DIAGNOSTIC AUTOANTIBODIES

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DIAGNOSTIC AUTOANTIBODIES

• Theyre not just for rheumatologists anymore

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The first autoantibody
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IIF ANA test- the starting point for modern
autoantibody screening
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Clinical associations with a positive ANA

• 1640

• SLE, MCTD
• Drug induced LE
• RA (especially with extraarticular sxs)
• Sjogrens syndrome
• Scleroderma, myositis
• Autoimmune hepatitis and thyroiditis
• Malignancy (especially lymphoma)
• SBE, HIV
• Oral contraceptive use
• Normal women

Titer
140
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Not all ANAs are the same
homogeneous
peripheral
nucleolar
speckled
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Ribosomal P protein Constitutive
protein in ribosome
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Some autoantibodies are highly specific E.G.
anti-nDNA antibodies
Anti-DNA ab prevalence ()
Elevated Greatly elevated
SLE
66 30
RA
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lt2 Malignancy
5 lt2 Discoid LE
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lt2 Autoimmune hepatitis (Type1)
5 lt2 Anti-TNF alpha Rx
7 lt5
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Anti-neutrophil cytoplasmic abs ANCA
C-ANCA
P-ANCA
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The genesis of autoantibodies

• All antibodies includng autoantibodies arise from
  B cell clones in the bone marrow de novo (without
  antigen)
• These antibodies are usually IgM and low avidity
• Most auto-reactive B cells are removed in thymus
  or tolerized in the periphery
• On exposure to antigen the responding B cells
  undergo somatic mutations to produce IgG of high
  avidity
• Most clinically specific (diagnostic and/or
  pathogenic) autoantibodies are IgG and high
  avidity
• Autoimmune disease is a result of failure of
  tolerance and exposure to antigen

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The autoantibody challenge

• For the diseases grouped by specialty on the next
  6 slides try to identify the most closely
  associated autoantibody (see last 2 slides of
  handout)

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CTD DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• SLE
• RHEUMATOID ARTHRITIS
• DIFFUSE SCLERODERMA
• CREST SYNDROME (LIMITED SCLERODERMA)
• DRUG INDUCED LE
• DERMATOMYOSITIS
• NEONATAL LE
• SJOGRENS SYNDROME
• WEGENERS GRANULOMATOSUS
• GOODPASTURES DISEASE

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GASTROINTESTINAL DISEASES ASSOCIATED WITH
DIAGNOSTIC AUTOANTIBODIES

• AUTOIMMUNE HEPATITIS TYPE 1
• AUTOIMMUNE HEPATITIS TYPE 2
• PRIMARY BILIARY CIRRHOSIS
• CELIAC DISEASE
• ULCERATIVE COLITIS

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DERMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• PEMPHIGUS VULGARIS
• BULLOUS PEMPHIGOID
• DERMATITIS HERPETIFORMIS
• GRAHAM LITTLE-PICCARDI-LASSUEUR SYNDROME

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NEUROMUSCULAR DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• Myasthenia gravis
• Stiff man (person) syndrome with diabetes
• Stiff man (person) syndrome paraneoplastic
• Paraneoplastic sensory neuronopathy
• Lambert Eaton syndrome
• Progressive cerebellar ataxia paraneoplastic
• CNS SLE
• Chronic Inflammatory Demyelinating Polyneuropathy
• Cerebral folate deficiency syndrome
• Primary autoimmune autonomic failure
• Devics syndrome

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ENDOCRINE DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• Hashimotos thyroiditis
• Graves disease
• Type 1 diabetes mellitus
• Addisons disease
• Acquired hypocalciuric hypercalcemia

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HEMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• ITP
• HIT
• Cold agglutinin disease
• Pernicious anemia
• Phospholipid antibody syndrome

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HEMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• ITP- Glycoprotein IIb/IIIa abs
• HIT- Platelet factor 4-heparin complex abs
• Cold agglutinin disease-Little i abs
• Pernicious anemia- parietal cell abs
• Phospholipid antibody syndrome- beta 2
  glycoprotein 1 abs

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DIAGNOSTIC AUTOANTIBODIES 1

• Anti- histone antibodies
• Anti- desmoglein 1 3 antibodies
• Anti- tissue transglutaminase antibodies
• Anti- fillagrin antibodies
• Anti- ribosomal P antibodies
• Anti- CYP 2D6 (LKM) antibodies
• Anti- glutamic acid decarboxylase antibodies

• Anti- Hu antibodies
• Anti- topoisomerase 1 antibodies
• Anti- Sm antibodies
• Anti- Collagen !V cross-link protein antibodies
• Anti- TSH receptor antibodies
• Anti- centromere antibodies
• Anti-Mi2 antibodies

