Diagnostics for Dermatologic Diseases with Autoantibodies

1.1 MB·English

by  Kristin M Leiferman, Jeremy P Snook, Mazdak A Khalighi, Melanie K Kuechle, John J Zone

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Diagnostics for Dermatologic Diseases with
Autoantibodies
KristinM.Leiferman,a,*JeremyP.Snook,aMazdakA.Khalighi,aMelanieK.Kuechle,a,band
JohnJ.Zonea
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Background: Dermatologic diseases with autoantibodies were recognized early as autoimmunity became ac- wn
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ceptedasapathogenicimmunologicconcept.Laboratorytestingtoidentifydisease-definingautoantibodiesand a
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investigatetheirroleinpathophysiologyhasevolvedsince. d fro
Content: Blistering dermatologic diseases, profiled by autoantibody production, target epithelial components m
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criticalincell–cellandcell–matrixadhesion,resultinginepithelialseparationandothercharacteristicfeaturesof ttp
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thedisorders.Thisreviewcoverstheclinicalindicationsfordermatologicdisease-relatedautoantibodytesting,the ://a
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specifics of procuring specimens to test, the available diagnostic tests, and information provided bythe testing. a
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Atypical,uncharacteristic,andlesswell-knownclinicalandautoantibodyprofilesaswellasseveralofthemanyfu- m
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tureprospectsforexpansionofthetestingapplicationsareelaboratedonintheonlineDataSupplement. .o
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Summary: Autoantibody-associateddermatologicdiseasesareacquiredimmunologicdisordersthathavecon- .c
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siderable clinical implications affecting essential barrier functions of skin and mucous membranes and causing /ja
discomfort, including pain and pruritus. Certain of the diseases can have life-threatening manifestations, and lm
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treatmentscanhavesignificantside-effects.Theskindiseasesmaypresageotherclinicalassociationsthatareim- rtic
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portanttorecognizeandtreat.Laboratorytestingaidsinthediagnosisofthesediseasesthroughidentificationof /7
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theautoantibodiesandisessentialforpromptandpreciseknowledgeofthediseasetypeforprognosis,further /1
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clinicalevaluations,andtreatmentdecisions. 5/6
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HISTORYANDINTRODUCTION immunodermatology testing, including its appli- 0
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cations in diagnosing, defining, and understand- y g
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The first description of autoantibodies in a ing autoimmune cutaneous immunopathology. es
dermatologic disease was published in 1964 (1). Clinically applicable information is summarized t on
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By the late 1960s, the diagnostic utility of immu- in Tables 1 and 2 (expanded in Table 1S in the 7 F
nodermatology testing had been established. online Data Supplement) and in additional eb
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This review focuses on the current state of SupplementalTablesandFigures. ary
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aImmunodermatologyLaboratory,DepartmentofDermatology,UniversityofUtah,UT,USA; bPugetSoundDermatology,Edmonds,WA.USA.
*Addresscorrespondencetothisauthorat:ImmunodermatologyLaboratory,DepartmentofDermatology,UniversityofUtah,417SWakaraWay,
Suite2151,SaltLakeCity,UT,USA.Fax[phone];[email protected].
ReceivedSeptember11,2021;acceptedOctober25,2021.
https://doi.org/10.1093/jalm/jfab147
VCAmericanAssociationforClinicalChemistry2021.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(https://creativecommons.org/licenses/
