Title: Sex Differences in Autoimmune Disease from a Pathological Perspective
1Sex Differences in Autoimmune Disease from a
Pathological Perspective
- Fairweather et al, American Journal of Pathology
- 173600, 2008
2Introduction
- 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.
3Sex 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.
4Acute 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.
5Auto-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.
6Cellular 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.
7Cellular 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.
8Regulatory 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.
9Acute 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.
10Acute 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.
11Chronic 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.
12AID 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.
13AID 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.
14Regulation 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.
15Regulation 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
16SLE 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.
17Rheumatoid 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.
18Multiple 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.
19Multiple 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.
20Systemic 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.
21Different patterns of inflammation in LyP
22Association 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).
23Hashimotos 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.
24Myocarditis/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.
25Conclusions
- 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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27Autoimmune 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
28Autoimmune diseases with increased incidence in
males
- Myocarditis
- Wegner granulomatosis
- Idiopathic pulmonary fibrosis
- Gastritis- pernicious anemia
- Diabetes (type 1)
- Ankylosing spondylitis
29Generation 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.
30Toll-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.
31T 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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