Sex Differences in Autoimmune Disease from a Pathological Perspective

1
Sex Differences in Autoimmune Disease from a
Pathological Perspective

• Fairweather et al, American Journal of Pathology
• 173600, 2008

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Introduction

• Autoimmune diseases (AID) affect 8 of the
  population.
• 3rd most common group of diseases in US after
  cancer and cardio-vascular disease.
• 78 of affected individuals are women.
• Women respond to infection, vaccination and
  trauma with increased antibody production, a Th2
  predominant immune response
• A Th1 response and inflammation are more severe
  in men.
• AID progress from an acute pathology associated
  with an inflammatory response to chronic
  pathology associated with fibrosis in both sexes.

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Sex Differences in AID

• Predominantly male AID include myocarditis,
  Wegners granulomatosis, idiopathic pulmonary
  fibrosis, type 1 diabetes, ankylosing
  spondylitis, and pernicious anemia.
• Predominantly female AID include multiple
  sclerosis, dermatomyositis, thrombocytopenia,
  myasthenia gravis, rheumatoid arthritis, systemic
  lupus, autoimmune hepatitis, Sjogren syndrome and
  Hashimotos thyroiditis.

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Acute phase AID

• AID more prevalent in males occur before age 50
  and are characterized by acute inflammation,
  auto-antibodies and a pro-inflammatory Th1
  response.
• Female predominant AID that manifest during the
  acute phase, e.g. Graves disease and systemic
  lupus, are diseases with an Ab-mediated
  pathology.

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Auto-antibodies in AID

• Auto-antibodies induce damage by binding
  self-antigens and activating complement.
• The number of different auto-antibodies in an
  individual is a good predictor of the risk to
  develop AID.
• The number of auto-antibodies increases with age,
  regardless of sex.

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Cellular immunity

• Immune cells damage tissues directly by killing
  cells, or indirectly by releasing cytotoxic
  cytokines, enzymes, or reactive nitrous oxide
  intermediates.
• Cytokines released by mast cells and macrophages
  recruit inflammatory cells, e.g. neutrophils,
  macrophages and T cells, to sites of damage.
• IL4 recruits B cells and eosinophils and
  activates B cells to produce auto-antibodies
  associated with immune-complex mediated AID, e.g.
  Graves disease and SLE.

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Cellular immunity

• CD4 T cells are classified as Th1, Th2,, or Th17
  cells depending on the release of IFNg, IL4 or
  IL17 respectively.
• IFNg and IL-17 are proinflammatory cytokines
  associated with inflammatory organ-specific AID
  e.g. myocarditis.
• IL17 is involved in both AID and allergic
  diseases, and acts synergistically with TNFa and
  IFNg, or IL1b to increase fibrosis or Th1
  responses, respectively.

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Regulatory T cells

• Tregs down-regulate Th1, Th2 and Th17 responses
  and decrease acute inflammation in AID.
• Tregs inhibit inflammation via cell-to-cell
  contact-induced apoptosis and production of
  anti-inflammatory cytokines IL-10 and TGF-b.

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Acute vs. chronic pathology in AID

• Acute inflammation can involve a Th1
  (macrophage/neutrophil) and/or Th17 (neutrophil)
  response after viral or bacterial infections,
  injury, or a Th2 response (predominantly
  eosinophils) in allergy and asthma.
• Th17 responses increase neutrophil inflammation
  and chronic fibrosis.
• Most acute inflammatory responses do not manifest
  clinically as AID.
• AID with an increased incidence in females after
  age 50 are associated with a chronic fibrotic Th2
  mediated pathology.

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Acute vs. chronic pathology in AID

• For most AID, the early acute phase is silent
  unless inflammation persists.
• Mechanisms responsible for resolving acute
  inflammation include Tregs, anti-inflammatory
  cytokines IL-4, IL-10 or TGF-b and apoptosis of
  inflammatory cells.
• If acute inflammation cannot be resolved or
  tissues are incapable of regeneration, the acute
  response may progress to chronic inflammation
  with a mononuclear infiltrate, tissue
  destruction, and fibrosis.

