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Aims

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Aims Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis. Readings: Robbins, Chapter 5 Sj gren s Syndrome A systemic ... – PowerPoint PPT presentation

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Title: Aims


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

2
Sjögrens 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
3
Sjögrens 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
  • _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 Cotrans Pathologic Basis of Disease
24-8
5
(No Transcript)
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 Cotrans Pathologic Basis
of Disease 24-35
13
(No Transcript)
14
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
15
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.
  • Cows milk

Adopted from Robbins Basic Pathology 17-7 7th 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.
  • 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.

18
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
19
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.

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
Hashimotos 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
Hashimotos Thyroiditis
  • HLA association with HLA-DR5 and DR-3 as well as
    HLA-B8 alleles.

23
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
  • 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
TGF-b
Th3
suppresses Th1 and Th2 activation,
proliferation, and cytokine production
27
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
  • Crohns 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.
  • Sjogrens syndrome, Graves disease, Autoimmune
    hypothyroidism, Multiple sclerosis, Type I
    diabetes, Rheumatois arthritis, Hashimotos
    thyroiditis
  • Describe the treatment options for these various
    autoimmune diseases.
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