Autoimmunity

1
Autoimmunity
2
Classification of autoimmune diseases by tissues
affected

• develops when a specific adaptive immune response
  is mounted against a self antigen(s)
• sustained because of inability to eliminate
  antigen - chronic inflammation

3
Immunopathogenic Mechanisms in Autoimmune Diseases

• mechanisms of damage similar to protective
  immunity and hypersensitivity diseases
• effector actions of both T and B cells can be
  involved
• antigen that is the target of response and
  mechanism of tissue damage determine the
  pathology and clinical expression of the disease

4
Classification of autoimmune diseases by
pre-dominant immunopathogenic effector mechanism
-1
5
Classification of autoimmune diseases by
pre-dominant immunopathogenic effector mechanism
-2
6
Autoantibodies can cause disease through several
distinct mechanisms
1. Antibodies specific for cell-surface antigens
can destroy cells

• egs. Autoimmune hemolytic anemia, Autoimmune
  thrombocytopenic purpura

7
2. Autoantibodies specific for tissue antigens
can elicit inflammation

• Activation of complement - release of
  inflammatory mediators and chemoattractant
  molecules
• recruitment of inflammatory cells - activation by
  ligation of Fcg receptors
• egs. Hashimotos thyroiditis, Goodpastures
  syndrome

8
Goodpastures Syndrome

• type IV collagen is a component of the renal
  glomerular basement membrane
• linear deposition of autoantibody along
  glomerular basement membrane
• proliferation of mononuclear cells and influx
  of neutrophils

9
Pemphigus Vulgaris

• Autoantibodies produced against an epidermal
  cadherin, desmoglein 3
• Component of desmosome, one of the intercellular
  junctions that link skin cells tightly together

10
3. Autoantibodies can alter cell function

• Antibody binding to cell receptor can lead to
  internalization and degradation - block function
• eg. Myasthenia gravis

11
In Graves Disease binding of autoantibody to a
thyroid cell surface receptor stimulates the cell
Graves Disease
12
4. Autoantibodies may form part of an
immune-complex

• leads to type III hypersensitivity reaction
• immune complexes are produced when there is a
  response to a soluble antigen
• circulating immune complexes usually cause
  systemic disease
• immune complexes lodge in a variety of tissues
  where they elicit inflammation - skin, joints,
  kidney
• organs involved depends upon the size and nature
  of antigen within the complex
• prototypic immune-complex mediated autoimmune
  disease - SLE

13
Diseases mediated by auto-antibodies can cross
the placenta
14
Autoreactive T-cells promote autoimmune disease
through a variety of mechanisms
1. CD8 cytotoxic T cells may directly attack
cells

• eg. Insulin-Dependent Diabetes Mellitus
• cytotoxic T cells recognize self-antigens on
  the surface of b islet cells of the pancreas and
  lyse the cells
• death of b islet cells leads to deficient
  insulin production

15
2. Self-reactive CD4 T cells release lymphokines

• IL-2 allows expansion of T cells
• IFN-g and TNF recruit and activate macrophages
  that can directly damage target tissue
• egs. Rheumatoid Arthritis - macrophage activation
  leads to destruction of joint cartilage
• Insulin-Dependent Diabetes Mellitus - CD4 T
  cells required for expansion of CD8 T cells and
  lead to damage through macrophage activation

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Typically multiple limbs of the immune system are
recruited in autoimmune disease

• production of high affinity pathogenic IgG
  autoantibodies requires T cell help
• self-reactive T cells identified in many
  autoantibody-mediated autoimmune diseases

17
In many autoimmune diseases B cells function as
antigen presenting cells driving T cell
activation

• Autoreactive B cells have enhanced uptake and
  presentation of self-antigens
• In NOD mice B cells are required for disease
  initiation
• Activation of autoreactive T cells is reduced in
  lupus-prone mice lacking B cells or with B cells
  expressing a monoclonal non-self reactive
  transgene
• Rheumatoid Arthritis can be treated with B cell
  depletion using anti-CD20

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Susceptibility to Autoimmune Disease - 1

• genetic factors are crucial determinants of
  susceptibility
• evidence is based upon familial clustering
• higher rate of concordance for disease in
  monozygotic twins than in dizygotic twins
• in most autoimmune diseases multiple
  susceptibility genes work in concert to produce
  the abnormal phenotype
• Polymorphisms also occur in normal people and are
  compatible with normal immune function
• only when present with other susceptibility genes
  do they contribute to autoimmunity