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Chronic Inflammation and fibrosis

• Fibrosis is the hallmark of chronic inflammation.
• Fibroblast proliferation and collagen deposition
  is increased by TNF, IL-1b, IL-4, IL-13, IL-17
  and TGF-b.
• In AID, chronic pathology is characterized by
  fibrosis, increased auto-antibodies, and features
  of a Th2 or Th17 immune response.

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AID in males

• In males, it is possible that a gradual shift
  from a Th1 to Th2 response with age increases
  with progression to fibrosis in susceptible
  individuals or that a Th17 response leads to
  chronic fibrosis.
• The heightened pro-inflammatory Th1 response to
  infection by males increases severity of acute
  inflammation and risk of early death so males
  susceptible to develop chronic AID might not
  survive to develop disease.

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AID in females

• Female predominant AID in early life are
  associated with antibody mediated pathology, e.g.
  thrombocytopenic purpura, multiple sclerosis,
  myasthenia gravis, SLE and Graves disease.
• AID in females in later life are characterized by
  chronic inflammation, fibrosis, increased
  autoantibodies and a Th2 response, e.g.
  dermatomyositis, systemic sclerosis, autoimmune
  hepatitis, Sjogren syndrome and Hashimotos
  thyroiditis.

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Regulation of Inflammation by Sex Hormones

• Estrogen, progesterone, and testosterone appear
  to mediate sex-based differences in the
  prevalence of AID.
• Estrogens and androgens directly influence the
  immune response by interacting with hormone
  receptors on immune cells.
• Estrogen directly down-regulates NF-kB and Th1
  responses in human and murine cells.
• Estrogen increases fibrosis by stimulating IL4,
  TGF-b, and Basic FGF.

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Regulation of Inflammation by Sex Hormones

• Androgens stimulate a Th1 response.
• Androgens activate both androgen and estrogen
  receptors by aromatase conversion of testosterone
  to estrogen.
• In both sexes, testosterone levels decrease with
  age, which may contribute to increasing Th2
  responses observed in men over age 50.
• The increased prevalence of autoimmune disease in
  women may be attributable to an increased Th2
  response after infection that promotes antibody
  production, chronic inflammation and fibrosis,
  possibly explaining why giving estrogen to women
  after menopause worsens their heart disease

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SLE Acute antibody mediated disease

• There is a correlation between high estrogen
  levels and increased auto-reactive B cells in
  SLE.
• Pregnancy increases SLE.
• In mice, estrogen increases survival of
  auto-reactive B cells, auto-antibodies and kidney
  disease.
• Male patients with SLE have high estrogen to
  androgen ratios.

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Rheumatoid arthritis Acute mixed cell and
antibody mediated disease

• RA is more prevalent in women before age 50 but
  disease severity is greater after age 50.
• Women are protected from RA during pregnancy
  because high estrogen levels reduce acute
  cell-mediated pathology.
• The incidence rates in males increase with age as
  androgen levels fall and Th2 responses increase.

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Multiple sclerosis Acute mixed cell and antibody
mediated disease

• MS is thought of as a Th1/Th17 mediated disease
  similar to experimental autoimmune encephalitis
  (EAE) in mice.
• Most patients develop MS when lt50 years
  suggesting a cell mediated pathology.
• Estrogen increases Tregs and decreases EAE if
  administered before disease starts in mice.
• The possibility that EAE is a Th1 mediated
  disease is supported by the observation that male
  SJL mice only develop acute EAE whereas female
  SJL mice develop chronic disease.

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Multiple sclerosis Acute mixed cell and antibody
mediated disease

• Additional evidence that MS is Th1 mediated comes
  from studies in which patients disease is
  exacerbated by IFNg.
• Men develop more severe inflammation whereas
  pregnancy in humans and mice decrease disease
  severity.
• There may be two subsets of MS with either Th1
  cell mediated or Th2 antibody mediated disease.

