ww w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Original
article
Mild
and
moderate
Mannose
Binding
Lectin
deficiency
are
associated
with
systemic
lupus
erythematosus
and
lupus
nephritis
in
Brazilian
patients
夽
Sandro
Félix
Perazzio
a,b,
Neusa
Pereira
da
Silva
a,
Magda
Carneiro-Sampaio
c,
Luis
Eduardo
Coelho
Andrade
a,b,∗aDivisionofRheumatology,EscolaPaulistadeMedicina(EPM),UniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,Brazil bGrupoFleury,SãoPaulo,SP,Brazil
cDepartmentofPediatrics,FaculdadedeMedicina,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received18December2014 Accepted17September2015 Availableonline21March2016
Keywords: MBLdeficiency
Systemiclupuserythematosus Immunodeficiency
Lupusnephritis
a
b
s
t
r
a
c
t
Objective:Thepotentialassociationofmannosebindinglectin(MBL)deficiencyandsystemic lupuserythematosus(SLE)hasbeeninvestigatedinseveralstudies,butresultshavebeen mixed.Oneexplanationfortheconflictingresultscouldbedifferencesinethnicbackground ofstudysubjects.InthisstudyweinvestigatedtheassociationofMBLdeficiencyandSLEin alargecohortofBrazilianSLEpatientsandcontrols.
Methods:SerumMBLandComplementlevelsweredeterminedfor286BrazilianadultSLE patientsand301healthyBrazilianadultsascontrols.MBLdeficiencywasclassifiedasmild (<1000and≥500g/L),moderate(<500and≥100g/L)orsevere(<100g/L).
Results:SLEpatientspresentedhigherfrequencyofmildandmoderateMBLdeficiency com-paredtocontrols.SLEpatientswithMBLdeficiencypresentedhigherfrequencyoflupus nephritiscomparedtothosewithoutMBLdeficiency.MBLdeficiencywasnotassociated withanyotherclinicalmanifestation,useofimmunosuppressanttherapy,diseaseactivity, diseaseseverityserumorComplementlevels.
Conclusion:ThisstudyshowsthatanassociationbetweenMBLdeficiencyandSLEdoesexist intheBrazilianpopulation.WealsofoundanassociationbetweenMBLdeficiencyandlupus nephritis.ThesefindingssupportthehypothesisthatMBLdeficiency contributestothe developmentofSLEandlupusnephritis.
©2015ElsevierEditoraLtda.Allrightsreserved.
夽
Manuscript winner of the “Young scientist prize of the year from the Brazilian Society of Rheumatology-Clinical area” for SandroF.PerazzioinXXXIBrazilianCongressofRheumatology,BeloHorizonte,MG,Brazil,2014.
∗ Correspondingauthor.
E-mail:[email protected](L.E.C.Andrade). http://dx.doi.org/10.1016/j.rbre.2016.01.002
As
deficiências
leve
e
moderada
de
lectina
ligadora
de
manose
estão
associadas
ao
lúpus
eritematoso
sistêmico
e
à
nefrite
lúpica
em
pacientes
brasileiros
Palavras-chave: DeficiênciadeLLM
Lúpuseritematososistêmico Imunodeficiência
Nefritelúpica
r
e
s
u
m
o
Objetivo:Váriosestudosjáinvestigaramapotencialassociac¸ãoentreadeficiênciadelectina deligac¸ãoamanose(LLM)eolúpuseritematososistêmico(LES),masosresultadosobtidos sãomistos.Umaexplicac¸ãoparaessesresultadosconflitantespoderiaestarnasdiferenc¸as étnicasdosindivíduosestudados.Esteestudoinvestigouaassociac¸ãoentreadeficiênciade LLMeoLESemumagrandecoortedepacientesbrasileiroscomLESecontroles.
Métodos: Determinaram-seos níveisséricosde LLMe complementoem 286pacientes adultosbrasileiroscomLESe301adultosbrasileirossaudáveisqueatuaramcomo con-troles. A deficiência de LLM foi classificada como leve (<1000e≥500g/L), moderada (<500e≥ 100g/L)ougrave(<100g/L).
Resultados: OspacientescomLESapresentaramumamaiorfrequênciadedeficiêncialevee moderadadeLLMemrelac¸ãoaoscontroles.OspacientescomLEScomdeficiênciadeLLM apresentaramumamaiorfrequênciadenefritelúpicaemcomparac¸ãocomaquelessem deficiênciadeLLM.AdeficiênciadeLLMnãoesteveassociadaaqualqueroutramanifestac¸ão clínica,usodeterapiaimunossupressora, atividadeda doenc¸a,gravidadedadoenc¸aou níveisséricosdecomplemento.
