1. (from Webster’s Online)
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
How is autoimmunity induced?
What could go wrong here?

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. Cross-Reactivity

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

7. 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.

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

9. 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.

10. 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.

11. Animal Models for Autoimmune Diseases
Why have them?
Animal models of autoimmune diseases contribute valuable insights into the mechanisms of autoimmunity and to our understanding of autoimmunity in humans and how we may treat autoimmune diseases.

12. 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

13. Spontaneous Autoimmunity in Some Animals
Exhibits important clinical and pathogenic similarities to certain autoimmune diseases in humans
Example: New Zealand Black Mice (NZB) and F1 hybrids of NZB and New Zealand White Mice (NZW) spontaneously develop autoimmune diseases that closely resemble lupus erythematosus
Incidence of autoimmunity in hybrids is more common in females than in males

14. New Zealand Mice
NZB spontaneously develops autoimmune hemolytic anemia between 2-4 months of age
At this point various antibodies can be detected. These antibodies include antibodies to erthyocytes, nuclear proteins, DNA and T lymphocytes
F1 hybrids develop glomerulonephritis from immune-complex deposits in the kidneys and die within 18 months
Glomerulonephritis: nephritis marked by inflammation of the capillaries of renal glomeruli
Glomeruli: a tuft of capillaries at the point of origin of each vertebrate nephron that passes a protein-free filtrate to the surrounding Bowman’s capsule

15. Mouse MRL/lpr/lpr (Mouse strain)
Systemic Lupus Erthematosus develops in the mouse strain MRL/lpr/lpr
Mice are homozygous for the lpr gene, which has been identified as a defective fas gene.
The fas/lpr gene product is a cell surface protein in the TNF family
When the normal fas protein interacts with its ligand, signals are sent out leading to apoptic death of the fas bearing cells: target of CTLs
Fas is also known to be important for the death of hyperactive CD4+ cells
Without fas mature peripheral T cells do not die, and they continue to proliferate and produce cytokines that result in enlarged lymph nodes and spleen

16. Nonobese Diabetic (NOD) Mouse Model
Found to develop a form of diabetes that resemble human insulin dependent mellitus
As in humans, NOD in mice begins with lymphatic infiltration into the islets of the pancreas
There is an association between certain MHC and development of diabetes in the mice
Experiments have shown that t cells from diabetic mice can transfer diabetes to nondiabetic mice
When bone marrow of a normal mouse is replaced with NOD bone marrow, diabetes develops
When bone marrow from NOD mouse is replaced with healthy bone marrow, diabetes doesn’t develop

17. Spontaneous Autoimmunity
A final example….
- Other animals: Obese strain chickens can develop humoral and cellmediated reactivity thyroglobulin resembling Hashimoto’s Thyroiditis

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

19. Myasthenia Gravis
1973: rabbits were immunized with acetylcholine receptors purified from electric eels. The rabbits then developed muscular weakness similar to myasthenia gravis
Myasthenia gravis: disease characterized by progressive weakness and exhaustibility of voluntary muscles without atrophy or sensory disturbance and caused by an autoimmune attack on acetylcholine receptors at the neuromuscular junction
Experimental myasthenia gravis resulted when the antibodies to the acetylcholine receptors blocked muscle stimulation by the acetylcholine in the synapse
From this experiment: the discovery that auto-antibodies to the acetylcholine receptors were the cause of myasthenia gravis in humans

20. CFA: Complete Freund’s Adjuvant
An effective means of potentiating humoral antibody response to injected immunogens
CFA is considered to be an emulsion consisting of equal volumes of CFA to antigen (1 part CFA or less to 1 part antigen).
Improper or unnecessary use leads to excessive inflammation, induration, and/or necrosis in laboratory animals.

21. Experimental Autoimmune Encephalomyelitis (EAE)
Experimental autoimmune encephalomyelitis (EAE): one of the best studied models of autoimmune diseases
Encephalomyelitis: concurrent inflammation of the brain and spinal cord
EAE is mediated by T cells and can be induced in many species by immunization with a myelin basic protein (MBP) or protolipid protein (PLP) in complete Freund’s adjuvant (20-7)
Within 2-3 weeks animals develop cellular infiltration of the myelin sheaths of the central nervous system: resulting in demyelination or paralysis.
Most animals die, but some have milder symptoms. Some develop chronic symptoms that resemble multiple sclerosis in humans.
Animals that recover are resistant to more MBP injections
EAE model is used to investigate treatment testing for human MS
Recent mouse experiments suggest that orally administered MBP may make these antigen-specific peripheral T cell clones self-tolerant
Paved the way for clinical trials in MS patients

22. Experimental AutoimmuneThyroiditis (EAT)
Induced in a number of animals by immunizing them with thyroglobulin using CFA: humoral and Tdth cell responses cause inflammation of the thyroid.
EAE resembles human hashimoto’s thyroiditis
Autoimmune Arthritis is induced by immunizing rats with Mycobacterium tuberculosis in CFA
Animals develop symptoms similar to human rheumatoid arthritis

23. Other Autoimmune Animal Models

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

25. I. Current Therapies Immunosuppressive drugs Cyclosporin A Thymectomy
- 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

26. 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

27. (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

28. 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

29. 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

30. Sex-based Differences
Pregnancy
- during this, ♀ mount more of a TH2-like response
- the change in hormones creates an anti inflammatory environment (high cortisol levels)
- diseases enhanced by TH2-like responses are exaggerated and diseases that involve inflammatory responses are suppressed
- fetal cells can persist in the mother’s blood or the mother’s cells may appear in the fetus (microchimerism)
- can result in autoimmunity if the fetal cells mount an immune response in the mother’s body (or vice versa)

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

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

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

34. Mechanism of Tissue Damage

35. Treatment Options NSAIDs Cox-2 Inhibitors Methotrexate Herbal Remedies
Glucosamine
Chondroitin

36. Grave’s Disease
Production of thyroid hormones is regulated by thyroid-stimulating hormones (TSH)
The binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of two thyroid hormones: thyroxine and triiodothyronine
A person with Grave’s Disease makes auto-antibodies to the receptor for TSH. The binding of these auto-antibodies to the receptor mimics the normal action of TSH, without the regulation, leading to overstimulation of the thyroid
The auto-antibodies are called long-acting thyroid stimulating hormones

37. Grave’s Disease
Beta-blockers such as propranolol are often used to treat symptoms of rapid heart rate, sweating, and anxiety until the hyperthyroidism is controlled.
Hyperthyroidism is treated with antithyroid medications, radioactive iodine or surgery.
Both radiation and surgery result in the need for lifelong use of replacement thyroid hormones, because these treatments destroy or remove the gland.

38. Autoimmune Anemias What is it? What causes it?
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

39. 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