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Autoantibody Assessment in Rheumatic Disease
Dana Ascherman, M.D.Division of Rheumatology
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Case #1Ø 19 year old female presenting with 2 year history of
Raynaud’s-type vasospasm
Ø slight fatigue, mild arthralgias
Ø ROS otherwise negative
Ø Physical examination:• no oral ulcerations• no skin rash, peri-ungual blush• no synovitis
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Case #1
Ø Any additional physical exam maneuvers?
Ø Should we order autoantibodies?
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Case #2Ø 37 year old female presenting with intermittent fever,
polyarthralgia/polyarthritis x 6 months
Ø slight fatigue, mild xerophthalmia, Raynaud’s, difficulty climbing stairs
Ø ROS otherwise negative
Ø Physical examination:• afebrile• slightly diminished tear pool• sclerodactyly; no skin rash• no synovitis, but multiple tender joints• 4+/5 deltoid, iliopsoas, quadriceps strength
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Case #2
Ø Labs: leukopenia, mild anemia, ESR=47
Ø ANA positive 1:640 in speckled pattern
Ø What tests to order next?
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Case #3Ø 43 year old male referred for evaluation of ILD and
possible autoimmune disorder
Ø Developed “pneumonia” in 2007—no response to antibiotics
Ø Diagnosis revised to “pulmonary fibrosis”• treated with prednisone for 1 year with clinical,
functional, and radiologic improvement
Ø Pulmonary evaluation: • restrictive PFTs with reduced FVC, TLC, DLCO• HRCT with basilar ground glass, minimal
honeycombing• Serology: -ANA, +SS-A, -Jo-1
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Bilateral lower lobe air space disease with ground glass opacities consistent with active alveolitis; minimal fibrosis in lung bases peripherally
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Case #3ØReview of Systems:
• no constitutional symptoms (F/C, NS, weight loss)• denies xerophthalmia/xerostomia, Raynaud’s• denies skin thickening or rashes beyond patchy
hyperpigmentation of palms• currently no cough, significant dyspnea• denies dysphagia, reflux, abdominal pain, change in
bowel habits• no joint pain/swelling/stiffness• mild proximal upper extremity aching without proximal
weakness
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Case PresentationØPhysical Examination:
• afebrile, normal blood pressure, respiratory rate• grossly adequate tear, salivary pools• without palpable LAD• lungs with good air movement, no use of accessory
muscles; CTA without rales/rhonchi/wheezing• normal radial, posterior tibial pulses• musculoskeletal exam without synovitis• normal proximal, distal muscle strength• skin without Gottron’s rash/papules
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Case #3Summary
Ø mechanic’s hands, no muscle weakness
Ø steroid-responsive ILD
Ø -ANA, -Jo-1, +SS-A cytoplasmic staining
What to do next (besides call a rheumatologist)?
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Case #4
Ø 53 year old male presenting with polyarthritis,
intermittent fever, and weight loss
Ø associated fatigue, sinus congestion, epistaxis
Ø ROS otherwise negative except subjective hearing loss
Ø Physical examination:
• Gen: fatigued appearing
• T=38.3
• slight proptosis (right)
• purpuric skin lesions distal lower extremities
• mild synovitis PIPs, knees
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Case #4
Ø Labs: Hgb=9.7, Cr=2.4, U/A: 1+ protein, 43 RBCs; ESR=83
Ø Imaging studies?
Ø Additional serology?
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Overview
1) Mechanisms of autoantibody formation
3) Disease associations
2) Methods of autoantibody detection
4) Autoantibodies as markers of clinical phenotype
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Autoimmunity
Ø“Horror Autoxicus”--Paul Ehrlich
ØSelf-antigens targeted
ØPrice of adaptive immunity
ØQuestion: why isn’t autoimmunity even more common?