Conclusão: Esteestudomostraqueháumaassociac¸ãoentreadeficiênciadeLLMeoLES napopulac¸ãobrasileira.Encontrou-setambémumaassociac¸ãoentreadeficiênciadeLLM eanefritelúpica.EssesresultadosapoiamahipótesedequeadeficiênciadeLLMcontribui paraodesenvolvimentodoLESedanefritelúpica.
©2015ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
Mannosebindinglectin(MBL), animportantcomponent of theinnateimmunedefensesystem,hasthecapacitytobind microorganism surface polysaccharides and subsequently activate the Complement system through the MASP (MBL associatedserineproteases)familyofproteases.MBLis func-tionallysimilarandstructurallyhomologoustoC1q,thefirst componentoftheclassicalComplementpathway.1
TheMBLgenecontains4exonsanditschromosome loca-tion is 10q11.2–q21. Five single nucleotide polymorphisms (SNPs)havebeenreportedtobeassociatedwithreducedMBL serumproteinlevels.ThemostcommonSNPsarelocatedon exon1,atcodons52(+223),54(+230),and57(+239), respec-tivelydesignatedallelesD,BandC(the“wild”typealleleis designatedA).2Inaddition,polymorphismsoftheMBL pro-moter region are also reported to influenceserum protein levels.3Thefrequencyoftheabnormalallelesdiffers signif-icantlyaccordingtoethnicbackground.4
MBLpolymorphismhasbeenreportedinassociationwith severalautoimmunediseases,includingtypeIdiabetes5and rheumatoidarthritis.6Severalstudiessuggestanassociation between MBL deficiency or gene polymorphism and sys-temic lupus erythematosus (SLE).7 It has been postulated thatMBL deficiencymightresult ininefficientclearance of apoptoticcellsandpredispositiontoinfections.This,inturn, mayleadtoover-expressionofautoantigensthatcould con-tribute to autoantibody generation and SLE development.7 Ameta-analysisof8studiespublishedin2001showedthat thepresenceofabnormalallelesconfersa1.6foldincreasein
riskfordevelopingSLE.8Fouryearslater,Leeetal.9 demon-stratedthataSNPatMBLcodon54(designatedalleleB)and polymorphismsintheMBLpromoterregionwereriskfactors ofSLEdevelopment.However,severalotherstudiesfailedto demonstrateanassociationbetweenSLEandMBLdeficiency. Thisdiscrepancymay berelatedtotheheterogeneous eth-nicbackgroundsofsubjectsinthosestudies.10,11Itispossible that other geneticfactors, perhapsrelated to ethnic back-ground,arerequiredforthedevelopmentofSLEinindividuals withMBLdeficiencyorgenepolymorphism.2Therefore,itis importanttoinvestigatetheinfluenceofMBLdeficiencyon developmentofSLEindistinctethnicgroups.
HerewereportonastudyofalargecohortofBrazilianlupus patientsandhealthycontrolsaimedtodeterminewhetherlow serumMBLlevelisariskfactorforSLEinthispopulation.
Materials
and
methods
Studysubjects
Table1–Distributionofsubjectswithsystemiclupuserythematosusaccordingtodemographicvariables,presenceof co-morbidity,clinicalcharacteristicsandmedicationstaken.
n(%) n(%)
Gender(F:M)a 271:15 Currentimmunosuppressantd 196(68.5)
Age(years)b 39.29±12.23 •Antimalarialse 198(69.2)
Diseaseduration(years) 10.58±7.91 •Corticosteroids 153(53.4)
SLICC-DI(median/25%–75%) 1/0–2 ≥20mg(prednisone) 67(23.4)
SLEDAI(median/25%–75%) 0/0–2 <20mg(prednisone) 86(30.1)
Autoimmunerheumaticdiseases 20(6.9) •Azathioprine 65(22.7)
•APS 14(4.9) •Methotrexate 48(16.8)
•Sjögren’ssyndrome 6(2.1) •Cyclophosphamide 23(8)
Othernon-rheumaticautoimmunediseases 14(4.8) •Mycophenolate 25(8.7)
•Hashimoto’sthyroiditis 14(4.8) •Leflunomide 14(4.9)
Miscellaneousc 134(43.8) •Cyclosporine 7(2.4)
•Tacrolimus 4(1.4)
•Dapsone 3(1.0)
•Thalidomide 2(0.7)
Previousimmunosuppressant 186(65)
APS,antiphospholipidsyndrome;SLEDAI,SystemicLupusErythematosusDiseaseActivityIndex;SLICC-DI,SystemicLupusInternational CollaboratingClinics-DamageIndex.
a Healthycontrols:286:15(p=0.856).
b Healthycontrols:35.1±11.10(p=0.070).
c Miscellaneous:nonautoimmunediseases,suchasarterialhypertension,dyslipidemia,osteoarthritis,etc.Healthycontrols:43(14.2%;
p<0.001).
dThesumofsubjectsusingeachdrugresultsinanumbergreaterthanthetotalnumberofpatientsbecausesomesubjectsusedtwoormore
medications.
e Antimalarialwasnotconsideredimmunosuppressant.
