Autoimmunity I

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Autoimmunity I
Matt McReynolds
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Outline

• Definition
• Direct proof
• Indirect evidence
• Circumstantial
• Diseases
• Antibody-mediated
• Immunecomplex-mediated
• T cell-mediated
• Models

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Autoimmunity

• Friendly-fire Immune response to self
• Autoimmune disease
• When the immunological recognition of self with
  the involvement of antibody, complement, immune
  complexes, and cell-mediated immunity progresses
  from being benign to pathologic.

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Autoimmunity

• Autoimmune responses occur all the time with
  little to no consequence.
• Theory of autoimmune diseases was only recently
  accepted in the 1950s and 60s.

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Autoimmunity

• Prevalence of autoimmune diseases in Western
  countries has been estimated at 3 - 7 (Marmont,
  AM. 2000 Ann Rev Med 51115-134)
• Organ specific or non-specific
• Humoral or Cell-mediated

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Defining a disease as autoimmune

• Direct Proof requires transmissibility
• Antibody or lymphocyte transfer
• Animal models
• Humans to animals (pemphigus vulgaris and bullous
  pemphigoid)
• Humans
• Mother to fetus (eg. myasthenia gravis)
• T cell transfer not feasible MHC
• Diseases Idiopathic thrombocytopenic purpura,
  Graves' disease

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Defining a disease as autoimmune

• Indirect Proof
• Identify target Ag in humans
• Reproduce model disease with homologous Ag in
  animal
• AChR ? EAMG, collagen I ? EAA, myosin ? EAM,
  myelin ? EAE
• Majority of autoimmune diseases

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Defining a disease as autoimmune

• Indirect Proof
• Identify target Ag in humans
• Reproduce model disease with homologous Ag in
  animal
• AChR ? EAMG, collagen I ? EAA, myosin ? EAM,
  myelin ? EAE
• Study genetically predisposed animal models
• (NZB x NZW)F1 mice ? model of SLE

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Defining a disease as autoimmune

• Indirect Proof
• Identify target Ag in humans
• Study genetically predisposed animal models
• Isolate self-reactive Ab or T cells from target
  organs
• Anti-erythrocyte Abs hemolytic anemia
• Anti-DNA Abs SLE

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Defining a disease as autoimmune

• Circumstantial evidence - "markers" descriptive
  of autoimmune disease
• Familial tendency
• Lymphocyte infiltration
• Specific MHC II allele association
• Immune complex deposition
• Clinical improvement with immunosuppressive agents

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Diseases

• Antibody Mediated
• Immune-complex mediated
• T-cell mediated

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Diseases

• Antibody Mediated - produced either by antibodies
  binding to antigens on cells or tissue or by
  Ag-Ab complex deposition in vessel walls.
• Autoimmune Hemolytic Anemia
• Myasthenia Gravis
• Graves Disease
• Rheumatic Fever
• Immune-complex mediated
• T-cell mediated

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Autoimmune Hemolytic Anemia

• Self Ag red blood cells (RBCs)
• Can be associated with systemic lupus
  erythematosus
• Mechanisms of Ab-mediated destruction
• Opsonization and digestion by macrophage
• Complement cascade and lysis of RBC
• Also the principal mechanism for thrombocytopenic
  purpura

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Autoimmune Hemolytic Anemia

• Antibody/agglutinins groups
• Warm react at 37?C, Rh antigen
• IgG ? phagocytosis
• Cold react lt37?C, I or i antigens
• IgM ? complement and lysis
• Occurs in limbs or skin upon temperature drop
• Induced
• Penicillin (hapten), Methyldopa (warm),
  Mycoplasma pneumoniae or viruses (cold)

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Myasthenia Gravis (MG)

• Self Ag Acetylcholine Receptor (AChR) at the
  neuromuscular junction
• Women in late 20s / Men in their 50s
• Prevalence in the US is estimated at 14/100,000
  population, approximately 36,000 cases
• Thymus hypertrophy, 10 have thymoma
• HLA class II
• Blood test, Acetylcholinesterase (AChE) inhibitor
  (edrophonium) used for diagnosis

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MG

• Changes in motor endplate
• Abs bind complement
• Inflammatory cell response
• Destruction of endplate and AChR
• Abs block cation channels of the receptor and
  prevent propagation of action potentials

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MG
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MG

• Seronegative or positive for antiAChR Abs
• 95 pos in generalized disease
• 60 pos in localized (occular) disease
• Seropositivity is not associated with disease
  severity, but Ab titers decrease with
  immunosuppression

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Occular MG

• Functional Hypothesis slight weakness in ocular
  and eye-lid muscles is far less tolerable than
  generalized weakness.
• Immunologic Hypothesis Difference in Abs
  associated with ocular muscle.
• Physiological Hypothesis Ocular muscles are
  predisposed to MG because of their
  size,innervation and activity.

