Jou nal o Au oimmuni y 122 (2021) 102683
A ailable online 11 June 2021
0896-8411/© 2021 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND license
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Au oan ibodies agains ACE2 and angio ensin ype-1 ecep o s inc ease
se e i y o COVID-19
Ana I. Rod iguez-Pe ez
a
,
b
,
1
, Ca men M. Labandei a
a
,
c
,
1
, Ma ia A. Ped osa
a
,
b
,
Ri a Valenzuela
a
,
b
, Juan A. Sua ez-Quin anilla
d
, Ma ía Co es-Ayaso
e
, Placido May´
an-Conesa
e
,
Jose L. Labandei a-Ga cia
a
,
b
,
*
a
Resea ch Cen e o Molecula Medicine and Ch onic Diseases (CIMUS), IDIS, Uni e si y o San iago de Compos ela, San iago de Compos ela, Spain
b
Ne wo king Resea ch Cen e on Neu odegene a i e Diseases (CIBERNED), Spain
c
Hospi al Al a o Cunquei o, Uni e si y Hospi al Complex, Vigo, Spain
d
P ima y Heal h-Ca e Uni Fon i˜
nas, IDIS, Uni e si y o San iago de Compos ela, San iago de Compos ela, Spain
e
Eme gency Depa men , Uni e si y Clinical Hospi al o San iago, San iago de Compos ela, Spain
ARTICLE INFO
Keywo ds:
Au oan ibody
Au oimmuni y
LIGHT
Ou come p edic ion
Renin-angio ensin sys em
SARS-CoV-2
ABSTRACT
The enin-angio ensin sys em (RAS) plays a majo ole in COVID-19. Se e i y o se e al in lamma ion- ela ed
diseases has been associa ed wi h au oan ibodies agains RAS, pa icula ly agonis ic au oan ibodies o angio-
ensin ype-1 ecep o s (AA-AT1) and au oan ibodies agains ACE2 (AA-ACE2). Disease se e i y o COVID-19
pa ien s was de ined as mild, mode a e o se e e ollowing he WHO Clinical P og ession Scale and de e -
mined a medical discha ge. Se um AA-AT1 and AA-ACE2 we e measu ed in COVID-19 pa ien s (n =119) and
non-in ec ed con ols (n =23) using speci ic solid-phase, sandwich enzyme-linked immunoso ben assays. Se um
LIGHT (TNFSF14; umo nec osis ac o ligand supe amily membe 14) le els we e measu ed wi h he co e-
sponding assay ki . A diagnosis, AA-AT1 and AA-ACE2 le els we e signi ican ly highe in he COVID-19 g oup
ela i e o con ols, and we obse ed signi ican associa ion be ween disease ou come and se um AA-AT1 and
AA-ACE2 le els. Mild disease pa ien s had signi ican ly lowe le els o AA-AT1 (p <0.01) and AA-ACE2 (p <
0.001) han mode a e and se e e pa ien s. No signi ican di e ences we e de ec ed be ween males and emales.
The inc ease in au oan ibodies was no ela ed o como bidi ies po en ially a ec ing COVID-19 se e i y. The e
was signi ican posi i e co ela ion be ween se um le els o AA-AT1 and LIGHT (TNFSF14;
Pea son
=0.70, p <
0.001). Bo h AA-AT1 (by agonis ic s imula ion o AT1 ecep o s) and AA-ACE2 (by educing con e sion o
Angio ensin II in o Angio ensin 1-7) may lead o inc ease in AT1 ecep o ac i i y, enhance p oin lamma o y
esponses and se e i y o COVID-19 ou come. Pa ien s wi h high le els o au oan ibodies equi e mo e cau ious
con ol a e diagnosis. Addi ionally, he esul s encou age u he s udies on he possible p o ec i e ea men
wi h AT1 ecep o blocke s in COVID-19.
1. In oduc ion
Many ecen s udies ha e highligh ed he majo ole o enin-
angio ensin sys em (RAS) in se e i y o COVID-19 [1–3]. Angio ensin
con e ing enzyme 2 (ACE2) plays a key ole in he p ocess and i is
usually conside ed ha ACE2 ac s as a double-edged swo d [4,5]. Fi s ,
ACE2 ans o ms componen s o he p o-in lamma o y RAS axis such as
angio ensin I (Ang I) and pa icula ly Ang II in o componen s o he
an i-in lamma o y RAS axis such as Ang1-9 and pa icula ly Ang 1–7.
Ang II ac s on angio ensin ype 1 (AT1) ecep o s and ac i a es he
NADPH-oxidase complex p oducing supe oxide and p omo ing cell
p o-oxida i e and p o-in lamma o y esponses [6,7], while Ang 1–7 ac s
on Mas and Mas- ela ed ecep o s p omo ing cell an ioxida i e and
an i-in lamma o y esponses. The e o e, an inc ease in ACE2 ac i i y is
essen ial o balance he RAS owa ds he an i-in lamma o y esponse.