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DIAGNOSTIC AUTOANTIBODIES 2

• Anti- calcium receptor antibodies
• Anti- endomysial antibodies
• Anti-folate receptor antibodies
• Anti-PR3 antibodies
• Anti- acetyl choline receptor antibodies
• Anti- histidyl RNA transferase antibodies
• Anti- glycoprotein IIb/IIIa antibodies
• Anti- amphiphysin antibodies
• Anti- parietal cell antibodies
• Anti- platelet factor 4-heparin complex
  antibodies
• Anti-voltage gated Ca channel P/Q type antibodies
• Anti- Purkinje cell antibodies
• Anti-lactoferrin antibodies
• Anti-ganglionic acetylcholine antibodies
• Anti-INCENP protein antibodies

• Anti- thyroidal peroxidase antibodies
• Anti- Islet cell antibodies
• Anti- RNA polymerase I, II, III antibodies
• Anti- 21-a-hydroxylase antibodies
• Anti-NMO (neuromyelitis optica) antibodies
• Anti- hemidesmosome antibodies
• Anti-myeloperoxidase antibodies
• Anti- Ro/La antibodies
• Anti- little i antibodies
• Anti- pyruvate dehydrogenase complex antibodies
• Anti- F actin antibodies
• Anti-signal recognition particle antibodies
• Anti-a fodrin antibodies
• Anti-RNP antibodies
• Anti-ganglioside antibodies

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Conclusions

• Autoantibodies are antigen driven
• Autoantibodies are often diagnostic of many
  diseases in many organs
• Autoantibodies frequently correlate with disease
  activity and may mediate cell and tissue damage.
• Autoantibodies are like the purple pimpernel
  You see them here, you see them there, you see
  them everywhere.

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CTD DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• SLE Sm abs, ribosomal P abs, nDNA abs
• RHEUMATOID ARTHRITIS- CCP abs, fillagrin abs
• DIFFUSE SCLERODERMA- topoisomerase 1 abs, RNA
  polymerase abs
• CREST SYNDROME (LIMITED SCLERODERMA)- centromere
  abs
• DRUG INDUCED LE- histone abs
• DERMATOMYOSITIS- Jo1(histidyl RNA transferase
  abs, signal recognition particle abs
• NEONATAL LE- Ro/La abs
• SJOGRENS SYNDROME- SSA/SSB(Ro/La) abs, alpha
  fodrin abs
• WEGENERS GRANULOMATOSUS- PR3 (proteinase 3) abs
• GOODPASTURES DISEASE- Type IV collagen cross
  link protein abs

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GASTROINTESTINAL DISEASES ASSOCIATED WITH
DIAGNOSTIC AUTOANTIBODIES

• AUTOIMMUNE HEPATITIS TYPE 1- F actin (smooth
  muscle) abs
• AUTOIMMUNE HEPATITIS TYPE 2- LKM (liver/kidney
  microsomal, CYP 2D6) abs
• PRIMARY BILIARY CIRRHOSIS- mitochondrial
  (pyruvate dehydrogenase complex) abs
• CELIAC DISEASE- Tissue transglutaminase abs,
  endomysial abs
• ULCERATIVE COLITIS- Lactoferrin abs

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DERMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• PEMPHIGUS VULGARIS- Desmoglein 1 3 abs
• BULLOUS PEMPHIGOID- Hemidesmosomal abs
• DERMATITIS HERPETIFORMIS- endomysial abs, Tissue
  transglutaminase abs

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NEUROMUSCULAR DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• Myasthenia gravis- acetyl choline receptor abs
• Stiff man (person) syndrome with diabetes- GAD
  abs
• Stiff man (person) syndrome paraneoplastic-
  amphiphysin abs
• Paraneoplastic sensory neuronopathy- Hu (dorsal
  horn cell) abs
• Lambert Eaton syndrome- Voltage gated Ca channel
  P/Q type abs

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NEUROMUSCULAR DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES contd

• Progressive cerebellar ataxia- paraneoplastic-
  Purkinje cell abs
• CNS SLE- ribosomal P abs
• Chronic Inflammatory Demyelinating
  Polyneuropathy- ganglioside abs
• Cerebral folate deficiency syndrome- choroid
  plexus folate receptor abs
• Primary autoimmune autonomic failure- ganglionic
  acetylcholine receptor abs

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ENDOCRINE DISEASES ASSOCIATED WITH DIAGNOSTIC
AUTOANTIBODIES

• Hashimotos thyroiditis- Thyroidal peroxidase abs
• Graves disease- TSH receptor abs
• Type 1 diabetes mellitus- Islet cell abs,
  glutamic acid decarboxylase (GAD) abs
• Addisons disease- alpha 21 hydroxylase abs
• Acquired hypocalciuric hypercalcemia- calcium
  receptor abs