Imun Toxo 1
Imun Toxo 1
Imun Toxo 1
Received 3 December 2019, Accepted 29 January 2020, Published online 7 February 2020
Abstract – Background: Primary infection by Toxoplasma gondii in pregnant women can result in serious outcomes
for the foetus. A false-positive IgG result during pregnancy can lead to a misdiagnosis of past infection and to stopping
preventive measures. We collected 189 sera with positive ArchitectÒ Toxo IgG assay (Abbott Laboratories) and neg-
ative IgG results with at least two other serological tests, in order to find an explanation for the suspected false-positive
IgG results. We used the recomLine Toxoplasma IgGÒ immunoblot (Mikrogen Diagnostik) to search for specific
antigenic reactivities of the sera, and the LDBio Toxo II IgGÒ immunoblot (LDBio Diagnostics) as a confirmatory test.
Results: The bands GRA8 and/or GRA7 were positive for 148 samples (78.3%). GRA8 was the most frequent band,
appearing in 133 patterns (70.4%), whereas GRA7 was present for 49 samples (25.9%). Of the 81 samples tested with
LDBioÒ, 23 (28.4%) turned out to be positive. Of the 58 negative LDBioÒ tests (71.6%) (real false-positive ArchitectÒ
IgG), 23 samples (39.6%) did not show either a GRA8 or p30 band by recomLineÒ. Their false positivity with
ArchitectÒ remains unexplained since Abbott uses these two recombinant antigens for their assay. Conclusions: The
ArchitectÒ IgG false positivity for T. gondii seems to be due to reactivity against GRA8 for the majority of the sera and
GRA7 to a lesser extent. The hypothesis of past contact with parasites genetically close to T. gondii such as
Hammondia hammondi or Neospora caninum seems promising and should be assessed further.
Résumé – Diagnostic sérologique de Toxoplasma gondii : analyse des IgG faux positifs et implications.
Contexte : La primo-infection à Toxoplasma gondii chez la femme enceinte peut avoir de graves conséquences pour le
fœtus. Un résultat IgG faussement positif pendant la grossesse peut mener à un diagnostic erroné d’infection ancienne
et à stopper les mesures préventives. Nous avons collecté 189 sérums présentant un résultat ArchitectÒ Toxo IgG
(Abbott Laboratories) positif ainsi qu’un résultat IgG négatif par au moins deux autres tests sérologiques, dans le but de
trouver une explication aux résultats IgG suspectés faux positifs. Nous avons utilisé l’immunoblot recomLine
Toxoplasma IgGÒ (Mikrogen Diagnostik) pour chercher certaines réactivités antigéniques spécifiques des sérums et
l’immunoblot LDBio Toxo II IgGÒ (LDBio Diagnostics) comme test de confirmation. Résultats : Les bandes GRA8
et/ou GRA7 étaient positives pour 148 (78,3 %) échantillons. GRA8 était la bande la plus fréquente, apparaissant dans
133 (70,4 %) profils alors que GRA7 était présente pour 49 (25,9 %) échantillons. Sur les 81 échantillons testés en
LDBioÒ, 23 (28,4 %) se sont révélés positifs. Sur les 58 (71,6 %) tests LDBioÒ négatifs (réels faux positifs IgG
ArchitectÒ), 23 (39,6 %) échantillons n’ont montré ni bande GRA8 ni bande p30 en recomLineÒ et leur fausse
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 L. Simon et al.: Parasite 2020, 27, 7
positivité reste donc inexpliquée puisque Abbott utilise ces deux antigènes recombinants dans son test. Conclusions :
La fausse positivité IgG ArchitectÒ pour T. gondii semble être due à une réactivité envers la protéine GRA8 pour la
majorité des sérums et envers GRA7 dans une moindre mesure. L’hypothèse d’un contact passé avec des parasites
génétiquement proches de T. gondii comme Hammondia hammondi ou Neospora caninum semble prometteuse et
devrait être approfondie.
Table 1. Origin of the samples. MAG1 (= p65, p68), and MIC3. An additional antigen called
rSAG1 (= p30, low concentration) is loaded to the strip as a
City Number of sera
marker of past infection. We hijacked the initial purpose of this
Private laboratories
diagnostic test and used it solely to elaborate a pattern of
Embrun 2
Lisieux 2
antibody reactivity, by noting the positive bands among the
Miramas 1 eight recombinant antigens coated, for each serum tested.