by/4.0/),whichpermitsunrestrictedreuse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
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IMPACT STATEMENT
Blistering characterizes dermatologic diseases with autoantibodies targeting components in skin and
mucous membranes essential for cell–cell and cell–matrix adhesion. Certain of these diseases are increas-
ing in incidence.The diseases are distinctive but demonstrate clinical overlap.Common presentations such
as pruritus, eczema, urticaria, and mucositis, with or without blistering, often are dominant and prolonged,
especially in prodromal stages, leading to diagnostic delays. Laboratory tests identifying disease-associated
autoantibodies are important for diagnosis and disease monitoring. Prompt and precise diagnosis is D
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needed for treatment decisions, prognosis, and addressing potential associations, including intestinal disor- n
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ders, otherautoimmune diseases,neurologic diseases,drugexposures,and,especially, malignancy. d
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INDICATIONSFORTESTING potentially associated, significant medical condi- ic
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tions, such as dermatitis herpetiformis (DH) with p
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Clinical immunodermatology tests are diagnos- celiac disease (CD), pemphigus and pemphigoid om
tic aids in many diseases that affect skin and mu- as manifestations of drug hypersensitivity, and a /jalm
cous membranes. The clinical presentations are subtype of pemphigoid with risk for underlying or /a
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varied with overlapping features in diseases with developingmalignancy. le
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different specific diagnostic markers. Table 1 lists /1
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diseasesforwhichtestingisindicated.Blisteringis DIAGNOSTICTESTINGFOR 65
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aclassical,butnotexclusiveorrequired,findingin AUTOIMMUNEDERMATOLOGIC 4
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the immunobullous diseases in which autoanti- DISEASES 2
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bodies target epithelial adhesion components. b
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Disorders included in the differential diagnosis of Advances in autoantibody testing for dermato- gu
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autoimmune dermatologic diseases should be logic diseases have burgeoned since the original st o
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considered for testing, including common condi- descriptionidentifying epithelialintercellularauto- 2
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tions such as eczema, urticaria, pruritus, aphtho- antibodies in the sera of patients with pemphigus F
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sis, and mucositis that are, otherwise, of (1, 3). Direct immunofluorescence (DIF) to localize ru
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unexplained etiology (Supplemental Table 2). autoantibodies and markers of their activities in ry 2
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Immunodermatology testing helps to establish an cutaneous tissue remains the mainstay of diag- 2
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immunopathological diagnostic profile and iden- nostic testing. Indirect immunofluorescence (IIF)
tify autoantibodies with which to monitor disease serum testing provides semiquantitative assess-
expression and activity. The findings are highly ments of the antibody presence and reveals cer-
sensitiveandspecificforcertaindiseases,andlev- tain categories of diseases based on antibody
els of autoantibodies determined by the testing localization. Autoantibodies in pemphigoid and
oftencorrelatewithdiseaseactivity.Also,thetest- epidermolysisbullosaacquisita(EBA)eachlocalize
ing can be valuable in recognizing other onseparatesidesofsplit skinsubstrate,roof,and