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Genes associated with susceptibility to
autoimmune disease
1. Genes in the MHC locus

• For may autoimmune diseases susceptibility is
  associated with specific MHC alleles
• most associations are for Class II but
  occasionally for Class I

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HLA associations with various autoimmune diseases
Relative risk - observed number of patients
carrying a particular HLA allele compared to the
expected number based on the prevalence of the
HLA allele in the general population
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Affected siblings share HLA alleles more
frequently than expected by chance
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The HLA region contains many genes which are
closely linked to each other
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In IDDM disease susceptibility is most closely
associated with a DQb polymorphism at position 57

• Original association with DR3 and DR4 alleles is
  due to tight genetic linkage between these
  alleles and DQb alleles that confer
  susceptibility
• most abundant DQb has aspartic acid at position
  57, in diabetic individuals valine, serine, or
  alanine is found at this position

No salt bridge end of MHC molecule is open
leading to altered peptide binding
Aspartic acid forms salt bridge
24
Studies of animal models of ankylosing
spondylitis, diabetes, and rheumatoid arthritis
indicate that class I or II molecules themselves
confer disease susceptibility

• Transgenic rats genetically manipulated to
  express HLA-B27 develop ankylosing spondylitis
• Non-obese Diabetic (NOD) mice share the same
  class II polymorphism that is associated with
  diabetes in humans

25
Genetic polymorphisms in the MHC class III region
may be associated with development of SLE

• TNF alleles associated with decreased production
  of TNF promote development of SLE
• SLE is frequently found in patients with
  complement deficiencies

26
How do class I and class II MHC alleles confer
disease susceptibility- 1

• Self-peptides associated with MHC are
  responsible for the negative and positive
  selection of T cells.
• Autoantigenic peptides may bind too weakly to
  induce negative selection.

eg. The NOD class II molecule binds peptides
poorly and may less effectively delete T cells
reactive for self-peptides in the thymus
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How do class I and class II MHC alleles confer
disease susceptibility- 2
2. The MHC molecule dictates the array of
peptides that can be presented to autoreactive T
cells.
eg. In pemphigus vulgaris, disease is associated
with a particular class II DRb chain, DRb10402.
Only this DRb chain can bind the antigenic
peptide from the desmoglein-3 and present it to T
lymphocytes, and therefore only these individuals
can generate a pathogenic autoantibody response
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MHC alleles that bind peptides of self-antigens
with intermediate to low affinity pose the
greatest risk for autoimmunity
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Genes associated with susceptibility to
autoimmune disease - cont.
2. Genes outside the MHC locus Studies of
Genetically Manipulated Mice

• have led to identification of a large number of
  genes that promote the development of
  autoimmunity when they are deleted or
  overexpressed
• these include cytokines, antigen co-receptors,
  molecules involved in signaling cascades,
  costimulatory molecules, molecules involved in
  apoptosis, and molecules that clear antigen or
  immune complexes.

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Genetic Manipulations associated with development
of autoimmune disease in mice
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Studies of Genetically Manipulated Mice - cont

• ability of a particular gene to cause disease
  depends on the background of the host - both
  disease susceptibility and disease phenotype vary
  depending on the presence of other genes
• some genetic defects predispose individuals to
  more than one autoimmune disease

32
Non-MHC genes associated with autoimmune disease
in humans

• clinically different autoimmune diseases often
  coexist within a family
• Many genetic loci appear to be involved in the
  pathogenesis of more than one autoimmune disease

33
CTLA-4 Polymorphisms are associated with several
different autoimmune diseases

• Delivers an inhibitory signal to activated T
  cells
• polymorphisms cause a decrease in the inhibitory
  signal
• associated with diabetes, thyroid disease, and
  primary biliary cirrhosis

34
What are the factors leading to breakdown of
tolerance and initiation of autoimmunity?
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The presence of self-reactive T cells that have
evaded tolerance can be readily demonstrated by
induction of autoimmunity following immunization
of mice with certain self-antigens

• Injection of susceptible mouse strains with
  components of collagen together with adjuvant
  results in a rheumatoid arthritis-like illness
  called collagen-induced arthritis
• similar injections with components of the myelin
  sheath results in an Multiple Sclerosis-like
  illness called experimental allergic
  encephalomyelitis
• the ability to induce autoimmunity depends upon
  the MHC haplotype of the recipient together with
  other non-MHC susceptibility genes