Exclusion criteria were:(a) any kind ofinfection within30 daysbeforedatacollection;(b)useofimmunobiological med-ication (infliximab, adalimumab, etanercept, rituximab or abatacept)withinthelast6months;(c)coexistenceof malig-nant diseases;and (d) HIVinfection. Patients underwent a detailed clinical evaluation, with emphasison SLEclinical manifestations, recurrent infections, current and previous medications, age at SLE onset, evidence of other autoim-munediseases,familyhistory,anddeterminationofSystemic LupusErythematosusDiseaseActivityIndex(SLEDAI)13and SystemicLupusInternational Collaborating Clinics-Damage Index (SLICC-DI).14 Patientswith inactive autoimmune dis-easeandalteredMBLtestshadasecondbloodsampledrawn after60daysforre-testing.Patientswithanyevidenceofactive autoimmunedisease(SLEDAI≥1)andMBLdeficiencywere fol-loweduptotheendoftheflareandonlythenweresubmitted toasecondblood drawand retesting.Patientswere classi-fiedasdeficientexclusivelyaftertheconfirmation ofinitial results.Inall the caseswho weresubmitted toretest, lab-oratorialdataanalyzedwererestrictedtothe secondblood drawn.Inregardstotheclinicalmanifestationsanddisease activity,clinicaldatausedwere restrictedtothe last activ-ityperiod.Lupusnephritissubtypesweredefinedaccording topreviousbiopsies,whenavailable.Patientswithabnormal resultswhocontinuedtoexhibitactivediseasethroughoutthe studyperiodwereexcluded.
EvaluationofserumComplementandMBLlevels
TheanalysisoftheComplementcomponentsincluded deter-mination of total Hemolytic Complement (CH50), C2, C3, andC4.CH50andC2weredeterminedbyimmunohemolytic
assays, as previously reported.15 C3 was determined by immunoturbidimetry(Olympus®,SanMateo,USA)andC4by
immunonephelometry(BeckmanCoulter®,Brea,USA).Serum
MBLwasdetermined byELISA(BioportoDiagnostics®,
Gen-tofte, Denmark) and MBL deficiency wasdefined as serum levels lower than 1000g/Land graded according to sever-ity into mild (<1000 and ≥500g/L), moderate (<500 and ≥100g/L) and severe (<100g/L), as validated by previous studies.16–20
Statisticalanalysis
Continuous variables with normal distribution were ana-lyzed with Student’st test and those with non-parametric distribution were analyzed with the Mann–Whitney test. Qualitative parameters were analyzed by the Chi-square test and the Fisher’s exact test when appropriate. Mul-tiparametric analyses were calculated with the ANOVA one-way test and post-ANOVA tests (Bonferroni) when appropriate.Correlationanalysiswasperformedbythe Pear-son’s correlationmethod.Statisticalinferencelevel wasset at0.05.
Results
Studypopulationcharacteristics
P<.01
P<.01
Normal Mild Severe Moderate
P<.01 200
150
100
50
0
Number of individuals
SLE Controls
MBL deficiency severity
6000
5000
4000
3000
2000
1000
0
SLE Controls
MBL serum levels (
μ
g/L)
A
B
Fig.1–Systemiclupuserythematosus(SLE)isassociatedwithmildandmoderateMBLdeficiency.A,distributionofSLE patientsandcontrolsaccordingtoseverityofMBLdeficiency;B,MBLserumlevelsinSLEpatientsandcontrols.Definitionof MBLdeficiency(presentin146controlsand175SLEpatients),serumMBL<1000g/L;mild,serumMBL<1000and
≥500g/L;moderate,serumMBL<500and≥100g/L;severe,serumMBL<100g/L.
genderdistribution,and allofthemwere descendantfrom ablendofdifferentethnicities,presenting,therefore,amixed background.PatientspresentedSLEDAIvaryingfrom0to14 (1.62±2.81, median: 0) and SLICC-DI varying from 0 to 5 (0.95±1.12,median:1).Durationofdiseasevariedfrom1to 53years(10.58±7.91).Table1depictsthedistributionofSLE patientsaccordingtothepresenceofdistinctclinical mani-festationsandmedicationsused.