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Systemic Sclerosis Chronic fibrotic disease

• Pathological characteristics of human disease and
  animal models include over-expression of TGF-b,
  autoreactivity against extracellular matrix
  proteins, increased mast cells, eosinophils and
  basophils- all associated with chronic pathology.
  
• Systemic sclerosis has been associated with fetal
  microchimerism in which maternal and fetal cells
  generate a GVH- like disease.

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Different patterns of inflammation in LyP
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Association of Lymphomatoid Papulosis with
Hashimotos thyroiditis

• The prevalence of thyroiditis in our cohort of
  95 LyP patients was significantly higher, 10.52
  (n10) (plt0.0001) when compared with the US
  general population (791.7 per 100,000).
• All 11 LyP patients with thyroiditis were
  female, compared to 52.0 of those without
  thyroiditis (p0.004).

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Hashimotos thyroiditis Antibody-mediated and
fibrotic disease

• The acute and chronic phases occur predominantly
  in women.
• In mice, disease severity is linked to estrogen.
• There is an extensive infiltrate of lymphocytes,
  plasma cells, macrophages and germinal centers.
• Thyroid follicles are progressively destroyed by
  immune complex deposition, and complement
  resulting in necrosis, fibrosis and
  hypothyroidism.

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Myocarditis/Dilated Cardiomyopathy Acute cell
mediated to chronic fibrotic disease

• Myocarditis and atherosclerosis are more
  prevalent in men.
• A Th17 response is necessary for development of
  experimental autoimmune myocarditis and amplifies
  the fibrotic stage.
• Toll like receptor signaling increases
  proinflammatory cytokines in both sexes while a
  Th2 response in females reduces the acute
  inflammatory response.

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Conclusions

• The incidence of autoimmune diseases falls into a
  male/female pattern based on pathology.
• Male predominant AID usually manifest before age
  50 and are characterized by acute inflammation
  and a Th1 response.
• AID in females that occur early in life have an
  antibody mediated pathology.
• AID in females in later life are associated with
  increased auto-antibodies, chronic inflammation
  and fibrosis.
• Some AID may be triggered by microchimerism.

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Autoimmune diseases with increased incidence in
females

• Multiple sclerosis 21 ratio of female to
  male
• Dermatomyositis 21
• Thrombocytopenic purpura 31
• Myasthenia gravis 31
• Rheumatoid arthritis 31
• Systemic sclerosis 41
• Autoimmune hepatitis 4-61
• Hashimotos thyroiditis 3-5.11
• Graves disease 71
• Systemic lupus erythematosis 91
• Sjogren syndrome 91

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Autoimmune diseases with increased incidence in
males

• Myocarditis
• Wegner granulomatosis
• Idiopathic pulmonary fibrosis
• Gastritis- pernicious anemia
• Diabetes (type 1)
• Ankylosing spondylitis

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Generation of Th responses by pattern recognition
receptors

• The immune system recognizes infectious organisms
  and tissue damage via pattern recognition
  receptors, e.g. Toll-like receptors (TLRs).
• Tissue damage releases extra-cellular matrix
  proteins which stimulate TLR4 on macrophages.
• TLR signaling generates a Th1 response by
  transcriptional induction of IFNg, NF-kB, IL-12
  and caspase 1 activation of IL-18.
• TLR signaling also inhibits a Th2 response.

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Toll-like receptors

• TLR expression on antigen presenting cells is
  up-regulated in response to infection with
  bacteria, viruses or inoculation with
  self-antigens to induce AID in animal models.
• AID disease models using complete Freunds
  adjuvant (CFA) generate a Th17 response because
  of the Mycobacterium component of CFA.
• CFA is used to induce AID in experimental
  autoimmune encephalitis (EAE), collagen induced
  arthritis, and autoimmune myocarditis.

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T cell immunoglobulin mucin-3

• Tregs up-regulate a receptor on mast cells and
  macrophages called T cell Ig mucin 3 (Tim-3).
• Tim-3 reduces TLR4 expression in females during
  innate immunity.
• The pro-inflammatory response is attenuated in
  females by inhibition of TLR4 expression by
  Tim-3, and increased Tregs.

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