lymphocytes and macrophages,
which infiltrate the tissue.
􀁠 In certain circumstances, DTH is damaging and this may be seen in the
following conditions:
◦ Tuberculosis
◦ Drug allergy
◦ Allergic response to insect bites and stings
◦ Contact dermatitis
◦ Rejection of grafts

29. Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity.
The classical example of this hypersensitivity is tuberculin (Montoux) reaction
Reaction peaks 48 hours after the injection of antigen (PPD or old tuberculin). The lesion is characterized by induration and erythema

30. Type IV Hypersensitivity Reactions
Type IV Hypersensitivity Reactions

33. Another form of delayed hypersensitivity is contact dermatitis (poison ivy (figure 6), chemicals, heavy metals, etc.) in which the lesions are more papular
Type IV hypersensitivity can be classified into three categories depending on the time of onset and clinical and histological presentation

34. Fig 5 Type Reaction time Clinical appearance Histology
Antigen and site
contact
48-72 hr
eczema
lymphocytes, followed by macrophages; edema of epidermis
epidermal ( organic chemicals, poison ivy, heavy metals, etc.)
tuberculin
local induratio
lymphocytes, monocytes, macrophages
intradermal (tuberculin, lepromin, etc.)
granuloma
21-28 days
hardening
macrophages, epitheloid and giant cells, fibrosis
persistent antigen or foreign body presence (tuberculosis, leprosy, etc.)
Fig 5

35. Mechanism:
The mechanism includes T lymphocytes and monocytes and/or macrophages.
Cytotoxic T cells (Tc) cause direct damage whereas helper T (TH1) cells secrete cytokines which activate cytotoxic T cells, recruit and activate monocytes and macrophages, which cause the bulk of the damage
The delayed hypersensitivity lesions mainly contain monocytes and a few T cells.

36. Diagnosis
Diagnostic tests in vivo include delayed cutaneous reaction (e.g. Montoux test )
In vitro tests for delayed hypersensitivity include mitogenic response, lympho-cytotoxicity and IL-2 production.
Corticosteroids & other immunosuppressive agents are used in treatment.