Basic Principles of Hypersensitivity Reactions

1. Hypersensitivity
DR. HADI MUNIB
ORAL AND MAXILLOFACIAL SURGERY
RESIDENT

2. Outline
▪ Definition
▪ Causes
▪ Classification
▪ References

3. Definition
▪ Immune responses that normally are protective also are capable of
causing tissue injury.
▪ Hypersensitivity; Injurious immune reactions
▪ This term originated from the idea that persons who mount immune
responses against an antigen are sensitized to that antigen, so pathologic
or excessive reactions represent manifestations of a hypersensitive state.
▪ Normally, an exquisite system of checks and balances optimizes the
eradication of infecting organisms without serious injury to host tissues.

4. Causes of Hypersensitivity
▪ Pathologic immune responses may be directed against different types
of antigens
▪ Autoimmunity; Reactions against self antigens. Self Tolerance
▪ Reactions against Microbes
▪ Reactions against environmental antigens; Almost 20% of the
population is allergic to common environmental substances
▪ These diseases tend to be chronic and debilitating and are therapeutic
challenges.
▪ Since inflammation is a major component of the pathology of these
disorders, they are sometimes grouped under the term immune-
mediated inflammatory diseases.

5. Classification of Hypersensitivity
▪ Hypersensitivity reactions can be subdivided into four types based on
the principal immune mechanism responsible for injury.
▪ Three are variations on antibody-mediated injury, and the fourth is T-
cell mediated

7. Type I Hypersensitivity
▪ Tissue reaction that occurs rapidly (typically within minutes) after the
interaction of antigen with IgE antibody bound to the surface of mast
cells.
▪ The reaction is initiated by entry of an antigen, which is called an allergen
because it triggers allergy
▪ TH2 cells and IgE are responsible for the clinical and pathologic
manifestations of the reaction.
▪ Immediate hypersensitivity may occur as a local reaction that is merely
annoying (e.g., seasonal rhinitis, hay fever), severely debilitating (asthma),
or even fatal (anaphylaxis).

9. Type I Immediate Hypersensitivity
▪ Susceptibility to immediate hypersensitivity reactions is genetically
determined.
▪ Atopy; increased propensity to develop immediate hypersensitivity
reactions.
▪ Atopic individuals tend to have higher serum IgE levels and more IL-4–
producing TH2 cells than does the general population.
▪ A positive family history of allergy is found in 50% of atopic individuals.
▪ It is estimated that 20% to 30% of immediate hypersensitivity reactions
are triggered by non-antigenic stimuli such as temperature extremes and
exercise, and do not involve TH2 cells or IgE.

10. The incidence of many allergic diseases is increasing in
developed countries and seems to be related to a
decrease in infections during early life.

11. Clinical Manifestations of Type I Hypersensitivity
▪ The immediate response;
▪ Stimulated by mast cell granule contents and lipid mediators and is
characterized by
▪ Vasodilation
▪ Vascular leakage
▪ Smooth muscle spasm
▪ Usually evident within 5 to 30 minutes after exposure to an allergen
and subsiding by 60 minutes;

12. Clinical Manifestations of Type I Hypersensitivity
▪ Late Phase reaction
▪ Stimulated mainly by cytokines
▪ Usually sets in 2 to 8 hours later, may last for several days, and is
characterized by
▪ Inflammation as well as tissue destruction, such as mucosal
epithelial cell damage.
▪ The dominant inflammatory cells are neutrophils, eosinophils, and
lymphocytes, especially TH2 cells

16. Type II Hypersensitivity – Antibody Mediated
▪ Caused by antibodies directed against target antigens on the surface of
cells or other tissue components.
▪ The antigens may be normal molecules intrinsic to cell membranes or in
the extracellular matrix, or they may be adsorbed exogenous antigens
(e.g., a drug metabolite).
▪ Antibodies cause disease by targeting cells for phagocytosis, activating
the complement system, or interfering with normal cellular functions
▪ Opsonization and phagocytosis

17. Type II Hypersensitivity
▪ Antibody-mediated cell destruction and phagocytosis occur in the following
clinical situations:
1. Transfusion reactions, in which cells from an incompatible donor react
with preformed antibody in the host
2. Hemolytic disease of the newborn (erythroblastosis fetalis), in which IgG
anti–red blood cell antibodies from the mother cross the placenta and
cause destruction of fetal red blood cells
3. Autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia,
in which individuals produce antibodies to their own blood cells
4. Certain drug reactions, in which a drug attaches to plasma membrane
proteins of red blood cells and antibodies are produced against the drug-
protein complex.

18. Type II Hypersensitivity Reaction
▪ Mechanisms of Antibody Mediated Hypersensitivity
▪ Opsonization and Phagocytosis
▪ Inflammation. Antibodies bound to cellular or tissue antigens
activate the complement system by the classical pathway
▪ Antibody-mediated cellular dysfunction. In some cases, antibodies
directed against a host protein impair or dysregulate important
functions without directly causing cell injury or inflammation

21. Type III Hypersensitivity (Immune-Complex Mediated)
▪ Antigen–antibody (immune) complexes that are formed in the
circulation may deposit in blood vessels, leading to complement
activation and acute inflammation.
▪ In Situ Immune Complexes; Less frequently, the complexes may be
formed at sites where antigen has been “planted”.
▪ The antigens that form immune complexes may be exogenous, such as
a foreign protein or an infectious microbe
▪ Endogenous if the individual produces antibody against self antigens
(autoimmunity).

