Transcript 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.