RESEARCH ARTICLE Open Access
Small-in es inal TG2-speci ic plasma cells a
di e en s ages o coeliac disease
Minna Hie ikko
1
, Ou i Koskinen
1
, Kalle Ku ppa
2,3
, Kaija Lau ila
1
, Päi i Saa alainen
4
, Teea Salmi
1,5
, Tui e Ilus
1,6
,
Heini Huh ala
7
, Ka i Kaukinen
1,8
and Ka i Lind o s
1*
Abs ac
Backg ound: In coeliac disease, inges ion o glu en induces he p oduc ion o ansglu aminase 2 (TG2)- a ge ed
au oan ibodies by TG2-speci ic plasma cells p esen a high equency in he small in es inal mucosa in un ea ed
disease. Du ing ea men wi h a glu en- ee die (GFD), he numbe o hese cells dec eases conside ably. I has no
been p e iously in es iga ed whe he he cells a e also p esen p io o de elopmen o illous a ophy, o in non-
esponsi e pa ien s and hose wi h die a y lapses. We aimed o de ine he equency o small bowel mucosal TG2-
speci ic plasma cells in coeliac disease pa ien s wi h a ying disease ac i i y, and o in es iga e whe he he equency
co ela es wi h se um and small in es inal TG2- a ge ing an ibodies as well as mucosal mo phology and he numbe o
in aepi helial lymphocy es.
Resul s: Mucosal TG2-speci ic plasma cells we e ound in 79% o pa ien s p io o de elopmen o mucosal
damage, in all pa ien s wi h illous a ophy, and in 63% o he pa ien s a e 1 yea on GFD. In hese disease
s ages, TG2-speci ic plasma cells accoun ed o median o 2.3, 4.3, and 0.7% o all mucosal plasma cells, espec i ely.
A e long- e m ea men , he cells we e p esen in 20% o he pa ien s in clinical emission (median 0%) and in 60%
o he pa ien s wi h poo die a y adhe ence (median 5.8%). In pa ien s wi h non- esponsi e coeliac disease despi e
s ic GFD, he cells we e ound in only one (9%) subjec ; he cells accoun ed o 2.4% o all plasma cells. A posi i e
co ela ion be ween he pe cen age o TG2-speci ic plasma cells and se um TG2 an ibody le els (
S
=0.69,P<0.001)
and he in ensi y o mucosal TG2- a ge ing IgA deposi s (
S
= 0.43, P < 0.001) was obse ed.
Conclusions: Ou esul s show ha TG2-speci ic plasma cells a e al eady de ec able p io o illous a ophy, and ha
gene ally hei equency inc eases du ing o e disease. By con as , on GFD, he pe cen age o hese cells dec eases.
O e all, he p esence o TG2-speci ic plasma cells in he small bowel mucosa mi o s he p esence o glu en in he die ,
bu he equency is no always pa allel o he le el o se um o in es inal TG2 an ibodies. These indings inc ease he
knowledge abou he de elopmen o he TG2 plasma cell esponses especially in he ea ly phases o coeliac disease.
Keywo ds: Coeliac disease, Glu en, T ansglu aminase 2, Au oan ibody, Small in es ine
Backg ound
In coeliac disease, die a y glu en in whea , ye, and
ba ley unc ions as a d i ing an igen o an abno mal
immune esponse ha de elops in gene ically suscep ible
indi iduals ca ying he human leukocy e an igen
(HLA)-DQ2 o -DQ8 haplo ypes. The disease is cha ac-
e ised by small-bowel mucosal damage which de elops
g adually om no mal illous mo phology o in lamma-
ion and inally o illous a ophy wi h c yp hype plasia
diagnos ic o coeliac disease. The in es inal damage is
o en coupled wi h nume ous gas oin es inal symp oms,
al hough a ious ex ain es inal mani es a ions a e also
p e alen . A speci ic cha ac e is ic o coeliac disease is
he gene a ion o immunoglobulin class A (IgA)
an ibodies owa ds he main au oan igen, ansglu ami-
nase 2 (TG2) [1]. These au oan ibodies a e gene ally
ound in he ci cula ion o coeliac disease pa ien s [2]
and as deposi s in he small in es inal mucosa below he
subepi helial basemen memb ane and a ound blood
essels [3]. In e es ingly, in es inal TG2- a ge ed
deposi s can be de ec ed e en p io o mani es mucosal
damage and in he absence o se um an ibodies [4–6].
