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