MildandmoderateMBLdeficiencyismorefrequentinSLE
patients
SLEpatients(n=175;61.18%)presentedhigherfrequencyof MBLdeficiencycomparedtocontrols(n=146;48.50%;p<0.01), especiallyduetomildandmoderateMBLdeficiency(Fig.1A). However,theoveralldistributionofMBLserumlevelswas sim-ilarinSLEpatientsandhealthycontrols(Fig.1B).Therewasno correlationbetweenMBLdeficiencyandserumComplement componentlevels,regardlessoftheseverityofMBLdeficiency (Table2).
ClinicalfeaturesofSLEpatientswithMBLdeficiency
As the laboratory data referred to patients without rele-vant disease activity (clinical quiescence), all the clinical data refer to previous manifestations. Patients with MBL
deficiency presented higher frequency of previous lupus nephritis (class II, III, IVor V) compared tothose without MBL deficiency,regardlessoftheseverityofMBLdeficiency (Table 3). No other clinical manifestation, including recur-rentinfections,presenteddifferentfrequencyinSLEpatients with andwithout MBL deficiency (Table 3). There wasalso no difference between these two subgroups regarding the presence of other autoimmune rheumatic diseases, non-rheumaticautoimmunediseasesorother non-autoimmune diseases (miscellaneous),disease severity,cumulative dam-age,currentage,diseaseduration,ageatSLEonset(Table3), andpreviousorcurrentuseofimmunosuppressant(Table4). Finally,nocorrelationbetweenMBLserumlevelsanddisease severityorcumulativedamagewasobserved(Table5).
Discussion
Inthepresentstudy,wedeterminedthefrequencyand pos-sibleclinicalimplicationsofMBLdeficiencyinalargecohort ofBrazilianSLEpatients.Weobservedanincreasedfrequency ofmildand moderateMBL deficiencyinSLEpatients com-paredtohealthy controls.Interestingly,ourresultsshowed higherfrequencyoflupusnephritisinassociationwithMBL deficiency regardlessoftheseverity ofMBL deficiency.One concernwasthepossibilitythatthelowserumMBLobserved
Table2–LackofcorrelationbetweenserumMBLlevelsandComplementlevelsinsubjectswithsystemiclupus erythematosus.
MBL deficiency
CH50 C2 C3 C4
Pearson p Pearson p Pearson p Pearson p
Overall 0.041 0.491 0.118 0.067 0.019 0.751 −0.125 0.233
Mild 0.064 0.657 −0.026 0.857 0.154 0.285 0.215 0.363
Moderate 0.113 0.284 0.204 0.051 0.024 0.819 0.022 0.907
Severe −0.044 0.807 −0.037 0.839 −0.289 0.102 −0.011 0.979
Table3–DistributionofsubjectswithsystemiclupuserythematosusaccordingtotheseverityofMBLdeficiencyandthe previousclinicalmanifestationanddemographiccharacteristicsofthedisease.
Clinical features
NoMBL deficiency n=111
MBLdeficiency
Overall n=175
Mild n=50
Moderate n=92
Severe n=33
Gender M:F 3:108 12:163 2:48 7:85 3:30
Cutaneous %a 94.6 89.7 92.0 88.0 90.9
Oralulcers % 18.9 22.9 32.0 21.7 12.11
Arthritis % 83.8 88.6 88.0 88.0 90.9
Nephritis % 47.7 60.6b 74.0c 61.1b 66.7b
II % 1.3 1.8 2.1 1.5 1.6
III % 8.6 8.5 8.1 9.6 7.9
IV % 13.2 12.2 13.6 13.2 13.9
V % 5.7 6.2 6.1 4.8 5.0
Nobiopsyavailable % 18.9 19.4 18.5 18.9 19.8
Hematologicdisease % 68.5 65.1 60.0 66.3 69.7
Serositis % 21.6 32.0 24.0 33.7 39.4
Neuropsychiatric % 18.9 22.9 28.0 20.7 21.2
Recurrentinfection % 9.0 8.6 2.0 10.9 12.11
OtherSARD % 8.1 6.9 4.0 7.6 9.1
NRAID % 1.8 6.9 12.0 3.3 9.1
Miscellaneous % 48.6 45.7 56.0 40.2 45.5
Age Mean±SD 38.7±11.8 39.2±12.9 38.7±12.1 37.9±13.0 43.3±13.0
Diseaseduration 9.7±7.1 10.8±8.0 10.3±7.4 11.0±8.5 11.0±7.6
AgeatSLEonset 28.9±10.4 28.3±11.0 28.4±10.9 26.8±10.7 32.2±11.14
SLEDAI Median(min–max) 0(0–11) 0(0–12) 0(0–6) 0(0–8) 1(0–12)
SLICC-DI 1(0–4) 1(0–5) 1(0–4) 1(0–5) 1(0–3)
MBLdeficiency,serumlevelslowerthan1000g/L;mild,serumMBLlevel<1000and≥500g/L;moderate,serumMBLlevel<500and≥100g/L; severe,serumMBLlevel<100g/L;SARD,systemicautoimmunerheumaticdiseases;NRAID,non-rheumaticautoimmunediseases; miscella-neous,anynon-rheumaticandnon-autoimmunedisease;SLEDAI,SystemicLupusErythematosusDiseaseActivityIndex;SLICC-DI,Systemic LupusInternationalCollaboratingClinics-DamageIndex.