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Laboratorytestsandfindings:aTissuedirectimmunofluorescence(DIF),b(IIF),andSerumindirectimmunofluorescenceSerumELISA(s) d6,BMZIgGC3orC3aloneTissueDIF:Linear,n-serrated SerumIIF:IgGBMZantibodies,epidermal(roof)orcombinedepidermal-dermal(roofandfloor)withSSS,IgGBMZantibodieswithME SerumELISAs:IgGBP180and/orIgGBP230antibodylevelsincreased d6,BMZIgG,IgAC3TissueDIF:Linear,n-serrated SerumIIF:IgGBMZantibodies,epidermal(roof)ordermal(floor)withSSS,IgGBMZantibodieswithME,(IgGlaminin-332antibodyassayinvalidation) SerumELISAs:IgGBP180and/orIgGBP230antibodylevelsmaybeincreased 6TissueDIF:LinearBMZC3typicallyintense,linearBMZIgG SerumIIF:Complement-fixingBMZantibodies,epidermal(roof)withSSSherpesgestationisfactor(HGF);also,IgG¼BMZantibodies,epidermal(roof)withSSSandIgGBMZantibodieswithMEin25% SerumELISA:IgGBP180antibodylevelincreased Continu Downloaded from https://academ
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s. Target(s)ofautoantibodies:Structure(s)Component(s)withinstructure seases hemidesmosomeandlaminalucida BP180(NC16A),BP230 hemidesmosomeandlaminalucidaandlaminadensa BP180,laminin-332,laminin-311,BP230,alpha6beta4integrin(alpha6epitopesinoralpemphigoid;beta4epitopesinocularpemphigoid) hemidesmosomeandlaminalucida BP180(NC16A),alsorarelyBP23 up.com/jalm/article/7/1/165/64982
Table1.Dermatologicdiseaseswithautoantibodie ImmunobullousdiseaseClinicalpresentation Basementmembranezone(BMZ)antibody-associateddi Pemphigoid Bullouspemphigoid(BP)cTensebullaeoftenonurticarialbase,Asboe–Hansensignelicitable,persistenturticarialpapulesandplaques,flexuraldistribution,erosions,prominentprurituswithandwithoutblistering,developsinolderadults.Clinicalvariants:infantile/childhood;localized(lowerextremities);erythrodermic(generalizederythema);vulvar(prepubertal);vegetatingplaque(groinandaxillae);herpetiform(vesicles);dyshidrosiform(palmarandplantarresemblingdyshidroticeczema);pemphigoidnodularis(prurigonodularis-likelesionsonextremities);lichenplanuspemphigoides(seelater),anddrug-induced. Mucousmembranepemphigoid(MMP)CicatricialpemphigoidOcularcicatricialpemphigoidBrunsting–PerrypemphigoidAnti-laminin-332pemphigoid(formerlyanti-epiligrinpemphigoidandanti-laminin-5pemphigoid) Rupturedbullaeanderosions,rarelyintactvesicles,primarilyoralandocularmucousmembranesbutanymucosaandskin;scarringsequelae.Antilaminin-332pemphigoidassociatedwithmalignancy(upto30%).Brunsting–Perrywithscarringheadandneckandnonscarringmucosalinvolvement Pemphigoidgestationis(PG)(formerlyherpesgestationis)Tensebullae,similartoBP,pruriticurticarialpapuleswithonsetduringorimmediatelyafterpregnancy,periumbilicallesionstypical;mayflarewithmensesand/orhormonaltreatmentandrecurwithsubsequentpregnancies. 60 by guest on 27 February 2022
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Laboratorytestsandfindings:aTissuedirectimmunofluorescence(DIF),b(IIF),andSerumindirectimmunofluorescenceSerumELISA(s) d6,BMZIgGC3TissueDIF:Linear,n-serratedSerumIIF:IgGBMZantibodies,dermal(floor)withSSS,IgGBMZantibodieswithMESerumELISAs:ConsiderIgGtypeVIIcollagen,IgGBP180,andIgGBP230antibodylevelstoassessforotheroroverlappingexpression(SerumIgGp200antibodyassayindevelopment) d6,BMZIgGC3,IgA,IgMTissueDIF:Linear,u-serrated SerumIIF:IgGBMZantibodies,dermal(floor)withSSSandIgGBMZantibodieswithME;lesscommon,IgABMZ,dermal(floor)withSSSand/orIgABMZantibodieswithME SerumELISA:IgGtypeVIIcollagenantibodylevelincreased dincommonlaminalucidatype,TissueDIF:Linear,n-serrateddinuncommonsublaminadensatype,andlinear,u-serratedBMZIgA SerumIIF:IgABMZantibodies,epidermal(roof);lesscommon,dermal(floor)orcombinedepidermal-dermal(roofandfloor)withSSSand/orIgABMZantibodieswithME 6TissueDIF:LinearBMZIgG,IgA,C3 SerumIIF:IgAandIgGBMZantibodies,commonepidermal(roof);lesscommon,dermal(floor)orcombinedepidermal-dermal(roofandfloor)withSSS,IgAand/orIgGBMZantibodieswithME SerumELISAs:IgGBP180and/orIgGBP230and/orIgGtypeVIIcollagenantibodylevelsincreased Continue Downloaded from https://academ
