DIAGNOSTIC DIAGNOSTIC AUTOANTIBODIESAUTOANTIBODIES

They’re not just for They’re not just for rheumatologists anymorerheumatologists anymore

The first autoantibodyThe first autoantibody

IIF ANA test- the starting point for IIF ANA test- the starting point for modern autoantibody screeningmodern autoantibody screening

Clinical associations with a positive ANAClinical associations with a positive ANA

1:6401:640 SLE, MCTDSLE, MCTDDrug induced LEDrug induced LERA (especially with extraarticular sxs)RA (especially with extraarticular sxs)Sjogren’s syndromeSjogren’s syndromeScleroderma, myositisScleroderma, myositisAutoimmune hepatitis and thyroiditisAutoimmune hepatitis and thyroiditisMalignancy (especially lymphoma)Malignancy (especially lymphoma)SBE, HIVSBE, HIVOral contraceptive useOral contraceptive useNormal womenNormal women

1:40

Titer

Not all ANA’s are the sameNot all ANA’s are the same

peripheralperipheral homogeneoushomogeneous

speckledspecklednucleolarnucleolar

Ribosomal P protein Constitutive protein in ribosome

Some autoantibodies are highly specific E.G. anti-nDNA antibodies

SLE 66 30 RA 5 <2Malignancy 5 <2Discoid LE 5 <2Autoimmune hepatitis (Type1) 5 <2Anti-TNF alpha Rx 7 <5

Anti-DNA ab prevalence (%)

Elevated Greatly elevated

P-ANCA C-ANCA

Anti-neutrophil cytoplasmic abs ANCAAnti-neutrophil cytoplasmic abs ANCA

The genesis of autoantibodiesThe genesis of autoantibodies

All antibodies includng autoantibodies arise from B cell All antibodies includng autoantibodies arise from B cell clones in the bone marrow de novo (without antigen) clones in the bone marrow de novo (without antigen)

These antibodies are usually IgM and low avidityThese antibodies are usually IgM and low avidity

MostMost auto-reactive B cells are removed in thymus or auto-reactive B cells are removed in thymus or tolerized in the peripherytolerized in the periphery

On exposure to antigen the responding B cells undergo On exposure to antigen the responding B cells undergo somatic mutations to produce IgG of high avidity somatic mutations to produce IgG of high avidity

Most clinically specific (diagnostic and/or pathogenic) Most clinically specific (diagnostic and/or pathogenic) autoantibodies are IgG and high avidityautoantibodies are IgG and high avidity

Autoimmune disease is a result of failure of tolerance Autoimmune disease is a result of failure of tolerance and exposure to antigenand exposure to antigen

The autoantibody challengeThe autoantibody challenge

For the diseases grouped by specialty For the diseases grouped by specialty on the next 6 slides try to identify the on the next 6 slides try to identify the most closely associated autoantibody most closely associated autoantibody

(see last 2 slides of handout)(see last 2 slides of handout)

CTD DISEASES ASSOCIATED WITH DIAGNOSTIC CTD DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES AUTOANTIBODIES

SLESLE

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

DIFFUSE SCLERODERMADIFFUSE SCLERODERMA

CREST SYNDROME (LIMITED SCLERODERMA)CREST SYNDROME (LIMITED SCLERODERMA)

DRUG INDUCED LEDRUG INDUCED LE

DERMATOMYOSITISDERMATOMYOSITIS

NEONATAL LENEONATAL LE

SJOGREN’S SYNDROMESJOGREN’S SYNDROME

WEGENER’S GRANULOMATOSUSWEGENER’S GRANULOMATOSUS

GOODPASTURE’S DISEASEGOODPASTURE’S DISEASE

GASTROINTESTINAL DISEASES ASSOCIATED WITH GASTROINTESTINAL DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES DIAGNOSTIC AUTOANTIBODIES

AUTOIMMUNE HEPATITIS – TYPE 1AUTOIMMUNE HEPATITIS – TYPE 1

AUTOIMMUNE HEPATITIS – TYPE 2AUTOIMMUNE HEPATITIS – TYPE 2

PRIMARY BILIARY CIRRHOSISPRIMARY BILIARY CIRRHOSIS

CELIAC DISEASECELIAC DISEASE

ULCERATIVE COLITISULCERATIVE COLITIS

DERMATOLOGIC DISEASES ASSOCIATED WITH DERMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIESDIAGNOSTIC AUTOANTIBODIES

