This document provides an overview of hypersensitivity, specifically type 1 or immediate hypersensitivity reactions. It discusses the mechanisms, classification, causes, cells and mediators involved. Type 1 reactions are IgE-mediated and occur rapidly upon re-exposure to an allergen. Mast cell and basophil degranulation releases histamine and other mediators, causing symptoms. Reactions can be systemic anaphylaxis or localized atopy. Treatment focuses on allergen avoidance, desensitization, and anti-IgE antibodies.
2. INTRODUCTION
• Hypersensitivity is an immune response mobilizes a battery of effector
molecules that act to remove antigen by various mechanisms.
• Generally, these effector molecules induce a localized inflammatory
response that eliminates antigens without extensively damaging the host’s
tissue.
• Under certain circumstances, however, this inflammatory response can
have deleterious effects, resulting in tissue damage or even death.
• This inappropriate immune response is termed hypersensitivity
or allergy.
3. • The word ‘hypersensitivity’ implies an increased response.
• It may develop in the course of either humoral or cell-mediated
immunity.
• Hypersensitivity reaction denotes an immune response resulting in
exaggerated or inappropriate reaction in a sensitized individual on re-
exposure to the same antigen.
7. • Hypersensitivity essentially has two components : First, priming dose (
first dose ) of antigen is essential which is required to prime the
immune system, followed by a shocking dose ( second dose ) of the
same antigen that results in the injurious consequences.
PRINCIPLE OF HYPERSENSITIVITY
8. CLASSIFICATION OF
HYPERSENSITIVITY
• Based on the time taken for the reactions
and the mechanisms that cause the tissue
damage,
i. Delayed Type Hypersensitivity
(DTH)
ii. Immediate Hypersensitivity
9. GELL AND
COOMBS
CLASSIFICATION
• P.G.H Gell and R.R.A Coombs ( 1963 )
classified hypersensitive reactions into Four
Categories based on the time elapsed from
the exposure to antigen to the reaction and
the arm of the immune system involved.
HUMORAL
BRANCH
• IgE mediated (type I)
• Ab mediated (type II)
• Immune complex
mediated (type III)
CELL
MEDIATED
BRANCH
• Delayed type
hypersensitivity or DTH
(type IV)
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17. IgE MEDIATED (TYPE I)
HYPERSENSITIVITY
• Induced by certain types of ‘antigens’ referred to as allergens and has all the
hallmarks of a normal humoral response.
• So that type I reactions are known as allergic or immediate hypersensitivity
reactions.
• Type I reaction is always rapid, occurring within minutes of exposure to an
antigen and always involves IgE mediated degranulation of basophils or
mast cells.
• Type I reactions are also known as IgE mediated hypersensitivity reactions.
• IgE is responsible for senzitising mast cells and providing recognition of
antigen for immediate hypersensitivity reactions.
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20. GENERAL MECHANISM OF
TYPE I REACTION
• Exposure to an allergen activates B cells to form
IgE secreting plasma cells.
• The secreted IgE molecules bind to IgE specific
Fc receptors on mast cells and blood basophils.
• Second exposure to the allergen leads to
crosslinking of the bound IgE, triggering the
release of pharmacologically active mediators,
vasoactive amines, from mast cells and
basophils.
• The mediators cause smooth-muscle contraction,
increased vascular permeability and vasodilation.
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25. CAUSES
• ALLERGENS
oAfter an individual has been exposed to an antigen, serum IgE levels
increase and remain high until the parasite is successfully cleared from the
body.
oThe IgE regulatory defects suffered by atopic individuals allow nonparasitic
antigens to stimulate inappropriate IgE production, leading to tissue
damaging type I hypersensitivity.
oThe term ‘allergens’ refers specifically to nonparasitic antigens capable of
stimulating type I hypersensitivity responses in allergic individuals.
26. oThe abnormality called ‘atopy’ is a hereditary predisposition to the
development of immediate hypersensitivity reactions against common
environmental antigens. This condition is partly genetic.
oThey have abnormally high levels of circulating IgE and eosinophils.
oThey have mainly two loci: One locus, on chromosome 5q, is linked to
cytokines, that includes IL-3, IL-4, IL-9, IL-13 and GM-CSF.
oSecond locus, on chromosome 11q, is linked to a region that encodes
the ß chain of the high affinity IgE receptor.
27. • Most allergic IgE responses occur on
mucous membrane surfaces in response
to allergens that enter the body by either
inhalation or ingestion.
