1. Lecture #13
Aims
Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis.
Readings: Robbins, Chapter 5

2. Sjögren’s Syndrome A systemic autoimmune disease
Lecture #13
Sjögren’s Syndrome
A systemic autoimmune disease
Inflammatory destruction of _exocrine_ glands.
Several secretory gland may be affected.
salivary gland -dry mouth
lacrimal gland -dry eye
Enlargement of the salivary gland 6-38 Robbins, lymphocytic and plasma cell infiltration with ductal epithelial cell hyperplasia.
Robbins’ Basic Pathology 5-26

3. Sjögren’s Syndrome
Antibodies against a cytoplasmic RNA-protein complex, SS-A (Ro) and SS-B (La).
Associated with other systemic autoimmune diseases
SLE RA
scleroderma

4. Graves Disease Antibody mediated
Lecture #13
Graves Disease
Antibody mediated
_Hyperthyroidism_ induced by antibodies against TSH receptor.
Tissue-specific (thyroid gland) with systemic manifestations
exophthalmos
Associated with specific alleles of HLA-DR3.
Women 7X more likely than men.
Figure 24-8 A patient with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one of the features of this disorder. In Graves disease, one of the most important causes of hyperthyroidism, accumulation of loose connective tissue behind the eyeballs also adds to the protuberant appearance of the eyes.
Robbins and Cotran’s Pathologic Basis of Disease 24-8

6. Graves Disease
Thyroid stimulating immunoglobulin (TSI) binds to and activates the TSH receptor.
Increased rate of thyroid hormone secretion.
TSH levels are lower than normal.

7. Graves Disease
Symptoms can be passively transferred

8. Autoimmune Hypothyroidism
TSH-binding inhibitor immunoglobulins (TBIIs)
Antibodies block TSH receptor activity rather than mimicking TSH as in Graves disease.
Antibody binding and recognition of a different epitope than that of Graves disease makes for a considerable difference in the clinical outcome.

9. Multiple Sclerosis Primarily a T cell-mediated disease.
CD4+ and CD8 + cells
MHC class _II_ expressing cells.
Type IV hypersensitivity
Results in a progressive demyelinization of CNS leading to a loss of neuronal transmission.
Adopted from WebPath

10. Multiple Sclerosis
Is defined as “ Distinct episodes of neurologic deficits separated in time and separated by space.”
Relapsing-remitting form
Myelin is destroyed, action potential is lost and neurological function is decreases.
Neurological function returns slowly as the nerves generate more Na2+ channels to compensate for loss of action potential.
Chronic progressive form
Myelin and axons are destroyed, no remissions, no return or restoration of function
Very rare acute progressive form (FYI)

11. Multiple Sclerosis
Pathogenesis due to a genetic predisposition and environmental exposure.
Linked to specific _HLA-DR2_ alleles.
Possibly linked to viral infections:
EBV
adenovirus-2
hepatitis B
A similar disease can be induced in mice immunized with myelin basic protein and a strong adjuvant.

12. Type I Diabetes Mellitus
Mostly T cell-mediated disease.
CD8+ CTL destroy b cells of the pancreatic islets of Langerhans that produce insulin
Early
Insulitis
Lymphocyte infiltrate
Similar to Robbins & Cotran’s Pathologic Basis of Disease 24-35

14. Type I Diabetes Mellitus
Lecture #13
Type I Diabetes Mellitus
Genetic susceptibility
In some cases, there is a hereditary tendency for b cell degeneration.
40% concordance in twins.
Associated with DR3 and secondarily with DR4, and relative risk is almost 100 in those carrying DR3 and DQw8
Robins’ Basic Pathology 17-7
Adapted from Robbins’ Basic Pathology th Ed

15. Type I Diabetes Mellitus
Lecture #13
Type I Diabetes Mellitus
Environment
Emigrants assume the risk of type I diabetes closer to that of their destination country than their country of origin.
Viral infections.
Coxsackie virus
Chemicals.
Cow’s milk
Robins’ Basic Pathology 17-7
Cow’s milk.1.5X more likely to get type I diabetes if you ingested cow’s milk before 4-6 months of age. Especially if there is a family history of type I diabetes.
Cow proteins A1 and B beta-casein may be autoimmune targets.
Pediatric News (33:2, 1999), Diabetes (49:1657, 2000), Diabetes Nutr Metab. (2002)
Adopted from Robbins’ Basic Pathology th Ed

16. Type I Diabetes Mellitus
Organ-specific with systemic manifestations.
~10% of patient have some other autoimmune disorder.
Anti-insulin antibodies may be generated.
Anti-islet cell antibodies (70-80-% of patients).

