Immunologic Tolerance

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Immunologic Tolerance

• Tolerance unresponsiveness to an antigen
• Self-tolerance unresponsiveness to ones own
  antigens
• In generating billions of B and T cells, some
  will react against self antigens!
• There are two ways of muzzling these cells
  central tolerance and peripheral tolerance

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Immunologic Tolerance
1. Central Tolerance carried out during fetal
development in the PRIMARY LYMPHOID ORGANS I.
Thymus for T cells ii. Bone marrow fetal liver
for B cells 2. Peripheral Tolerance operates in
the SECONDARY LYMPHOID ORGNAS, in the periphery
after birth
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Central tolerance

• 1. Clonal deletion (apoptotic cell death)
• During maturation of lymphocytes in the
  thymus for T cell or in the bone marrow for B
  maturation, immature lymphocytes that recognize
  ubiquitous self-antigen with high affinity are
  deleted by negative selection
• 2. Clonal anergy
• functional inactivation without cell death
  lack co-stimulatory signal
• 3. Immunological ignorance
• reactive lymphocytes and their target antigen
  are both detectable within an individual, yet no
  autoimmune attack occurs.
• 4. Receptor editing
• autoreactive B cells escape anergy or deletion
  by further rearranging their immunoglobulin genes
  

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Anergy Induction Lack of Co-stimulation or
Presence of CTLA-4B7 Interaction
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FEATURES OF B-CELL TOLERANCE

• The fate of self-reactive B cells depends on the
  amount and affinity of the BCR and the amount and
  nature of the antigen
• soluble self antigens Anergy
• membrane self antigens Deletion
• High affinity BCR to self antigens Deletion
• Moderate affinity BCR to self antigens Anergy
• Low affinity BCR to self antigens Ignorance

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Peripheral tolerance

• clonal deletion Fas-FasL mechanism
• clonal anergy
• clonal ignorance
• AICD
• supression by Ts cell (T CD4)
• - Suppress T-cell proliferation via rapid
  secretion of IL-10 and TGF-ß
• - Express high levels of CTLA-4

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Autoimmunity Origins

• Horror autotoxicus Literally, the horror of
  self-toxicity.
• A term coined by the German immunologist Paul
  Ehrlich (1854-1915) to describe the body's innate
  aversion to immunological self-destruction.

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Autoimmunity

• 5 to 7 adult affected.
• Two third women.
• More than 40 human diseases autoimmune in origin.

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Causes of Autoimmunity
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Mechanisms of autoimmunity

• Ag released from hidden location (by injury or
  infection)
• Antigen generated by molecular changes
  (Development of completely new epitopes on normal
  protein. eg RF)
• Molecular mimicry (Crossreaction)
• Alteration in Ag processing In IDDM, ß cells
  from pancreas express high levels of Class I and
  Class II MHC molecules.
• Infection Polyclonal lymphocytes activation
  (LPS, Super Ag) inhanced stimulation of co
  stimulator
• Lymphocytes abnormalities
• Cytokine Imbalance (?IL-2 in SLE)
• Deficiencies (Fas, complement, CTL-4)
• Toxins, Drugs, Chemicals (including food), UV,
  Stress
• Hormon (estrogens, lack of androgens)
• LEFT handed individuals
• Genetic factors

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Association between HLA and susceptibility to
autoimmune disease
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Role of Infection in Autoimmunity
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Rheumatic fever is a classic example of molecular
mimicry
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Pathogens
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Association of infection with autoimmune disease
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Drugs and Toxins

• Drugs
• Examples Procainamide (Pronestyl)
• Drug induced lupus
• Toxins
• Examples Toxic Oil Syndrome
• Occurred in Spain in 1981 after people ate
  contaminated olive oil.
• People developed unique illness marked by lung
  disease, eosinophilia, and excessive IgE

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Estrogens and Autoimmunity
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Complement Deficiencies

• CD59 or CD55
• Paroxysmal nocturnal hemoglobinuria
• autoimmune hemolytic anemia
• autoimmune thrombocytopenia
• lupus lymphopenia
• Deficiencies in the classical complement pathway
  renders pts more likely to develop immune complex
  diseases
• SLE
• RA