• The strength of the allergen causing
hypersensitivity depends on the dose,
sensitizing route, adjuvant and most
important, the genetic constitution of the
recipient.
28. REAGINIC ANTIBODY (IgE)
• The existence of a human serum factor that reacts with allergens was
first demonstrated by K. Prausnitz and H. Kustner in 1921.
• The local wheal and flare response that occurs when an allergen is
injected into a sensitized individual is called the P-K reaction.
• Although, the half life of IgE in the serum is only 2-3 days, once IgE
has been bound to its receptor on mast cells and basophils, it is stable
in that state for a number of weeks.
29. MAST CELLS AND BASOPHILS
• Basophils are granulocytes that circulate in the blood of most
vertebrates, in humans they account for 0.5-1.0 percent of the
circulating WBCs.
• Mast cell precursors are formed in bone marrow during
haematopoiesis and are carries to virtually all vascularized peripheral
tissues, where they differentiate into mature cells.
• Mast cells secrete a large variety of cytokines that affect a broad
spectrum of physiologic, immunologic, and pathologic processes.
CELLS INVOLVED IN TYPE 1
HYPERSENSITIVITY
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31. IgE CROSSLINKAGE INITIATES
DEGRANULATION
• IgE mediated degranulation begins when an allergen (divalent or
multivalent) crosslinks IgE that is bound to the Fc receptor on the surface of
a mast cell or basophil.
• The importance of crosslinkage is indicated by the inability of monovalent
allergens, which cannot crosslink the fixed IgE, to trigger degranulation.
• The essential step in degranulation is the crosslinkage of two or more Fc€RI
molecules- with or without bound IgE.
• Anaphylatoxins (C3, C4, and C5a) and various drugs can trigger
degranulation.
32. BIOLOGICAL MEDIATORS OF
ANAPHYLAXIS
• Mediators are pharmacologically active agents that act on local tissues
as well as on populations of secondary effector cells such as
eosinophils, neutrophils, T lymphocytes, monocytes and platelets.
• During parasitic infection, these mediators initiate vasodilation and
increase vascular permeability ,which brings an influx of plasma and
inflammatory cells to attack the pathogen.
• Mediators can be classified into two: primary and secondary
33. • The primary mediators are produced before degranulation and are
stored in granules. It includes histamine, proteases, eosinophil
chemotactic factor, neutrophil chemotactic factor and heparin.
• The secondary mediators either are synthesized after target-cell
activation or are released by the breakdown of membrane
phospholipids during the degranulation process. It includes platelet-
activating factor, leukotrienes, prostaglandins, bradykinins and various
cytokines.
35. HISTAMINE
• Primary mediators
• Formed by decarboxylation of the amino acid histidine
• Major component of mast cell granules
• Biological effects are observed within minutes of mast cell activation
• Once released from mast cell, it initially binds to specific receptors on
various target cells
36. • 3 types of histamine receptors:
• H1: present on smooth muscles of bronchi and actions stop by
antihistamines.
• H2 : present on stomach and action stops by cimetidine
• H3 : present in CNS. It is under research
37. • Biological effects of histamine in allergic reactions are mediated by the
binding of histamine to H1 receptors.
• This binding induces contraction of intestinal and bronchial smooth
muscles, increased permeability of venules, and increased mucus secretion
by goblet cells.
• Interaction of histamine with H2 receptors increases vasopermeability and
dilation and stimulates exocrine glands.
• Binding of histamine to H2 receptors on mast cells and basophils suppresses
degranulation; thus, histamine exerts negative feedback on the release of
mediators.
38. • Histamine clinically leads to:
Wheal and flare
Broncho-constriction
Increase mucous secretions
Hypotension due to increased vasodilation and increased vascular
permeability
Cardiac arrhythmia
39. • Histamine target area show:
oSkin- edema and hives
oTrachea and bronchi-asthma and increased mucous secretions
oEyes and nose-increased secretions and red eye
oUterus- abortion and pain
oGastrointestinal tract- nausea, vomiting, diarrhea, abdominal pain
40. SEROTONIN
• Found in preformed state in mast cells and platelets
• It causes vasoconstriction, increased permeability and smooth muscle
contraction.
41. LEUKOTRIENES AND
PROSTAGLANDINS
• As secondary mediators, the leukotrienes and prostaglandins are not
formed until the mast cell undergoes degranulation and the enzymatic
breakdown of phospholipids in the plasma membrane.
• These are more pronounced and long lasting than histamine.