36
Persistence of self-reactive T cells in the
periphery with low affinity for self-peptide MHC
complexes

• T cells strongly reactive with self-antigens are
  deleted in the thymus during development
• T cells that recognize peripheral self-antigens
  are rendered anergic
• many antigens are present at too low a level to
  stimulate any form of tolerance immunological
  ignorance
• State of tolerance depends upon the density of
  self-peptide/MHC complexes and presence of
  costimulatory signals

37
Self-reactive B cells also persist and can become
activated to produce autoantibodies by
interaction with antigen and T cells

• in general, induction of tolerance in B cells
  requires a higher concentration of self-antigen
  than induction of T cell tolerance so that
  tolerance to many self-antigens is maintained
  predominantly by T cell tolerance

38
Immune defects that lead to impaired deletion of
autoreactive T cells in the thymus contribute to
the development of autoimmunity

• self-reactive T cells removed in thymus - but
  how are peripheral self-reactive cells removed?
• Humans with defective aire gene develop
  multi-organ autoimmune disease - autoimmune
  polyendocrinopathy-candidiasis-ectodermal
  dystrophy (APECED)
• RNA transcripts encoding many predominantly
  tissue-expressed genes are found in thymus in
  medullary epithelial cells
• knockout of the aire gene prevents expression
  of peripheral antigens in thymic epithelial cells
  and is associated with autoimmunity

39

• Autoimmune disease in aire knockout mice takes
  time to develop indicating that other tolerance
  mechanisms hold autoimmunity in check for a time
• in diabetes genetic variants of the insulin gene
  that lead to higher levels of transcription of
  the insulin gene in the thymus tend to protect
  against development diabetes

Conversely genes that increase thymic expression
of self-antigens are protective
40
Surviving T and B cells that bind self-antigens
with low affinity can become activated

• DNA contains unmethylated CpG sequences, these
  can be recognized by TLR9. DNA-specific B cells
  can take up DNA containing these motifs and be
  activated by a co-stimulatory signal through
  TLR-9
• Massive tissue death or inflammation can lead to
  release of intracellular self-antigens and
  activation of ignorant T and B cells. Eg.
  Following heart attack, but usually transient.
  In the context of an abnormal immune system can
  become sustained.

41
Antigens in immunologically privileged sites do
not stimulate T cells but can serve as targets
for activated T cells

• unique in that extracellular fluid does not
  pass through conventional lymphatics
• anti-inflammatory cytokines produced by tissue
  such as TGF-b prevent activation of T cells that
  damage tissue
• FasL expressed by tissue may induce apoptosis
  of Fas-bearing lymphocytes that enter these sites

42

• damage to an immunologically privileged site
  can lead to release of self-antigens and
  induction of an autoimmune response
• eg. sympathetic ophthalmia

43
In normal individuals auto-reactive cells that
have broken tolerance can be regulated so that
they do not cause disease

• Regulatory T cells that are CD4 CD25 have been
  shown to suppress disease in several autoimmune
  diseases including diabetes, colitis, SLE, and
  experimental allergic encephalomyelitis.
• Develop in response to moderately expressed
  self-antigens in thymus.
• FoxP3 transcription factor essential for
  differentiation
• Suppress by direct contact, IL-10 and TGF-b
  effects on APCs, including dendritic cells, and T
  cells.
• Other suppressing populations described that
  secrete TGF-b and can be CD4 or CD8
• A relative deficiency of these populations is
  thought to contribute to disease development in
  several autoimmune diseases

44
For many autoimmune diseases environmental
triggers appear to play a role in inducing
autoimmunity

• Based upon lack of concordance between identical
  twins
• regional differences in the prevalence of
  autoimmune diseases following migration of
  populations
• for most autoimmune disease the trigger is
  unknown however infectious agents are a prime
  candidate

45
Proposed mechanisms by which infectious agents
could break self-tolerance - 1
46
Proposed mechanisms by which infectious agents
could break self-tolerance - 2
47
Once tolerance is broken to one self-antigen
epitope spreading allows spreading of the immune
response to other self-antigens expressed by the
same tissue
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Systemic Lupus Erythematosus (SLE)

• autoimmune disease
• prevalence 1/500 - 1/1000
• predominantly affects women

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SLE - skin

• The lupus rash is typically brought on by sun
  exposure photosensitivity
• antibody, complement, and inflammatory cells seen
  in the skin

50
SLE -kidney

• Deposition of immunoglobulin and complement
  within loops of glomerulus leads to abnormal
  kidney function

