1. DIAGNOSTIC AUTOANTIBODIES
They’re not just for rheumatologists anymore

2. The first autoantibody

4. IIF ANA test- the starting point for modern autoantibody screening

5. Clinical associations with a positive ANA
1:640
SLE, MCTD
Drug induced LE
RA (especially with extraarticular sxs)
Sjogren’s syndrome
Scleroderma, myositis
Autoimmune hepatitis and thyroiditis
Malignancy (especially lymphoma)
SBE, HIV
Oral contraceptive use
Normal women
Titer
1:40

6. Not all ANA’s are the same
homogeneous
peripheral
nucleolar
speckled

7. Ribosomal P protein Constitutive protein in ribosome

8. Some autoantibodies are highly specific E.G. anti-nDNA antibodies
Anti-DNA ab prevalence (%)
Elevated Greatly elevated
SLE
RA <2
Malignancy <2
Discoid LE <2
Autoimmune hepatitis (Type1) <2
Anti-TNF alpha Rx <5

9. Anti-neutrophil cytoplasmic abs ANCA
C-ANCA
P-ANCA

11. 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

12. 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)

13. CTD DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES
SLE
RHEUMATOID ARTHRITIS
DIFFUSE SCLERODERMA
CREST SYNDROME (LIMITED SCLERODERMA)
DRUG INDUCED LE
DERMATOMYOSITIS
NEONATAL LE
SJOGREN’S SYNDROME
WEGENER’S GRANULOMATOSUS
GOODPASTURE’S DISEASE

14. GASTROINTESTINAL DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES
AUTOIMMUNE HEPATITIS – TYPE 1
AUTOIMMUNE HEPATITIS – TYPE 2
PRIMARY BILIARY CIRRHOSIS
CELIAC DISEASE
ULCERATIVE COLITIS

15. DERMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES
PEMPHIGUS VULGARIS
BULLOUS PEMPHIGOID
DERMATITIS HERPETIFORMIS
GRAHAM LITTLE-PICCARDI-LASSUEUR SYNDROME

16. 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
Devic’s syndrome

17. ENDOCRINE DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES
Hashimoto’s thyroiditis
Grave’s disease
Type 1 diabetes mellitus
Addison’s disease
Acquired hypocalciuric hypercalcemia

18. HEMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES
ITP
HIT
Cold agglutinin disease
Pernicious anemia
Phospholipid antibody syndrome

19. 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

20. 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

21. 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-α-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-α fodrin antibodies
Anti-RNP antibodies
Anti-ganglioside antibodies

22. 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.”

23. 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
SJOGREN’S SYNDROME- SSA/SSB(Ro/La) abs, alpha fodrin abs
WEGENER’S GRANULOMATOSUS- PR3 (proteinase 3) abs
GOODPASTURE’S DISEASE- Type IV collagen cross link protein abs

24. 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

25. DERMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES
PEMPHIGUS VULGARIS- Desmoglein 1 & 3 abs
BULLOUS PEMPHIGOID- Hemidesmosomal abs
DERMATITIS HERPETIFORMIS- endomysial abs, Tissue transglutaminase abs

26. 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

27. NEUROMUSCULAR DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES cont’d
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

28. ENDOCRINE DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES
Hashimoto’s thyroiditis- Thyroidal peroxidase abs
Grave’s disease- TSH receptor abs
Type 1 diabetes mellitus- Islet cell abs, glutamic acid decarboxylase (GAD) abs
Addison’s disease- alpha 21 hydroxylase abs
Acquired hypocalciuric hypercalcemia- calcium receptor abs