17. Rheumatoid Arthritis Both antibody and T cell mediated disease.
Lecture #13
Rheumatoid Arthritis
Both antibody and T cell mediated disease.
Systemic disease.
Characterized by chronic inflammation of the synovium and other connective tissues.
The inflammation is initiated by the deposition of IC and sustained by chronic inflammatory cells.
Adopted from the American College of Rheumatology web site
Joints are swollen and deformed.
Muscles are atrophied

18. Pathogenesis of Rheumatoid Arthritis
Lecture #13
Pathogenesis of Rheumatoid Arthritis
Molecular mimicry
Unknown antigen
Genetic susceptibility
Associated with HLA-DR4.
T cell activation
Rheumatoid factor production
Anti-Ig antibody (usually IgM) in a high percentage of patients.
Pannus formation
Adapted from Robbins’ Basic Pathology 5-30
Adopted from Robbins’ Basic Pathology 5-25

19. Pannus _Fibrovascular_ tissue.
Lecture #13
Pannus
_Fibrovascular_ tissue.
Consists of fibroblasts, macrophages, T cells and plasma cells.
Has the potential to invade surrounding tissues including the bone, cartilage, and tendon.
Adopted from the American College of Rheumatology web site

20. Some notes on Rheumatoid Factor and ANA
A minority of RA patients do not have elevated RF and some with RF do not have RA.
Relatively high ANA and RF may be found in some otherwise normal persons.
Certain infectious diseases induce high RF and ANA.
Titers of RF do not always correlate with severity and occurrence.
RA occurs in some agammaglobulinemic patients.
RF may be elevated in SLE and ANA in RA.
RF may be a marker but may not be a mechanism.

21. Hashimoto’s Thyroiditis
Autoimmune disease of the Thyroid gland.
Highly organ-specific.
Results in _Hypothyroidism.
Most likely T cell-mediated.
Due to presence of infiltrating mononuclear cells.
Characteristic of type IV hypersensitivity reaction.
There are autoantibodies present in these patients.
Antibodies against a cytoplasmic antigen.

22. Hashimoto’s Thyroiditis
HLA association with HLA-DR5 and DR-3 as well as HLA-B8 alleles.

23. Treatments of Autoimmune Diseases
Lecture #13
Treatments of Autoimmune Diseases
Metabolic control therapies.
factor replacement therapy
Graves’ disease
Myasthenia gravis
organ transplant
SLE nephritis
_plamapheresis
SLE

24. Treatments of Autoimmune Diseases
Immunosuppressive therapy
inhibit inflammation
examples
NSAIDs
corticosteroids
have no effect on cause of disease

25. Recent Therapies Bone marrow ablation and transplant IFN-b.1a
SLE and scleroderma
IFN-b.1a MS
TNF-alpha blockade RA

26. Oral Tolerance - Low Dose Ag
Ag administered orally induces specific regulatory T-cell (Th3)
Inhibits IgA isotype switch
Th3
TGF-b
suppresses Th1
and Th2 activation,
proliferation, and
cytokine production

27. Oral Tolerance - High Dose Ag
Lecture #13
Oral Tolerance - High Dose Ag
Induces Systemic T-cell tolerance
probably through clonal exhaustion

28. Oral Tolerance Clinical trials involving oral tolerance:
Bovine myelin basic protein in MS
Type II collagen in RA
Retinal S-antigen in posterior uveitis
Insulin in type I diabetes mellitus
Oral feeding of HLA molecules to prevent graft rejection
Crohn’s and Ulcerative Colitis patients may have deficient oral tolerance mechanisms.

29. Review
Tolerance is the process by which the body ensures that immune responses are directed against foreign or altered self antigens and not normal self.
There is central and peripheral tolerance.
Autoimmune diseases result from a breakdown of tolerance.
Autoimmune diseases can be organ specific or systemic.
Autoimmune diseases can be antibody mediated, cell mediated, or both.
Autoimmune diseases can be types II, III, or IV hypersensitivity reactions.
Autoimmune diseases are treated through direct metabolic control, by immunosuppression, and by immunomodulation.

30. Next Time Define autograft, isograft, allograft, and Xenograft.
Compare and contrast hyper acute, acute, and chronic graft rejection and graft vs. host and host vs. graft disease.
Quantitative and qualitative deficiencies in neutrophils (phagocytosis).
Readings: Abbas & Lichtman, Chapter 10

31. Objectives
Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis.
Sjogren’s syndrome, Graves disease, Autoimmune hypothyroidism, Multiple sclerosis, Type I diabetes, Rheumatois arthritis, Hashimoto’s thyroiditis
Describe the treatment options for these various autoimmune diseases.