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Occular MG

• Symptoms
• Inability to align eyes
• Droopy eye-lids

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MG

• Muscle weakness improves with rest
• Chewing, swallowing (dysphagia), breathing
  (dyspnea), speaking (dysarthria)
• Ptosis (droopy eye lids), diplopia (2x vision)
• Inner ear hyperacusis (acute hearing due to
  heightened irritability of nerve pathway)
• Neck flexor muscles, limb

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Pourmand R. 1997.
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Graves Disease

• Self Ag Thyroid-stimulating Hormone Receptor
  (TSHR)
• Hyperthyroidism
• TSH receptor is activated independent of the
  pituitary
• Familial, HLA II, Ab titerDisease severity,
  neonatal hyperthyroidism from maternal IgG

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Normal
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Normal
Graves Disease
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Graves Diagnosis

• Blood test
• T3 and T4 are markedly elevated
• TSH levels are low or absent.
• Serum Ab detection
• Goiter

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Graves Symptoms

• Cardiac arrhythmias (a-fib), tachycardias,
  widened pulse pressure
• Endocrine weight loss, increased basal
  metabolic rate
• Dermatological profuse sweating, clubbing of
  fingernails
• Neurological tremor, weakness, proximal
  myopathy
• Ophthalmological thyroid eye disease,
  proptosis.

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Proptosis
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Rheumatic Fever

• Self Ag Cardiac proteins
• Follows pharyngeal infection with group A
  streptococci
• Arthritis, carditis, chorea, s.c. nodules
• Chronic, progressive valve damage
• Major cause of acquired heart disease in many
  lesser developed countries
• Molecular mimicry

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Diseases

• Antibody Mediated
• Immune-complex mediated
• Systemic Lupus Erythematosus (SLE)
• T-cell mediated

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SLE

• Self Ags ssDNA, dsDNA, nucleohistones
• Causes
• Genetic predisposition
• Environmental causes
• Drug interactions
• Response to nuclear proteins
• Normal IgM SLE IgG
• Cellular Ags exposed during apoptosis incite an
  immune response
• Increased Fas expression in B T cells
• Sunlight (keratinocytes)

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SLE Incidence

• 1 / 1,000 white persons
• 1 / 250 black women
• Concordance
• 25 monozygotic twins
• 1-2 dizygotic twins

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SLE Complications

• Musculoskeletal osteoporosis, joint pain
• Dermatologic malar rash, photosensitivity
• CNS psychosis, seizures
• Hematological anemia
• Renal failure (complex deposition)
• CV antiphospholipid Abs ? hypercoagulability
• Lupus anticoagulant, anticardiolipin Ab
• Thrombosis, thrombocytopenia, pregnancy loss

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Diseases

• Antibody Mediated
• Immune-complex mediated
• T cell-mediated
• Multiple Sclerosis
• Insulin-Dependent Diabetes Mellitus
• Rheumatoid Arthritis

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MS

• Self Ag Myelin sheath
• Demyelinating plaques
• Optic nerve, periventricular and spinal cord
  white matter, brain stem, cerebellum
• Symptoms
• changes in sensation in the arms, legs or face
  (33), complete or partial vision loss (optic
  neuritis) (16), weakness (13), double vision
  (7), unsteadiness when walking (5), and balance
  problems (3)

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MS

• Diagnosis
• Clinical presentation
• Cerebrospinal Fluid (CSF) abnormalities
• Evoked potentials (visual, somatosensory)
• Neurological dysfunction becomes disseminated in
  space and time
• Magnetic Resonance Imaging (MRI)

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An axial FLAIR (fluid-attenuated inversion
recovery) image shows multiple ovoid and
confluent hyperintense lesions in the
periventricular white matter (Panel A). Nine
months later, the number and size of the lesions
have substantially increased (Panel B).
Noseworthy, et al. NEJM 2000.
After the administration of gadolinium, many of
the lesions demonstrate enhancement, indicating
the breakdown of the BBB (Panel C). In Panel D, a
parasagittal T1-weighted MRI scan shows "black
holes" in the periventricular white matter and
corpus callosum (chronic lesions).
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MS