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Target(s)ofautoantibodies:Structure(s)Component(s)withinstructure laminadensa cp200(laminin-3111subunit) anchoringfibrils typeVIIcollagen hemidesmosomeandlaminalucidaLAD-1(LABD97),BP180(NC16),BP230 laminadensatypeVIIcollagen hemidesmosomeandlaminalu-cidaandlaminadensa BP180,laminin-332,laminin-311,BP230,typeVIIcollagen up.com/jalm/article/7/1/165/64982
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Table1.(continued) ImmunobullousdiseaseClinicalpresentation p200(laminingamma-1)pemphigoidTensebullaesimilartoBP,vesicles,andurticarialplaques;alsopalmoplantar,cephalic,andmucosalinvolvement;frequentdevelopmentofscars/milia;possiblepsoriasisassociationinapproximately30%. Epidermolysisbullosaacquisita(EBA) Tensebullae,commoninareasoftraumaandoralmucosa.Variants:classical/mechanobullous(skinfragility,tensebullae,vesicles,anderosionsthathealwithscarringandmilia);nonclassical/nonmechanobullous(similarfeaturestoBP);mu-cousmembrane(predominantlyaffectingmucosawithsqua-mousepithelia);Brunsting–Perrytype(primarilyheadandnecklesions);IgApresentswithlinearIgA,insteadofIgG(simi-laritytolinearIgAdiseasebutmoreseverescarringsequelae);inflammatorytype(tensebullaeonerythematous,urticarialbase). LinearIgAdisease(LAD)(formerlylinearIgAbullousdermatosisandchronicbullousdiseaseofchildhood) Annularerythemaorurticarialplaqueswithtensebullaeandvesiclesonskin,describedas“necklace-like,”“string-of-pearls,”“crownofjewels”arrangement,erythemamultiforme-like,commonoralinvolvementinadults.TwotypesbasedonIgABMZlocalizationonsplitskinsub-strate,laminalucidatype,epidermal(roof)localizationin91%,andsublaminadensatype,dermal(floor)localizationin9%. LinearIgA/IgGbullousdermatosis Bullae,erosions,erythematousplaques,oralandgenitalmucosalinvolvement 0 by guest on 27 February 2022
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ngs:a(DIF),ncebce(IIF),and 6C3orC3alonestrongerwithME evelincreased 6C3orC3alonestrongerwithME evelincreased 6C3orC3alone withMEand evelincreased 6C3orC3alone withMEand evelincreased 6C3orC3alone withMEsubstrate evelincreasedesmoglein3 Continu
LaboratorytestsandfindiTissuedirectimmunofluoresceSerumindirectimmunofluorescenSerumELISA(s) TissueDIF:Epidermal/epithelialCS/ICSIgGe:IgGepithelialCS/ICSantibodies;SerumIIFthanNS e:IgGdesmoglein3antibodylSerumELISAswithorwithoutlesserIgGdesmoglein1 TissueDIF:Epidermal/epithelialCS/ICSIgGeSerumIIF:IgGepithelialCS/ICSantibodies;thanNS e:IgGdesmoglein3antibodylSerumELISAswithorwithoutlesserIgGdesmoglein1 TissueDIF:Epidermal/epithelialCS/ICS,IgG e:IgGepithelialCS/ICSantibodiesSerumIIFtypicallyprominentwithNS e:IgGdesmoglein1antibodylSerumELISAsandnormalIgGdesmoglein3 TissueDIF:Epidermal/epithelialCS/ICS,IgGandgranularimmunedepositsalongBMZ e:IgGepithelialCS/ICSantibodiesSerumIIFtypicallyprominentwithNS e:IgGdesmoglein1antibodylSerumELISAsandnormalIgGdesmoglein3 TissueDIF:Epidermal/epithelialCS/ICS,IgG e:IgGepithelialCS/ICSantibodiesSerumIIFandtypicallyprominentwithNS e:IgGdesmoglein1antibodylSerumELISAsandnormal/lesscommonlyincreasedIgGd Downloaded from https://academ
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Target(s)ofautoantibodies:Structure(s)Component(s)withinstructure ssociateddiseases desmosomedesmoglein3(mucosaldominant),desmoglein3withdesmoglein1(mucocutaneousandcutaneous) desmosomedesmoglein3withorwithoutdesmoglein1,desmocollin3 desmosome desmoglein1 desmosome desmoglein1and/ordesmoglein3(antinuclearantibodiesalsoaredetected) desmosomedesmoglein1,lesscommonlydesmoglein3(othertargetantigenshavebeenreportedsuchasdesmocollin1,desmocollin3178-kDaantigen,BP180C-terminus,andclaminin-3322subunit) .oup.com/jalm/article/7/1/165/64982
