Tolerance, Immune Regulation, and Autoimmunity

Aims • Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis.

• Readings: Robbins, Chapter 5

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

Robbins’ Basic Pathology 5-26

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

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.

Robbins and Cotran’s Pathologic Basis of Disease 24-8

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.

Graves Disease • Symptoms can be passively transferred

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.

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

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)

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.

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

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 Adapted from Robbins’ Basic Pathology 17-7 7th Ed

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

Adopted from Robbins’ Basic Pathology 17-7 7th Ed

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).

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.

Pathogenesis of Rheumatoid Arthritis • Molecular mimicry  Unknown antigen

• Genetic susceptibility  Associated with HLADR4.

• T cell activation • Rheumatoid factor production  Anti-Ig antibody (usually IgM) in a high percentage of patients.

• Pannus formation Adopted from Robbins’ Basic Pathology 5-25

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.

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.

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.

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

Treatments of Autoimmune Diseases • Metabolic control therapies. factor replacement therapy • Graves’ disease • Myasthenia gravis

organ transplant • SLE nephritis

_plamapheresis • SLE

Treatments of Autoimmune Diseases • Immunosuppressive therapy inhibit inflammation examples • NSAIDs • corticosteroids

have no effect on cause of disease

Recent Therapies • Bone marrow ablation and transplant SLE and scleroderma

• IFN-b.1a MS

• TNF-alpha blockade RA

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

Oral Tolerance - High Dose Ag • Induces Systemic T-cell tolerance probably through clonal exhaustion

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.

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.

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

Objectives 1. Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis. 1. Sjogren’s syndrome, Graves disease, Autoimmune hypothyroidism, Multiple sclerosis, Type I diabetes, Rheumatois arthritis, Hashimoto’s thyroiditis

2. Describe the treatment options for these various autoimmune diseases.