Saint-Etienne-du-Rouvray 2
Saint-Laurent-du-Var 1
LDBioÒ immunoblot
Salon-de-Provence 1
Hospital laboratories
Whenever possible, the LDBio Toxo II IgGÒ immunoblot
Ajaccio (Corsica) 3
Angers 4
(LDBio Diagnostics, Lyon, France) was performed on the sam-
Antibes 1 ples. We used this assay as a confirmatory test of the absence or
Arras 4 presence of specific anti-T. gondii IgG [14]. According to the
Fréjus 4 manufacturer, a positive LDBioÒ immunoblot is defined by
Grenoble 3 three apparent bands including p30 among the five T. gondii
Nantes 30 natural antigens coated, of molecular weights 30 kDa
Nice 60 (= p30), 31 kDa, 33 kDa, 40 kDa, and 45 kDa. This assay
Orléans 10 was used to conclude whether the positive ArchitectÒ Toxo
Reims 4 IgG test results were true- or false-positives.
Saint-Denis 3
Saint-Laurent-du-Maroni (French Guiana) 3
Strasbourg 5 Protein BLAST analysis (Basic Local Alignment
Toulon 1 Search Tool)
Toulouse 45
Total 189 Protein sequences were blasted with NCBI’s online
alignment tool using substitution matrix BLOSUM62.
Similarity scores are expressed in bits, and Expect values
(E-values) 10e–10 demonstrate significant homologies.
“alternative tests”. Thus, each serum was positive by ArchitectÒ
Toxo IgG and negative by at least two assays among the
alternative tests. Additionally, ArchitectÒ Toxo IgM (Abbott
Laboratories) was performed for all the sera in the study, and
Results
test results were all negative (index <0.6 according to the man- Serological tests results
ufacturer’s instructions), except for one individual (ArchitectÒ
IgM index = 1.8) whose positive IgM were later confirmed Across the 189 ArchitectÒ Toxo IgG performed, the IgG
on another sample as non-specific IgM. values ranged from 3.0 to 235.1 IU/mL; the median was
5.6 IU/mL with an interquartile range of 6.5 IU/mL. Among
To increase the power of the study, grey-zone IgG results
the alternative tests, 157 (83.1%) Toxo-screenÒ and
by ArchitectÒ were considered negative and were not included.
134 (70.9%) VidasÒ were performed. All the other alternative
Concerning the other three quantitative tests performed
tests performed are detailed in Table 2.
(VidasÒ, PlateliaÒ, and AxSymÒ), all IgG results obtained were
below the grey-zone.
RecomLineÒ immunoblot results
Study population We carried out 189 recomLineÒ tests in total and analysed
the pattern of positive bands among the eight recombinant anti-
In total, 189 samples collected from 176 individuals gens for each serum (Fig. 1). In our full sample set, we found
presenting positive IgG ArchitectÒ (3 IU/mL) and negative 20 different profiles in which zero to maximum three bands per
IgG with at least two other serological tests were included in immunoblot were found. The majority of the samples were only
the study over a period of 9 years. The study population positive for the GRA8 band (46.6%) but other frequent patterns
included 155 females (88.1%) and 21 males (11.9%). The mean were found, especially GRA8 + GRA7 (14.3%) and GRA7
age was 31.5 years, ranging from 1 to 87 years (including six only (6.9%). The remaining patterns included: SAG1 only
children under 17 years). (1.6%), GRA8 + SAG1 (1.6%), GRA8 + ROP1c (1.6%),
ROP1c only (1.1%), GRA8 + SAG1 + ROP1c (1.1%),
RecomLineÒ immunoblot GRA8 + GRA7 + GRA1 (1.1%), GRA8 + GRA7 + ROP1c
(1.1%), GRA8 + GRA7 + SAG1 (1.1%), MIC3 only (0.5%),
The recomLine Toxoplasma IgGÒ immunoblot (Mikrogen GRA1 only (0.5%), GRA8 + GRA1 (0.5%), GRA8 + MAG1
Diagnostik, Neuried, Germany) was performed on the 189 sera. (0.5%), GRA8 + MIC3 (0.5%), GRA7 + GRA1 (0.5%),
This immunoblot is able to discriminate antibodies against the GRA8 + GRA7 + MAG1 (0.5%), and GRA7 + GRA1 +
recombinant proteins of T. gondii ROP1c (= p66), GRA1 ROP1c (0.4%). In 18% of the samples, the immunoblots did
(= p24), GRA7 (= p29), GRA8 (= p35), SAG1 (= p30), not show any positive band.