PEMPHIGUS VULGARISPEMPHIGUS VULGARIS

BULLOUS PEMPHIGOIDBULLOUS PEMPHIGOID

DERMATITIS HERPETIFORMISDERMATITIS HERPETIFORMIS

GRAHAM LITTLE-PICCARDI-LASSUEUR SYNDROMEGRAHAM LITTLE-PICCARDI-LASSUEUR SYNDROME

NEUROMUSCULAR DISEASES ASSOCIATED WITH NEUROMUSCULAR DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES DIAGNOSTIC AUTOANTIBODIES

Myasthenia gravisMyasthenia gravisStiff man (person) syndrome – with diabetesStiff man (person) syndrome – with diabetesStiff man (person) syndrome – paraneoplasticStiff man (person) syndrome – paraneoplasticParaneoplastic sensory neuronopathyParaneoplastic sensory neuronopathyLambert Eaton syndromeLambert Eaton syndromeProgressive cerebellar ataxia – paraneoplasticProgressive cerebellar ataxia – paraneoplasticCNS SLECNS SLEChronic Inflammatory Demyelinating PolyneuropathyChronic Inflammatory Demyelinating PolyneuropathyCerebral folate deficiency syndromeCerebral folate deficiency syndromePrimary autoimmune autonomic failurePrimary autoimmune autonomic failureDevic’s syndromeDevic’s syndrome

ENDOCRINE DISEASES ASSOCIATED WITH ENDOCRINE DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIESDIAGNOSTIC AUTOANTIBODIES

Hashimoto’s thyroiditisHashimoto’s thyroiditis

Grave’s diseaseGrave’s disease

Type 1 diabetes mellitusType 1 diabetes mellitus

Addison’s diseaseAddison’s disease

Acquired hypocalciuric hypercalcemiaAcquired hypocalciuric hypercalcemia

HEMATOLOGIC DISEASES ASSOCIATED WITH HEMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIESDIAGNOSTIC AUTOANTIBODIES

ITPITP

HITHIT

Cold agglutinin diseaseCold agglutinin disease

Pernicious anemiaPernicious anemia

Phospholipid antibody syndromePhospholipid antibody syndrome

HEMATOLOGIC DISEASES ASSOCIATED WITH HEMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIESDIAGNOSTIC AUTOANTIBODIES

ITP- Glycoprotein IIb/IIIa absITP- Glycoprotein IIb/IIIa abs

HIT- Platelet factor 4-heparin complex absHIT- Platelet factor 4-heparin complex abs

Cold agglutinin disease-Little i absCold agglutinin disease-Little i abs

Pernicious anemia- parietal cell absPernicious anemia- parietal cell abs

Phospholipid antibody syndrome- beta 2 glycoprotein 1 Phospholipid antibody syndrome- beta 2 glycoprotein 1 absabs

DIAGNOSTIC AUTOANTIBODIES 1

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

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

DIAGNOSTIC AUTOANTIBODIES 2

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

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

ConclusionsConclusions

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

CTD DISEASES ASSOCIATED WITH DIAGNOSTIC CTD DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES AUTOANTIBODIES

SLE – Sm abs, ribosomal P abs, nDNA absSLE – Sm abs, ribosomal P abs, nDNA absRHEUMATOID ARTHRITIS- CCP abs, fillagrin absRHEUMATOID ARTHRITIS- CCP abs, fillagrin absDIFFUSE SCLERODERMA- topoisomerase 1 abs, RNA DIFFUSE SCLERODERMA- topoisomerase 1 abs, RNA polymerase abspolymerase absCREST SYNDROME (LIMITED SCLERODERMA)-CREST SYNDROME (LIMITED SCLERODERMA)-

centromere abscentromere absDRUG INDUCED LE- histone absDRUG INDUCED LE- histone absDERMATOMYOSITIS- Jo1(histidyl RNA transferase abs, signal DERMATOMYOSITIS- Jo1(histidyl RNA transferase abs, signal recognition particle absrecognition particle absNEONATAL LE- Ro/La absNEONATAL LE- Ro/La absSJOGREN’S SYNDROME- SSA/SSB(Ro/La) abs, alpha fodrin absSJOGREN’S SYNDROME- SSA/SSB(Ro/La) abs, alpha fodrin absWEGENER’S GRANULOMATOSUS- PR3 (proteinase 3) abs WEGENER’S GRANULOMATOSUS- PR3 (proteinase 3) abs GOODPASTURE’S DISEASE- Type IV collagen cross link protein GOODPASTURE’S DISEASE- Type IV collagen cross link protein

absabs

GASTROINTESTINAL DISEASES ASSOCIATED WITH GASTROINTESTINAL DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES DIAGNOSTIC AUTOANTIBODIES