• An ensuing enzymatic cascade generates the prostaglandins and the
leukotrienes.
• The leukotrienes mediate bronchoconstriction, increased vascular
permeability and mucus production.
• Prostaglandin D2 causes bronchoconstriction.
42. LEUKOTRIENES
• Metabolites of arachidonic acid metabolism
• More potent and strong than histamine
• These are vasoactive and spasmogenic leads to contraction of smooth
muscles and increase vascular permeability
• Eg: LTB4 – chemotactic for monocytes, eosinophils.
• LTC4 – called as SRS-A
43. PROSTAGLANDINS (PGD2)
• Produced by human mast cells and leads to an increase in the
secretion, edema and smooth muscle contraction
• Bridging of antigen and antibody over the surface of the mast cell or
basophil leads to release of mediators
44. PLATELET ACTIVATING FACTOR (PAF)
• Generated from the complex lipids stored in the cell membrane
It leads to : Platelet aggregation and their lysis leading to histamine
release
It activates neutrophils and eosinophils
Most potent eosinophil chemotactic factor
45. CYTOKINES
• Cytokines are produced from mast cells and eosinophils.
• Human mast cells secrete IL-4, IL-5, IL-6 and TNF-๕, which leads to
the recruitment of inflammatory cells such as neutrophils and
eosinophils.
• IL-4 increases IgE production by B cells.
• IL-5 is important in the recruitment and activation of eosinophils.
• TNF-๕ secreted by mast cells may contribute to shock in systemic
anaphylaxis.
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48. TYPES OF TYPE 1 REACTIONS
• SYSTEMIC ANAPHYLAXIS
• Systemic anaphylaxis is a shock like and often fatal state whose onset
occurs within minutes of a type 1 hypersensitive reaction.
• Observed by Portier and Richet
• ALLERGENS : Venom of bee, wasp, hornet, and ant stings; drugs
such as penicillin, insulin and antitoxins, and seafood and nuts.
• Epinephrine is the drug of choice for systemic anaphylaxis.
49. • Epinephrine is the drug of choice in the
systemic anaphylaxis.
• By reducing the vascular permeability
and relaxing the smooth muscles, it
counteracts the effects of histamine and
the leukotrienes.
• It improves the cardiac output and
prevent the vascular collapse.
• It increases cAMP levels in the mast
cell, thereby block degranulation.
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51. LOCALIZED ANAPHYLAXIS (ATOPY)
• Reaction is limited to a limited target tissue or organ
• Coined by Coca and Cookie (1923)
• The tendency to manifest localized anaphylactic reactions is inherited
and is called atopy.
• Atopy is recurrent, non-fatal and local manifestation of immediate
hypersensitivity reaction.
• Common manifestations include asthma, allergic rhinitis (hay fever),
atopic dermatitis (eczema) and food allergies.
52. • ALLERGIC RHINITIS: the most common
atopic disorder, commonly known as hay fever.
• CAUSE: the airborne allergens with sensitized
mast cells in the conjunctivae and nasal mucosa
to induce the release of pharmacologically active
mediators from mast cells; these mediators then
cause localized vasodilation and increased
capillary permeability.
• SYMPTOMS: watery exudation of the
conjunctivae, nasal mucosa, and upper
respiratory tract as well as sneezing and
coughing.
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54. • FOOD ALLERGIES: Allergen
crosslinking of IgE on mast cell along
the upper or lower gastrointestinal
tract can induce localized smooth
muscle contraction and vasodilation.
• Mast cell degranulation along the gut
increase the permeability of the
mucous membranes, so that the
allergen can be entered into the
bloodstream.
• Symptoms depends on where the
allergen is deposited.
55. • ATOPIC DERMATITIS: Inflammatory disease of
skin
• Most frequently observed in young children,
during infancy
• Serum IgE levels are elevated
• The allergic individuals develops skin eruptions
that are erythematous and filled with pus
56. LATE-PHASE
REACTION
• As a type 1 hypersensitive reaction
begins to subside, mediators released
during the course of the reaction often
induce localized inflammation called
late-phase reaction.
• Late phase reaction begins to develop 4-
6h after initial type 1 reaction and
persists for 1-2 days.
• Mediated by neutrophils, eosinophils,
macrophages, partly by cytokines
produced by mast cells.
59. TREATMENT
• Avoid contact with known allergens
• Repeated injections of increasing dose of
allergens (hyposensitization)
• Use of humanized monoclonal anti-IgE