* Co espondence: [email p o ec ed]
1
Celiac Disease Resea ch Cen e , Facul y o Medicine and Li e Sciences,
Uni e si y o Tampe e, P.O. Box 100, 33014 Tampe e, Finland
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Hie ikko e al. BMC Immunology (2018) 19:36
h ps://doi.o g/10.1186/s12865-018-0275-7
Upon emo al o glu en om he die , he only cu en ly
a ailable ea men , he clinical symp oms and his o-
pa hological changes in he small in es ine esol e, and
bo h he ci cula ing and in es inal an ibodies disappea
wi hin 1 yea in mos pa ien s [7]. Howe e , a subse o
pa ien s ails o espond o he die a y ea men and he
illous a ophy pe sis s despi e a s ic glu en- ee die
(GFD). The mos common eason o pe sis en illous
a ophy is ei he ad e en o inad e en glu en in ake
o , in a e cases, e ac o y coeliac disease [8].
TG2- a ge ing an ibodies we e long hough o be
gene a ed by in es inal plasma cells [9–11], bu ecen
da a sugges s ha hey migh also be p oduced in
lymphoid issues ou side he gu [12]. In he small in es-
ine, he TG2-speci ic plasma cells a e p esen a high
equency du ing he ac i e disease [10,11], and hey
dec ease conside ably wi hin 6–12 mon hs a e com-
mencemen o a s ic GFD [11]. Howe e , no da a exis
ega ding he p esence o hese cells in he ea ly phases
o coeliac disease when he mucosal mo phology is s ill
no mal. In addi ion, hei exis ence in non- esponding
coeliac disease pa ien s o hose wi h die a y lapses has
no been p e iously in es iga ed. Wi h his in mind, we
enume a ed he TG2-speci ic plasma cells in un ea ed
and ea ed coeliac pa ien s wi h a ying deg ees o
disease ac i i y, and in es iga ed whe he he numbe o
hese cells co ela es wi h se um TG2 an ibody le els,
he in ensi y o mucosal TG2- a ge ing IgA deposi s,
and small in es inal mucosal mo phology and
in lamma ion.
Me hods
Pa ien s and s udy design
The s udy coho comp ised 46 coeliac disease pa ien s
who unde wen uppe gas oin es inal endoscopy a he
Depa men o Gas oen e ology and Alimen a y T ac
Su ge y o Tampe e Uni e si y Hospi al (Table 1).
