Autoimmunity and Susceptibility in WomenPresentation Transcript
and Susceptibility of Women
• Disease states
• Mouse Models of human disease
• Predisposition of women to autoimmune diseases
T cells B cells
immunity against self.
A condition that occurs
when the immune
attacks and destroys
healthy body tissue.
Literally, the horror
A term coined by
• 1960s: Elimination of all self-reactive
• 1970s: Not all self-reactive lymphocytes are
• Affects 7.6% to 9.4%
of the human population.
• Two third women.
• More than 40 human diseases
are autoimmune in origin.
• Tendency of co-existence of autoimmune
– MS-Rheumatoid Arthritis
– Vitiligo- Autoimmune Thyroid Disease (40% Indians)-
NALP1 gene malfunctioning.
Failure of tolerance and disease Outcome
MS, Uveitis, Male
RA, SLE, Crohn’s
Failure of Central Tolerance
•Middle Aged Women.
•Sensitized TH-1 for Thyroid
•Thyroid Gland infiltration
Macrophages and Plasma
•Abs against thyroglobulin
and thyroid peroxidase.
• Pernicious Anemia
–Auto-Abs against intestinal protein on
parietal cells- hampers uptake of vit
• Autoimmune Hemolytic Anemia
–Auto-Ab against RBC Antigens
–Complement Lysis- Phagocytosis of
Lungs of a patient
basement membrane Ags.
•Glomeruli and Alveoli
•Kidney Faliure and
•IgG and C3b deposit on
the basement membrane.
+ Lytic Enzymes
binds to receptors
on thyroid cells
• Progressive weakening of skeletal muscles.
• Auto-Abs bind to acetylcholine receptors on
the motor end of the muscle cells.
• AcTh cannot bind.
• Antibodies ultimately
destroy the muscle cells.
• Antibodies act as
Examples of Systemic Autoimmunity
Sytemic Lupus Erythromatosus
• Women 20 to 40 years
• F:M Ratio 10:1
• Prevalent in African-American and Hispanic women
• Auto-Abs against RBCs & Platelets- Complement
mediated lysis- hemolytic anemia and
• Auto-Abs against nuclear antigens- complement
system activation- damage to blood vessels- vasculitis
• Neutropenia: Expression of a type 3 complement
receptor (CR3) on neutrophils.
T Lymphocytes enter cerebrospinal fluid. Certain viruses
pre-dispose a person for developing MS.
• Chronic Inflammation of Joints.
• Auto-Abs or Rheumatoid Factors react with
determinants in the Fc region of IgG.
• Classsic Rheumatoid Factor: IgG Antibody.
• IgM-IgG complexes deposit into the joints.
• Triggers Type-III Hypersensitivity Reaction.
Causes of Autoimmunity
Mechanisms of autoimmunity
• MHC Polymorphism
• Release of Sequestered Antigens
• Molecular mimicry
• Failure of Central Tolerance
Autoimmunity Associated with MHC
1. Ankylosing Spondylitis: Inflammatory disease of
– HLA-B27 allele of HLA-B gene present.
– 90% of the cases are males.
1. IDDM: Pancreatic beta cells express high levels of
class I and class II MHC.
2. Grave’s Disease: Thyroid Acinar Cells express high
levels of class II MHC.
– Sensitization of TH1 against cell Ags.
CTLs get activated.
1. Phytohemaglutinin (PHA): Induces thyroid cells to
express class II MHC.
• Increases the class II MHC molecules on:
– Pancreatic Beta Cells
– Intestinal Epithelial Cells
– Thyroid Acinar Cells
• Trauma or Viral Infection can induce an
increase in INF production. (Improper T-
helper cell activation)
• High INF Titre found in SLE patients.
• Induces production of IL-1 and TNF.
Release of Sequestered Self-Antigens
Trauma or Bacterial Infection
Self-Antigens come into circulation
Interact with T cells which have escaped
negative selection in thymus
Auto-Abs produced; autoimmune response
• Vasectomy: Sperm Ag released into
• Eye Damage: Lens Protein released into the
• Myocardial Infarction: Heart Muscle Antigens
released into blood stream.
• Myelin Basic Protein released from the Blood
Brain Barrier into the circulation.
Damage to immunologically
privileged sites can lead to
• Virus and Bacteria possess Ag peptides similar
to host cell components. (Michael Oldstone)
• More that 3% virus specific Abs also bound to
normal tissue of the host.
• May affect migrant populations.
• Ex 1: Post-rabies encephalitis:
– Rabies vaccination developed by growing rabies
virus in rabbit brain cells.
– Ab production against rabbit brain cells which
cross-react with host brain cells.
• Ex 2: Rheumatic Fever: Streptococcus
• Ex 3: Encephalitogenic MBP
– Amino Acid residues from 61 to 69 are
homologous to P3 peptide of the measles virus.
– Amino Acid residues 66-67 homologous to
Influenza Virus, Adenovirus, Epstein-Barr Virus,
Hep-B etc (60% homology).
Polyclonal B-Cell Activation
• Virus and Bacteria also cause non-specific polyclonal B
• Activators: Gram Negative Bacteria, EBV,
• B Cells reactive to self antigens activated
• Ex 1: Mononucleosis: EBV
• Ex 2: SLE: Large quantity of IgM in serum.
• Ex 3: AIDS: Auto-Abs to RBCs and Platelets as patients
are usually co-infected with EBV and Cytomegalovirus.
Toxic Oil Syndrome
Occurred in Spain in 1981 after people ate
contaminated olive oil.
lung disease and excessive IgE.
• Smoking can trigger Goodpasture’s syndrome
Alveolar basement membrane normally not
exposed to immune system.
Smoking damages alveoli, exposes collagen
Anti-collagen Ab damages lung and kidney.
Human Disease Mouse Model
Diabetes Non Obese Diabetic (NOD)
(Lpr = lupus prone)
New Zealand Black
•Hemolytic Anemia (2 to 4
• Females mount a more robust immune response
than the males.
• TH1 pro-inflammatory response was seen to be
• Estrogen is immunostimulatory- pro-inflammatory.
• Prolactin receptors present on B and T Cells.
• Endometriosis and preeclampsia are both thought to
be autoimmune in nature
Hypothesis: estrogen response
elements (EREs) in several genes
Estrogens and Autoimmunity
Nature Immunology 2, 777 - 780 (2001)
Sex differences in autoimmunity