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able1.(continued) ImmunobullousdiseaseClinicalpresentation Cellsurface(CS)/intercellularsubstance(ICS),antibody- Pemphigus PemphigusvulgariscFlaccidbullaeonnoninflamedskin,crusting,Nikolskiysigncelicitable,Asboe–Hansensignelicitable,commonlyaffectsoralmucosa,scalp,chest,andintertriginousareas,thefragilebullaeruptureanddonotremainintact,large,painfulerosionsareprominentinmucosaand/orskin.Types:mucosaldominant,mucocutaneous,cutaneous PemphigusvegetansErythematous,vegetatingandpustularintertriginousplaques,crusting PemphigusfoliaceusEndemicpemphigus(alsoknownasfogoselvagem)Superficialbullae,erosions,andscalewithcrusting(fine“corncelicitable.Drug-inducedflake-like”scaling),Nikolskiysignfmostoftenthisvariant.Generalized,erythrodermicpresentationalsoobserved.Endemicpemphigus(variantofpemphigusfoliaceuswithgeneticandenvironmentalcofactors,primarilyinBrazil;alsoknownasfogoselvagem)superficialerosions,erythema,crusting,localizedtoseborrheicareas,head,andupperchest Pemphiguserythematosus(alsoknownasSenear–Ushersyndrome)Variantofpemphigusfoliaceuswithfeaturesoflupuserythematosus.Superficialerosions,erythema,crusting,oftenofmalarandseborrheicareas PemphigusherpetiformisErythematous,bullous,vesicular,pustular,orpapularlesions,typicallywithseverepruritusandinaherpetiformpattern;mucosalinvolvementisuncommon. 0 by guest on 27 February 2022
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Laboratorytestsandfindings:a(DIF),TissuedirectimmunofluorescencebSerumindirectimmunofluorescence(IIF),andSerumELISA(s) TissueDIF:Epidermal/epithelialCS/ICS,IgASerumIIF:IgAepithelialCS/ICSantibodieswithMEandmaybeprominentwithNS TissueDIF:Epidermal/epithelialCS/ICS,IgGandIgA SerumIIF:IgGandIgAepithelialCS/ICSantibodieswithMEandNS SerumELISAs:IgGdesmoglein1and/orIgGdesmoglein3antibodylevelsincreased ody-associateddisease 6TissueDIF:Epidermal/epithelialCS/ICSandBMZ,IgGC3 SerumIIF:IgGepithelialCS/ICSandBMZantibodieswithrodent(ratand/ormouse)bladdersubstrateepitheliumischaracteristic,IgGintercalateddiscswithrodentheartsubstrateandIgGportaltractswithrodentliversubstrate;also,CS/ICSandBMZantibodiesonME SerumELISA:IgGenvoplakinantibodylevelmaybeincrease(invalidation) 6TissueDIF:GranularorfibrillarBMZstipplingindermalpapillae,IgA SerumIIF:IgAEMAwithdistalMEand/orhumanumbilicalcordsubstrate SerumELISAs:IgA(tTG/TG2)andIgA(eTG/TG3)antibodylevelsincreased Contin Downloaded from https://academic
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Target(s)ofautoantibodies:Structure(s)Component(s)withinstructure desmosomedesmocollin1,desmocollin2,desmocollin3,desmoglein1and/ordesmoglein3 desmosome desmoglein1,desmoglein3,desmocollin1,desmocollin2,desmocollin3 entmembranezone(BMZ)anti desmosomeandhemidesmosomeinmultipleepithelia(simple,columnar,transitional) desmoglein3,envoplakin,periplakin,desmoplakin1,desmoplakin2,BP230,epiplakin,plectin,BP230,desmoglein1,desmocollin1,desmocollin2,desmocollin3,alpha-2-macroglobulin-like-1(A2ML1),laminin-332,and/orBP180 keratinocyteproduced epidermaltransglutaminase(eTG/TG3)alsotissuetransglutaminase(tTG/TG2)inendomysium,principaltargetofendomysialantibodies(EMA) up.com/jalm/article/7/1/165/64982
able1.(continued) ImmunobullousdiseaseClinicalpresentation IgApemphigusFragileblistersfilledwithfluidthatevolveintopustules;mucosalinvolvementisuncommon;pruritus.Variants:subcornealpustulardermatosis(annular/circinatelesionpattern)andintraepidermalneutrophilicIgAdermatosis(atypicalpustuleswith“sunflower”-likeconfiguration). IntercellularIgG/IgAdermatosisBullousandpustularskinlesions,preferentiallyontrunkandextremities,alsomucosalinvolvement Cellsurface(CS)/intercellularsubstance(ICS)andbasem Paraneoplasticpemphigus(PNP),alsoreferredtoasparaneoplasticautoimmunemultiorgansyndrome(PAMS)Flaccidand/ortensebullae,erosions,urticarial,lichenoid,orerythemamultiforme-like,andflatscalypapules;usuallyinvolvesoralandocularmucosa,oftenextensiveincludingesophagealandrespiratorymucosa. Miscellaneous-associateddiseases Dermatitisherpetiformis(alsoknownasDuhringdisease)Pruritic,small,symmetrical,groupedvesiclesandpapulesonextensorsurfaces(elbows,knees,buttocks);maybereplacedbysecondarylesionsduetoconsequentscratching;associ-atedwithsmallintestinalgluten-sensitivity/celiacdisease(CD). 60 by guest on 27 February 2022
