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DIAGNOSTIC AUTOANTIBODIES

DIAGNOSTIC AUTOANTIBODIES. They’re not just for rheumatologists anymore. The first autoantibody. IIF ANA test- the starting point for modern autoantibody screening. Clinical associations with a positive ANA. 1:640. SLE, MCTD Drug induced LE RA (especially with extraarticular sxs)

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DIAGNOSTIC AUTOANTIBODIES

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

  2. The first autoantibody

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

  4. 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

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

  6. Ribosomal P protein Constitutive protein in ribosome

  7. Some autoantibodies are highly specific E.G. anti-nDNA antibodies Anti-DNA ab prevalence (%) Elevated Greatly elevated SLE 66 30 RA 5 <2 Malignancy 5 <2 Discoid LE 5 <2 Autoimmune hepatitis (Type1) 5 <2 Anti-TNF alpha Rx 7 <5

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

  9. 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

  10. 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)

  11. 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

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

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

  14. 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

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

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

  17. 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

  18. 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 aciddecarboxylase 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 DIAGNOSTIC AUTOANTIBODIES 1

  19. 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 DIAGNOSTIC AUTOANTIBODIES 2

  20. 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.”

  21. 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

  22. 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

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

  24. 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

  25. 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

  26. 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

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