Transcript The Immune System Second Edition

Peter Parham
The Immune System
Second Edition
Chapter 11
Disruption of Healthy Tissue by the
Immune Response
Copyright © 2005 by Garland Science Publishing
Autoimmune diseases
Autoimmunity or autoimmune disease - the process of developing an
immune response to self antigens (autoantigens).
leads to chronic inflammatory damage to tissues.
Classified based on the types of immune responses with which you are
already familiar (i.e., hypersensitivity reactions, types II, III and IV).
(autoimmune diseases are never caused by IgE, the source of type I
hypersensitivity reactions).
Type II hypersensitivity-related autoimmune diseases
Antibody responses against red blood cells.
Autoimmune hemolytic anemia. Antibodies are raised against
cell surface antigens on red blood cells, resulting in destruction of red cells
and anemia.
two primary antigens are recognized:
an IgG response against Rh antigens
an IgM response against I antigens present in glycophorin
The IgM response leads to a version of hemolytic anemia termed cold
hemagglutinin disease (CHAD). The antibodies agglutinate cells with
increasing strength as the temperature drops. Extensive hemolysis occurs
when arms, legs and extremities drop below 37oC in cold weather.
Graves’
disease.
Antibodies
developed
against
receptors
for thyroidstimulating
hormone
(TSH)
Myasthenia gravis. Autoantibodies against acetylcholine receptors at the
neuromuscular junction.
Type III hypersensitivity-related autoimmune diseases (Immune-complex
mediated autoimmune disease).
Systemic lupus erythematosus (SLE).
Circulating IgG antibodies against common cellular constituents like cell
surface components and constituents of cytoplasm and nucleus (e.g., doublestranded DNA, nucleosomes (DNA-histone complexes), spliceosomes, and a
small cytoplasmic ribonucleoprotein complex.
Soluble immune complexes
Poor at fixing complement
Y
Not cleared
blood vessel walls
YY
Y
Joints
+
Complement
Activated neutrophils
large aggregates
Renal glomerulus
inflammation and tissue damage
T-cell-mediated autoimmune diseases. Resulting from T cells specific for
self antigens- (like type IV hypersensitivity reactions)
Multiple sclerosis. Autoimmune response against the myelin sheath
of nerve cells. Involves demyelination of central nervous system tissue
resulting in sclerotic plaques of demyelinated tissue.
The initial lesion development appears dependent on T cell infiltration
into the CNS. Best guess is activated TH1 CD4 cells that secrete interferon-g,
which activates macrophages, which are the direct cause of demyelination.
. Model for multiple sclerosis: experimental allergic encephalomyelitis
(EAE)
caused by immunizing mice or rats with myelin basic protein. Develop
T cells specific for myelin basic protein, a protein found in the myelin sheath that
surrounds nerve cell axons in the brain and spinal cord.
Mouse – inject with MBP + adjuvant (heat-killed bacteria)
paralysis
mediated by MBP-specific TH1 cells (inflammatory T cells). MBP is processed
for presentation by MHC class II molecules to CD4+ T cells. Transfer of CD4+ T
cells to another inbred mouse with same MHC causes transfer of the disease as
well.
TH1
IFN-g, TNF-a
MHCII
similar to T cell-mediated delayed-type hypersensitivity or type IV
hypersensitivity. When TH1 cells encounter MBP, can produce
inflammation.
Type I diabetes mellitus (insulin-dependent diabetes mellitus, IDDM).
Destruction of the insulin-producing b cells of the pancreas by CD8 T cells
(cytotoxic T cells) that recognize peptides from a b cell specific protein and kill
the b cell.
cells make: glucagon insulin somatostatin
Islet cell type
a
b
g
express on surface different cell-specific peptides.
Effector CD8 T cell
Candidate autoantigens :
glutamic acid decarboxylase, tyrosine phosphatase IA-2, SOX13
transcription factor, and insulin or proinsulin itself.
Antibody and T cell-mediated autoimmune disease.
Rheumatoid arthritis.
Chronically inflamed joints infiltrated by multiple immune cells.
TH1 cells recognizing a specific antigen present within the joint
triggers them to release inflammatory cytokines to initiate local inflammation
plasma cells make a IgM, IgG and IgA that binds to the Fc region
of patients’ own IgG - called rheumatoid factor (RF). These are deposited
in the joints and activate complement cascade to increase inflammatory
response.
All autoimmune diseases involve a breach of the normal mechanisms of self
tolerance.
Self-reactive B cells are eliminated during maturation in the bone marrow
Self reactive B cells in the periphery die by apoptosis or become anergic.
Autoimmune diseases require a breakdown in T cell tolerance
Negative selection of self-reactive T cells occurs during development in
the thymus
epithelial cells in the thymus express lots of relatively rare proteins
under the control of a transcription factor known as the autoimmune regulator
(AIRE).
defective alleles of AIRE lead to incomplete negative selection and
inherited autoimmune polyglandular disease.
Self-reactive (naive) T cells that do escape negative selection are usually not
activated by binding cells expressing specific peptide-MHC complexes because
these don’t express B7 (needed for co-stimulatory signal by binding CD28).
Induces anergy.
Genetic predisposition to development of autoimmune disease.
Certain inbred strains of mice reliably develop spontaneous
autoimmune diseases.
20% of monozygotic twins show disease concordance; <5% of
dizygotic twins show concordance.
genetic studies indicate the inheritance of susceptibility is polygenic
– meaning several independently segregating disease susceptibility loci exist.
The genes most consistently associated with susceptibility to
autoimmune diseases are those of the MHC or HLA (human MHC) complex.
Environmental contributions to loss of self-tolerance.
genetically predisposed individuals at highest risk develop disease at a
maximum frequency of about 20%.
trauma can cause disruption of cell or tissue barrier allowing a formerly
sequestered antigen to become recognized. An example of this is sympathetic
ophthalmia.
Infectious agents.
Infections trigger an autoimmune response.
Molecular mimicry. Antibodies or T cells generated in response to
an infectious agent cross-react with self antigens.
chronic autoimmune diseases caused by autoreactive T cells that arise in the
course of combating infection.
Most tissue specific antigens are not presented by APC’s and are not, therefore,
on cells that express B7 co-stimulatory molecules (induces anergy). However,
perhaps dead or infected cells are taken up by APC’s, which present selfantigens and activate effector T cells.
Inflammatory
cytokines like
IFN-g can
induce some
cells to express
HLA class II
molecules.
Epitope
spreading
in SLE
Senescence of the T cell population
The hygiene hypothesis arises again!
Incidence of autoimmune disease is increasing in developed countries. Lack
of exposure of children to pathogens alters the way in which the immune
system develops so they are less skilled in attacking pathogens while
maintaining T cell tolerance.