Consis en wi h his, he p o ec i e e ec s o ACE2 and i s p oduc
* Co esponding au ho . Resea ch Cen e o Molecula Medicine and Ch onic diseases (CIMUS), Uni e si y o San iago de Compos ela, 15782, San iago de
Compos ela, Spain.
E-mail add ess: [email p o ec ed] (J.L. Labandei a-Ga cia).
1
Equal con ibu ion.
Con en s lis s a ailable a ScienceDi ec
Jou nal o Au oimmuni y
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h ps://doi.o g/10.1016/j.jau .2021.102683
Recei ed 6 May 2021; Recei ed in e ised o m 30 May 2021; Accep ed 1 June 2021
Jou nal o Au oimmuni y 122 (2021) 102683
2
Ang1-7 agains expe imen al lung inju ies ha e p e iously been
demons a ed [8]. Second, ACE2 is also he en y ecep o o he i us
[9], and up egula ion o ACE2 exp ession may enhance cell in ec ion.
Thi d, bo h ACE2 unc ions in e ac each o he , since SARS-CoV-2
binding o ACE2 dec eases he le els o ACE2 a he cell su ace [10,
11], hus shi ing he RAS balance owa ds he p o-in lamma o y Ang
II/AT1 axis, which leads o in lamma ion, ib osis and p og ession o
disease se e i y.
I is known ha di e ences in immunological esponses in di e en
pa ien s play a majo ole in p og ession and se e i y o COVID-19.
P og ession and se e i y o se e al in lamma ion- ela ed p ocesses
ha e been associa ed wi h he p esence o au oan ibodies agains majo
componen s o he RAS. Pa icula ly, he p esence o au oan ibodies o
AT1 ecep o s (AA-AT1), which ac as AT1 ecep o agonis s, enhanced
he p oin lamma o y RAS ac i i y in se e al issues and p ocesses [12].
In addi ion, he p esence o au oan ibodies agains ACE2 (AA-ACE2) has
also been de ec ed in se e al p ocesses, and AA-ACE2 ha e been
in ol ed in p og ession o in lamma ion [13]. ACE2 au oan ibodies
ha e been ela ed o inhibi ion o ACE2 unc ion [13], which dec eases
he an i-in lamma o y a m ac i i y and shi he balance owa ds he
p oin lamma o y RAS. The mechanisms esponsible o gene a ion o
he abo e-men ioned au oan ibodies ha e no been o ally cla i ied.
Howe e , he inc ease in le els o cy okines such as IL-6 and TNF-
α
[14,
15], and pa icula ly TNFSF14 ( umo nec osis ac o ligand supe amily
membe 14, LIGHT) [16] has been associa ed o he inc ease in gene -
a ion o AA-AT1. An inc ease in le els o p o-in lamma o y cy okines
also plays a majo ole in se e i y o COVID-19 ou come. Howe e , i is
no known whe he hese au oan ibodies (AA-AT1, AA-ACE2) a e
inc eased in COVID-19 pa ien s and whe he he le els o RAS au oan-
ibodies could be associa ed o p og ession o COVID-19 se e i y. In he
p esen s udy, we in es iga ed he le els o AA-AT1 and AA-ACE2 an-
ibodies a he ime o diagnosis in COVID-19 pa ien s ela i e o
non-in ec ed con ols, and whe he le els o hese au oan ibodies a
diagnosis a e associa ed wi h mild, mode a e and se e e COVID-19
ou come de e mined a medical discha ge on he basis o WHO Clin-
ical P og ession Scale.
2. Me hods
2.1. S udy design
In he p esen s udy, a o al o 23 adul non-in ec ed con ols and 119
adul pa ien s es ing posi i e o SARS-CoV-2 RT-PCR we e included.