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Laboratorytestsandfindings:aTissuedirectimmunofluorescence(DIF),b(IIF),andSerumindirectimmunofluorescenceSerumELISA(s) 6TissueDIF:Cytoidbodies,fewtonumerous,IgMcommonIgG,IgA,C3,fibrinogen,and“shaggy”BMZfibrinogen Serum:Noepithelial-directedantibodies d6,BMZ,IgGC3,cytoidbodies,TissueDIF:Linear,n-serrated6fewtonumerous,IgMcommonIgG,IgA,C3,fibrinogen,and“shaggy”BMZfibrinogen SerumIIF:IgGBMZantibodies,epidermal(roof)orcombinedepidermal-dermal(roofandfloor)withSSS,IgGBMZantibodieswithME SerumELISAs:IgGBP180and/orIgGBP230antibodylevelsincreased d6,BMZ,IgGC3orC3aloneTissueDIF:Linear,u-serratedandgranularBMZ SerumIIF:IgGBMZantibodies,dermal(floor)withSSS;lesscommon,IgABMZ,dermal(floor)withSSSand/orIgABMZantibodieswithME;antinuclearantibodiesandotherconnectivetissuediseaseserologicmarkers SerumELISAs:IgGBP180and/orIgGBP230antibodylevelsincreased,positivelupus/connectivetissuediseaseserologies;6abnormalcomplementlevels TissueDIF:Coarse,granular,continuousBMZ(anyorall)IgG,6IgM,IgA,C3lichenoidfeatures 6Serum:Positivelupus/connectivetissuediseaseserologies;abnormalcomplementlevels Continue Downloaded from https://academ
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Target(s)ofautoantibodieStructure(s)Component(s)withinstructure noantibodytarget;cytoidsrepresentnonspecificstainingdeadanddyingkeratinocytesand/orpiecesofBMZ;“shaggy”fibrinogenreflectsepidermal-dermaljunctioninterfaceinflammation hemidesmosomeandlaminalucida BP180,BP230 anchoringfibrilstypeVIIcollagen(mostcommohemidesmosomeandlaminalucidaandlaminadensaBP180,BP230,laminin-332,laminin-311uncharacterizedepidermalreactivitywithorwithoutdermfindings antinuclearantibodies p.com/jalm/article/7/1/165/6498
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able1.(continued) ImmunobullousdiseaseClinicalpresentation Lichenplanus Intenselypruritic,papulosquamous,flat-topped,violaceouspapularskinlesions,alsomucousmembrane(oralandgenitalmostcommon),scalp,andnailinvolvementwithfinewhitelines,termed“Wickham’sstriae,”onlesionsurfaces.Drug-inducedpresentationsandassociationswithhepatitisBinfectionandvaccineandhepatitisC-inducedliverinsuffi-ciencyandotherautoimmunediseases.Lichenoidreactionsmaybepremalignantandepithelialmalignancyassociated. Lichenplanuspemphigoides Tensebullaeonpruriticviolaceouspolygonalpapulesandplaques(lichenoid),“Wickham’sstriae,”onlesionsurfaces,mucousmembrane(oralandgenitalmostcommon),andnailinvolvement. Bullouslupuserythematosus 6Tensebullae,photodistributed,systemicLEothercutaneousLE Cutaneouslupuserythematosus Malarerythemaandswelling,“butterflyrash,”photodistributedtransientdiffuseorpapularerythemaupperandexposedbodyandface,sparesknucklesondorsalhands,toxicepidermalnecrolysis-likewithsystemicdisease;discoidscaleyplaqueswithfollicularprominence(“carpettacksign”),scarringalopeciaandcutaneousscarring,post-inflammatorydyspigmentation;mucositis,cheilitis,nailfoldtelangiectasias.Drug-inducedpresentations. 60 by guest on 27 February 2022
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Table1.(continued) Target(s)ofautoantibodies:Laboratorytestsandfindings:aStructure(s)Tissuedirectimmunofluorescence(DIF),bImmunobullousdiseaseComponent(s)within(IIF),andSerumindirectimmunofluorescenceClinicalpresentationstructureSerumELISA(s) 66Subacutecutaneouslupuserythematosusextractablenuclearantigens,SSATissueDIF:ParticulateintercellularIgG,IgM,IgAC3and(Ro)andSSB(La)granularBMZPsoriasiform,papulosquamousorannular,polycyclicplaqueswithcentralclearing;dyspigmentationandtelangiectasias.Serum:Positivelupus/connectivetissuediseaseserologies,Drug-inducedpresentations.particularlytoextractablenuclearantigen,Ro/SSA Vasculitisantineutrophilantibodies(un-TissueDIF:IgM,IgG,and/orIgA,C3,orfibrinogeninand6Immunecomplex,smallvesselcommonwhenskinpositive);aroundupperdermalbloodvesselwalls,andgranularIgAvasculitis(Henoch–Scho¨nleinpurpura)anti-C1qinhypocomplementemicBMZ;HypocomplementemicurticarialvasculitisurticarialvasculitisGranularandpredominantvascularIgAinIgAvasculitisCryoglobulinemic(Henoch–Scho¨nleinpurpura);IgMandIgGvascularpredominantandglobularinPetechiae,palpablepurpura,nodules,livedoreticularis;cryoglobulinemicvasculitisresolvewithhemosiderindeposition.SystemicinvolvementincludinggastrointestinalandrenalSerum:Positivelupus/connectivetissuedisease/vasculitis6Associatedwithchronicinfections,autoimmunedisease,serologies,C1qantibodies,and/orcryoglobulins;abnormallymphoproliferativedisorders,anddrug-induced.complementlevels