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Tolerance
ØRegulatory mechanism(s) to prevent uncontrolled autoreactivity
ØB vs. T cell tolerance
ØCentral vs. peripheral tolerance
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Autoimmunity: Mechanisms
1) Molecular mimicry•Rheumatic fever, HSK, Guillain-Barre
2) Release of sequestered antigen•Trauma, infection
4) Upregulation of MHC Class II•Release of IFN-g
3) Generation of cryptic/neo-epitopes•Apoptosis--Granzyme B cleavage•?tissue-specific•Defective clearance--C1q deficiency (SLE)
5) Polyclonal B cell activation•EBV infection
6) Immune system defects, alterations•cytokine milieu--IBD
Antigen Processing/Presentation
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Generation and Presentation of Autoantigens:Post-translational modifications
Ø influence Ag structure, immunogenicity–examples include deimination of arginine to citrulline (anti-CCP), deamidaiton of aspartic acid to isoaspartic acid, glycosylation, transglutamination, oxidative damage
Ømodifications can be triggered by aging, cellular stress induced by infection, trauma, apoptosis
Ømodifications may not occur in thymus--escape central tolerance
Øpost-translational changes could also influence subsequent processing, generation of epitopes
Ømay promote epitope spreading--B cell cross reactivity to modified, native version
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Antibody DetectionØ Immunofluorescence
• ANA, ANCA
Ø ELISA• CCP• U1RNP• SS-A/SS-B• Scl70
Ø Immunoprecipitation• tRNA synthetases (e.g., Jo-1)• myositis- and scleroderma-specific autoantibodies
Ø Immunodiffusion—tRNA synthetases
Ø Nephelometry—RF
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MethodologyImmunofluorescence
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MethodologyImmunofluorescence
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ANA--Patterns
PatternsA) Rim (dsDNA/chromatin) B) HomogenousC) Speckled (Ro/La, Sm/RNP) D) Nucleolar (Scl-70)
A) B)
C) D)
ACR slide collection
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ANA Interpretation
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ANCA
C-ANCA (PR3) P-ANCA (MPO)
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Limitations- IIFØ antigen must be present in sufficient copy
number in the cell substrate • fixation solvent may strip antigen• cell may not produce sufficient quantity of Ag
Ø somewhat subjective
Ø limited standardization of pattern reporting
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MethodologyELISA
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MethodologyELISA
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Limitations- ELISAØpurity of Ag often a problem
• recombinant Ag often expressed in bacteria• Ag purified from animal tissues may include other
antigenic proteins
Ø some assays use only fragments of Ag
Øpatients may have Ab to blocking agent
Ø small operator inconsistencies can result in large errors
ØAg coating on plates can be damaged by shipping and handling conditions
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MethodologyImmunoprecipitation
PrincipleØpatient’s Ab is bound to Protein
A Sepharose-coated beads and then incubated with an extract derived from human cells
Ø target antigen binds to the Ab
Ø immunprecipitate is eluted, bound Ag is separated by electrophoresis and visualized
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190150138
12680
7062
43343227
PL-12 110 kd Band
NormalRNA
PolymerasesKuSRP SclerodermaAbs
RNA Pol
KuBands
SRP 54 kd Band
SRPPL-12
Immunoprecipitation
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ImmunoprecipitationLimitations
Ø proteins must be soluble, present in sufficient amount, and contain sufficient methionine for labeling
Ø very large and very small antigens cannot be visualized
Ø some antigens cannot be distinguished because they are of similar sizes