Con ols we e ec ui ed om use s o a den al clinic a he P ima y
Heal h-Ca e Uni Fon i˜
nas (San iago de Compos ela). COVID-19 pa ien s
we e p ospec i ely ec ui ed om Ap il 2020 o Decembe 2020 a
Uni e si y Hospi al Complex o San iago de Compos ela. The sample
size pe g oup was calcula ed assuming a minimum la ge e ec size in -
es o 0.4 be ween any pai o g oups (n =4) [17] and accep ing an
alpha isk o 0.05 and a be a isk o 0.2 in a wo-sided es . A minimum
numbe o 20 subjec s is necessa y in each g oup o ecognize s a is i-
cally signi ican di e ences. I has been an icipa ed a missing da a a e
o 10% due o incomple e p ima y endpoin s. This calcula ion was
ca ied ou using he PWR package [18] in R [19]. Pa ien ’s e-
qui emen s o be ec ui ed we e a posi i e RT-PCR o SARS-CoV-2; o
be olde han 18 yea s old and o sign an in o med consen (designed o
his pu pose). A he ime o ec ui men , a blood sample was ob ained,
and se um was sepa a ed by cen i uga ion a 1500g o 20 min. Then,
aliquo s o se um samples we e s o ed a −80 ◦C un il p ocessed o
quan i ica ion o AA-AT1, AA-ACE2 and LIGHT le els. Clinical ou come
o pa ien s was ollowed un il medical discha ge, and inally pa ien s
we e di ided in o h ee g oups acco ding o WHO Clinical P og ession
Scale [20]: mild, mode a e, o se e e. Mild disease (sco es 1–3; n =31)
pa ien s we e en olled om he Eme gency Room Depa men . Samples
om mode a e (sco es 4–5; n =68) and se e e (sco es 6–10; n =20)
hospi alized pa ien s we e ini ially ob ained om he Eme gency Room
Depa men be o e hospi aliza ion. Samples we e also ob ained om he
Uni e si y Hospi al Complex o San iago de Compos ela Biobank and
om Mu cian Ins i u e o Biosani a y Resea ch Biobank. All pa ien s
we e ollowed-up wi h elec onic heal h in o ma ion sys em un il
Janua y 2021. Clinical da a assessing demog aphics, como bidi ies,
symp oms, physical and adiological indings, disease s age, ea men
and labo a o y es s esul s we e collec ed om elec onic medical e-
co ds. The s udy was app o ed by he Galician D ug Resea ch E hics
Commi ee (CEIm-G), p o ocol 2020/212. The esea ch was ca ied ou
in acco dance wi h he p inciples o he Helsinki Decla a ion.
2.2. Se um samples and an i-AT1 and an i-ACE2 au oan ibody
measu emen s
Se um samples we e s o ed a −80 ◦C un il he biochemical analysis.
Se um AA-AT1 and AA-ACE2 we e measu ed using wo speci ic solid-
phase, sandwich enzyme-linked immunoso ben assays (ELISAs) o
quan i a i e de e mina ion o hese au oan ibodies (Ca alog Numbe
12000 and 16000, espec i ely; Cell T end; Luckenwalde, Ge many).
Manu ac u e ’s ins uc ions we e s ic ly ollowed. Abso bance was
measu ed a 450/620 nm using an In ini e M200 mul iwell pla e eade
(TECAN) and AA-AT1 and AA-ACE2 concen a ions we e quan i ied
using speci ic s anda d cu es om each one (4PL cu e i ). In bo h
cases, samples wi h alues o e he s anda d cu e we e dilu ed wi h
assay bu e o ge hei abso bances wi hin he s anda d cu e.
2.3. LIGHT/TNFSF14 de e mina ion
To analyse he se um concen a ion o TNFSF14, also known as
LIGHT, a comme cially a ailable speci ic ELISA Ki was used (EH
TNFSF14, In i ogen) acco ding o he manu ac u e ’s ins uc ions.
P o ein le els we e quan i ied using speci ic s anda d cu e (4PL cu e
i ).
2.4. S a is ical analysis
Da a we e exp essed as median (in e qua ile ange [IQR]). To es i
he popula ions ollow a no mal dis ibu ion, Shapi o–Wilk es was
used. Two g oup compa isons we e ca ied ou by wo ailed - es and
mul iple compa isons by one-way ANOVA ollowed by pos -hoc - es s.
When no mali y assump ion was iola ed, Wilcoxon es o wo g oup
compa isons and K uskal-Wallis es ollowed by pos -hoc Mann-Whi -
ney U es s o mul iple compa isons we e used. Bon e oni co ec ion
o mul iple compa isons was used on pos -hoc p- alues. When wo
esponse a iables we e p esen , wo-way ANOVA we e used i da ase
passed he no mali y es and o nonpa ame ic da a, an Aligned Rank
T ans o ma ion (ART) s ep was pe o med be o e he ANOVA es .
Spea man’s co ela ion coe icien ( ) was used o s udy he co ela ion
be ween di e en pa ame e s. Associa ions be ween ca ego ical a i-
ables we e es ed by using he chi-squa e es o he Fishe ’s exac es i
expec ed alue is less han 6 in a cell o he con ingency able. P <0.05
was conside ed signi ican o all he analyses. All he analyses we e
done using R so wa e [19].
3. Resul s
3.1. Pa ien cha ac e is ics
A o al o 23 con ols (mean age: 66.13 yea s old ±6.77 SD; ange
55–76 o which 14 we e women and 9 men) and 119 COVID-19 pa ien s
we e en olled in he s udy. The pa ien g oup included 31 mild, 68
mode a e and 20 se e e pa ien s, conside ing he clinical cou se o he
disease a hei medical discha ge (Table 1). The se e e g oup included
16 pa ien s who equi ed mechanical o non-in asi e en ila ion (sco es
6–9) and 4 pa ien s who died (sco e 10). Mean age o pa ien s was 56.5
yea s old (56.5 ±14.9 SD; ange 20–93) and 48.3% we e males. The
A.I. Rod iguez-Pe ez e al.