AUTOIMMUNE HEPATITIS – TYPE 1- F actin (smooth AUTOIMMUNE HEPATITIS – TYPE 1- F actin (smooth muscle) absmuscle) abs

AUTOIMMUNE HEPATITIS – TYPE 2- LKM (liver/kidney AUTOIMMUNE HEPATITIS – TYPE 2- LKM (liver/kidney microsomal, CYP 2D6) absmicrosomal, CYP 2D6) abs

PRIMARY BILIARY CIRRHOSIS- mitochondrial PRIMARY BILIARY CIRRHOSIS- mitochondrial (pyruvate dehydrogenase complex) abs(pyruvate dehydrogenase complex) abs

CELIAC DISEASE- Tissue transglutaminase abs, CELIAC DISEASE- Tissue transglutaminase abs, endomysial absendomysial abs

ULCERATIVE COLITIS- Lactoferrin absULCERATIVE COLITIS- Lactoferrin abs

DERMATOLOGIC DISEASES ASSOCIATED WITH DERMATOLOGIC DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIESDIAGNOSTIC AUTOANTIBODIES

PEMPHIGUS VULGARIS- Desmoglein 1 & 3 absPEMPHIGUS VULGARIS- Desmoglein 1 & 3 abs

BULLOUS PEMPHIGOID- Hemidesmosomal abs BULLOUS PEMPHIGOID- Hemidesmosomal abs

DERMATITIS HERPETIFORMIS- endomysial abs, DERMATITIS HERPETIFORMIS- endomysial abs, Tissue transglutaminase absTissue transglutaminase abs

NEUROMUSCULAR DISEASES ASSOCIATED WITH NEUROMUSCULAR DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES DIAGNOSTIC AUTOANTIBODIES

Myasthenia gravis- acetyl choline receptor absMyasthenia gravis- acetyl choline receptor abs

Stiff man (person) syndrome – with diabetes- GAD absStiff man (person) syndrome – with diabetes- GAD abs

Stiff man (person) syndrome – paraneoplastic- Stiff man (person) syndrome – paraneoplastic- amphiphysin absamphiphysin abs

Paraneoplastic sensory neuronopathy- Hu (dorsal horn Paraneoplastic sensory neuronopathy- Hu (dorsal horn cell) abscell) abs

Lambert Eaton syndrome- Voltage gated Ca channel Lambert Eaton syndrome- Voltage gated Ca channel P/Q type absP/Q type abs

NEUROMUSCULAR DISEASES ASSOCIATED NEUROMUSCULAR DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIES cont’dWITH DIAGNOSTIC AUTOANTIBODIES cont’d

Progressive cerebellar ataxia- paraneoplastic- Purkinje Progressive cerebellar ataxia- paraneoplastic- Purkinje cell abscell abs

CNS SLE- ribosomal P absCNS SLE- ribosomal P abs

Chronic Inflammatory Demyelinating Polyneuropathy- Chronic Inflammatory Demyelinating Polyneuropathy- ganglioside absganglioside abs

Cerebral folate deficiency syndrome- choroid plexus Cerebral folate deficiency syndrome- choroid plexus folate receptor absfolate receptor abs

Primary autoimmune autonomic failure- ganglionic Primary autoimmune autonomic failure- ganglionic acetylcholine receptor absacetylcholine receptor abs

ENDOCRINE DISEASES ASSOCIATED WITH ENDOCRINE DISEASES ASSOCIATED WITH DIAGNOSTIC AUTOANTIBODIESDIAGNOSTIC AUTOANTIBODIES

Hashimoto’s thyroiditis- Thyroidal peroxidase absHashimoto’s thyroiditis- Thyroidal peroxidase abs

Grave’s disease- TSH receptor absGrave’s disease- TSH receptor abs

Type 1 diabetes mellitus- Islet cell abs, glutamic acid Type 1 diabetes mellitus- Islet cell abs, glutamic acid decarboxylase (GAD) absdecarboxylase (GAD) abs

Addison’s disease- alpha 21 hydroxylase absAddison’s disease- alpha 21 hydroxylase abs

Acquired hypocalciuric hypercalcemia- calcium Acquired hypocalciuric hypercalcemia- calcium receptor absreceptor abs