a Percentagesrefertothefrequencyofanygivenclinicalmanifestation.
b p<0.05. c p<0.01.
Table4–DistributionofsubjectswithsystemiclupuserythematosusaccordingtotheseverityofMBLdeficiencyanduse ofimmunosuppressanttherapy.
NoMBLdeficiency MBLdeficiency
n=111 Overall
n=175
Mild n=50
Moderate n=92
Severe n=33
Currentimmunosupressanta %b 64.0 71.4 68.0 71.7 75.8
Previousimmunosupressanta % 63.6 66.7 74.0 63.7 63.6
Corticosteroids
Totala % 52.3 54.9 66.0 45.7 57.6
Lowdosesa % 32.4 28.6 32.0 26.1 36.4
Highdosesa % 19.80 25.7 34.0 19.6 21.2
Anti-malarialsa % 73.0 66.9 70.0 59.8 81.8
Azathioprinea % 21.6 23.40 24.0 25.0 18.2
Mycophenolatea % 9.9 8.0 8.0 6.5 12.1
Methotrexatea % 13.5 18.9 16.0 17.4 27.3
Cyclophosphamidea % 7.2 8.6 6.0 10.9 6.1
Leflunomidea % 5.4 4.6 4.0 3.3 9.1
Dapsonea % 1.8 0.6 2.0 0 0
Thalidomidea % 0.9 0.6 0 1.1 0
Tacrolimusa % 0.9 1.7 2.0 2.2 0
Cyclosporinea % 1.8 2.9 6.0 1.1 3.0
MBLdeficiency,serumlevelslowerthan1000g/L;mild,serumMBLlevel<1000and≥500g/L;moderate,serumMBLlevel<500and≥100g/L; severe,serumMBLlevel<100g/L.
a Nostatisticallysignificantassociation.
Table5–LackofcorrelationbetweenMBLserumlevelsanddiseaseactivityorcumulativedamageinsubjectswith systemiclupuserythematosus.
MBLdeficiency SLEDAI SLICC-DI
Correlationa p Correlation p
Overall −0.068 0.256 −0.05 0.945
Mild 0.037 0.800 −0.090 0.631
Moderate 0.107 0.310 0.163 0.160
Severe 0.036 0.840 −0.322 0.154
SLEDAI,SystemicLupusErythematosusDiseaseActivityIndex;SLICC-DI,SystemicLupusInternationalCollaboratingClinics-DamageIndex; MBLdeficiency,serumlevelslowerthan1000g/L;mild,serumMBLlevel<1000and≥500g/L;moderate,serumMBLlevel<500and≥100g/L; severe,serumMBLlevel<100g/L.
a CalculatedaccordingtoPearson’stest.
insomepatients could besecondary todisease activity or immunosuppressanttherapy.However,thisseemsnottobe thecase,sincefollowupassessmentafterSLEdisease activ-ityhasconfirmedtheinitialMBLdeficientclassificationinall cases.Inaddition,therewasnodifferenceinthefrequency of MBL deficiency according to SLE activity and severity. No association was observed between MBL deficiency and immunosuppressantuseorrecurrentinfections.
Traditionally,immunodeficientstatesareassociatedwith increasedsusceptibilitytoinfection.MBLdeficiencyhasbeen describedas ariskfactorforinfectious diseases.21–23 How-ever, microbicide activity is not the sole function of MBL: itcanalsobind apoptoticcellsand initiatetheiruptakeby macrophages.24,25Therefore,itispossiblethatMBLdeficiency could lead to decreased clearance of autoantigens, which couldinturncontributetothedevelopmentofautoimmunity. Weproposethatmildormoderateimmunologicdeficitssuch asMBLdeficiencymayimpacttheinflammatoryprocessand eventualdevelopmentofautoimmunediseasesevenwithout increasingsusceptibilitytoinfections.