Jou nal o Au oimmuni y 122 (2021) 102683
3
mos ele an como bidi ies in pa ien ’s g oup included hype ension
(33.8%), diabe es (12.8%), dyslipidemia (38.5%), obesi y (35.3%),
hea disease (7.6%), lung disease (8.2%) and enal disease (2.7%). Main
clinical ea u es a e p esen ed in Table 1. No signi ican di e ences in
equency o como bidi ies we e obse ed be ween con ol g oup and
COVID-19 g oup. Rela ionships be ween COVID-19 se e i y and
di e en como bidi ies we e s udied using chi-squa e es o Fishe ’s
exac es (see Me hods). A signi ican associa ion (X
2Pea son
(2) =7.82;
p =0.020) was ound be ween se e i y and diabe es; se e i y and
obesi y (X
2Pea son
(2) =13.92; p =0.001) and se e i y and o me
smoke s (X
2Pea son
(2) =6.56; p =0.038).
3.2. Se um an i-AT1 and an i-ACE2 au oan ibodies
Blood samples om con ols and COVID-19 pa ien s we e analysed
o de e mine se um AA-AT1 and AA-ACE2. Median o AA-AT1 concen-
a ions we e 5.070 [In e qua ile ange (IQR) 3.775–8.170] U/mL o
he con ol g oup and 8.209 [IQR 6.006–10.061] U/mL o COVID-19
pa ien s. Median o AA-ACE2 concen a ions we e 4.691 [IQR
2.841–9.863] U/mL in he con ol g oup and 9.403 [IQR 4.485–21.552]
U/mL o COVID-19 pa ien s. Two-way ART-ANOVA analysis e ealed
signi ican ly highe se um le els o AA-AT1 (p =0.002) and o AA-
ACE2 (p =0.013) in COVID-19 g oup han in he con ol g oup. How-
e e , no signi ican di e ences we e de ec ed be ween males and e-
males o se um le els o AA-AT1 (p =0.845) and AA-ACE2 (p =0.342)
when sex di e ences we e es ed oge he wi h con ols/pa ien s, being
he in e ac ion e ms no signi ican o bo h le els o au oan ibodies.
(Fig. 1A and B).
Then, we compa ed esul s om he h ee g oups o pa ien s wi h
di e en se e i y. We obse ed signi ican di e ences, demons a ing
associa ion be ween disease se e i y and se um AA-AT1 and AA-ACE2
(Fig. 2A and B; Supplemen a y Table 1). Fo he analysis o AA-AT1
and AA-ACE2 we used a K uskal-Wallis compa ison. Mild disease pa-
ien s had signi ican ly lowe le els o AA-AT1 and AA-ACE2 han
mode a e and se e e pa ien s (Mild: AA-AT1 Median 4.627 [IQR
3.857–9.529] U/mL and AA-ACE2 Median 3.588 [IQR 2.124–9.076] U/
mL; Mode a e pa ien s: AA-AT1 Median 8.387 [IQR 6.852–10.300] U/
mL and AA-ACE2 Median 9.895 [IQR 5.428–26.585] U/mL; Se e e
pa ien s: AA-AT1 Median 8.705 [IQR 6.687–10.158] U/mL and AA-
Table 1
Main clinical ea u es o pa ien s and associa ion wi h se e i y (p <0.05).
Mild (n
=31)
Mode a e
(n =68)
Se e e
(n =20)
To al (N
=119)
p alue
Obesi y
•Yes 7
(36.8%)
47
(79.7%)
8
(50.0%)
62
(66.0%)
<0.001*
•No 12
(63.2%)
12
(20.3%)
8
(50.0%)
32
(34.0%)
Hype ension
•Yes 9
(29.0%)
23
(33.8%)
8
(40.0%)
40
(33.6%)
0.719
•No 22
(71.0%)
45
(66.2%)
12
(60.0%)
79
(66.4%)
Diabe es melli us
•Yes 1 (3.3%) 8 (11.8%) 6
(30.0%)
15
(12.7%)
0.020*
•No 29
(96.7%)
60
(88.2%)
14
(70.0%)
103
(87.3%)
Dyslipidemia
•Yes 7
(22.6%)
19
(27.9%)
9
(45.0%)
35
(29.4%)
0.211
•No 24
(77.4%)
49
(72.1%)
11
(55.0%)
84
(70.6%)
Smoking
•Yes 2
(14.3%)
7 (35.0%) 9
(60.0%)
18
(36.7%)
0.038*
•No 12
(85.7%)
13
(65.0%)
6
(40.0%)
31
(63.3%)
Ca dio ascula
disease
•Yes 2 (6.5%) 6 (8.8%) 3
(15.0%)
11
(9.2%)
0.558
•No 29
(93.5%)
62
(91.2%)
17
(85.0%)
108
(90.8%)
Ch onic Respi a o y disease
•Yes 3 (9.7%) 2 (2.9%) 2 (10%) 7 (5.9%) 0.217
•No 28
(90.3%)
66
(97.1%)
18
(90%)
112
(94.1%)
Ch onic kidney
disease
•Yes 0 (0.0%) 3 (4.4%) 1 (5.3%) 4 (3.4%) 0.485
•No 31
(100.0%)
65
(95.6%)
18
(94.7%)
114
(96.6%)
Fig. 1. Le els o AA-AT1 and AA-ACE2 in con ols and COVID-19 pa ien s. COVID-19 pa ien s had signi ican ly highe se um le els o AA-AT1 (A; wo-way ART-
ANOVA, p =0.002) and AA-ACE2 (B; wo-way ART-ANOVA, p =0.013) han he con ol g oup. Howe e , no signi ican di e ences we e de ec ed be ween males
and emales o se um le els o AA-AT1 ( wo-way ART-ANOVA, p =0.845) and AA-ACE2 ( wo-way ART-ANOVA, p =0.342). In e ac ion e ms we e no signi ican
o bo h le els o an ibodies. Da a dis ibu ion is shown using a box plo wi h boxes ep esen ing he IQR and he median (black line) and whiske s ep esen ing ±1.5
IQR. IQR: In e qua ile ange.