23. Systemic Immune Complex Disease
▪ Acute serum sickness is the prototype of a systemic immune complex
disease.
▪ Was once a frequent sequela to the administration of large amounts of
foreign serum.
▪ In modern times, the disease is infrequent and usually seen in individuals
who receive antibodies from other individuals or species.
▪ The pathogenesis can be divided into three phases
1. Formation of Immune Complexes; 1 week after protein injection
2. Deposition of Immune Complexes
3. Inflammation and Tissue Injury; 10 days, vasculitis if it occurs in blood
vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it
occurs in the joints.

25. Systemic Immune Complex Disease
▪ A form of chronic serum sickness results from repeated or
prolonged exposure to an antigen.
▪ This occurs in several diseases, such as systemic lupus
erythematosus
▪ In many diseases, the morphologic changes and other findings
suggest immune complex deposition, but the inciting antigens are
unknown.
▪ Included in this category are membranous glomerulonephritis and
several vasculitides.

26. Local Immune Complex Disease
▪ A model is the Arthus reaction, in which an area of tissue necrosis appears
as a result of acute immune complex vasculitis.
▪ The reaction is produced experimentally by injecting an antigen into the skin
of a previously immunized animal with preformed antibody.
▪ Immune complexes form as the antigen diffuses into the vascular wall at the
site of injection.
▪ Arthus lesions evolve over a few hours and reach a peak 4 to 10 hours after
injection
▪ When the injection site develops edema and hemorrhage, occasionally
followed by ulceration.

27. T-Cell Mediated Hypersensitivity – Type IV
▪ Several autoimmune disorders, as well as pathologic reactions to
environmental chemicals and persistent microbes, are now known
to be caused by T cells
▪ Two types of T cell reactions are capable of causing tissue injury
and disease:
1. Cytokine-mediated inflammation, in which the cytokines are
produced mainly by CD4+ T cells
2. Direct cell cytotoxicity, mediated by CD8+ T cells

30. CD4+ T Cell–Mediated Inflammation
▪ Cytokines produced by the T cells induce inflammation that may be chronic and
destructive.
▪ The prototype is delayed-type hypersensitivity (DTH), a tissue reaction to antigens
given to immune individuals.
▪ An antigen administered into the skin of a previously immunized individual results
in a detectable cutaneous reaction within 24 to 48 hours
▪ Naïve T cells are activated in secondary lymphoid organs by recognition of peptide
antigens displayed by dendritic cells.
▪ The T cells differentiate into effector cells under the influence of various cytokines
▪ Classical T cell–mediated hypersensitivity is a reaction of TH1 effector cells, but
TH17 cells also may contribute to the reaction
▪ Especially when neutrophils are prominent in the inflammatory infiltrate.

31. CD4+ Cell Mediated Inflammation
▪ The classic example of DTH is the tuberculin reaction (known as the PPD
skin test)
▪ Which is produced by the intracutaneous injection of purified protein
derivative (PPD, also called tuberculin)
▪ A protein-containing antigen of the Mycobacterium tuberculosis bacillus.
▪ In a previously exposed individual, reddening and induration of the site
appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter
slowly subside.
▪ Morphologically, delayed-type hypersensitivity is characterized by the
accumulation of mononuclear cells, mainly CD4+ T cells and macrophages,
around venules, producing perivascular “cuffing”

32. CD4+ Cell-Mediated Inflammation
▪ Prolonged DTH reactions against persistent microbes or other stimuli
may result in a reaction called granulomatous inflammation.
▪ The initial perivascular CD4+ T cell infiltrate is progressively replaced
by macrophages over a period of 2 to 3 weeks.
▪ These accumulated macrophages typically exhibit morphologic
evidence of activation, they become large, flat, and eosinophilic, and
are called epithelioid cells.
▪ The epithelioid cells occasionally fuse under the influence of cytokines
(e.g., IFN-γ) to form multinucleate giant cells.
▪ An aggregate of epithelioid cells, typically surrounded by a collar of
lymphocytes, is called a granuloma

33. CD4+ Cell Mediated Inflammation
▪ Contact dermatitis is a common example of tissue injury resulting
from DTH reactions.
▪ It may be evoked by contact with urushiol, the antigenic
component of poison ivy or poison oak, and presents as a vesicular
dermatitis.
▪ The environmental chemical binds to and structurally modifies self
proteins, and peptides derived from these modified proteins are
recognized by T cells and elicit the reaction.

36. Granulomatous
Inflammation

37. CD8+ T-Cell Mediated Cytotoxicity
▪ In this type of T cell–mediated reaction, CD8+ CTLs kill antigen-expressing
target cells.
▪ Tissue destruction by CTLs may be an important component of some T cell–
mediated diseases, such as type 1 diabetes.
▪ They also play a role in reactions against viruses.
▪ In a virus infected cell, viral peptides are displayed by class I MHC molecules
and the complex is recognized by the TCR of CD8+ T lymphocytes.
▪ The killing of infected cells leads to elimination of the infection, but in some
cases, it is responsible for cell damage that accompanies the infection.
▪ CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in
inflammatory reactions resembling DTH, especially following virus infections
and exposure to some contact sensitizing agents.

38. References
▪ Chapter 5: Hypersensitivity: Immunologically Mediated Tissue
Injury (134 – 145)

39. THANK YOU!