Theassociationbetween MBLdeficiency andSLEisstill controversial and disparate results have been obtained in differentethnicgroups,includingAmerican11 andAfrican10 populations.Inthisregard,thepresentstudymakesan impor-tantcontribution,sinceitconfirmstheassociationinasample oftheBrazilianpopulation,whichrepresentsauniqueblend of European, African and native American Indian descen-dants. Anothersourceof controversyisthe lackofa clear definitionofMBL deficiency.Inthisstudy wedefinedthree degreesofMBLdeficiencyseveritybasedonserumMBL lev-els,ashasbeendoneinseveralpreviousstudies.16–20There issomeconcernthatanti-MBLautoantibodiesintheserum ofSLEpatientsmightleadtosecondaryMBLdeficiency with-outunderlyingMBLgeneticabnormality.Thiscouldpartially explainconflictingfindingsontheassociationbetweenMBL deficiencyandSLE.8,11,26Asanalternative,somestudieshave usedMBLpolymorphismsinthepromoterregionorthecoding regionascriteriafordefinitionofMBLdeficiency.3,4,7–9 How-ever,thereisnoperfectcorrelationbetweenthepresenceof MBLpolymorphisms and proteinexpression, andtherefore therealvalueofthisapproachisstillunclear.
In this study, we observeda higher frequency of lupus nephritisinsubjectswithSLEandMBLdeficiencythanin sub-jectswithSLEandnormalMBLlevels.Severalpreviousstudies havesuggestedlinksbetweenMBLlevelsandlupusnephritis.
Anti-MBL autoantibodiescanbind toMBL deposited in tis-suesandcontributetolocalinjury,asdemonstratedinkidneys ofSLEpatients.27 Ithasbeenalsoreportedthatthenucleic acid-bindingcapacityofMBLplaysanimportantroleinthe clearanceofDNA,animportantautoantigenforlupus nephri-tisdevelopment.28Piaoetal.29inaNorthAmericanpopulation andAsgharzadehetal.30inanAzerbaijanpopulationinIran demonstratedthathomozygosisforMBLvariantsisa disease-modifyingfactor,particularlyforrenalinvolvement.However, therelationshipbetweenMBLdeficiencyandlupusnephritis maybeaffectedbyethnicbackground,sinceBertolietal.31 showed in a large multiethnic lupus cohort composed by Hispanics,AfricanAmericanandCaucasiansthatcarriersof variant alleles forMBL gene had lower frequency oflupus nephritisandserositis,buthigherfrequencyofleukopenia.
Besidesthedecreaseinantigenclearance,homozygosisfor MBLvariantallelesisalsoassociatedwithanincreaseinrisk ofinfections,mainlyinchildren.32,33Consequently,patients withMBLdeficiencyareathigherriskofbeingexposedmore frequentlyandforlongerperiodsoftimetopathogensthat may play a role inSLE pathogenesis. Itshould be pointed outthatapreviousreportfoundnoassociationbetweenMBL deficiency andsevere infections inSLEpatients,34 and this wasconfirmedinthepresentstudy.Furthermore,ithasbeen reportedthatMBL-deficientadultsdonotpresentincreased frequencyofinfectiousdiseases,leadingtotheassumption thatasecondimmunedefectmightbeneededtotrigger sus-ceptibilitytoinfection.35
TheexactmechanismunderlyingtheeffectofMBL defi-ciencyonthepathogenesisandclinicaloutcomeofSLEisnot clear.Takahashietal.36showedpositive,althoughweak, cor-relationbetweenserumCH50activityandserumMBLlevels, suggestingthatMBLcouldalsobeusedasamarkerfor dis-easeactivityinSLEpatients.Inthepresentstudy,wecould notdemonstrateanycorrelationbetweenserumMBLlevels and Complement levels, SLEdisease activity orcumulative damage. Regardless of the pathophysiology involved, MBL deficiencyper seisprobablynotenoughtoinduce autoim-munity.Additional,yetunknownfactorsmayactinconcert withMBLdeficiencytotriggerdevelopmentofautoimmunity. Furtherstudiesareneededtoaddressthisquestion.
patientswithMBLdeficiencyhadhigherprevalenceoflupus nephritis,regardlessoftheseverityofMBLdeficiency,thanSLE patientswithnormalMBLlevels.Theseresultsobtainedinthe ethnicallyunique andcomplex Brazilianpopulation frame-workadd anotherpiecetothe puzzleofthe associationof MBLdeficiencyandSLE.
Funding
Thisstudy was supportedby FAPESP (Fundode Amparo à PesquisadoEstadode SãoPaulo)grant#2009/53449-0.Luis EduardoC.Andradereceivesagrant(#476356/2008-3)fromthe BrazilianresearchagencyCNPq.