Fi een o he pa ien s we e clinically suspec ed o ha ing
coeliac disease based on gas oin es inal symp oms and
posi i e coeliac disease-speci ic au oan ibodies (endomy-
sial and/o TG2 an ibodies) despi e ha ing no mal small
bowel mucosa ( illous heigh c yp dep h a io (Vh/
C D) ≥2). These pa ien s we e p ospec i ely ollowed up
while hey con inued on a no mal glu en-con aining die
Table 1 Demog aphic da a and he small-bowel mucosal and se ological indings o pa ien s pa icipa ing in he s udy
P ospec i ely s udied coeliac pa ien s
(n= 15)
Long- e m ea ed coeliac pa ien s
(n= 31)
Disease con ols
(n= 25)
CD p io
o a ophy
n=14
O e CD
n=15
1 yea GFD
n=11
Pa ien s in
emission
n=15
Non-
esponding CD
n=11
Pa ien s wi h
die a y lapses
n=5
Glu en
sensi i i y
n=18
Dyspepsia
n=7
Female; n (%) 10 (71) 10 (67) 7 (64) 10 (67) 7 (64) 5 (100) 16 (89) 1 (14)
Age; median ( ange), yea s 55 (16–70) 55 (17–71) 57 (28–72) 59 (24–66) 49 (40–76) 51 (31–77) 49 (24–65) 47 (24–76)
Du a ion o GFD; median
( ange), yea s
00 1(1–1) 8 (3–34) 7 (3–24) 10 (9–17) 0 0
HLA-DQ2 o -DQ8-posi i e; n
(%)
14 (100) 15 (100) 11 (100) 15 (100) 11 (100) 4
a
(100) 9 (50) 1 (14)
EmA; median ( ange), i e 1:100 (0–
1:2000)
1:100 (0–
1:4000)
0(0–1:50) 0 (0) 0 (0–1:5) 1:200 (0–
1:2000)
0 (0) 0 (0)
TG2 abs; median ( ange),
U/ml
9.4 (3.3- >
100)
11.9 (4.2- >
100)
3.9 (0–8.6) 0.5 (0–2.8) 1.3 (0–9.9) 56.9 (12.9- >
100)
1.4 (0–4.1) 0.6 (0–2.8)
Mucosal TG2-IgA deposi s
p esen ; n (%)
14 (100) 14
a
(100) 7
b
(88) 5 (33) 10
a
(100) 3
c
(100) 4 (22) 0 (100)
Vh/C D; mean (95% CI), a io 2.9 (2.6–3.1) 1.4 (1.1–1.7) 3.4 (2.4–4.5) 3.4 (3.2–
3.6)
0.2 (0.0–0.4) 0.5 (−0.3–1.3) 3.5 (3.0–
4.1)
3.5 (3.0–4.1)
CD3
+
IELs; median
( ange), cells/mm
54 (12–79) 67 (38–116) 39 (23–80) 42 (25–77) 60 (30–109) 50 (38–69) 21 (7–59) 26 (16–40)
αβ
+
IELs; median
( ange), cells/mm
30 (12–50) 43 (21–75) 22 (14–43) 31 (20–46) 44 (26–105) 38 (35–56) 16 (5–26) 22 (17–31)
γδ
+
IELs; median
( ange), cells/mm
18.8 (0–38.5) 23.7 (14–58.7) 13.6 (1.4–
56.3)
14.0 (7.3–
27.8)
12.1 (0–37.8) 13.0 (4.4–20.5) 2.7 (0–
10.2)
1.6 (0.7–
16.1)
abs an ibodies, CD coeliac disease, CI con idence in e al, EmA endomysial an ibodies, GFD glu en- ee die , GS glu en sensi i e; IgA immunoglobulin A; IELs
in aepi helial lymphocy es; TG2-abs, ansglu aminase 2 an ibodies; Vh/C D illous heigh c yp dep h a io
Re e ence alues se a 2.0 o Vh/C D, 37 cells/mm o CD3
+
IELs, 25 cells/mm o αβ
+
IELs, and 4.3 cell/mm o γδ+ IELs (Jä inen e al., [15])
Cu -o alue o TG2 an ibodies ≥5 AU/ml
a
Da a missing om one pa ien
b
Da a missing om h ee pa ien s
c
Da a missing om wo pa ien s
Hie ikko e al. BMC Immunology (2018) 19:36 Page 2 o 7
o 1 yea , du ing which illous a ophy de eloped (Vh/
C D < 2) in all pa ien s. The ea e , he pa ien s s a ed a
GFD, and a e 1 yea on he die , hei mucosal mo ph-
ology had eco e ed. Small bowel samples om 14 o
he pa ien s a he ime o he no mal mucosal mo ph-
ology, all 15 pa ien s a he ime o he illous a ophy,
and 11 o he pa ien s a e 1 yea on a GFD we e a ail-
able o he cu en s udy (Table 1).
