1. AUTOIMMUNITY
and Susceptibility of Women
Priya Phadtare

2. Outline
• History
• Disease states
• Causes
• Mouse Models of human disease
• Predisposition of women to autoimmune diseases

3. Immune Regulation
T cells B cells

4. Self/Non-Self Discrimination
Basically means
immunity against self.
A condition that occurs
when the immune
system mistakenly
attacks and destroys
healthy body tissue.

5. Autoimmunity Origins
Horror autotoxicus:
Literally, the horror
of self-toxicity.
A term coined by
the German
immunologist Paul
Ehrlich (1854-1915)

6. History Continued
20th
Century Perceptions:
• 1960s: Elimination of all self-reactive
lymphocytes.
• 1970s: Not all self-reactive lymphocytes are
eliminated.

7. 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.

9. Failure of tolerance and disease Outcome
Disease Example
APS-1
MS, Uveitis, Male
infetility
IDDM, Hashimoto’s
IPEX
ALPS
RA, SLE, Crohn’s

10. Failure of Central Tolerance

12. 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.

13. 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.

14. 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.

15. DiabetesCTL Infiltration
Macrophage
Activation
Cytokines Released
+ Lytic Enzymes
Auto-Abs also
Present
IDDM

16. Grave’s Disease
•TSH (from
pituitary gland)
binds to receptors
on thyroid cells
•Hormones
Thyroxine and
Triiodothyroxine.
•Auto-Abs
agonists.
Overstimulation
of Gland.

18. 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.

20. Examples of Systemic Autoimmunity

21. 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.

22. Multiple Sclerosis
T Lymphocytes enter cerebrospinal fluid. Certain viruses
pre-dispose a person for developing MS.

23. • 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

25. Causes of Autoimmunity

26. Mechanisms of autoimmunity
• MHC Polymorphism
• Release of Sequestered Antigens
• Molecular mimicry
• Failure of Central Tolerance
• Toxins

28. 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.
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.

29. 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.

30. 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

31. 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.

32. Damage to immunologically
privileged sites can lead to
autoimmunity

33. 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.

34. • Ex 2: Rheumatic Fever: Streptococcus
infection

35. • 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).

36. 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.

37. Toxins
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.

38. Mouse Models
Human 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)

39. 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

40. Estrogens and Autoimmunity

41. Nature Immunology 2, 777 - 780 (2001)
Sex differences in autoimmunity