4 L. Simon et al.: Parasite 2020, 27, 7
Figure 3. Description of the immunoblot profiles of the 58 negative LDBioÒ tests (true false-positives with ArchitectÒ). (A) Proportion of
recomLineÒ profiles positive for GRA8, SAG1, GRA8+SAG1, other bands or no band, among the 58 negative LDBioÒ tests. (B) LDBioÒ
profiles of the GRA8-positive recomLineÒ profiles. (C) LDBioÒ profiles of the SAG1-positive recomLineÒ profiles. (D) LDBioÒ profiles of
the “no band” recomLineÒ profiles.
showed high similarity to the Hammondia hammondi GRA8 Toxo IgG assay is currently one of the most commonly used
protein (dense granule) in the Protein BLAST analysis. In the for T. gondii serological diagnosis in France. In this study,
same way, the T. gondii GRA7 protein showed strong similarity we collected all suspected false-positive ArchitectÒ IgG test
with the H. hammondi GRA7 protein. Moreover, it also seems results, regardless of the gender. Despite proven high speci-
to have sequence homology with the uncharacterised protein ficity, the few false-positive test results are still a serious issue,
NCLIV_021640 from the parasite Neospora caninum. On the particularly for pregnant women. In immunocompromised
other hand, there is no significant homology between T. gondii patients, reactivation of a past infection can be fatal, mainly
GRA7 and GRA8 proteins. Concerning T. gondii p30, its from brain damage. In this specific population, a false-positive
sequence homology with N. caninum surface protein P36 is IgG test result can be misleading and appear to indicate cerebral
substantial. toxoplasmosis, thus neglecting other differential diagnoses
(e.g., cryptococcal meningitis or primary central nervous sys-
tem lymphoma). In pregnant women, acute infection or reacti-
Discussion vation of T. gondii can lead to a fatal outcome for the foetus.
Importantly, a false-positive IgG test result in a pregnant
All serological methods can provide false-positive results, woman can lead to stopping preventive measures, leading to
irrespective of the infectious disease tested. The ArchitectÒ the risk of an acute infection during pregnancy. In addition,
6 L. Simon et al.: Parasite 2020, 27, 7
false-positive IgG test results will make it difficult to diagnose Our results show that several negative serological tests do
an acute infection as it will be more difficult to differentiate the not guarantee true IgG negativity of the sera, given the positiv-
false-positive IgG from the neosynthesized ones of the acute ity of 28.4% of the tested samples with the LDBio Toxo II
infection. In such a situation, testing IgM, IgA, and avidity will IgGÒ confirmatory test. The main assumption that could
be of utmost importance for the diagnosis. On the basis of our explain this result is that individual variations in the quantity
results, it seems that ArchitectÒ IgG false positivity may be due of circulating IgG are high after T. gondii infection. Very low
to reactivity against GRA8 for the majority of the sera and titres could point out the lack of sensitivity of the automated
GRA7 to a lesser extent. We also noted that a significant part assays compared to the LDBioÒ test facing such antibody titres.
of our samples did not present reactivity against any of the As a reminder, the ArchitectÒ automated assay is based on
seven different recombinant proteins loaded on the recomLineÒ the immune reactivity of the sera against the proteins p30 and
immunoblot. GRA8. The discrepancies we found between the positivity with
Previous studies on T. gondii cross-reactivity and the ArchitectÒ and yet the absence of GRA8 or p30 bands in
BLAST analyses performed in this work have led us to take immunoblots make us wonder whether the antigens chosen
an interest in the protozoan H. hammondi. Hammondia for automated assays are the most suitable ones. Most manufac-
hammondi is another obligate intracellular parasite that infects turers do not in fact indicate what antigens are used in their test,
cats. It is closely relative to T. gondii in terms of morphology, and this can also be entire T. gondii antigenic extracts. A com-
biology and genetics [19, 35]; however, this parasite is not parison between the different assays is then difficult to perform.
known to be infective in humans [45]. Its range of intermediate We might wonder why the GRA8 antigen was initially added to
hosts seems to be more restrictive and includes mainly rodents the ArchitectÒ IgG assay. Was the aim to increase sensitivity in
[16]. Hammondia hammondi also produces a GRA8 protein the detection of past T. gondii infection or to allow earlier diag-
(dense granule) so the hypothesis of cross-reactivity with some nosis of recent infection? Some previous studies seems to show
of its antigens should be assessed. that the recombinant GRA8 antigen allows for better diagnosis
Given the BLAST analysis results, it would be interesting to of acute toxoplasmosis rather than chronic infection [11, 21].
