Module 6: Hypersensitivity
Hygiene hypothesis
Incidences of infectious disease have been reduced and autoimmune and inflammatory disorders
have increased by a change in life-style in industrialized countries hygiene hypothesis
Maybe due to imbalance Th1 vs. Th2
o Th1-promoting viral and bacterial infections would educate the immune system
o Preventing the development of excessive and allergy-promoting Th2
o Would only explain Th2 disorders (asthma and allergies) not Th1/Th17 disorders
(multiple sclerosis, type 1 diabetes)
Maybe due to prevalence of helminth infections
o Inversely correlated with the prevalence of inflammatory disorders
o Both helminths and allergens elicit Th2-mediated immune responses
o Infected children produce much anti-inflammatory cytokine IL-10
o IL-10 is regulated by Tregs just like anti-inflammatory TGF-β1
o IL-10 and TGF-β1 are able to control both Th2-mediated allergies as well as
Th1/Th17-mediated inflammatory disorders
Therefor, infections, and infection experience, are believed to be key in maintaining the
balance between regulatory T cells, on one side, and active Th1, Th2 and Th17 cells on the
other
Stimuli of hypersensitivity diseases
Hypersensitivity inducing antigen sources:
Excessive response to invading microbes causing chronic inflammation
Reactions against environmental antigens by overproducing IgE causing allergy/type 1
hypersensitivity
Reactions can be triggered against auto-antigens causing auto-immunity
With hypersensitivity the response is triggered and maintained inappropriately caused by distortion
of the delicate balance between different T helper subsets (Th1, Th2, Th17, Treg) and within specific
T helper cell responses
Classification of hypersensitivity disorders
Four categories of hypersensitivity:
Immediate hypersensitivity (type I)
o Caused by IgE specific for environmental antigens
o Called allergic or atopic disorder
o Predisposition in the T helper cell balance towards the Th2 subset
o Excessive Th2 response stimulates IgE production
o Sensitization phase: initial exposure to allergens and loading of IgE
o Innate cells will release histamine and trigger inflammation upon re-exposure
Antibody-mediated/ cytotoxic hypersensitivity (type II)
o Caused by IgG and IgM reacting to the antigens on the cell membrane
o Antibodies activate complement system, recruit inflammatory cells and interfere
with normal cellular functions
o Antigens either own cells or foreign
Immune complex-mediated hypersensitivity (type III)
o Caused by IgG and IgM
o Antibodies form soluble antigen-antibody complexes in the circulation and are
deposited in tissues
o Causing tissue necrosis by activating the complement cascade and recruitment of
neutrophils
1
, Cell-mediated/delayed type hypersensitivity (type IV)
o Caused by T lymphocytes that induce inflammation or directly kill target cells
o T lymphocytes become sensitized on initial exposure to the antigen and release
cytokines in subsequent exposure resulting in chronic inflammation
Mechanisms causing hypersensitivity
1. Diseases caused by IgM or IgG antibodies
Type II and type III
Antibodies induce inflammation and tissue damage
Diseases are often not systemic but are restricted to certain organs, causing disease by three
main mechanisms:
o Antibodies bind to cell surface antigens directly opsonize cells or activate the
complement system, resulting in deposition of complement proteins on the cell. The
cells are then marked for phagocytosis
o Antibodies deposited in tissues recruit leukocytes, mainly neutrophils and
macrophages. Activated leukocytes secrete products including lysosomal enzymes
and reactive oxygen species, which cause tissue injury
o Antibodies that bind to normal cellular receptors or other proteins may interfere
with the functions of these and cause disease without inflammation or tissue
damage
Type III is not dependent on the cellular source of the antigen, but on the site of deposition
o These diseases affect multiple tissues and organs
o Antigen-antibody complexes cause disease when produced in excessive amounts or
are not efficiently cleared and become deposited in tissues
2
Hygiene hypothesis
Incidences of infectious disease have been reduced and autoimmune and inflammatory disorders
have increased by a change in life-style in industrialized countries hygiene hypothesis
Maybe due to imbalance Th1 vs. Th2
o Th1-promoting viral and bacterial infections would educate the immune system
o Preventing the development of excessive and allergy-promoting Th2
o Would only explain Th2 disorders (asthma and allergies) not Th1/Th17 disorders
(multiple sclerosis, type 1 diabetes)
Maybe due to prevalence of helminth infections
o Inversely correlated with the prevalence of inflammatory disorders
o Both helminths and allergens elicit Th2-mediated immune responses
o Infected children produce much anti-inflammatory cytokine IL-10
o IL-10 is regulated by Tregs just like anti-inflammatory TGF-β1
o IL-10 and TGF-β1 are able to control both Th2-mediated allergies as well as
Th1/Th17-mediated inflammatory disorders
Therefor, infections, and infection experience, are believed to be key in maintaining the
balance between regulatory T cells, on one side, and active Th1, Th2 and Th17 cells on the
other
Stimuli of hypersensitivity diseases
Hypersensitivity inducing antigen sources:
Excessive response to invading microbes causing chronic inflammation
Reactions against environmental antigens by overproducing IgE causing allergy/type 1
hypersensitivity
Reactions can be triggered against auto-antigens causing auto-immunity
With hypersensitivity the response is triggered and maintained inappropriately caused by distortion
of the delicate balance between different T helper subsets (Th1, Th2, Th17, Treg) and within specific
T helper cell responses
Classification of hypersensitivity disorders
Four categories of hypersensitivity:
Immediate hypersensitivity (type I)
o Caused by IgE specific for environmental antigens
o Called allergic or atopic disorder
o Predisposition in the T helper cell balance towards the Th2 subset
o Excessive Th2 response stimulates IgE production
o Sensitization phase: initial exposure to allergens and loading of IgE
o Innate cells will release histamine and trigger inflammation upon re-exposure
Antibody-mediated/ cytotoxic hypersensitivity (type II)
o Caused by IgG and IgM reacting to the antigens on the cell membrane
o Antibodies activate complement system, recruit inflammatory cells and interfere
with normal cellular functions
o Antigens either own cells or foreign
Immune complex-mediated hypersensitivity (type III)
o Caused by IgG and IgM
o Antibodies form soluble antigen-antibody complexes in the circulation and are
deposited in tissues
o Causing tissue necrosis by activating the complement cascade and recruitment of
neutrophils
1
, Cell-mediated/delayed type hypersensitivity (type IV)
o Caused by T lymphocytes that induce inflammation or directly kill target cells
o T lymphocytes become sensitized on initial exposure to the antigen and release
cytokines in subsequent exposure resulting in chronic inflammation
Mechanisms causing hypersensitivity
1. Diseases caused by IgM or IgG antibodies
Type II and type III
Antibodies induce inflammation and tissue damage
Diseases are often not systemic but are restricted to certain organs, causing disease by three
main mechanisms:
o Antibodies bind to cell surface antigens directly opsonize cells or activate the
complement system, resulting in deposition of complement proteins on the cell. The
cells are then marked for phagocytosis
o Antibodies deposited in tissues recruit leukocytes, mainly neutrophils and
macrophages. Activated leukocytes secrete products including lysosomal enzymes
and reactive oxygen species, which cause tissue injury
o Antibodies that bind to normal cellular receptors or other proteins may interfere
with the functions of these and cause disease without inflammation or tissue
damage
Type III is not dependent on the cellular source of the antigen, but on the site of deposition
o These diseases affect multiple tissues and organs
o Antigen-antibody complexes cause disease when produced in excessive amounts or
are not efficiently cleared and become deposited in tissues
2