Fu he mo e, 15 coeliac disease pa ien s on a
long- e m GFD wi hou symp oms and e incing ull
his ological eco e y, 11 non- esponsi e coeliac disease
pa ien s wi h pe sis en illous a ophy despi e a s ic
GFD, and i e pa ien s wi h poo die a y adhe ence we e
in es iga ed. Twen y pa ien s wi h sel - epo ed glu en
sensi i i y expe iencing abdominal symp oms a e con-
sump ion o glu en-con aining p oduc s [13] and se en
pa ien s wi h dyspepsia se ed as he non-coeliac con-
ols in he s udy. All con ols had been excluded o
coeliac disease, as demons a ed by nega i e se ology
and no mal small bowel mucosal mo phology. The
demog aphic da a and small-bowel mucosal and se o-
logical indings o all subjec s a e epo ed in Table 1.
The s udy p o ocol was app o ed by he E hics
Commi ee o he Pi kanmaa Hospi al Dis ic , Tampe e,
Finland, and w i en in o med consen was ob ained
om all pa icipa ing subjec s.
Small-in es inal mucosal mo phology and in lamma ion
Small-in es inal mucosal biopsies we e ob ained upon
uppe gas oin es inal endoscopy. Fo mo phological
s udies, one o malin- ixed biopsy sample was s ained
wi h haema oxylin and eosin o de e mine he illous
heigh -c yp dep h a ios (Vh/C D) acco ding o a p e i-
ously published p ocedu e [14]. A a io o ≥2 was con-
side ed no mal. One o he biopsies was subme ged in
op imal cu ing empe a u e compound (OCT;
Tissue-Tek, Saku a Fine ek Eu ope, Holland), ollowed
by snap- eezing in liquid ni ogen. The ea e ,
5-μm- hick sec ions we e cu . Acco ding o an es ab-
lished p o ocol [15], he sec ions we e s ained o CD3
+
,
αβ
+
, and γδ
+
in aepi helial lymphocy e (IEL) subse s.
The e e ence alues we e 37 cells/mm, 25 cells/mm,
and 4.3 cells/mm o CD3
+
IELs, γδ
+
IELs and αβ
+
IELs,
espec i ely [15].
Se ological measu emen s and HLA geno yping
Se um endomysial an ibodies (EmA) in IgA class we e
de e mined by an indi ec immuno luo escence me hod
exploi ing human umbilical co d as subs a e. A dilu ion
o 1:≥5 was conside ed posi i e [16]. Se um IgA-class
TG2 an ibodies we e measu ed by a comme cially a ail-
able enzyme-linked immunoso ben assay (Celikey®,
Phadia, F eibu g, Ge many) in samples dilu ed 1:100. A
i e o ≥5 AU/ml was se as he cu -o o posi i i y.
SSP DQB1 low- esolu ion ki (Ole up SSP AB, Sal sjö-
baden, Sweden), DELFIA Celiac Disease Hyb idiza ion
Assay (Pe kinElme Li e and Analy ical Sciences, Wallac
Oy, Tu ku, Finland) o HLA- agging single-nucleo ide
pep ides [17] we e used o HLA geno yping.
Small-in es inal TG2-speci ic IgA deposi s
Fo he de e mina ion o mucosal TG2- a ge ing IgA
deposi s, ozen sec ions we e s ained wi h mouse
monoclonal an i-TG2 an ibody (CUB7402; NeoMa ke s,
F emon , Cali o nia, USA), ollowed by de ec ion wi h
luo escein iso hiocyana e (FITC) -labelled abbi
an i-human IgA an ibody (Dako A/S, Glos up,
Denma k) [3]. Based on hei in ensi y along he base-
men memb ane in he illous-c yp a ea, he deposi s
we e g aded blinded as a nega i e, o a weak, mode a e,
o s ong posi i e, as desc ibed p e iously [6].
