Transcript Immunology - Biology - Missouri State University

Immunology
Chapter 20
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Richard L. Myers, Ph.D.
Department of Biology
Southwest Missouri State
Temple Hall 227
Springfield, MO 65804
417-836-5307
[email protected]
Homepage:
http://science.smsu.edu/~myers
Autoimmunity
• Autoimmunity results when the immune
system responds to self-components
– tolerance usually protects an individual
– protection is through clonal anergy or clonal
suppression
• A breakdown in tolerance can lead to selfreactive clones of T or B cells
– can cause serious damage to cells and organs
Organ-specific disease
• Humoral or cell-mediated damage can be
directed to target organs
• Cellular damage
– antibodies or lymphocytes bind to cellmembrane antigens
– cause cellular lysis/inflammatory response
– function of the organ is gradually lost
Hashimoto’s thyroiditis
• Autoantibodies are produced
– also sensitized TTDH cells
• Characterized by infiltration of
lymphocytes, macrophages and plasma cells
into the thyroid
– the inflammatory response causes a goiter
– an enlargement of the thyroid gland
• Autoantibodies react with thyroid proteins,
interfering with iodine uptake
Autoimmune anemias
• Includes 1) pernicious anemia, 2)
autoimmune hemolytic anemia and 3) druginduced hemolytic anemia
• Pernicious anemia caused by antibodies to
an intestinal protein, intrinsic factor
– prevents uptake of vitamin B12
• Autoimmune hemolytic anemia caused by
autoantibodies to RBC antigens
– results in complement-mediated lysis or
antibody-mediated opsonization
Goodpasture’s syndrome
• Autoantibodies specific for basement
membrane antigens produced
– bind to membranes of kidney glomeruli and
alveoli of the lungs
– complement activation leads to cell damage and
inflammatory response
• Damage is progressive kidney damage
– and pulmonary hemorrhage
Insulin-dependent diabetes
• Insulin-dependent diabetes mellitus (IDDM)
– caused by autoimmune attack on the pancreas
– large numbers of TDTH cells and macrophages
– directed to insulin-producing cells (beta cells)
• Result is decreased production of insulin
– therefore increased levels of blood glucose
• Beta cell destruction mediated by cytokines
– also lytic enzymes from activated macrophages
– autoantibodies may also contribute
Normal islets (left) and diabetic (right). Note
selective loss of beta cells (brown) and
infiltlration by lymphocytes
Diseases caused by autoantibodies
• Antibodies bind to hormone receptors
– stimulate inappropriate activity
• Graves’ disease is a good example
– thyroid-stimulating hormone (TSH) binds to a
receptor on thyroid cells
– activates adenylate cyclase to stimulate thyroid
hormones
• In Graves’ an autoantibody is produced to
the receptor for TSH
Diseases caused by blocking-autoantibodies
• Autoantibodies bind to hormone receptors
– act as antagonists
– inhibit receptor function
• Myasthenia gravis is the prototype disease
– autoantibodies are produced to the
acetylcholine receptors
– on motor end-plates of muscles
– inhibits muscle activation
Systemic autoimmune diseases
• Represent a generalized defect in immunity
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hyperactive T and B cells
cause tissue damage
from autoantibodies and cell-mediated also
immune complexes important
Systemic lupus erythematosus
• SLE is the best example of a systemic
autoimmune disease
• Usually occurs in young women
– characterized by fever, weakness, joint pain,
erythematous lesion, pleurisy and kidney
dysfunction
• Patients produce autoanibodies to a variety
of tissue antigens like DNA, histones, etc.
– diagnosis made by identifying ANA
Animal models for autoimmunity
• We understand more about autoimmunity
because of animal models
– autoimmunity develops spontaneously
– can also be induced experimentally
• Examples of spontaneous autoimmunity
– systemic lupus erythematosus
– nonobese diabetic (NOD) mouse
Experimentally induced autoimmunity
• Several experimental animal models are
very similar to certain autoimmune diseases
• Experimental autoimmune
encephalomyelitis
– an excellent model for understanding
autoimmunity
– produced by immunizing animals with MBP
• in Freund’s adjuvant
– animals develop cellular infiltration of myelin
sheaths resulting in demyelination and paralysis
– model for multiple sclerosis
Role of CD4 in autoimmunity
• CD4 is the primary mediator of
autoimmunity
• However, to become autoimmune
– must possess MHC and T-cell receptors capable
of binding self-antigens
Evidence for association of MHC
• There is association between expression of
a particular MHC allele and suceptibility to
autoimmunity
• Can be shown by using antibodies to HLA
alleles
– some allelles occur at higher frequency amoung
autoimmune individuals
– association expressed as relative risk
– values above 1 indicate association
Mechanism for induction
• Autoimmunity usually develops from a
number of different events
• Sequestered antigens
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myelin basic protein is a good example
normally sequestered from the immune system
by the blood brain barrier
trauma or an infection releases antigens
i.e., sperm after vasectomy, lens protein after
eye damage and heart antigens after infarction
• Molecular mimicry
– Some bacteria and viruses possess antigens
identical to the host
– fairly common
– i.e., cross-reacting antibodies causing rheumatic
fever
– another example are the heat-shock proteins
– produced by cells following temperature
– these proteins found in a variety of pathogens
– therefore, when you make a response to a
pathogen’s heat-shock proteins, it will crossreact through molecular mimicry
• Inappropriate expression of class II MHC
– in insulin-dependent diabetes mellitus (IDDM)
healthy beta cells do not express class II MHC
– same for thyroid acinar cells
– an inappropriate expression sensitizes T cells to
peptides derived from the beta cells or thyroid
cells
Treatment of autoimmune disease
• Treatments are aimed at reducing symptoms
• They provide nonspecific suppression of the
immune response
– does not differentiate between good and bad
• Use immunosuppressive drugs
– i.e., corticosteroids, azathioprine and
cyclophamide
– patients at greater risk for infections or cancer
Assignment
• Read Chapter 21,
Immunodeficiency
Diseases
• Review question 3 (pg
521)