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Sex Differences in Autoimmune Disease from a Pathological Perspective

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Title: 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

2
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.

3
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.

4
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.

5
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.

6
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.

7
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.

8
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.

9
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.

10
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.

11
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.

12
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.

13
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.

14
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.

15
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

16
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.

17
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.

18
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.

19
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.

20
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.

21
Different patterns of inflammation in LyP
22
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).

23
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.

24
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.

25
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.

26
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27
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

28
Autoimmune diseases with increased incidence in
males
  • Myocarditis
  • Wegner granulomatosis
  • Idiopathic pulmonary fibrosis
  • Gastritis- pernicious anemia
  • Diabetes (type 1)
  • Ankylosing spondylitis

29
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.

30
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.

31
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.

32
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