A.I. Rod iguez-Pe ez e al.
Jou nal o Au oimmuni y 122 (2021) 102683
4
ACE2 Median 19.597 [IQR 9.306–39.471] U/mL).
The co ela ion coe icien be ween AA-AT1 and AA-ACE2 was s a-
is ically signi ican ; howe e , i is oo low o conside ha he e is a
ele an co ela ion be ween hese a iables and sugges s ha o he
majo ac o s con ibu e o he inc ease obse ed in se um AA-ACE2
le els (see Discussion). Sex di e ences we e s udied oge he wi h
se e i y (Fig. 2C and D; Supplemen a y Table 1). Howe e , no signi i-
can di e ences we e de ec ed in ou pa ien s be ween males and e-
males o se um le els o AA-AT1 ( wo-way ART-ANOVA coe icien , p
=0.95) and AA-ACE2 ( wo-way ART-ANOVA coe icien , p =0.14).
3.3. RAS au oan ibodies and como bidi ies associa ed o COVID-19
pa ien s
In o de o know whe he he inc ease in au oan ibodies obse ed in
ou pa ien s could be ela ed o como bidi ies po en ially a ec ing
COVID-19 se e i y, se um le els o AA-AT1 and AA-ACE2 we e s udied
in di e en como bidi ies (Wilcoxon-Mann-Whi ney es ). Howe e ,
only AA-ACE2 le els we e signi ican ly highe in pa ien s wi h diabe es
(Median 16.630 [IQR 10.480–27.356] U/mL) han in non-diabe ic pa-
ien s (Median 7.957 [IQR 4.339–19.715] U/mL) (Table 2 and Fig. 3A).
Mo eo e , we s udied he possible ela ionship be ween COVID-19
Fig. 2. Le els o AA-AT1 and AA-ACE2 in pa ien s wi h di e en le els o COVID-19 disease se e i y. Mild disease pa ien s had signi ican ly lowe le els o AA-AT1
(A) and AA-ACE2 (B) han mode a e and se e e pa ien s (K uskal–Wallis one-way analysis o a iance on anks ollowed by Wilcoxon es ). In he p esen s udy, no
signi ican di e ences we e de ec ed be ween emales and males o se um le els o AA-AT1 (C; wo-way ART-ANOVA, p =0.95) and AA-ACE2 (D; wo-way ART-
ANOVA, p =0.14) in any o he se e i y le els o he disease. Da a dis ibu ion is shown using a box plo wi h boxes ep esen ing he IQR and de median (black line)
and whiske s ep esen ing ±1.5 IQR. IQR: In e qua ile ange.
Table 2
S a is ical analysis o AA-AT1 and AA-ACE2 in di e en como bidi ies.
AA-AT1 (Mann-Whi ney es ) AA-ACE2 (Mann-Whi ney es )
S a is ic p- alue Signi S a is ic p- alue Signi
Obesi y 1707 0.61871 ns 1702 0.63844 ns
Hype ension 2325 0.76768 ns 2623 0.11398 ns
Diabe es melli us 1353 0.46662 ns 1573 0.04669 <0.05*
Dyslipidemia 2345 0.32846 ns 2668 0.7706 ns
Smoking 579 0.84562 ns 626 0.44267 ns
Ca dio ascula disease 761 0.8607 ns 813 0.5729 ns
Ch onic Respi a o y disease 458 0.20585 ns 350 0.9019 ns
Ch onic kidney disease 332 0.60699 ns 369 0.34116 ns
Ns: no signi ican ; Signi : Signi icance.
A.I. Rod iguez-Pe ez e al.
Jou nal o Au oimmuni y 122 (2021) 102683
5
se e i y and diabe es using chi-squa e es . A signi ican associa ion
(X
2Pea son
=7.82; p =0.020) was ound be ween se e i y and diabe es.