Small-in es inal TG2-speci ic plasma cells
An ea lie desc ibed echnique was used o de ec muco-
sal TG2-speci ic plasma cells [10]. Ini ially, 5-μm- hick
ozen sec ions we e ai -d ied o 20 min a oom
empe a u e (RT). A e washing in PBS, he sec ions
we e incuba ed wi h bio inyla ed human ecombinan
TG2 (2 μg/ml; T002, Zedi a) o 45 min a RT. Bio inyl-
a ion was pe o med using EZ-Link®
Sul o-NHS-LC-Bio in (The mo Scien i ic, Wal ham,
MA, USA) acco ding o he ins uc ions p o ided by he
manu ac u e . The ea e , he sec ions we e incuba ed
wi h hodamine-labelled s ep a idin (1:1000; KPL,
Gai he sbu g, MD, USA) o 30 min a RT. Plasma cells
we e iden i ied using a mouse monoclonal CD138 an i-
body (1:25; B-A38, Bio-Rad), ollowed by goa
an i-mouse IgG Alexa Fluo 488 (1:2000; A-11001,
The mo-Fishe Scien i ic). S ainings we e analysed a
20x and 40x magni ica ion (Olympus BX60F5, Olympus
Op ical Co. LTD, Japan) on wo consecu i e small in es-
inal biopsy sec ions and he pe cen age o TG2-speci ic
cells ou o all lamina p op ia plasma cells in he en i e
sec ion was de e mined.
S a is ical analyses
Da a a e exp essed as he numbe o subjec s (n) and
pe cen ages, o as medians and anges. S a is ical
analyses we e pe o med using he Wilcoxon es o
Mann–Whi ney es as app op ia e. Co ela ion was
e alua ed using Spea man’s co ela ion. S a is ical es ing
was pe o med using s a is ical analysis so wa e (IBM
SPSS S a is ics, SPSS Inc., Chicago, IL, USA). A P- alue
< 0.05 was conside ed s a is ically signi ican .
Resul s
O he 15 p ospec i ely s udied coeliac disease pa ien s,
TG2-speci ic plasma cells we e al eady p esen in 11 ou
Hie ikko e al. BMC Immunology (2018) 19:36 Page 3 o 7
o he 14 a ailable small bowel samples (79%) om he
pa ien s be o e he de elopmen o illous a ophy. The
median pe cen age o he cells was 2.3% ( ange 0–
12.7%) o all lamina p op ia plasma cells (Fig. 1a and b).
A e con inuing on a glu en-con aining die o 1 yea
and de eloping o e small bowel mucosal damage, all
i een pa ien s had in es inal TG2-speci ic plasma cells,
and he median pe cen age o he cells was 4.3% ( ange
1.8–8.8%) (P= 0.055 when compa ed o pa ien s wi h
ea ly-s age coeliac disease). By con as , a e 1 yea on a
GFD, he cells we e ound in 7 ou o 11 (64%) pa ien s
wi h a ailable samples, and he median pe cen age o
he cells signi ican ly dec eased o 0.7% ( ange 0–2.9%,
P= 0.003) when compa ed o he o e disease.
In long- e m GFD- ea ed pa ien s in clinical emis-
sion esponding well o die a y ea men , only a ew
emaining TG2-speci ic plasma cells (median 0.0%,
ange 0–1.1%) we e de ec ed in 3 ou o 15 (20%) o he
pa ien s (Fig. 1a and b). In non- esponding coeliac
disease pa ien s on a s ic GFD, he cells we e mos ly
absen , being p esen in only one pa ien (9%) who had
2.4% o TG2-speci ic cells ou o all lamina p op ia
plasma cells. O he coeliac disease pa ien s wi h die a y
lapses, h ee ou o i e (60%) had TG2-speci ic plasma
cells, he median being 5.8% ( ange 0–7.0%). No
TG2-speci ic plasma cells we e ound in any o he
non-coeliac con ol pa ien s wi h ei he glu en sensi i i y
o dyspepsia.