test our samples for N. caninum too. This parasite, like Moreover, we can question whether the antibodies directed
H. hammondi, is not known to be infective in humans and is only against GRA8, as we highlighted in our study in 46.6%
found in dogs and other mammals. As remarkably reviewed of samples, are sufficient to consider the patient immunised
by Gondim et al., several studies in the past forty years have against T. gondii? In this regard, among the recomLineÒ tests
shown serological cross-reactivities and cross-immunity only positive for GRA8 and tested by LDBioÒ, we found
between T. gondii, H. hammondi, and N. caninum [19]. In vivo, 36.4% positive and 63.6% negative confirmatory tests. Thus,
rodents infected with H. hammondi developed immunity and in our sample set, some antibodies directed only against
were protected against T. gondii lethal dose infection [15]. It is GRA8 could be considered true positive. The research is ongo-
interesting to note that the immunogenic potential seems to ing to find new efficient antigens. Innovative tools like bioinfor-
depend on the strains used for experiments [3]. Immunisation matic analyses or epitope mapping have been developed and
with H. hammondi protects goats from abortion induced by recent studies used chimeric antigens and multiepitope peptides
T. gondii [31]. Serological cross-reactivities have also been for the diagnosis of acute and chronic infections [8, 10, 36].
found between these two parasites in mice, rabbits, dogs, and Promising results in terms of sensitivity and specificity are
pigs using immunofluorescence, haemagglutination, dye-test or available with these antigens, but more tests are needed to
ELISA [19]. In another study reviewed by Gondim et al., five implement them in routine diagnostic practice [7, 20].
T. gondii antigens of molecular weight 30, 32, 35, 66, and Since the selection of antigens for immunoassays remains
90 kDa were recognised using polyclonal anti-H. hammondi an issue, the question becomes whether serological methods
serum [35]. could be supplemented by other tests for the diagnosis of
Concerning N. caninum, Gondim et al. reviewed studies Toxoplasma infection. Humoral response of the host to the
showing that cross-immunity and protection of mice against infection increases levels of circulating anti-Toxoplasma
T. gondii, after immunisation by N. caninum, are dependent immunoglobulins. The different isotypes IgG, IgM, IgA, and
on strains and doses used for experimental infections [19]. IgE are currently used for diagnosis and estimation of the date
Serological cross-reactivities with T. gondii have also been a of infection in serological tests [8, 38]. However, immune
problem for the production of monoclonal antibodies against response to T. gondii is processed for a significant part by
N. caninum [28, 39]. These findings highlight the fact that cell-mediated immunity [9, 12]. The first mechanism involved
the strains of pathogens such as H. hammondi, T. gondii, and is a T-cell-independent response. T. gondii activates microbici-
N. caninum are important in terms of cross-reactivity issues. dal functions of macrophages and synthesis of gamma
Moreover, the number of recomLineÒ immunoblots interferon (IFN-c) by natural killer cells [9]. The second mech-
without any positive bands raises additional questions. Despite anism involves interleukin-12 release by the macrophages, in
the fact that none of them had a positive LDBioÒ test (defined response to the infection, to allow synthesis of IFN-c by
by three bands including p30), some nonetheless showed a p30 Toxoplasma-specific CD4+ and CD8+ T-cells through a Th1
band not found by recomLineÒ. This inconsistency from one immune response [9, 12]. IFN-c is thus important to control
assay to another could be due to a difference of sensitivity parasite replication during the acute and chronic phases of the
between these two immunoblots. The LDBioÒ strips are indeed infection.
coated with natural T. gondii antigens, whereas recomLineÒ New tools based on cell-mediated immunity should be
uses recombinant proteins. developed in order to be used in routine laboratories for the
L. Simon et al.: Parasite 2020, 27, 7 7
diagnosis of T. gondii infection. First, fluorescence-activated 5. Ciardelli L, Meroni V, Avanzini MA, Bollani L, Tinelli C,
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always confirming IgG positivity with at least another assay. Discovery of new Toxoplasma gondii antigenic proteins using
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11. Drapała D, Holec-Gaôsior L, Kur J. 2015. New recombinant
tests have perhaps reached their limits and innovative tools such
chimeric antigens, P35-MAG1, MIC1-ROP1, and MAG1-
as cell-mediated immunity-based assays could become a ROP1, for the serodiagnosis of human toxoplasmosis. Diag-
valuable aid for toxoplasmosis diagnosis in the near future. nostic Microbiology and Infectious Disease, 82, 34–39.
12. Dupont CD, Christian DA, Selleck EM, Pepper M, Leney-
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involvement of infected cells in the induction of CD4+ and
The authors declare that Abbott Laboratories provided the CD8+ T cell responses to Toxoplasma gondii. PLoS Pathogens,
recomLineÒ kits used to perform part of the analyses. 10, e1004047.
13. Fatoohi AF, Cozon GJN, Gonzalo P, Mayencon M, Greenland T,
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L. Simon et al.: Parasite 2020, 27, 7 9
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