Then, we analysed whe he he ela ionship o disease se e i y and
au oan ibodies was de e mined by diabe es. Howe e , a e con olling
he possible con ounding e ec o diabe es by pe o ming a wo-way
ART-ANOVA he ela ionship o an ibodies and disease se e i y was
s ill signi ican (F(2) =17.505, p <0.001).
Finally, we in es iga ed he possible in ol emen o LIGHT
(TNFSF14) in he inc ease in AA-AT1 obse ed in he p esen s udy. As
commen ed below, conside able e idence suppo s he ole o LIGHT in
gene a ion o AA-AT1 in o he diseases. Consis en wi h his, a signi i-
can posi i e co ela ion be ween se um le els o AA-AT1 and LIGHT
was obse ed (
Pea son
=0.70, p <0.001). Fu he mo e, a signi ican
linea co ela ion was shown when applying a log ans o ma ion o he
le els o AA-AT1 (
Pea son
=0.83, p <0.001) (Fig. 3B).
4. Discussion
In he p esen s udy, we obse ed a signi ican inc ease in le els o
AA-AT1 and AA-ACE2 in COVID-19 pa ien s ela i e o non-in ec ed
con ols. Fu he mo e, ou esul s show a signi ican inc ease in le els
o AA-AT1 and AA-ACE2 in mode a e and se e e COVID-19 pa ien s
ela i e o pa ien s wi h mild ou come. In e es ingly, le els o AA-AT1
showed a high co ela ion wi h le els o LIGHT. Le els o AA-AT1
showed a lowe co ela ion wi h AA-ACE2. The esul s also sugges
ha inc eased le els o au oan ibodies a e ela ed o di e ences in he
esponse o SARS-CoV-2 in ec ion a he han p e ious pa ien como -
bidi ies. As could be expec ed, he e is some deg ee o a iabili y in
le els o an ibodies be ween pa ien s in he same g oup o se e i y,
which is p obably ela ed o indi idual di e ences in he immunological
esponse and e ec s o some p e ious como bidi ies such as diabe es.
Howe e , we obse ed ha he ela ionship o an ibodies and disease
se e i y was s ill signi ican in diabe ic pa ien s.
AT1 ecep o au oan ibodies we e ini ially iden i ied in p eeclampsia
[21]. Mo e ecen ly, an inc ease in ci cula ing AA-AT1 has been ela ed
o se e al in lamma o y diseases and p og ession o hype ension and
ca dio ascula p ocesses [12,22]. Le els o AA-AT1 in ou coho o
mode a e and se e e COVID-19 pa ien s a e simila o hose epo ed by
o he au ho s in some au oimmune diseases such lupus neph i is [23],
heuma oid a h i is o Raynaud’s phenomenon [24]. Howe e , highe
le els o au oan ibodies ha e been epo ed o sys emic scle osis and
p ima y Sj¨
og en’s synd ome [24]. The p esen esul s sugges ha
AA-AT1 con ibu e o COVID-19 se e i y, as AA-AT1 bind AT1 ecep o s
and, oge he wi h Angio ensin II, inc ease he ac i i y o he RAS
p o-in lamma o y axis (summa ized in Fig. 4). I has been shown ha
Ang II enhances se e i y o se e al SARS expe imen al models, which is
educed by AT1 blocke s [8,10]. In a ecen s udy, we ha e obse ed
ha AT1 blocke s (i. e. ARAII, ARBs, sa ans) inc eased le els o ans-
memb ane ACE2 in he lung while dec eased in e naliza ion o i al
spike p o ein by se e al mechanisms [10]. The p esen esul s sugges
ha pa ien s wi h high le els o AA-AT1 a e pa icula ly sui able can-
dida es o ea men wi h AT1 ecep o blocke s, which ha e been
conside ed bene icial o COVID-19 ou come in se e al ecen s udies
[25–27]. Inc easing e idence indica es ha ea men s wi h AT1 e-
cep o blocke s should no be discon inued in pa ien s wi h COVID-19 o
a isk o COVID-19. Now, he ques ion is i we should ini ia e ea men
wi h AT1 blocke s a e COVID-19 diagnosis o in pa ien s a isk o
in ec ion o isk o se e i y. Al hough he abo e-men ioned expe i-
men al and clinical s udies sugges bene icial e ec s, addi ional clinical
s udies, speci ically add essing his ques ion, a e necessa y.