A posi i e co ela ion be ween he pe cen age o
TG2-speci ic plasma cells and se um TG2 an ibody
le els (
S
= 0.690, P< 0.001, Fig. 2a) as well as EmA (
S
=
0.712, P < 0.001) was obse ed when da a om all
coeliac disease pa ien g oups we e included in he ana-
lysis. Simila ly, he pe cen age o he TG2-speci ic
plasma cells co ela ed wi h he in ensi y o he small
in es inal IgA deposi s in all coeliac disease pa ien s (
S
=
0.430, P< 0.001) (Fig. 2b). Howe e , he pe cen age o
TG2-speci ic plasma cells did no co ela e wi h se um
Fig. 1 a. The pe cen age o small-bowel mucosal ansglu aminase 2 (TG2) -speci ic plasma cells ou o all lamina p op ia plasma cells in he
di e en pa ien g oups. b. Immuno luo escence s aining o ansglu aminase 2 (TG2) an ibodies and plasma cells in small-bowel mucosal
sec ions. Rep esen a i e pic u e o a coeliac disease pa ien p io o illous a ophy showing posi i e s aining o TG2-speci ic plasma cells
(a ows). Recombinan TG2 ( ed), plasma cell ma ke CD138 (g een), and hei colocalisa ion (yellow) a 20x magni ica ion. Scale ba = 100 μm.
Abb e ia ions: CD, coeliac disease; GFD, glu en- ee die
Hie ikko e al. BMC Immunology (2018) 19:36 Page 4 o 7
o mucosal TG2 an ibodies in any o he indi idual
coeliac disease pa ien g oups (Addi ional ile 1Table
S1). Conside ing all coeliac disease pa ien s, he e was
no co ela ion be ween he pe cen age o he plasma
cells and Vh/C D. O he IELs, he e was a modes co -
ela ion be ween he pe cen age o TG2-speci ic plasma
cells and γδ
+
IELs. De ailed in o ma ion abou he co e-
la ions is p esen ed in Addi ional ile 1Table S1.
Discussion
In he cu en s udy, we ha e disco e ed ha
TG2-speci ic plasma cells a e al eady p esen in mos
pa ien s p io o de ec able mucosal damage. Mo eo e ,
we showed ha in he majo i y o cases he pe cen age
o hese cells inc eases upon con inuous glu en in ake
and he subsequen de elopmen o illous a ophy. On
a s ic GFD, he pe cen age o hese cells declines. A e
long- e m ea men , he cells a e mos ly absen bo h in
pa ien s in clinical emission and in non- esponding
pa ien s wi h pe sis en illous a ophy. By con as ,
TG2-speci ic plasma cells can be de ec ed in pa ien s
wi h die a y lapses. In con ols, e en hose wi h
glu en- ela ed symp oms, no cells we e de ec ed.
Ou esul s om un ea ed and ea ed coeliac disease
pa ien s a e in line wi h p e ious s udies [10,11], show-
ing ha he amoun o TG2-speci ic plasma cells is ele-
a ed in he small in es inal mucosa a he ime o
diagnosis and his amoun dec eases on a GFD. I has
ea lie been shown ha he pe cen age o hese cells ou
o all lamina p op ia plasma cells accoun s o up o
24% in o e disease, being on a e age 10% [10,11].
Howe e , in he cu en s udy, he co esponding pe -
cen ages we e lowe . Ou pa ien s had been ec ui ed o
he s udy while s ill ha ing no mal mucosal mo phology,
and hey de eloped o e illous a ophy wi hin a
one-yea ollow-up on a glu en-con aining die . Thus, i
is concei able ha he pa ien s had had la mucosal
lesion o a easonably sho e ime han in he p e ious
a
b
Fig. 2 Co ela ion be ween he pe cen age o small in es inal ansglu aminase 2 (TG2) -speci ic plasma cells and se um IgA class TG2 an ibody
le els (a) and he in ensi y o small in es inal TG2- a ge ing immunoglobulin a (IgA) deposi s (b) in all coeliac disease pa ien s. G ading o IgA
deposi s as ollows: 0 = nega i e, 1 = weak, 2 = mode a e, 3 = s ong
Hie ikko e al. BMC Immunology (2018) 19:36 Page 5 o 7

s udies, which migh explain he lowe pe cen ages o
TG2-speci ic plasma cells in ou s udy.