aForallsuspectedimmunobullousdisease,itisbesttoobtainbiopsyfordiagnosisfromperilesionaltissuebecauseimmunoreactantsmaynotbedetectedbydirectimmunofluorescence(DIF)inlesional(blistered)tissue;perilesionalisdefinedasimmediatelyadjacenttobutnotinvolvingablisterorerosionandmayincludeinflamed,intactskinormucosa.Serumstudiesmaybeneededtodistinguishdiseases.bSubstratesforindirectimmunofluorescencetestingincludesplitskin,alsoknownassalt-splitskin(SSS),substrate,monkeyesophagus(ME)substrate,intactnormalskin(NS)substrate.cTheAsboe–Hansensignisthe“bullaspreadsign”andreferstotheextensionofablistertoadjacent,unblisteredskinwithpressureontopoftheblister;itispositiveinvariousblisteringdiseases.Theblisterextension,inpemphigoid,hasaroundedborderand,inpemphigus,hasasharpangle.TheNikolskiysignistheformationofanewblisterorextensionofablisterfromshearingpressureappliedonnormal-appearingskin(directNikolskiysign)orattheedgeofanexistingblister(marginalNikolskiysign).Ofnote,NikolskiyoftenisspelledNikolsky(withoutan“i”);however,themorecorrecttranslationisNikolskiy(2).TheAsboe–Hansensignhasbeenreferredtoasan“indirectNikolskiysign”oras“NikolskiyIIsign.”.dSeeSupplementalFig.1forimageexamplesofserrationpatterns.eLimiting-dilution,end-pointtitersbyIIFandIgGdesmoglein1and/orIgGdesmoglein3antibodylevelsbyELISAscorrelatewithdiseaseactivityinIgGpemphigusvariants.fDrug-inducedpemphigustypicallyresemblespemphigusfoliaceusbutalsopossiblypemphiguserythematosus,pemphigusvulgaris,orparaneoplasticpemphigus.BP230bullouspemphigoidantigen1(BPAg1);BP180bullouspemphigoidantigen2(BPAg2),alsoknownastypeXVIIcollagen(COLXVII);cellsurface(CS)intercellularsubstance(ICS);¼¼¼epidermalreferstothe“roof”anddermalreferstothe“floor”localizationofserumbasementmembranezone(BMZ)antibodiesonhumansplitskin(alsoknownassalt-splitskin)substrate(SSS)byindirectimmunofluorescence(IIF).Abbreviations:DIF-directimmunofluorescence,IIF—indirectimmunofluorescence,ELISA—enzyme-linkedimmunosorbentassay,BMZ—basementmembranezone,CS—cellsurface,ICS—intercellularsubstance,SSS—splitskin(salt-splitskin)substrate,ME—monkeyesophagussubstrate,NS—intactnormalskinsubstrate,BP—bullouspemphigoid,EBA—epidermolysisbullosaacquisita,LAD—linearIgAdisease,DH—dermatitisherpetiformis,LE—lupuserythematosus,PNP—paraneoplasticpemphigus,PAMS—paraneoplasticautoimmunemultiorgansyndrome,EMA—endomysialantibodies,eTG—epidermaltransglutaminase,TG3—transglutaminase3,tTG—tissuetransglutaminase,TG2—transglutaminase2,NC—noncollagenous,HGF—herpesgestationisfactor. Downloaded from https://academic.oup.com/jalm/article/7/1/165/6498260 by guest on 27 February 2022
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Fig.1. Schematicrepresentationsofepithelialadhesioncomponentsandcomplexesthataretargetsof st o
autoantibodyreactivityindermatologicdiseases.(A)Thehemidesmosomeisaspecializedmultiprotein n
2
junctional complex that functions to attach epithelial cells to the underlyingbasementmembrane in 7
F
stratifiedandothercomplexepithelia,includingskin,cornea,partsofthegastrointestinalandrespira- e
b
tory tracts, and the amnion. Hemidesmosomes also have signaling functions that critically modulate ru
a
the organization of the cytoskeleton, proliferation, apoptosis, and differentiation. Autoantibodies in ry
2
dermatologicdiseaseswithbasementmembranezone(BMZ)reactivityaredirectedtoconstituentsof 0
2
thehemidesmosomaladhesioncomplex,schematicallyrepresentedinthediagram,whilemutationsin 2
theirgenesresultininheritedbullousdisordersoftenwithasimilarphenotype(5).Disease-associated
targetedhemidesmosomalandBMZstructuresandproteinsschematicallyrepresentedinthediagram
are recorded in Table 1. Red dotted line indicates where the BMZ split occurs in salt split skin in the
lowerlaminalucida.(B)Full-lengthmolecularmapofBP180,alsoknownasbullouspemphigoidantigen2
(BPAg2)andtypeXVIIcollagen(COLXVII),atransmembraneproteinwithanintracellulardomaininthe
hemidesmosomal dense plaque of basal keratinocytes extending beyond the cell membrane with an
ectodomain into the lamina densa of the BMZ. The ectodomain of BP180 contains 15 collagenous
domains,labeledbynumbers1through15.ThenoncollagenousextracellulardomainofBP180,known
asNC16A,istheprimarysiteforantibodybindinginbullouspemphigoidandpemphigoidgestationis.