Conflicts
of
interest
Theauthorsdeclarenoconflictofinterest.
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1. HolmskovU,MalhotraR,SimRB,JenseniusJC.Collectins: collagenousC-typelectinsoftheinnateimmunedefense system.ImmunolToday.1994;15:67–74.
2. TsutsumiA,TakahashiR,SumidaT.Mannosebindinglectin: geneticsandautoimmunedisease.AutoimmRev.
2005;4:364–72.
3. MadsenHO,GarredP,ThielS,KurtzhalsJA,LammLU,Ryder LP,etal.Interplaybetweenpromoterandstructuralgene variantscontrolbasalserumlevelofmannan-binding protein.JImmunol.1995;155:3013–20.
4. MadsenHO,SatzML,HoghB,SvejgaardA,GarredP.Different moleculareventsresultinlowproteinlevelsof
mannan-bindinglectininpopulationsfromsoutheastAfrica andSouthAmerica.JImmunol.1998;169:31169–75.
5. TsutsumiA,IkegamiH,TakahashiR,MurataH,GotoD, MatsumotoI,etal.Mannosebindinglectingene polymorphisminpatientswithtypeIdiabetes.Hum Immunol.2003;64:621–4.
6. GraudalNA,MadsenHO,TarpU,SvejgaardA,JurikG,Graudal HK,etal.Theassociationofvariantmannose-bindinglectin genotypeswithradiographicoutcomeinrheumatoid arthritis.ArthritisRheum.2000;43:515–21.
7. MonticieloOA,MucenicT,XavierRM,BrenolJCT,BogoChies JA.Theroleofmannose-bindinglectininsystemiclupus erythematosus.ClinRheumatol.2008;27:413–9.
8. GarredP,VossA,MadsenHO,JunkerP.Associationof mannose-bindinglectingenevariationwithdiseaseseverity andinfectionsinapopulation-basedcohortofsystemic lupuserythematosus.GenesImmunol.2001;2:442–50. 9. LeeYH,WitteT,MomotT,SchmidtRE,KaufmanKM,Harley
JB,etal.Themannose-bindinglectingenepolymorphisms andsystemiclupuserythematosus:twocase–controlstudies andameta-analysis.ArthritisRheum.2005;52:3966–74. 10.DaviesEJ,TiklyM,WordsworthBP,OllierWE.
Mannose-bindingproteingenepolymorphisminSouth Africansystemiclupuserythematosus.BrJRheumatol. 1998;37:465–6.
11.García-LaordenMI,Rúa-FigueroaI,Pérez-AciegoP, Rodríguez-PérezJC,CitoresMJ,AlamoF,etal.Mannose bindinglectinpolymorphismsasadisease-modulatingfactor inwomenwithsystemiclupuserythematosus.JRheumatol. 2003;30:740–6.
12.HochbergMC.UpdatingtheAmericanCollegeof Rheumatologyrevisedcriteriafortheclassificationof systemiclupuserythematosus.ArthritisRheum. 1997;40:1725.
13.BombardierC,GladmanDD,UrowitzMB,CaronD,ChangCH. DerivationoftheSLEDAI.Adiseaseactivityindexforlupus patients.TheCommitteeonPrognosisStudiesinSLE. ArthritisRheum.1992;35:630–40.
14.GladmanD,GinzlerE,GoldsmithC,FortinP,LiangM,Urowitz M,etal.Thedevelopmentandinitialvalidationofthe SystemicLupusInternationalCollaboratingClinics/American CollegeofRheumatologydamageindexforsystemiclupus erythematosus.ArthritisRheum.1996;39:363–78.
15.AraújoMN,LeserPG,GabrielJúniorA,AssadRL,AtraE.A simpleradialimmunohemolysisassayforthemeasurement offunctionalcomplementC2activity.BrazJMedBiolRes. 1991;24:49–57.
16.AlbertRK,ConnettJ,CurtisJL,MartinezFJ,HanMK,Lazarus SC,etal.Mannose-bindinglectindeficiencyandacute exacerbationsofchronicobstructive.IntJCOPD. 2012;7:767–77.
17.IpWK,ChanKH,LawHKW,TsoGH,KongEK,WongWH,etal. Mannose-bindinglectininsevereacuterespiratory
syndromecoronavirusinfection.JInfectDis.2005;191: 809–12.
18.EaganTM,AukrustP,BakkePS,DamåsJK,SkorgeTD,Hardie JA,etal.Systemicmannose-bindinglectinisnotassociated withchronicobstructivepulmonarydisease.RespirMed. 2010;104:283–90.
