Autoimmunity and Susceptibility in Women
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AUTOIMMUNITYand Susceptibility of Women
Priya Phadtare
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Outline
• History• Disease states• Causes• Mouse Models of human disease• Predisposition of women to autoimmune diseases
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Immune Regulation
T cells B cells
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Self/Non-Self Discrimination
Basically means immunity against self.
A condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue.
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Autoimmunity OriginsHorror autotoxicus:Literally, the horror of self-toxicity.
A term coined by the German immunologist Paul Ehrlich (1854-1915)
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History Continued
20th Century Perceptions:• 1960s: Elimination of all self-reactive
lymphocytes.• 1970s: Not all self-reactive lymphocytes are
eliminated.
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Prevalence
• 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
diseases. – MS-Rheumatoid Arthritis– Vitiligo- Autoimmune Thyroid Disease (40% Indians)-
NALP1 gene malfunctioning.
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Failure of tolerance and disease Outcome
Disease Example
APS-1
MS, Uveitis, Male infetility
IDDM, Hashimoto’s
IPEX
ALPS
RA, SLE, Crohn’s
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Failure of Central Tolerance
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Hashimoto’s Thyroiditis•Middle Aged Women.•Sensitized TH-1 for Thyroid Antigens.•Thyroid Gland infiltration by Lymphocytes, Macrophages and Plasma Cells.•Abs against thyroglobulin and thyroid peroxidase.•Hypothyroidism •Goitre.
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Autoimmune Anemia
• Pernicious Anemia–Auto-Abs against intestinal protein on
parietal cells- hampers uptake of vit B12.
• Autoimmune Hemolytic Anemia–Auto-Ab against RBC Antigens–Complement Lysis- Phagocytosis of
RBC.
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Goodpasture’s Syndrome
Lungs of a patient with Goodpasture’s
•Auto-Abs against basement membrane Ags.•Glomeruli and Alveoli affected.•Kidney Faliure and Pulmonary Hemorrhage.•IgG and C3b deposit on the basement membrane.
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DiabetesCTL Infiltration
MacrophageActivation
Cytokines Released+ Lytic EnzymesAuto-Abs also
Present
IDDM
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Grave’s Disease•TSH (from pituitary gland) binds to receptors on thyroid cells•Hormones Thyroxine and Triiodothyroxine.•Auto-Abs agonists. Overstimulation of Gland.
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Myasthenia Gravis
• 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 Antagonists.
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Examples of Systemic Autoimmunity
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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 thrombocytopenia
• Auto-Abs against nuclear antigens- complement system activation- damage to blood vessels- vasculitis and glomerulonephritis
• Neutropenia: Expression of a type 3 complement receptor (CR3) on neutrophils.
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Multiple Sclerosis
T Lymphocytes enter cerebrospinal fluid. Certain viruses pre-dispose a person for developing MS.
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• 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.
Rheumatoid Arthritis
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Causes of Autoimmunity
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Mechanisms of autoimmunity• MHC Polymorphism
• Release of Sequestered Antigens
• Molecular mimicry
• Failure of Central Tolerance
• Toxins
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Autoimmunity Associated with MHC
1. Ankylosing Spondylitis: Inflammatory disease of vertebral joints.– HLA-B27 allele of HLA-B gene present.– 90% of the cases are males.
2. IDDM: Pancreatic beta cells express high levels of class I and class II MHC.
3. Grave’s Disease: Thyroid Acinar Cells express high levels of class II MHC. – Sensitization of TH1 against cell Ags.
CTLs get activated.4. Phytohemaglutinin (PHA): Induces thyroid cells to
express class II MHC.
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4. INF-Gama:• 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.
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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
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Examples• Vasectomy: Sperm Ag released into
circulation• Eye Damage: Lens Protein released into the
circulation• Myocardial Infarction: Heart Muscle Antigens
released into blood stream.• Myelin Basic Protein released from the Blood
Brain Barrier into the circulation.
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Damage to immunologically privileged sites can lead to autoimmunity
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Molecular Mimcry• 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.
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• Ex 2: Rheumatic Fever: Streptococcus infection
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• 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).
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Polyclonal B-Cell Activation
• Virus and Bacteria also cause non-specific polyclonal B Cell Activation.
• Activators: Gram Negative Bacteria, EBV, Cytomegalovirus.
• B Cells reactive to self antigens activated Auto-Abs.• 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.
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ToxinsToxic Oil SyndromeOccurred in Spain in 1981 after people ate
contaminated olive oil.lung disease and excessive IgE.
• Smoking can trigger Goodpasture’s syndromeAlveolar basement membrane normally not exposed to immune system.Smoking damages alveoli, exposes collagen
Anti-collagen Ab damages lung and kidney.
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Mouse ModelsHuman Disease Mouse Model
Diabetes Non Obese Diabetic (NOD)
Lupus MRLlpr (Lpr = lupus prone)Fas Gene
New Zealand Black•Hemolytic Anemia (2 to 4 months)•Glomerulonephritis (18 months)
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Hormones• Females mount a more robust immune response
than the males.• TH1 pro-inflammatory response was seen to be
higher. • 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
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Estrogens and Autoimmunity
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Nature Immunology 2, 777 - 780 (2001)
Sex differences in autoimmunity