Bo h expe imen al [28,29] and clinical [30,31] s udies ha e shown
ha he inc ease in le els o cy okines such as IL-6 and TNF-
α
in
COVID-19 plays a majo ole in he se e i y o he disease. I has also
been shown ha in usion o IL-6 and TNF-
α
in animal models induces an
inc ease in le els o AA-AT1 [14,15]. Howe e , TNFSF14 (LIGHT) ap-
pea s pa icula ly in e es ing. Ci cula ing LIGHT is mainly sec e ed by
cells o he inna e and adap i e immune sys em, al hough can also be
p oduced by issue s uc u al cells [32,33]. LIGHT ac s on s uc u al and
in lamma o y cells o p omo e ini ia ion o in lamma o y and ib o ic
esponses and induces exp ession o se e al p o-in lamma o y media-
o s, including he abo e-men ioned cy okines [34], so ha LIGHT plays
a majo ole in lung issue emodeling, in lamma ion and ib osis [35]. I
is pa icula ly ema kable ha LIGHT, ac ing ia issue ans-
glu aminase 2 (TG2), has been e ealed as a majo mechanism o
gene a ion o AA-AT1. TG2 modi ies and s abilizes AT1 ecep o s [16,
36], and he epi ope sequence o AA-AT1 on he second ex acellula
loop o he ecep o can be c osslinked o TG2 ia glu amine esidue
Q187 [37]. TG2-modi ied AT1 ecep o s ac as neoan igens ha p o-
mo e AA-AT1 gene a ion [16] and AT1 ecep o sensi iza ion [38].
Consis en wi h his, we obse ed a signi ican co ela ion be ween
AA-AT1 and LIGHT le els in COVID-19 pa ien s.
A educ ion in ACE2 ac i i y a he cell su ace (i. e. ansmemb ane
ACE2) shi s he RAS balance owa ds he p o-in lamma o y axis, as
ACE2 ans o ms Ang II in o he an i-in lamma o y Ang 1–7. The
Fig. 3. Le els o AA-ACE2 in COVID-19 pa ien s wi h and wi hou diabe es and co ela ion be ween AA-AT1 le els and LIGHT le els. AA-ACE2 le els (A) we e
signi ican ly highe in pa ien s wi h diabe es han in non-diabe ic pa ien s. E en a e con olling he possible con ounding e ec o diabe es, he ela ionship o
an ibodies and disease se e i y was s ill signi ican . Da a dis ibu ion is shown using a box plo wi h boxes ep esen ing he IQR and he median (black line) and
whiske s ep esen ing ±1.5 IQR. *p <0.05 ela i e o non-diabe ic g oup (Wilcoxon-Mann-Whi ney es ). IQR: In e qua ile ange. AA-AT1 le els posi i ely
co ela ed wi h LIGHT le els (B). Sca e plo showing posi i e and linea associa ion (
Pea son
=0.83, CI
95%
=[0.74, 0.89]; p <0.001) be ween AA-AT1 le els and
LIGHT le els. The dis ibu ion o he a iables is shown in he his og ams. CI: Con idence In e al.
A.I. Rod iguez-Pe ez e al.
Jou nal o Au oimmuni y 122 (2021) 102683
6
p esence o SARS-CoV-2 in ec ion inc eases he shi owa ds he RAS
p o-in lamma o y axis. I is known ha binding o SARS-CoV-2 o ACE2
educes le els o ansmemb ane ACE2 and induces i us in e naliza ion
and shedding o ACE2 in o a soluble/ci cula ing o m, as a esul o
ac i a ion o he p o eases such ADAM17 (TACE, TNF-
α
-con e ing
enzyme) and TMPRSS ( ansmemb ane p o ease se ine 2) [39,40].
Ac i a ion o he p o-in lamma o y AT1 ecep o s also inc eases
ADAM17 and TMPRS ac i i y, inc easing i al en y and ACE2 shedding
[29,41,42]. In he case o COVID-19, gene a ion o AA-ACE2 may be
enhanced by he p esence o ci cula ing immunocomplexes o ACE2-
SARS-CoV-2 as a consequence o inc eased le els o ci cula ing ACE2,
due o i us-induced ACE2 shedding, and he p esence o high le els o
ci cula ing i uses. The p esence o high le els o AA-ACE2 may lead o
u he dec ease in ansmemb ane ACE2 ac i i y in he lung and o he
issues. The e o e, bo h AA-AT1 (by agonis ic s imula ion o AT1) and
AA-ACE2 (by a dec ease in ansmemb ane ACE2 ac i i y and a educ-
ion o con e sion o Ang II in o Ang 1–7) lead o inc ease in AT1 e-
cep o ac i i y, enhancing he p o-in lamma o y esponses, and possibly
i al in e naliza ion and ACE2 shedding [29,41,42], and a mo e se e e
ou come o he COVID-19 disease (Fig. 4).
Ou s udy has some limi a ions. A i s limi a ion o he s udy is he
ela i ely low sample size. Se e i y g oups we e no balanced, as mos o
he pa ien s belong o he mode a e g oup. Ano he limi a ion o his
s udy is ha we canno exclude any possible in luence o an i-COVID-19
medica ions in clinical ou comes, bu mos o he pa ien s om he same
se e i y g oup ecei ed simila ea men s. The c oss-sec ional me h-
odology canno de e mine causali y bu associa ion, and we did no
include changes in le els o au oan ibodies wi h ime. Howe e , we
we e pa icula ly in e es ed in he associa ion be ween ea ly (i. e. a
diagnosis) le els o au oan ibodies and p edic ion o se e i y o he
disease. Addi ional measu emen s du ing he cou se o he disease
would also be in e es ing. This may be possible in hospi alized pa ien s.