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Effects of autoimmunity
1) Tissue destruction Diabetes CTLs destroy
insulin-producing ß-cells in pancreas 2)
Antibodies block normal function Myasthenia
gravis Ab binds acetylcholine receptors 3)
Antibodies stimulate inappropriate
function Graves disease Ab binds TSH
receptor Mimics thyroid-stimulating
hormone Activates unregulated thyroid hormone
production 4) Antigen-antibody complexes affect
function Rheumatoid arthritis IgM specific for
Fc portion of IgG IgM-IgG complexes deposited in
joints inflammation
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Autoimmune diseases classified by mechanism of
tissue damage
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Autoimmune diseases mediated by cytotoxic
antibodies (Type II)
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Autoimmune diseases mediated by immune complexes
(Type III)
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Autoimmune diseases mediated by T-cells (Type IV)
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Diabetes

• Disease in which the body does not produce or
  properly use insulin
• T cell Disease
• T cells attack and destroy pancreatic beta cells

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Multiple Sclerosis
MS patients can have autoantibodies and/or self
reactive T cells which are responsible for the
demyelination
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Treatment for autoimmunity

• Immunosuppression (e.g., prednisone, cyclosporin
  A)
• Anti-inflammatory drugs (NSAIDS, Corticosteroids)
• Removal of thymus (some MG patients)
• Radiation
• Plasmapheresis (remove Ab-Ag complexes)
• T-cell vaccination (activate suppressing T cells)
• Block MHC with similar peptide
• Cell Blocking Reagents (monoclonal Ab)
• anti-CD20 (Rituxan)
• anti-CD3 (Teplizumab)
• anti-CD4
• Cytokine Blocking Reagents
• TNF (Humira, Enbrel)
• anti-IL2R monoclonal Ab

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Rheumatiod Arthritis

• Auto-immune disorder which results in
  inflammation of the synovial lining of the joint
  and cartilage destruction.
• This result in loss of function.
• Affects 1 of adults.

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Autoimmune Hemolytic Anemia

• IgG or IgM antibodies directed against red cell
  surface antigens (Coombs test is positive)
• Opsonization of red cells by antibody and
  complement leads to phagocytosis of red cells in
  liver and spleen
• May be triggered by infections, drugs or be
  idiopathic

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Goodpastures syndrome Immunopathology Autoanti
bodies to basement membrane of glomerulus and
lung alveoli. Specificity part of type IV
collagen
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Lupus

• Typical patient young woman with butterfly rash
• Symptoms unpredictable (relapsing/remitting)
• Multisystem (skin, kidneys, joints, heart)
• Antinuclear antibodies

Etiology

• Autoantibodies!
• Antinuclear Ab present in all patients with
  SLE... but found in other autoimmune diseases too
• Anti-RBC, -lymphocyte, -platelet, or
  phospholipid antibodies may be present too
• Underlying cause unclear
• Genetic predisposition
• plus triggers (UV radiation, drugs)

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Lupus
Whats so bad about having these autoantibodies?

• They cause tissue injury!
• Form immune complexes
• Cause destruction, phagocytosis of cells
• Multisystem effects
• Kidney (renal failure)
• Skin (butterfly rash)
• CNS (focal neurologic deficits)
• Joints (arthritis)
• Heart (pericarditis, endocarditis)

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Lupus
Things a dentist might see

• Young woman with polyarthritis and a butterfly
  (or other) skin rash
• Sensitivity to sunlight
• Oral lesions nonspecific, red-white, erosive
• Headaches, seizures, or psychiatric problems
• Pleuritic chest pain
• Unexplained fever

Whats the prognosis?

• Variable! Some have few symptoms, rare patients
  die within months.
• Most patients relapses/remissions over many
  years.
• Acute flare-ups controlled with steroids
• 80 10-year survival
• Most common cause of death renal failure

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Clinical CorrelationSystemic Lupus
Erythematosus (SLE)

• An 18 year old female with malaise, fatigue,
  rash, and joint pains.
• Exam butterfly rash, petechiae (from
  vasculitis), swollen joints
• Lab Positive Anti-Nuclear Antibody, positive
  Coombs and anemia. Urine examination casts,
  protein, red cells. Low C3, C4 and elevated
  anti-dsDNA antibody.

