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Aims. Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis. Readings: Robbins, Chapter 5. Sj ögren’s Syndrome. A systemic autoimmune disease Inflammatory destruction of _exocrine_ glands . Several secretory gland may be affected.

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slide1
Aims
  • Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis.
  • Readings: Robbins, Chapter 5
sj gren s syndrome
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

sj gren s syndrome1
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
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 disease1
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 disease2
Graves Disease
  • Symptoms can be passively transferred
autoimmune hypothyroidism
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
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 sclerosis1
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 sclerosis2
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
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 mellitus1
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 mellitus2
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 mellitus3
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
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
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
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
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
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 thyroiditis1
Hashimoto’s Thyroiditis
  • HLA association with HLA-DR5 and DR-3 as well as HLA-B8 alleles.
treatments of autoimmune diseases
Treatments of Autoimmune Diseases
  • Metabolic control therapies.
    • factor replacement therapy
      • Graves’ disease
      • Myasthenia gravis
    • organ transplant
      • SLE nephritis
    • _plamapheresis
      • SLE
treatments of autoimmune diseases1
Treatments of Autoimmune Diseases
  • Immunosuppressive therapy
    • inhibit inflammation
    • examples
      • NSAIDs
      • corticosteroids
    • have no effect on cause of disease
recent therapies
Recent Therapies
  • Bone marrow ablation and transplant
    • SLE and scleroderma
  • IFN-b.1a
    • MS
  • TNF-alpha blockade
    • RA
oral tolerance low dose ag
Oral Tolerance - Low Dose Ag

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

Inhibits IgA isotype switch

TGF-b

Th3

suppresses Th1

and Th2 activation,

proliferation, and

cytokine production

oral tolerance high dose ag
Oral Tolerance - High Dose Ag
  • Induces Systemic T-cell tolerance
    • probably through clonal exhaustion
oral tolerance
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
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
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
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.