Ø takes 1-2 weeks (batching)
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MethodologyImmunodiffusion
Øpatient sera and crude Ag mix are placed in wells in a gel an allowed to diffuse
Øat equivalence point, a visible preciptin line be formed
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Autoantibody AssessmentOverall Limitations
ØRF, ANA lack specificity
SLE Present + -
+ 3 300
AN
A
Result - 1 9696
Lupus prevalence : ~ 4 in 10,000 in general populationProb of ANA >= 1:320 in SLE: ~ 75%
Prob of ANA >= 1:320 in normals: ~ 3%
Positive predictive value = 3/303 = ~1%Negative predictive value = 9696/9697 = >99.98%
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Role of ANA TestingØANA is useful to exclude lupus, not to
diagnose it
Ø follow-up clinical assessment of ANA+ patients can be beneficial in high-risk populations
ØANA has no value in assessing prognosis or disease activity (i.e., do not follow titers)
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Autoantibodies:Markers of Clinical Phenotype
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Myositis--Autoantibodies
Ø target nuclear and cytoplasmic antigens: Mi-2, PM/Scl, SRP, Ku, tRNA synthetases
Antibody Target Subset Phenotype
Mi-2 NuRD DM Shawl, V-neck, Gottron’s
CADM-140 MDA-5 DM Amyopathic, ILD
SAE SUMO DM ILD, dysphagia
MJ NXP-2 JDM Calcinosis, Ulceration
p155/140 TIF1-g DM, JDM Severe skin, malignancy
SRP 72, 54 kDa PM Severe/refractory myositis
p200/100 HMGCR IMNM Necrotizing myopathy
Jo-1 ARS PM/DM Anti-synthetase syndrome
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Myositis--AutoantibodiesJo-1 (histidyl-tRNA synthetase): 25%
Ø defines clinically homogeneous patient population: anti-synthetase syndrome (fever, myositis, arthritis, Raynaud’s, mechanic’s hands, ILD)
Ø range of clinical manifestations varies depending upon targeted sytnthetase autoantigen
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Systemic Sclerosis:Antibody subsets and Clinical Phenotype
1) Anti-centromere: limited cutaneous, Raynaud’s, pulmonary HTN
2) Anti-Th/To: limited cutaneous, pulmonary HTN and/or ILD
3) Anti-toposisomerase I (Scl-70): diffuse cutaneous, GI, ILD, renal crisis
4) Anti-RNA polymerase III: diffuse cutaneous (rapid), renal crisis
5) Anti-PM/Scl: myositis/scleroderma overlap, ILD
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Case #1
Ø Any additional physical exam maneuvers?
Ø Should we order autoantibodies?
Ø 19 year old female with mild arthralgia, +Raynaud’s
1. Nailfold Capillaroscopy2. ANA
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Case #2--Summary
Ø fatigue, xerophthalmia, polyarthralgia, weakness, Raynaud’s
Ø ANA positive 1:640 in speckled pattern
Ø leukopenia, anemia, elevated ESR
ENA (SS-A, SS-B, Smith, RNP)--MCTD
Ø Additional serology?
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Case #3--SummaryØ mechanic’s hands, no muscle weakness
Ø steroid-responsive ILD
Ø -ANA, -Jo-1, +SS-A cytoplasmic staining
Anti-Synthetase Syndrome (incomplete)—anti-EJ
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Case #4--Summary
Ø Serology?
Ø 53 year old male with:• fever• weight loss, fatigue• epistaxis, hearing loss• polyarthritis
Ø anemia, Cr=2.3, hematuria, elevated ESR
ANCA (c-ANCA/PR3)—Granulomatosis with Polyangiitis
Ø Imaging?
Ø CXR: pulmonary nodules
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ConclusionØAutoantibody formation reflects breakdown of tolerance
•combination of T and B cell dysregulation
ØClinical picture should determine serological profiling•RF, CCP—rheumatoid arthritis
ØAutoantibodies serve as biomarkers of disease subsets
•ANA—SLE (dsDNA, Sm), Sjogren’s (SS-A, SS-B, RF), MCTD (RNP), systemic sclerosis (Scl-70, RNApol III, centromere)
•cytoplasmic ANA/ANA negative--myositis
•ANCA—GPA (c-ANCA/PR3), mPAN, EGPA (p-ANCA/MPO)
ØCaveat: RF, ANA lack specificity