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Rheumatoid Arthritis
Things You Must Know

• Symmetric, mostly small-joint arthritis
• Systemic symptoms (skin, heart, vessels, lungs)
• Rheumatoid factor
• Cytokines (especially TNF) cause damage

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Rheumatoid Arthritis
Etiology

• Genetically predisposed patient
• Something (bug? self-Ag?) activates T cells
• T cells release cytokines
• activate macrophages (causing destruction)
• cause B cells to make antibodies against joint
• Most important of these cytokines TNF
• Cytokines cause inflammation and tissue damage

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Rheumatoid Arthritis
Joint disease

• Mainly small joints (hands), but also knees,
  elbows, shoulders
• Symmetric characteristic hand features
• Chronic synovitis with pannus formation
• synovial cell proliferation
• inflammation
• granulation tissue

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Rheumatoid Arthritis
Systemic disease

• Weakness, malaise, fever
• Vasculitis
• Pleuritis, pericarditis
• Lung fibrosis
• Eye changes
• Rheumatoid nodules on forearms

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Rheumatoid Arthritis
Rheumatoid factor

• Circulating IgM antibody
• Directed against patients OWN IgG!
• Forms IgM-IgG immune complexes, which deposit in
  joints and cause badness
• Present in 80 of patients

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Rheumatoid Arthritis
Things a dentist might see

• Female patient with aching, stiff joints,
  especially in morning
• Symmetric joint swelling
• Fingers ulnar deviation, swan-neck deformities,
  boutonniere deformities
• Rheumatoid nodules

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Rheumatoid Arthritis
Whats the prognosis?

• Variable!
• A few patients stabilize
• Most patients have chronic course with
  progressive joint destruction and disability
• Lifespan shortened by 10-15 years
• Treatment steroids, anti-TNF agents

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Sjögren Syndrome
Things You Must Know

• Inflammatory disease of salivary and lacrimal
  glands
• Dry eyes, dry mouth
• T cells react against some Ag (self? viral?) in
  gland gland gets destroyed
• Increased risk of lymphoma

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Sjögren Syndrome
Etiology

• CD4 T cells attack self antigens in glands
  (why?!)
• Autoantibodies are present, but probably are not
  the primary cause of tissue injury
• ANAs
• RF
• Anti-SS-A, anti-SS-B
• Viral trigger?
• Genetic predisposition

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Sjögren Syndrome

• Salivary and lacrimal glands
• enlarged
• marked inflammation and gland destruction
• 40x increased risk of lymphoma!
• Systemic disease
• fatigue
• arthralgia/myalgia
• Raynaud phenomenon
• vasculitis
• peripheral neuropathy
• often, patient has another autoimmune disease too

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Sjögren Syndrome
Things a dentist might see

• Female between 35-45
• Enlarged salivary glands
• Raynaud phenomenon
• Keratoconjunctivitis sicca (dry eyes)
• Oral changes
• Xerostomia (dry mouth)
• mucosal atrophy
• candidiasis
• mucosal ulceration
• dental caries
• taste dysfunction

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Sjögren Syndrome
How do you treat it?

• Treatment is mostly supportive and symptom-based.
• Oral treatment adequate hydration, scrupulous
  dental hygiene, cholinergic agents (stimulate
  saliva release), frequent dental exams
• Eye treatment lubricating solutions, surgical
  procedures
• Systemic symptom treatment steroids, other
  immunosuppressive drugs

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Sjögrens Syndrome

• Chronic autoimmune disorder
• Major clinical manifestations resulting from
  changes in exocrine glands

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Forms of Sjögrens Syndrome

• Primary Sjögrens is characterized by
  inflammatory cell involvement of both the
  salivary and lacrimal glands
• Secondary Sjögrens includes other defined
  connective tissue disease
• Causes are unknown

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Features of Sjögrens Syndrome

• Glandular epithelial cells participate in the
  autoimmune disease process
• Epithelial cells produce a number of
  immunologically active mediators
• May serve as antigen-presenting cells
• Epithelial cell responses modulate mechanisms
  occurring in the salivary glands

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Is Sjögrens Syndrome an Autoimmune Disorder?

• Described as an autoimmune exocrinopathy (Strand
  and Talal, 1980)
• Grouped with other connective tissue diseases
• Rheumatoid arthritis
• Systemic lupus erythematosis (SLE)
• What is the evidence that it is an autoimmune
  disease?