TG2-speci ic plasma cells co ela ed posi i ely wi h
se um TG2 an ibody le els when he da a o all coeliac
disease pa ien s we e analysed oge he . This co ela ion
mos likely mi o s he esponsi eness o he plasma cells
o glu en exposu e which is no su p ising in he ligh ha
TG2 an ibodies ha e been sugges ed o a ise by a
hap en-ca ie -like mechanism in ol ing TG2-ca alysed
gene a ion o glu en-TG2 complexes [18,19]. On he
o he hand, co ela ions be ween he pe cen ages o he
plasma cells and se um an ibody le els we e no de ec ed
when di e en coeliac disease g oups we e analysed sepa -
a ely; his is in ag eemen wi h p e ious indings in
un ea ed coeliac disease pa ien s [11]. I has been p o-
posed ha he lack o co ela ion could be explained by
he p oduc ion o he an ibodies also ou side he gu [11].
This concep has ecen ly been u he suppo ed by he
inding ha coeliac pa ien se um and in es inal TG2 an i-
bodies a e clonally ela ed bu ha e di e en molecula
composi ions, poin ing o di e en si es o o igin [12].
Such ex ain es inal p oduc ion o TG2 an ibodies could
also explain why some pa ien s in ou s udy had se um
TG2 an ibodies in he absence o in es inal TG2-speci ic
plasma cells.
Al hough small in es inal TG2-speci ic plasma cells
a e no likely o be he majo sou ce o se um TG2 an i-
bodies [12], i would be logical o assume ha he TG2
an ibodies bound o hei an igen in he small in es inal
mucosa and p edic ing o hcoming mucosal damage a e
p oduced locally by lamina p op ia TG2-speci ic plasma
cells. In his s udy, we obse ed a co ela ion be ween
he pe cen age o he plasma cells and he in ensi y o
mucosal TG2-speci ic IgA deposi s, which suppo s his
hypo hesis. In e es ingly, howe e , TG2-speci ic plasma
cells we e mos ly absen in non- esponding coeliac
pa ien s, e en hough hey all p esen ed wi h s ong
TG2- a ge ing IgA deposi s in he small in es inal
mucosa despi e a s ic GFD. I has been p oposed ha
he long pe sis ence o small in es inal IgA deposi s in
non- esponsi e pa ien s on a s ic die may be
explained, o ins ance, by he high a idi y binding o he
IgA an ibodies o small in es inal TG2 [6,7]. This
could explain he p esence o IgA deposi s in he
absence o TG2 an ibody-sec e ing plasma cells in
ou non- esponsi e pa ien s. Howe e , i does no
p o ide an explana ion o he p esence o IgA
deposi s in he absence o plasma cells in he small
subse o pa ien s p io o de elopmen o illous
a ophy. Simila ly, i does no explain he p esence o
weak IgA deposi s wi hou TG2-an ibody sec e ing
plasma cells in a ew glu en-sensi i e con ol pa ien s.
Whe he ex ain es inal p oduc ion o TG2 an ibodies
occu ing o ins ance in he bone ma ow, spleen
and lymph nodes con ibu es o he appea ance o
mucosal IgA deposi s emains o be add essed in
u u e s udies.
