This document discusses autoimmunity, including its definition, molecular mechanisms, animal models, treatments, gender differences, and three common autoimmune diseases - rheumatoid arthritis, pernicious anemia, and hemolytic anemia. The molecular mechanisms of autoimmunity include cross-reactivity, release of sequestered antigens, inappropriate MHC expression, and polyclonal B cell activation. Current therapies aim to suppress the immune system, while experimental approaches try to induce specific immune responses.

1. Autoimmunity
“n. of, relating to, or caused by
autoantibodies or lymphocytes that attack
molecules, cells, or tissues of the organism
producing them.”
(from Webster’s Online)

2. The Study of Autoimmunity
• Molecular Mechanisms of Autoimmunity
• Animal Models for Autoimmune
Dysfunction
• Treatments for Autoimmune Diseases
• Gender Differences in Autoimmunity
• Three Common Autoimmune Diseases

3. Molecular Mechanisms of Autoimmunity
What could go wrong
here?
How is autoimmunity
induced?

4. Molecular Mechanisms of Autoimmunity
• Cross-reactivity (Molecular and Viral Mimicry)
Viral and nonviral peptides can mimic self-peptides and
induce autoimmunity
Example: papilloma virus (HPV) and insulin receptor

5. Molecular Mechanisms of Autoimmunity
• Release of Sequestered Antigen
Antibodies in blood can attack Myelin Basic Protein if
Blood-Brain barrier is breached.

6. Molecular Mechanisms of Autoimmunity
• Inappropriate MHC expression
Type I Diabetes: Pancreatic β cells express abnormally
high levels of MHC I and MHC II (?)
MHC II – APC only! This may hypersensitize TH cells to β
cell peptides.

7. Inappropriate MHC Expression
Normal Pancreas Pancreas with Insulitis
Fig. 20-3

8. Molecular Mechanisms of Autoimmunity
• Polyclonal B Cell Activation by Viruses and
Bacteria
If B cells reactive to self-peptides are activated,
autoimmunity can occur.
Example: Epstein-Barr Virus, which is the cause of
infectious mononucleosis.

9. Putting it all together…the big picture
• Autoimmunity can be caused by immunological, genetic,
viral, drug-induced, and hormonal factors.
• There are 4 immunological mechanisms of
autoimmunity.
• All mechanisms cause abnormal B or T cell activation.
• Centrality of the Ternary Complex
• Most instances of autoimmune diseases occur with
multiple mechanisms, which makes treatment difficult.

10. Autoimmunity in Animals is
Spontaneous or Induced
• Spontaneous: Autoimmunity develops
spontaneously in some inbred strains of
animals
• Induced: Autoimmunity develops after
being induced by certain experimental
manipulation

11. Induced Autoimmunity in Animals
• Autoimmune dysfunctions that are similar
to human autoimmune disease can be
induced into animals

12. Treatment of Autoimmune
Diseases
I. Current Therapies
II. - aimed at reducing symptoms by
providing non-specific suppression of the
immune system
II. Experimental Therapeutic Approaches
- try to induce specific immunity

13. I. Current Therapies
• Immunosuppressive drugs
- corticosteroids, azathioprine
- slows the proliferation of lymphocytes
• Cyclosporin A
- blocks signal transduction mediated by the TCR
(inhibits only antigen-activated T cells while sparing
non-activated ones)
• Thymectomy
- removal of thymus from patients with myasthenia
gravis
• Plasmapheresis
- removes antigen-antibody complexes for a short-
term reduction in symptoms

14. II. Experimental Therapeutic
Approaches
• T-cell Vaccination
- autoimmune T-cell clones elicit regulator T-cells
that are specific for the TCR on the autoimmune T-
cells
- results in suppression of the autoimmune cells
• Peptide Blockade of MHC molecules
- a synthetic peptide is used to bind in place of the
regular peptide on the MHC
- induces a state of clonal anergy in the autoimmune
T-cells

15. (Experimental Therapies continued)
• Monoclonal-Antibody Treatment
- monoclonal antibody against the IL-2 receptor
blocks activated TH-cells
- blockage of preferred TCRs with monoclonal
antibodies
- monoclonal antibody against an MHC molecule
that is associated with autoimmunity while sparing
the others
• Oral antigens
- tend to induce tolerance
- still in early clinical trials

16. Sex-based Differences in
Autoimmunity
• Differences can be traced to sex hormones
- hormones circulate throughout the body and alter
immune response by influencing gene expression
- (in general) estrogen can trigger autoimmunity and
testosterone can protect against it
• Difference in immune response
- ♀ produce a higher titer of antibodies and mount
more vigorous immune responses than ♂
- ♀ have a slightly higher cortisol secretion than ♂
- ♀ have higher levels or CD4+ T-cells and serum
IgM

17. Sex-based Differences
• Estrogen
- causes autoimmunity (generally)
- stimulates prolactin secretion (helps regulate
immune response)
- stimulates the gene for CRH (corticotropin-
releasing hormone) that promotes cortisol secretion
- causes more TH1-dominated immune responses
(promotes inflammation)
• Testosterone
- can cause autoimmunity or protect against it

18. Rheumatoid Arthritis (RA)
• Cause (s) and Demographics
• Molecular Mechanism
• Mechanism of Tissue Damage
• Treatment Options

19. Cause and Demographics
• Cause is unknown!
• Affects 1-2% of worldwide population
• Patients are 75% Women, between 40-60
years of age

20. Molecular Basis
• Rheumatoid Factor (Rf): Antibodies to IgG
• HLA-DR4 Antibody (MHC II!)

21. Mechanism of Tissue Damage

22. Treatment Options
• NSAIDs
• Cox-2 Inhibitors
• Methotrexate
• Herbal Remedies
– Glucosamine
– Chondroitin

23. Autoimmune Anemias
• Pernicious Anemia
What is it?
- deficiency in vitamin B12
What causes it?
- auto-antibodies to intrinsic factor
What happens?
- B12 remains in the stomach and is excreted
Treatment
- treated with injections of B12

24. • Hemolytic Anemia
- results from monoclonal antibodies to normal
RBC constituents
- antibodies coat the erythrocytes, causing clumping,
lysis, and premature clearance by the spleen
- can be induced by an “offending” agent (parasite,
drug, or toxin) that adheres to the RBC
- Drug-induced Hemolytic Anemia- drug binds
to RBC’s and causes them to become
antigenic
- antibodies that develop from the drug
recognize these cells and they are
lysed