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) Sjogren’s syndrome Scleroderma, myositis Autoimmune hepatitis and thyroiditis Malignancy (especially lymphoma) SBE, HIV Oral contraceptive use Normal women Titer 1:40

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

Ribosomal P protein Constitutive protein in ribosome

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

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

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

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)

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

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

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

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

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

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

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

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

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

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.”

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

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

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

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

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

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