Howe e , pa ien s o he mild g oup we e sen home o qua an ine, and
sequen ial measu emen s a e p ac ically impossible in his g oup. In a
g oup o se e e o mode a e pa ien s wi h se e al au oan ibody mea-
su emen s, we did no obse e signi ican changes be ween samples
du ing he disease cou se. Consis en wi h his, i was obse ed ha he
inc ease in AA-AT1 le els in p eeclampsia usually declines 50% by a
week a e deli e y [43], and pe sis s in pa ien s o mo e han 1 yea
pos pa um [44]. In a mo e ecen s udy, ci cula ing AA-AT1 we e ound
5–8 yea s a e deli e y in women wi h p eeclampsia, [45].
5. Conclusions
The p esen esul s sugges ha bo h AA-AT1 and AA-ACE2
con ibu e o inc ease in se e i y o COVID-19 ou come and could be
used as an index o p obable p og ession o COVID-19 owa ds se e i y.
Pa ien s wi h high le els o au oan ibodies equi e mo e cau ious con-
ol a e diagnosis o COVID-19. In addi ion, he esul s encou age
u he s udies on he possible p o ec i e ea men wi h AT1 ecep o
blocke s in COVID-19. Finally, he p esen esul s also e eal he need
o u he s udies whe e he epo ed indings a e associa ed wi h in-
dep h immunological in es iga ions, cha ac e izing adap i e and
inna e immune esponses in di e en COVID-19 phases.
Au ho con ibu ions
JLL-G, AIR-P and CML designed esea ch and in eg a ed he clinical
and labo a o y da a; MC-A, PM-C and JA S-Q we e esponsible o
subjec selec ion, collec ed samples and clinical da a; RV and MAP
conduc ed he AA measu emen s; AIR-P, CML and JLL-G w i ing, e iew
and c i ique; all au ho s edi ed he manusc ip .
Funding
Axencia Galega de Inno aci´
on (IN845D 2020/20). Spanish Minis y
o Economy and Compe i i eness (RTI2018-098830-B-I00). Spanish
Minis y o Heal h (PI17/00828, RD16/0011/0016 and CIBERNED).
Galician Go e nmen (XUGA, ED431C 2018/10, ED431G/05). FEDER
(Regional Eu opean De elopmen Fund).
Decla a ion o compe ing in e es
The au ho s decla e ha hey ha e no known compe ing inancial
in e es s o pe sonal ela ionships ha could ha e appea ed o in luence
he wo k epo ed in his pape .
Acknowledgemen s
We hank Pila Ald ey, I ia No oa and C is ina Gianzo o hei
echnical assis ance. Bios a ech (h p://bios a ech.com) o s a is ical
assis ance. Pla a o ma Biobanco del Ins i u o Mu ciano de In es igaci´
on
Biosani a ia Vi gen de la A ixaca (IMIB-A ixaca) h p://www.bio
banco.imib.es/and Biobanco CHUS (Hospi al Clínico Uni e si a io de
San iago): h ps://www.idisan iago.es/pla a o mas/biobanco, o
p o iding se um samples.
Fig. 4. P oposed model o AA-AT1 and AA-ACE2 e ec s. SARS-CoV-2 in ec-
ion induces inc ease in p o-in lamma o y cy okines, pa icula ly LIGHT, p o-
mo ing AA-AT1, which ac as AT1 ecep o agonis s and enhance he p o-
in lamma o y RAS axis. SARS-CoV-2 binds cell su ace ACE2 leading o a
dec ease in his ansmemb ane ACE2 and an inc ease in le els o soluble/
ci cula ing ACE2. A dec ease in ansmemb ane ACE2 u he enhances he p o-
in lamma o y RAS axis and educes an i-in lamma o y axis ac i i y. The in-
c ease in le els o ci cula ing ACE2-SARS-CoV-2 complexes may inc ease le els
o AA-ACE2, which u he educe ansmemb ane ACE2 ac i i y and he an i-
in lamma o y RAS unc ion. G een lines, bene icial e ec s; ed lines, de i-
men al e ec s.
A.I. Rod iguez-Pe ez e al.
Jou nal o Au oimmuni y 122 (2021) 102683
7
Appendix A. Supplemen a y da a
Supplemen a y da a o his a icle can be ound online a h ps://doi.
o g/10.1016/j.jau .2021.102683.
Abb e ia ions
AA-ACE2 au oan ibodies agains ACE2
AA-AT1 au oan ibodies o angio ensin ype-1 ecep o s
ACE2 Angio ensin con e ing enzyme 2
ADAM17, TACE, TNF-
α
con e ing enzyme; Ang, angio ensin
AT1 angio ensin ype 1 ecep o s
ELISA enzyme-linked immunoso ben assay
IQR In e qua ile ange
RAS enin-angio ensin sys em
TG2 ansglu aminase 2
TMPRSS ansmemb ane p o ease se ine 2
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