2. Intro: HYPERSENSITIVITY
• Immune responses that normally are protective also are capable of
causing tissue injury.
• Injurious immune reactions are grouped under hypersensitivity, and
the resulting diseases are called hypersensitivity diseases.
• 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
3. Causes
• Pathologic immune responses may be directed against different types
of antigens and may result from various underlying abnormalities
• Autoimmunity: reactions against self antigens
• Reactions against microbes
• Reactions against environmental antigens
4. Causes
• In all of these conditions, tissue injury is mediated by the same
mechanisms that normally function to eliminate infectious
pathogens—namely, antibodies, effector T lymphocytes, and various
other effector cells.
• The fundamental problem in these diseases is that the immune
response is triggered and maintained inappropriately.
• Because the stimuli for these abnormal immune responses are
difficult or impossible to eliminate, and the immune system has many
intrinsic positive feedback loops
• Once a hypersensitivity reaction starts, it is difficult to control or
terminate it.
6. Immediate (Type I) Hypersensitivity
• Immediate hypersensitivity is a 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.
• Many allergens are environmental substances that certain individuals
are predisposed to developing allergic reactions against.
• TH2 cells and IgE are responsible for the clinical and pathologic
manifestations of the reaction
10. Development of Allergies
• Susceptibility to immediate hypersensitivity reactions is genetically
determined.
• An increased propensity to develop immediate hypersensitivity
reactions is called atopy.
• 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
• Environmental factors are also important in the development of
allergic diseases
12. Antibody-Mediated Diseases (Type II
Hypersensitivity)
• Antibody-mediated (type II) hypersensitivity disorders are 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).
• These reactions are the cause of several important diseases
15. Immune Complex–Mediated Diseases (Type
III Hypersensitivity)
• Antigen–antibody (immune) complexes that are formed in the
circulation may deposit in blood vessels, leading to complement
activation and acute inflammation
• Less frequently, the complexes may be formed at sites where antigen
has been “planted” previously (called in situ immune complexes).
• The antigens that form immune complexes may be exogenous, such
as a foreign protein that is injected or produced by an infectious
microbe, or endogenous, if the individual produces antibody against
self antigens (autoimmunity)
18. T Cell–Mediated Diseases (Type IV
Hypersensitivity)
• 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
23. Immunologic Tolerance
• Immunologic tolerance is a state of unresponsiveness to an antigen
that is induced by exposure of specific lymphocytes to that antigen.
• Self-tolerance refers to lack of immune responsiveness to one’s own
tissue antigens
• Billions of different antigen receptors are randomly generated in
developing T lymphocytes and B lymphocytes, and it is not surprising
that during this process, receptors are produced that can recognize
self antigens
• Since these antigens cannot all be concealed from the immune
system, there must be a means of eliminating or controlling self
recognizing lymphocytes
25. Mechanisms of Autoimmunity
• The best guess is that breakdown of self-tolerance and development
of autoimmunity result from the combined effects of susceptibility
genes, which influence lymphocyte tolerance, and environmental
factors,
• Such as infections or tissue injury, that alter the display of and
responses to self antigens
• Most autoimmune diseases are complex multigenic disorders
28. Systemic Lupus Erythematosus
• SLE is an autoimmune disease involving multiple organs, characterized by a
vast array of autoantibodies, particularly antinuclear antibodies (ANAs),
• In which injury is caused mainly by deposition of immune complexes and
binding of antibodies to various cells and tissues
• Injury to the skin, joints, kidney, and serosal membranes is prominent, but
virtually every organ in the body may be affected.
• SLE is a fairly common disease, with a prevalence that may be as high as
400 per 100,000 in certain populations
• Although SLE often presents when a person is in the twenties or thirties, it
may manifest at any age, even in early childhood
31. Pathogenesis
• The fundamental defect in SLE is a failure of the mechanisms that
maintain self-tolerance.
• Although what causes this failure of self-tolerance remains unknown,
as is true of most autoimmune diseases, both genetic and
environmental factors play a role
• Recent studies in animal models and patients have revealed several
immunologic aberrations that collectively may result in the persistent
and uncontrolled activation of selfreactive lymphocytes
• UV irradiation and other environmental insults lead to the apoptosis
of cells. Inadequate clearance of the nuclei of these cells results in a
large burden of nuclear antigens
34. OTHERS
• Rheumatoid arthritis is an autoimmune disease that affects primarily
the joints but also may involve extraarticular tissues such as the skin,
blood vessels, lungs, and heart
• Sjögren syndrome is a chronic disease characterized by dry eyes
(keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from
immunologically mediated destruction of the lacrimal and salivary
glands
• Systemic sclerosis is an immunologic disorder characterized by
excessive fibrosis in multiple tissues, obliterative vascular disease, and
evidence of autoimmunity, mainly the production of multiple
autoantibodies.
36. REJECTION OF TRANSPLANTS
• Rejection is a process in which T lymphocytes and antibodies
produced against graft antigens react against and destroy the grafts
• The major antigenic differences between a donor and recipient that
result in rejection of transplants are differences in HLA alleles
• Graft rejection is classified into hyperacute, acute, and chronic, on the
basis of clinical and pathologic features
• Hyperacute rejection is mediated by preformed antibodies specific for
antigens on graft endothelial cells.
• Acute rejection is mediated by T cells and antibodies that are
activated by alloantigens in the graft
