Microchimerism A New Mechanism for Autoimmunity

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Microchimerism A New Mechanism for Autoimmunity?

• Dr. Manish M Sood
• PGY 3
• Rheumatology Rounds
• Sept 28, 2004

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Outline

• Definition
• Discovery and Etiologies
• Immunology 101
• Graft vs Host Disease
• Autoimmunity
• Mechanism and Pathogenic Role
• Conclusions

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Chimera (Defn) an individual organ, or part
consisting of tissues of diverse genetic
constitution
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Microchimerism (Definition)

• The presence within one individual of a small
  population of cells from another genetically
  distinct individual
• Adams and Nelson. JAMA. 2004. 29191127-1131.

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Microchimerism

• First described in early 1990s
• Found presence of Y chromosome in woman who
  previously gave birth to sons
• Led to discovery of fetal cells persisting in
  maternal circulation (4 weeks, 27 years)
• Bianchi et al. Proc Natl Acad Sci. 1996. 93
  705-708.

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TRANSPLANT
TWINS
FETAL
TRANSFUSIONS
MATERNAL
MICROCHIMERISM
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Microchimerism

• Cell trafficking can occur
• Mother fetus interactions
• Twin to twin
• Blood transfusion
• Organ transplantation Possible ? siblings,
  sexual interactions
• Occurs in small numbers (1 in millions of
  cells)

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Is there a clinical situation where foreign cells
are present inside the body?

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Hematopoietic Cell Transplantation

• Extensive literature on chimerism in cell
  transplantation
• The greater the chimerism, the greater the chance
  of developing CHRONIC GRAFT VERSUS HOST DISEASE

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Quick Aside - Immunology 101

• Recognition of self occurs by presenting antigens
  to the T Cell receptor with major
  histocompatiability complex (MHC)
• MHC proteins are encoded by genes named HLA
• There are many types of HLA genes possible and
  many combinations
• If the presenting antigen is recognized as
  foreign it will incite an immune response

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Chronic Graft Versus Host Disease (cGvHD)

• The transplanted immune cells recognize recipient
  tissue as foreign
• Classically affects skin, liver (cholestatic)
  jaundice, GI mucosa, lungs, Sjogrens syndrome
  and myositis

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cGvHD a Model for Systemic Sclerosis ?

• Common features - progressive skin induration,
  lung, gut involvement
• Common serology ANA, anti-topoisomerase I
• cGvHD similar to numerous other autoimmune
  conditions primary biliary cirrhosis, Sjogrens
  syndrome and myositis

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Microchimerism and Autoimmunity

• Woman are disproportionately affected by
  autoimmune disease
• Systemic sclerosis has peak incidence following
  child bearing years
• Is microchimerism responsible for systemic
  sclerosis?

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Systemic sclerosis

• Nelson et al found higher levels of male DNA in
  woman with systemic sclerosis
• Furthermore skin biopsies from SSc patients
  showed male DNA while none was detected in
  controls
• Is there a relationship between microchimerism
  and HLA type?
• Nelson et al. Lancet. 1998. 351 559-562.
• Artlett et al. NEJM. 1998. 338 1186-1191.

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Systemic Sclerosis and HLA-Compatibility
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Risk of SSc and HLA-compatibility of a Previously
Born Child Nelson. Lupus. 1999. 8370-4.
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Scleroderma

• Risk of SSc nine fold if previous HLA
  compatible child
• Risk further if homozygous
• Microchimerism as a secondary phenomenon?
  (Polyvinylchloride)

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Microchimerism and other autoimmune diseases
Nelson. Trends in Molecular Medicine. 2002. 8
109-13.
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Microchimerism and other autoimmune diseases

• Primary Biliary Cirrhosis resembles the liver
  damage seen in cGvHD, however no significant in
  microchimerism
• male DNA in thyroids from woman with Hashimotos
• Klintschar et al. J. Clin. Endo. Metab. 2001.
  862494-8.

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Maternal Microchimerism

• maternal cells where found in the AV node of male
  infants born with neonatal lupus syndrome and
  heart block
• Reed et al demonstrated maternal alleles in
  87 of kids with juvenile polymyositis and only
  14 of healthy controls
• Mouse model of SLE involves injecting parental
  cells into the progeny
• Stevens et al. Lancet. 2003. 3621617-23.
• Reed et al. Lancet. 2000. 356 2155-2156.

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Male Cell in Female Liver by Fluorescence in Situ
Hybridization Stevens et al. Lancet. 2003.
3621617-23.
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Maternal Cell with a Myocardial Tissue-Specific
Phenotype in a Male Infant Heart by Fluorescence
In Situ Hybridization
Stevens et al. Lancet. 2003. 3621617-23.
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Mechanism
Nelson. Trends in Molecular Medicine. 2002. 8
109-13
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Infectious Triggers
Environmental Triggers
Hormonal Factors
Maternal cells
Fetal cells
HLA Relationship Between Microchimerial Cells
Bidirectional cell trafficking
Persistence of Fetal Cells
Balance Between bystander microchimerism and
potential pathogenic mechanisms
Nelson. Trends in Molecular Medicine. 2002. 8
109-13
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Conclusions (?)

• Microchimerism is a novel scientific phenomenon
• Possible role in autoimmune diseases
• Unclear if causative, potential bystander or
  possibly involved in healing
• Compounding microchimerism

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Thanks and Have a Good Day