19.BronkhorstMW,BouwmanLH.Mannose-bindinglectin deficiency.UpToDate.2014.Availablefrom:
http://www.uptodate.com[accessedinFebruary1,2014]. 20.NethO,JackDL,DoddsAW,HolzelHJ,KleinMH,TurnerMW.
Mannose-bindinglectinbindstoarangeofclinicallyrelevant microorganismsandpromotescomplementdeposition. InfectImmun.2000;68:688–93.
21.GarredPH,MadsenHO,HofmannB,SvejgaardA.Increased frequencyofhomozygosityofabnormalmannan-binding proteinallelesinpatientswithsuspectedimmunodeficiency. Lancet.1995;346:941.
22.SummerfieldJA,SumiyaM,LevinM,TurnerMW.Association ofmutationsinmannosebindingproteingenewith childhoodinfectioninconsecutivehospitalseries.BrMedJ. 1997;314:1229.
23.CoelhoAV,BrandãoLA,GuimarãesLA,LoureiroP,deLima FilhoJL,deAlencarLC,etal.Mannose-bindinglectinand mannosebindinglectin-associatedserineprotease-2genes polymorphismsinhumanT-lymphotropicvirusinfection.J MedVirol.2013;85:1829–35.
24.OgdenCA,DeCathelineauA,HoffmannPR,BrattonD, GhebrehiwetB,FadokVA,etal.C1qandmannosebinding lectinengagementofcellsurfacecalreticulinandCD91 initiatesmacropinocytosisanduptakeofapoptoticcells.JExp Med.2001;194:781–95.
25.FeriottiC,LouresFV,FrankdeAraújoE,DaCostaTA,Calich VL.Mannosyl-recognizingreceptorsinduceanM1-like phenotypeinmacrophagesofsusceptiblemicebutanM2-like phenotypeinmiceresistanttoafungalinfection.PLoSOne. 2013;8:e54845.Availablefrom:http://dx.plos.org/10.1371/ journal.pone.0054845[accessedinDecember5,2014]. 26.GarredP,MadsenHO,HalbergP,PetersenJ,KronborgG,
SvejgaardA,etal.Mannose-bindinglectinpolymorphisms andsusceptibilitytoinfectioninsystemiclupus
erythematosus.ArthritisRheum.1999;42:2145–52. 27.HisanoS,MatsushitaM,FujitaT,EndoY,TakebayashiS.
28.PalaniyarN,NadesalingamJ,ClarkH,ShihMJ,DoddsAW, ReidsKB.Nucleicacidisanovelligandforinnate,immune patternrecognitioncollectinssurfactantproteinsA.JBiol Chem.2004;279:32728–36.
29.PiaoW,LiuCC,KaoAH,ManziS,VogtMT,RuffingMJ,etal. Mannose-bindinglectinisadiseasemodifyingfactorin NorthAmericanpatientswithsystemiclupuserythematosus. JRheumatol.2007;34:1506–13.
30.AsgharzadehM,KafilHS,EbrahimzadehME,BohlouliA. Mannosebindinglectingenepromoterpolymorphismand susceptibilitytorenaldysfunctioninsystemiclupus erythematosus.JBiolSci.2007;5:801–5.
31.BertoliAM,FernándezM,McGwinGJr,AlarcónGS,TanFK, ReveilleJD,etal.Systemiclupuserythematosusina
multiethnicUScohort:XXXVI.Influenceofmannose-binding lectinexon1polymorphismsindiseasemanifestations, course,andoutcome.ArthritisRheum.2006;54:1703–4. 32.Gröndahl-Yli-HannukselaK,VianderM,MertsolaJ,HeQ.
Increasedriskofpertussisinadultpatientswith
mannose-bindinglectindeficiency.APMIS.2013;121:311–5.
33.GhaziM,IsadyarM,GachkarL,MahmoudiS,GoudarziH, EslamiG,etal.Serumlevelsofmannose-bindinglectinand theriskofinfectioninpediatriconcologypatientswith chemotherapy.JPediatrHematolOncol.2012;34:128–30. 34.BultinkIE,HamannD,SeelenMA,HartMH,DijkmansBA,
DahaMR,etal.Deficiencyoffunctionalmannose-binding lectinisnotassociatedwithinfectionsinpatientswith systemiclupuserythematosus.ArthritisResTher. 2006;8:R183.
35.MomboLE,LuCY,OssariS,BedjabagaI,SicaL,
KrishnamoorthyR,etal.Mannose-bindinglectinallelesin subSaharanAfricansandrelationwithsusceptibilityto Infections.GenesImmun.2003;4:362–7.
