Transcript Autoimmunity I - University of Arizona

Autoimmunity I
Matt McReynolds
Outline
I.
Definition
a.
b.
c.
Direct proof
Indirect evidence
Circumstantial
II. Diseases
a.
b.
c.
Antibody-mediated
Immunecomplexmediated
T cell-mediated
III. Models
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.
Autoimmunity
• 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.
Autoimmunity
• 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 nonspecific
• Humoral or Cell-mediated
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
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
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
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
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
Diseases
1. Antibody Mediated
2. Immune-complex mediated
3. T-cell mediated
Diseases
1. 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
2. Immune-complex mediated
3. T-cell mediated
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 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)
• 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
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
MG
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
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 MG
Symptoms:
• Inability to align
eyes
• Droopy eye-lids
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
Pourmand R. 1997.
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
Normal
Normal
Graves’
Disease
Graves’ Diagnosis
• Blood test:
– T3 and T4 are markedly elevated
– TSH levels are low or absent.
– Serum Ab detection
– Goiter
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.
Proptosis
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
Diseases
1. Antibody Mediated
2. Immune-complex mediated
•
Systemic Lupus Erythematosus (SLE)
3. T-cell mediated
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)
SLE Incidence
• 1 / 1,000 white
persons
• 1 / 250 black women
• Concordance:
– 25% monozygotic
twins
– 1-2% dizygotic twins
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
Diseases
1. Antibody Mediated
2. Immune-complex mediated
3. T cell-mediated
•
•
•
Multiple Sclerosis
Insulin-Dependent Diabetes Mellitus
Rheumatoid Arthritis
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%)
MS
• 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 (fluidattenuated 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).
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
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
IDDM
• 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)
• Self Ag: cartilage
• HLA DR4, TNF genes, HSP gene
complex, infection (EBV)
• Varied age (common in 20’s-40’s)
• Women:Men 3:1
RA
•  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
RA
Autoimmune Models
• Immunization
– Self antigen
• Spontaneous
– Genetically susceptible strains
• Induced
– Virally, chemically, pharmacologically
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)
• 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,
EAE
EAE
• Synthetic peptides
– MBP 1-9: acute, no relapses
• single TCR
– PLP 43-64, MBP 89-101: chronicrelapsing
• epitope spreading, large TCR repertoire
Experimental autoimmune
arthritis (EAA)
• Collagen II Arthritis (CIA)
• Joint swelling and edema
• Heterologous collagen
– Active joint erosion; severe, selflimiting
• Autologous collagen
– Cartilage erosion; chronic disease
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
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
• 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 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
• 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
Questions?