IgG serum antibodies are detected via enzyme-linked immunosorbent assay (ELISA) in 80% to 90% of
Continued
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DermatologicDiseaseswithAutoantibodies
floor, respectively,byIIFand tospecific ultrastruc- and specificity; ELISA results alone do not give a
turally defined basement membrane zone (BMZ) complete picture of immunopathophysiology.
compartments, the lamina lucida and lamina Figure1 is a schematic diagram showingthe prin-
densa, respectively, by immunoelectron micros- cipaladhesiontargetsofautoantibodiesinderma-
copy. Western blotting and immunoprecipitation tologicdiseases.
provide molecular details about the antibody tar-
gets (4). This has permitted cloning of targeted
SpecimensandTests
structural epithelial components and production
of recombinant forms that can readily be used in Tests are performed on tissue biopsy speci- D
o
sensitive assays to provide conclusive evidence of mens from skin and mucous membranes as well w
n
antigen identity by antibodies in multiple speci- asserumspecimensfrompatientswithsuspected loa
d
e
mens, such as in enzyme-linked immunosorbent diseases. For autoantibody-associated diseases, d
assays (ELISA). Immunoelectron microscopy, im- both tissue and serum testing are most helpful. from
munoblotting, and immunoprecipitation are use- Biopsy testing initially may give indication for add- http
ful tools for studies of dermatologic diseases with ingserumtesting.Serumtestsmaynotbeassen- s://a
autoantibodies, but with limited scalability, are sitive as DIF on tissue but are essential to ca
d
generallyperformedinspecialistorresearchlabo- distinguish disease subtypes. Also, serum tests em
ic
ratories.ELISAtestingisreadilyavailableinclinical may be positive when tissue tests are not reveal- .o
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laboratories, and, together with IIF for sera and ing or when a biopsy is difficult to obtain. p.c
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DIFfortissues,allowscharacterizationofautoanti- Moreover,serumtestingcanbeusefulinmonitor- m
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bodies in dermatologic diseases with sensitivity ing disease expression because autoantibodies lm
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Fig.1(Continued) rtic
affectedpatients.TheproductionofantibodiestootherBP180epitopesmayhaveclinicalsignificance; le/7
forexample,antibodiesdirectedagainstepitopesintheC-terminalendofBP180havebeenassociated /1
/1
with mucosal disease (6). Fragments of BP180, designated as linear IgA disease antigen 1 (LAD-1), 120 6
5
kDa, and linear IgA bullous disease antigen of 97 kDa (LABD97) represent major antigenic targets of /6
4
autoantibodiesinpatientswithlinearIgAdisease.TheseIgAantibodiespreferentiallyreactwithLAD-1 9
8
2
and LABD97, but not with full-length BP180, indicating that cleavage of the ectodomain BP180 region 6
0
generatesnovelautoantigenicepitopes(7).TM,transmembranedomain;LAD-1,linearIgAdiseaseanti- b
y
gen 1; LABD97, linear IgA bullous disease antigen of 97 kDa. (C) The desmosome is an intracellularand g
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intercellularmultiproteinjunctionalcomplexthatprovidesmechanicalstrengthandcreatesstrongad- e
s
hesivebondsbetweencells.Desmosomesareparticularlyabundantintissuessubjectedtomechanical t o
n
forcessuchasepitheliumandmyocardium.Desmosomesadditionallyhavesignalingfunctions,partici- 2
7
pating in fundamental processes such as cell proliferation, differentiation, and morphogenesis. F
e
Autoantibodiesindermatologicdiseaseswithcellsurfacereactivityaredirectedtoconstituentsofthe b
ru
desmosomaladhesioncomplex,schematicallyrepresentedinthediagram,thatdirectlydisruptdesmo- a
ry
somaladhesion,suchthatthecellsloosenandfallapart(8).Disease-associatedtargeteddesmosomal 2
0
and intercellular structures and proteins represented in the schematic, mainly desmogleins and des- 2
2
mocollins,arerecordedinTable 1.SeealsoSupplementalFig.8withadditionalinformationregarding
desmogleinanddesmocollinepidermallocalization.Exfoliativetoxinsproducedbybacterialinfections
in bullous impetigo and staphylococcal scalded-skin syndrome can cleave desmoglein 1 at a specific
sitedisruptingkeratinocyteadhesion,anddesmoglein2hasbeenidentifiedasareceptorforasubclass
of adenoviruses that cause respiratory and urinary tractinfections triggering epithelialto mesenchy-
mal cell phenotypic transition. Inherited desmosomal disorders demonstrate broad-ranging pheno-
types with either or both cardiac disorders and hair abnormalities. Overexpression of desmosomal
proteinsoccursinsomemalignanciesinassociationwithtumorprogression(9,10).PM,plasmamem-
brane;ECM,extra-cellularmatrix.
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