• Relapsing-remitting (80)
• characterized by unpredictable attacks (relapses)
  followed by periods of months to years of
  relative quiet (remission) with no new signs of
  disease activity
• Chronic Progressive (20)
• Primary, secondary progressive
• Quadriparesis cognitive decline visual loss
  cerebellar, bowel, bladder, and sexual dysfunction

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Insulin-Dependent Diabetes Mellitus (IDDM)

• Self Ag insulin-secreting ?-islet cells of
  pancreas
• Type I, Juvenile-onset
• HLA DR3 and DR4
• Abs, T cells, adhesion molecules, ? serum
  cytokine inhibitors, sustained expression of
  cytokines and Rs
• TNF-?, IFN-?, IL-1

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IDDM

• Symptoms
• ? insulin ? abnormalities in glucose metabolism ?
  ketoacidosis, thirst, polyuria, vision
  disturbances
• Late stages progressive atherosclerotic vascular
  lesions ? arterial obstruction, renal failure,
  blindness

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Rheumatoid Arthritis (RA)

• Self Ag cartilage
• HLA DR4, TNF genes, HSP gene complex, infection
  (EBV)
• Varied age (common in 20s-40s)
• WomenMen 31

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RA

• ? synovial fluid with PMNs ? Cartilage replaced
  with fibrous tissue ? joint fusion
• Diagnosis
• gt80 Rheumatoid Factor (RF)
• IgM anti-IgG Fc
• Immune involvement
• Ag-Ab complex, C, PMNs, CD4, CD8, MØ, NK
  cells, TNF-?, IL-1

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RA
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Autoimmune Models

• Immunization
• Self antigen
• Spontaneous
• Genetically susceptible strains
• Induced
• Virally, chemically, pharmacologically

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Immunization Models

• Adjuvant any substance that enhances the immune
  response to an antigen with which it is mixed
• Does not form stable linkages w/ immunogen
• Mechanisms
• Convert soluble protein Ags into particulate
  material ? ingested by MØ
• Bacterial products signal MØ or DC
• ? cytokines

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Experimental Autoimmune/Allergic
Encephalomyelitis (EAE)

• Model of RR or chronic progressive MS
• Various mouse strains
• Intradermal immunization with myelin basic
  protein (MBP), proteolipid protein (PLP), myelin
  oligodendrocyte glycoprotein (MOG)
• Ascending paralyses of hind limbs, infiltration,
  demyelination

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EAE
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EAE

• Synthetic peptides
• MBP 1-9 acute, no relapses
• single TCR
• PLP 43-64, MBP 89-101 chronic-relapsing
• epitope spreading, large TCR repertoire

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Experimental autoimmune arthritis (EAA)

• Collagen II Arthritis (CIA)
• Joint swelling and edema
• Heterologous collagen
• Active joint erosion severe, self-limiting
• Autologous collagen
• Cartilage erosion chronic disease

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EAA

• Mechanism
• T-cell dependent B-cell activation ? Ab
  production ? Fc-mediated C activation
• IP injection of Abs ? synovial inflammation,
  erosive arthritis
• C depleted mice are resistant to EAA induction
• Adoptive transfer of T cells
• Subclinical disease

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Experimental Autoimmune Myasthenia Gravis (EAMG)

• Purified AChR
• Rodents
• Adoptive transfer to mice with Igs from MG
  patients
• C-mediated lysis ? rate of AChR
  internalization by muscle cell

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Spontaneous Models

• Murine Systemic Lupus Erythematosus
• Defects in Fas/FasL ? lymphoproliferation
• NZB/W mice B cell differentiation defect
• BXSB mice defective Y-linked gene
• (NZBxNZW)F1 mice mutations in TNF-? gene ?
  decreased production
• 10 gene loci associated with murine SLE

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Spontaneous Models

• Insulin-Dependent Diabetes Mellitus
• Non-obese diabetic (NOD) mice
• Initial epitope Glutamic Acid Decarboxylase
• 18-20 wks overt diabetes, ?-islet cells
  progressively destroyed
• MØ, T and B cells, dendritic cells accumulate
• Later epitope spreading (other GAD, insulin,
  HSP60)
• CD8 and CD4 cells necessary for islet
  destruction

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Induced Models

• Infectious
• Theilers murine encephalomyelitis virus
• Mice or rats, transferred with donor T cells
• Staphylococcus aureus strains
• Arthritogenic in mice (septic arthritis)
• Secretion of superantigenic endotoxin TSST 1
• V ? 11 T cell expansion in joints
• Bacterial cell wall fragments injected into rats
• T cell-dependent chronic polyarthritis from MØ
  activation

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Questions?