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 mouthlacrimal 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 diseasesSLERAscleroderma

Graves Disease• Antibody mediated• _Hyperthyroidism_ induced by antibodies against

TSH receptor.• Tissue-specific (thyroid gland) with systemic

manifestationsexophthalmos

• 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 formMyelin 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 cells of the pancreatic islets of Langerhans that produce insulin

• EarlyInsulitisLymphocyte 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 cell

degeneration.40% concordance in twins.Associated with DR3 and secondarily with DR4, and relative risk

is almost 100 in those carrying DR3 and DQw8Adapted 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 virusChemicals.

• 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).

• 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.

Rheumatoid Arthritis

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

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 therapyinhibit inflammationexamples

• NSAIDs

• corticosteroids

have no effect on cause of disease

Recent Therapies• Bone marrow ablation and transplant

SLE and scleroderma

• IFN-.1aMS

• TNF-alpha blockadeRA

Oral Tolerance - Low Dose Ag

Th3 TGF-

Inhibits IgA isotype switch

suppresses Th1 and Th2 activation, proliferation, and cytokine production

Ag administered orally induces specific regulatory T-cell (Th3)

Oral Tolerance - High Dose Ag

• Induces Systemic T-cell toleranceprobably through clonal exhaustion

Oral Tolerance

• Clinical trials involving oral tolerance:Bovine myelin basic protein in MS Type II collagen in RARetinal S-antigen in posterior uveitis Insulin in type I diabetes mellitusOral feeding of HLA molecules to prevent graft

rejectionCrohn’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.