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Autoimmunity I. Matt McReynolds. Definition Direct proof Indirect evidence Circumstantial Diseases Antibody-mediated Immunecomplex-mediated T cell-mediated Models. Outline. Autoimmunity. “Friendly-fire”: Immune response to self Autoimmune disease:

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autoimmunity i

Autoimmunity I

Matt McReynolds


Direct proof

Indirect evidence





T cell-mediated


  • “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.

  • Autoimmune responses occur all the time with little to no consequence.
  • Theory of “autoimmune diseases” was only recently accepted in the 1950’s and 60’s.
  • Prevalence of autoimmune diseases in Western countries has been estimated at 3 - 7% (Marmont, AM. 2000 Ann Rev Med 51:115-134)
  • Organ specific or non-specific
  • Humoral or Cell-mediated
defining a disease as autoimmune
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
defining a disease as autoimmune7
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
defining a disease as autoimmune8
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
defining a disease as autoimmune9
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
defining a disease as autoimmune10
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
  • Antibody Mediated
  • Immune-complex mediated
  • T-cell mediated
  • 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
autoimmune hemolytic anemia
Autoimmune Hemolytic Anemia
  • Self Ag: red blood cells (RBC’s)
  • 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
autoimmune hemolytic anemia14
Autoimmune Hemolytic Anemia
  • Antibody/agglutinins groups
    • Warm: react at 37C, Rh antigen
      • IgG  phagocytosis
    • Cold: react <37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)
myasthenia gravis mg
Myasthenia Gravis (MG)
  • Self Ag: Acetylcholine Receptor (AChR) at the neuromuscular junction
  • Women in late 20s / Men in their 50’s
  • 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
  • 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
  • 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
occular mg
Occular MG
  • Functional Hypothesis: slight weakness in ocular and eye-lid muscles is far less tolerable than generalized weakness.
  • Immunologic Hypothesis: Difference in Ab’s associated with ocular muscle.
  • Physiological Hypothesis: Ocular muscles are predisposed to MG because of their size,innervation and activity.
occular mg20
Occular MG


  • Inability to align eyes
  • Droopy eye-lids
  • 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
graves disease
Graves’ Disease
  • Self Ag: Thyroid-stimulating Hormone Receptor (TSHR)
  • Hyperthyroidism
  • TSH receptor is activated independent of the pituitary
  • Familial, HLA II, Ab titer:Disease severity, neonatal hyperthyroidism from maternal IgG




graves diagnosis
Graves’ Diagnosis
  • Blood test:
    • T3 and T4 are markedly elevated
    • TSH levels are low or absent.
    • Serum Ab detection
    • Goiter
graves symptoms
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.
rheumatic fever
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
  • Antibody Mediated
  • Immune-complex mediated
    • Systemic Lupus Erythematosus (SLE)
  • T-cell mediated
  • 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)
sle incidence
SLE Incidence
  • 1 / 1,000 white persons
  • 1 / 250 black women
  • Concordance:
    • 25% monozygotic twins
    • 1-2% dizygotic twins
sle complications
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
  • Antibody Mediated
  • Immune-complex mediated
  • T cell-mediated
    • Multiple Sclerosis
    • Insulin-Dependent Diabetes Mellitus
    • Rheumatoid Arthritis
  • 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%)
  • Diagnosis
    • Clinical presentation
    • Cerebrospinal Fluid (CSF) abnormalities
    • Evoked potentials (visual, somatosensory)
    • Neurological dysfunction becomes “disseminated in space and time”
    • Magnetic Resonance Imaging (MRI)

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).

  • 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
insulin dependent diabetes mellitus iddm
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
  • Symptoms:
    •  insulin  abnormalities in glucose metabolism  ketoacidosis, thirst, polyuria, vision disturbances
  • Late stages: progressive atherosclerotic vascular lesions  arterial obstruction, renal failure, blindness
rheumatoid arthritis ra
Rheumatoid Arthritis (RA)
  • Self Ag: cartilage
  • HLA DR4, TNF genes, HSP gene complex, infection (EBV)
  • Varied age (common in 20’s-40’s)
  • Women:Men 3:1
  •  synovial fluid with PMNs  Cartilage replaced with fibrous tissue  joint fusion
  • Diagnosis:
    • >80%: Rheumatoid Factor (RF)
    • IgM anti-IgG Fc
  • Immune involvement:
    • Ag-Ab complex, C’, PMNs, CD4+, CD8+, MØ, NK cells, TNF-, IL-1
autoimmune models
Autoimmune Models
  • Immunization
    • Self antigen
  • Spontaneous
    • Genetically susceptible strains
  • Induced
    • Virally, chemically, pharmacologically
immunization models
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
experimental autoimmune allergic encephalomyelitis eae
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
  • Synthetic peptides
    • MBP 1-9: acute, no relapses
      • single TCR
    • PLP 43-64, MBP 89-101: chronic-relapsing
      • epitope spreading, large TCR repertoire
experimental autoimmune arthritis eaa
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
  • 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
experimental autoimmune myasthenia gravis eamg
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
spontaneous models
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
spontaneous models55
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
induced models
Induced Models
  • Infectious
    • Theiler’s 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