51
Autoantibodies in SLE

• characterized by production of a variety of
  autoantibodies directed against predominantly
  nuclear antigens
• tissue damage usually caused by autoantibody
  deposition with responses similar to Type II and
  III hypersensitivity reactions

52
Association between autoantibodies and organ
involvement

• autoantibodies with different specificities are
  associated with different manifestions of disease
• related to the ability of the autoantibody to
  bind antigen on the cell leading to damage and/or
  altered cell function

53
Immune Mechanisms by which pathogenic anti-dsDNA
antibodies bind to the kidney
? Two proposed mechanisms
1. Nucleosome forms an antigen bridge
Positively charged histone residues on
nucleosomes have high affinity for renal
glomerular basement membrane
54
Immune Mechanisms by which pathogenic anti-dsDNA
antibodies bind to the kidney

• Anti-dsDNA reactive antibodies cross react with
  other negatively charged antigens in the kidney

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Immunopathogenesis of SLE

• What property do the nuclear antigens recognized
  in SLE share? How do they gain access to the
  immune system?
• Is SLE a genetic disease?
• 3 What kind of immune defects cause SLE to
  develop?

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Nuclear Antigens are exported to the cell surface
in apoptotic cells
Ro on surface of bleb
Apoptotic Keratinocyte
Apoptotic Keratinocyte (UV irradiated)
Viable Keratinocyte
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Antigens recognized in SLE share the property
that they are exported to the cell surface
following apoptosis
UV irradiation (sun exposure) induces
keratinocyte apoptosis ? link between sun
exposure and flares of disease
58
Evidence that SLE has a genetic origin

• Concordance rate monozygotic twins 25-69
  dizygotic twins 2-3
• familial aggregation with approximately 10 fold
  increased risk of sibling developing disease
  relative to unrelated individual
• association with multiple candidate genes
• linkage analysis results from genome scans
  supportive
• murine models of disease demonstrate multiple
  genes act in concert to produce disease

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Immune Defects leading to loss of tolerance to
nuclear antigens in SLE

• Defects allowing increased amounts of nuclear
  antigens access to the immune system
• Immune defects affecting B and T lympho-cyte
  function

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Defects allowing increased amounts of nuclear
antigens access to the immune system

• In normal individuals apoptotic material is
  rapidly cleared by phagocytic cells
• immune defects that impair clearance of apoptotic
  debris predispose to lupus
• Complement deficiency
• Dnase I or serum amyloid P deficiency

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Complement Deficiencies
62
Role of Complement in the Immune System
C1q

• Binds to surface of apoptotic cells
• Promotes clearance of cells by phagocytic cells

adapted from Navratil et al, J. Immunol.
1663231
63
C1q deficiency
Mice that have been genetically modified to be
deficient in C1q develop

• increased production of auto-antibodies
• immune-complex mediated glomerulonephritis
• increased numbers of apoptotic bodies in the
  kidney

64
Immune defects affecting B and T lymphocyte
function

• Immune defects that decrease the threshold for T
  and B cell activation
• Immune defects that impair deletion of
  autoreactive lymphocytes - apoptosis gene defects

65
Immune defects that decrease threshold of B cell
activation

• upregulation of stimulatory molecules such as
  in the hCD19 transgenic or a mutation of the
  inhibitory wedge of CD45 promote lupus

• deletion of inhibitory molecules such as CD22,
  lyn, or SHP1 promotes lupus

66
Apoptosis in the immune system

• Principal mechanism by which cells responding to
  self-antigens are deleted
• Critical role in removal of expanded immune
  populations following antigenic challenge

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Apoptosis Gene Defects
Fas

• Cell surface molecule
• One of the major initiators of apoptosis in the
  immune system
• critical role in removal of activated cells that
  are no longer needed following an immune response

68
MRL lpr/lpr mice

• lpr gene defect results in no Fas expression
• Generalized lymphoid expansion
• Autoimmune kidney disease and joint inflammation
• Multiple autoantibodies
• Fas gene defect leads to accumulation of immune
  cells (double negative T cells) and altered B
  cell tolerance

69
Role of Fas gene defects in Human SLE

• Majority of SLE patients do not have defects in
  Fas-mediated apoptosis
• Small subset of patients with Autoimmune
  Lymphoproliferative Syndrome (ALPS) have dominant
  negative mutations in Fas and develops phenotype
  similar to MRL lpr/lpr mice

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Genetic Defects implicated in development of SLE