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AUTOIMMUNITYand Susceptibility of Women
Priya Phadtare
Outline
• History• Disease states• Causes• Mouse Models of human disease• Predisposition of women to autoimmune diseases
Immune Regulation
T cells B cells
Self/Non-Self Discrimination
Basically means immunity against self.
A condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue.
Autoimmunity OriginsHorror autotoxicus:Literally, the horror of self-toxicity.
A term coined by the German immunologist Paul Ehrlich (1854-1915)
History Continued
20th Century Perceptions:• 1960s: Elimination of all self-reactive
lymphocytes.• 1970s: Not all self-reactive lymphocytes are
eliminated.
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.
Failure of tolerance and disease Outcome
Disease Example
APS-1
MS, Uveitis, Male infetility
IDDM, Hashimoto’s
IPEX
ALPS
RA, SLE, Crohn’s
Failure of Central Tolerance
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.
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.
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.
DiabetesCTL Infiltration
MacrophageActivation
Cytokines Released+ Lytic EnzymesAuto-Abs also
Present
IDDM
Grave’s Disease•TSH (from pituitary gland) binds to receptors on thyroid cells•Hormones Thyroxine and Triiodothyroxine.•Auto-Abs agonists. Overstimulation of Gland.
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.
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 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.
Multiple Sclerosis
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.
Rheumatoid Arthritis
Causes of Autoimmunity
Mechanisms of autoimmunity• MHC Polymorphism
• Release of Sequestered Antigens
• Molecular mimicry
• Failure of Central Tolerance
• Toxins
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.
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.
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
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.
Damage to immunologically privileged sites can lead to autoimmunity
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.
• Ex 2: Rheumatic Fever: Streptococcus infection
• 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 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.
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.
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)
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
Estrogens and Autoimmunity
Nature Immunology 2, 777 - 780 (2001)
Sex differences in autoimmunity