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Chapter 16
Tolerance and Autoimmunity
Dr. Capers
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Kuby IMMUNOLOGYSixth Edition
Chapter 16Tolerance and Autoimmunity
Copyright © 2007 by W. H. Freeman and Company
Kindt • Goldsby • Osborne
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“Horror Autotoxicus”
Failure of host’s humoral and cellular immune systems to distinguish self from non-self
AutoimmunityCan result in tissue and organ damage, can
be fatal
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Tolerance
# of mechanisms are in place to protect individual from self-reactive lymphocytesCentral tolerance – deleting T or B clones
before maturity if they have receptors that recognize self-antigens with great affinity
Peripheral tolerance – kills lymphocytes in secondary lymphoid tissue ○ Also, life span of lymphocytes regulated by
apoptosis
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Some antigens can produce toleranceTermed tolerogens rather than immunogens
○ High dosages of antigen○ Persistance of antigen in host○ IV or oral introduction○ Absence of adjuvants○ Low levels of costimulators
CD28 will bind to B7 and provide activating signals; however, it was discovered that another receptor, CTLA-4 will bind to B7 and inhibit
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AnergyUnresponsiveness to antigenic stimulus
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The F1 mouse does not have any B cells that Express anti-HEL antibodies
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Peripheral ToleranceMay be induced by T
reg
cells○ Unique group of CD4+
T cells○ Recognize self-
antigens on immune system cells and seem to be able to suppress immune system
○ Induce cell death in some immune cells
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Organ-specific autoimmune diseases Target antigen specific to organ or gland
Cellular lysis and chronic inflammation that can damage organ
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Hashimoto’s ThyroiditisMainly middle-aged womenTarget is thyroid antigensGoiter can formHypothyroidism - decrease
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Autoimmune anemiasPernicious anemia
○ Ab against membrane bound intestinal protein that uptakes B12 - needed for hematopoiesis
Hemolytic anemia○ Abs to red-blood cell antigens
Drug-induced anemia
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Goodpasture’s syndromeAbs against basement membranes in
glomeruli and aveoliLeads to kidney damage and pulmonary
hemmorhage
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Insulin-Dependent Diabetes MellitusAbs against beta cells that produce insulinInsulin is needed by cells to uptake glucose
needed for cellular respiration
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In some autoimmune diseases, antibodies act as agonistsBind inappropriately to receptors, resulting
in overproduction○ For example, up-regulating a hormonal
response without the presence of that hormone
○ Grave’s Disease – auto-Ab binds to receptor for thyroid stimulating hormone resulting in over-stimulation of thyroid
○ Myasthenia gravisAuto-Abs bind acetylcholine receptors on motor end
plate of muscles – progressively weakened skeletal muscles
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Systemic Autoimmune Diseases Response is directed toward wide range
of target antigens
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Systemic Lupus ErythematosusTypically middle-aged womenFever, weakness, arthritis, skin rash, kidney
problemsProduce auto-Abs to DNA, histones,
platelets, leukocytes, clotting factorsExcessive complement activation
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Multiple sclerosisNumbness, paralysis, vision lossInflammatory lesions in myelin sheath caused
by T cellsEpidemiology
○ Frequent in African American and Hispanic women
○ More common in Northern Hemisphere, more common north of 37th parallel
○ Environmental components as well as genetic components
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Rheumatoid ArthritisChronic inflammation of jointsProduce auto-Abs that bind Fc portion of
IgG circulating in blood that creates immune complexes
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Animal Models
Autoimmunity develops spontaneously in some lab animals and can be induced with manipulationRabbits injected with acetylcholine receptors
from eels○ Soon developed muscular weakness as seen
with Myasthenia gravis
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Animal models have implicated CD4+ T cells to be primary mediator of some autoimmune responsesTreatment with anti-CD4 antibodies can help
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Some studies have shown association between expressing particular MHC allele and susceptibility to autoimmunityIndividuals that express HLA-B27 have 90
times greater chance of having ankylosing spondylitis (spine inflammation)○ Interestingly, most of those are male even
though women are more likely to suffer from autoimmune disease
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Proposed mechanisms for induction of autoimmunityRelease of sequestered antigens
○ Blood-brain barrier, sperm released into tissues during vasectomy
Molecular mimicryInappropriate expression of Class II MHC
○ Non-antigen presenting cells will for some reason express Class II MHC
- Can be caused by viral infection
○ This allows them to present self antigen to T helper cells – leads to inappropriate reaction
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Treatment
Immunosuppressive drugs Removal of thymus (for example, with
myasthenia gravis) Plasmapheresis – removing plasma and
then returning RBCs (removes extra immune complexes)
Treating the inflammation Antigen given orally can induce
tolerance