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Evidence that Sjögrens Syndrome is an Autoimmune
Disease

• A specific auto-immunogen and pathogenic
  antibodies have not been identified
• Autoantibodies that have been found have not been
  shown to have any direct pathogenic effects on
  exocrine tissues
• There is substantial circumstantial evidence that
  tissue damage is the result of autoimmunity

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Polyclonal Hypergammaglobulinemia

• B-cell hyper-responsiveness
• Marked elevations of IgG Production of rheumatoid
  factors
• Presence of anti-nuclear antibodies
• Extractable nuclear antigens Anti-SS-A (Ro) and
  anti-SS-B (La)
• Antibodies are found directed against salivary
  duct cells (90 of patients)
• Primarily against extractable nuclear antigens
• Concentration does not correlate with gland
  destruction

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Other Characteristics

• Elevated sedimentation rates and decreased WBC
  counts, as seen in other autoimmune connective
  tissue diseases
• Specific extended MHC haplotype at a higher
  frequency than controls
• MHC-encoded proteins
• Induction of tolerance to self proteins
• Selection of the T-cell repertoire
• Binding and presentation of antigen to T-cells

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Histopathology

• Mononuclear infiltrate consisting primarily of
  T-cells (primarily CD4)
• Host of mediators
• Altered cell adhesion molecules expression
• Increased HLA class II antigens expression
• Immunosuppressive therapy often effective

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Classical Histopathological Lesion

• Lympho-epithelial lesion affecting the parotid
  gland
• Progressive replacement of the salivary tissue by
  dense lymphoid infiltrates
• Formation of proliferating islands of ductal
  epithelial cells
• Creates well-formed lymphoid follicles typical of
  MALT and may give rise to lymphomas of the MALT
  type as an expansion of monoclonal B-cells

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Conclusion

• Numerous changes in immune factors in Sjögrens
  Syndrome
• Salivary glands appears as a highly active,
  immune-mediated inflammatory sites
• Salivary epithelial cells are immunologically-acti
  ve participants in the disease process

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Systemic Sclerosis (Scleroderma)
Things You Must Know

• Excessive fibrosis throughout body skin, viscera
• Claw hands, mask-like face
• Microvascular disease also present
• Diffuse and limited types

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Systemic Sclerosis (Scleroderma)
Etiology

• CD4 T cells accumulate for some reason
• T cells release cytokines that activate mast
  cells and macrophages, which release fibrogenic
  cytokines
• B cell activation also occurs (diagnostic
  antibody anti-Scl 70) but doesnt play major
  role
• The cause of microvascular changes is unknown

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Systemic Sclerosis (Scleroderma)
Organs involved

• Skin diffuse, sclerotic atrophy. Fingers first.
• GI rubber-hose lower esophagus
• Lungs fibrosis, pulmonary hypertension
• Kidneys narrowed vessels, hypertension
• Heart myocardial fibrosis

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Systemic Sclerosis (Scleroderma)
Limited type vs. diffuse type

• Limited
• Mild skin involvement (face, fingers)
• Involvement of viscera occurs later
• Also called CREST syndrome
• Calcinosis
• Raynaud phenomenon
• Esophageal dysmotility
• Sclerodactyly
• Telangiectasia
• Benign course

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Systemic Sclerosis (Scleroderma)
Limited type vs. diffuse type

• Limited
• Diffuse
• Initial widespread skin involvement
• Early visceral involvement
• Rapid course

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Systemic Sclerosis (Scleroderma)
Things a dentist might see

• Female between 50-60
• Raynaud phenomenon
• Stiff, clawlike fingers
• Mask-like face
• Difficulty swallowing
• Dyspnea, chronic cough
• Difficulty getting dentures in

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Systemic Sclerosis (Scleroderma)
Prognosis

• Steady, slow, downhill course over years
• Limited scleroderma may exist for decades without
  progressing
• Diffuse scleroderma is more common and has worse
  prognosis
• Overall 10-year survival 35-70

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Myasthenia Gravis

• Disease marked by progressive weakness and loss
  of muscle control
• Classified as a B cell Disease
• Autoantibodies against nicotinic acetylcholine
  receptors