Conclusions
We conclude ha he TG2-speci ic plasma cells a e
al eady p esen in he ea ly phases o coeliac disease
when he mucosal mo phology is s ill no mal, hei
pe cen age inc eases upon he de elopmen o illous
a ophy and dec eases on a GFD. O e all, he equency
o TG2 an ibody-sec e ing plasma cells in he di e en
phases o coeliac disease e lec s he p esence o
glu en in he die , bu he equency o hese cells is
no always pa allel wi h se um TG2 an ibody le els o
he in ensi y o small in es inal TG2- a ge ing IgA
deposi s. Ou indings widen he unde s anding o
small-bowel mucosal TG2-speci ic plasma cells in
coeliac disease and hus p o ide u he insigh in o
he gene a ion o TG2 an ibody esponses.
Addi ional ile
Addi ional ile 1: Table S1. Co ela ions be ween he pe cen age o
TG2-speci ic plasma cells and o he s udy pa ame e s. (DOCX 15 kb)
Abb e ia ions
EmA: Endomysial an ibody; GFD: Glu en- ee die ; HLA: Human leukocy e
an igen; IEL: In aepi helial lymphocy e; IgA: Immunoglobulin A; RT: Room
empe a u e; TG2: T ansglu aminase 2; Vh/C D: Villous heigh -c yp dep h
a io
Acknowledgemen s
No applicable.
Funding
This s udy was suppo ed by he Academy o Finland, he Finnish Medical
Founda ion, he Resea ch Fund o he Finnish Coeliac Socie y, he Sig id
Juselius Founda ion, he Founda ion o Pedia ic Resea ch, and he
Compe i i e S a e Resea ch Financing o he Expe A ea o Tampe e
Uni e si y Hospi al.
A ailabili y o da a and ma e ials
The da ase s gene a ed and/o analysed du ing he cu en s udy a e no
publicly a ailable due o es ic ions de ined by he E hics Commi ee.
Au ho s’con ibu ions
Concei ed and designed he s udy: KL, KaKa. Concei ed, designed, and
pe o med he expe imen s: MH, OK, KL, PS. Analysed he da a: MH.
Pe o med he s a is ical analysis: MH, HH. Pa icipa ed in pa ien ec ui men
and ma e ial sampling: OK, KuKa, TS, TI, KaKa. All au ho s ha e ead, e ised,
and app o ed he inal manusc ip .
E hics app o al and consen o pa icipa e
The s udy p o ocol was app o ed by he E hics Commi ee o he Pi kanmaa
Hospi al Dis ic , Tampe e, Finland, and w i en in o med consen was
ob ained om all pa icipa ing subjec s.
Consen o publica ion
No applicable.
Compe ing in e es s
All au ho s ha e ead he jou nal’s policy on he disclosu e o po en ial
con lic s o in e es and ha e none o decla e.
Hie ikko e al. BMC Immunology (2018) 19:36 Page 6 o 7
Publishe ’sNo e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in
published maps and ins i u ional a ilia ions.
Au ho de ails
1
Celiac Disease Resea ch Cen e , Facul y o Medicine and Li e Sciences,
Uni e si y o Tampe e, P.O. Box 100, 33014 Tampe e, Finland.
2
Tampe e
Cen e o Child Heal h Resea ch, Uni e si y o Tampe e, Tampe e, Finland.
3
Depa men o Paedia ics, Tampe e Uni e si y Hospi al, Tampe e, Finland.
4
Depa men o Medical and Clinical Gene ics and he Resea ch P og ams
Uni , Immunobiology, Uni e si y o Helsinki, Helsinki, Finland.
5
Depa men o
De ma ology, Tampe e Uni e si y Hospi al, Tampe e, Finland.
6
Depa men o
Gas oen e ology and Alimen a y T ac Su ge y, Tampe e Uni e si y Hospi al,
Tampe e, Finland.
7
Facul y o Social Sciences, Uni e si y o Tampe e,
Tampe e, Finland.
8
Depa men o In e nal Medicine, Tampe e Uni e si y
Hospi al, Tampe e, Finland.
Recei ed: 31 Augus 2018 Accep ed: 27 No embe 2018
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