Dear Editor,
Gluten sensitivity (GS), a distinctly different immune response from celiac disease (CD), is believed to be associated with neurologic and psychiatric manifestations. Schizophrenia has been linked to enhanced immune reactivity to gluten (Jackson et al., 2012b). Recently, the production of AGA IgG antibodies has been proposed as a marker of GS. AGA IgG in schizophrenia have been associated with increased peripheral (Demyanovich et al., 2017) and central immune reactions (Rowland et al., 2017), and lower positive symptom scores as measured by the Brief Psychiatric Rating Scale (Jackson et al., 2014), suggesting that an AGA IgG positive population of schizophrenia could be a distinct subgroup. Additionally, a gluten free diet may improve symptoms of schizophrenia in those with elevated AGA IgG (Jackson et al., 2012a). Replication studies to determine the prevalence of elevated AGA IgG in schizophrenia are needed as well as the prevalence of other gliadin-related antibodies. Here we compare the presence of AGA (IgG and IgA), deamindated gliadin protein (DGP) (IgG and IgA), transglutaminase 2 (TG2) (IgA) and transglutaminase 6 (TG6) (IgG and IgA) antibodies in the sera of persons with schizophrenia compared to healthy controls (HC).
Participants between 18 and 64 years, with a diagnosis of schizophrenia or schizoaffective disorder (Diagnostic and Statistical Manual (DSM-IV-TR)), signed informed consent, participated in a blood draw and had basic demographic information collected. Johns Hopkins (JHU) University Immunologic Disorders Laboratory (CLIA and CAP certified clinical laboratory) analyzed sera for AGA IgA and IgG (INOVA Diagnostics 708650, 708655); DGP IgA and IgG (704520, 704525); TG2 IgA (INOVA Diagnostics 708760) and TG6 IgG and IgA (Zedira E003, E004). HC sera were analyzed from a JHU repository using IRB-approved samples with no DSM-IV-TR psychiatric diagnosis and best matched for gender, race and age (within 15 years). Dichotomous statistics were calculated using the Fisher exact test (Stata software). Quantitative antibody levels of all tests and age were compared using two-tailed t-tests. Multinomial logistic regression examined the relationship of covariates, age, gender and race to the AGA positivity. The work was IRB approved.
Table 1 lists demographic information and gliadin-related antibodies. Overall, the schizophrenia group was younger and composed of more African American participants. AGA IgG were the only gliadin-related antibody with higher prevalence in schizophrenia compared to HC (31.9% vs 10%, p < 0.001). AGA IgG positivity was more likely in older persons (p = 0.002) and not related to race or gender (p = 0.092 and p = 0.362, respectively).
Table 1.
Demographic information and gliadin-related antibody values.
| Schizophrenia (N = 160) | Healthy Controls (N = 80) | Statistics | |
|---|---|---|---|
| Age (years) | 41.2 ± 12.3 | 45.5 ± 4.3 | p = 0.003 |
| Gender (male) | 61.9% (N = 99) | 63.8% (N = 51) | p = 0.646 |
| Race | |||
| Caucasian | 35% (N = 56) | 50% (N = 40) | p = 0.018 |
| African-American | 61.9% (N = 99) | 47.5% (38) | p = 0.031 |
| Asian | 3.1% (N = 5) | 2.5% (2) | p = 0.630 |
| AGA IgGa | |||
| Mean values (U) | 17.9 ± 21.4 | 9.2 ± 13.2 | p < 0.001 |
| Percent positive | 31.9% (N = 51) | 10% (N = 8) | p < 0.001 |
| AGA IgA | |||
| Mean values (U) | 12.7 ± 12.3 | 14.7 ± 24.7 | p = 0.50 |
| Percent positive | 17.5% (N = 28) | 15% (N = 12) | p = 0.715 |
| DGP IgGb | |||
| Mean values (U) | 2.4 ± 2.1 | 3.1 ± 6.1 | p = 0.29 |
| Percent positive | 0% (N = 0)b | 1.3% (N = 1) | p = 1.00 |
| DGP IgAb | |||
| Mean values (U) | 5.1 ± 3.5 | 9.2 ± 21.4 | p = 0.09 |
| Percent positive | 2.5% (N = 1)b | 1.25% (N = 1) | p = 1.00 |
| TG2 IgA | |||
| Mean values (U) | 7.1 ± 8.2 | 5.7 ± 2.9 | p = 0.14 |
| Percent positive | 2.5% (N = 4) | 0% (N = 0) | p = 1.00 |
| TG6 IgG | |||
| Mean values (U) | 11.2 ± 18.7 | 7.0 ± 9.4 | p = 0.02 |
| Percent positive | 6.9% (N = 11) | 3.8% (N = 3) | p = 0.397 |
| TG6 IgA | |||
| Mean values (U) | 10.8 ± 8.9 | 23 ± 52.7 | p = 0.04 |
| Percent positive | 5.6% (N = 9) | 10% (N = 8) | p = 0.308 |
Positivity was >20 U for all tests with exception of TG6 with positive cutoff >26 U.
Of note all HC AGA IgG values were under 30 with the exception of 4 high outliers who had unknown reason for elevated values.
DGP IgGand IgA was tested in 40 patients, while all other test were performed on the N = 160 in the schizophrenia group. N = 80 controls were tested for all laboratory tests.
Here we replicate the finding that approximately 30% of people with schizophrenia are positive for AGA IgG (Sidhom et al., 2012) and that mean AGA IgG are elevated in schizophrenia (Dickerson et al., 2016; Okusaga et al., 2013). Important to note, some investigators create their own ELISAs (enzyme-linked immunosorbent assays) using crude gliadin extracts or purified alpha-gliadin fractions, possibly resulting in variability in assay performance and different cut-off values for positivity. We suggest standardization of techniques in measuring and reporting as we move forward in the progress of understanding the role of antibodies in schizophrenia. Additionally, TG2 and DGP are related to CD and only kits measuring AGA IgG (sometimes referred to as native gliadin) (e.g., LabCorp # 164125 Gluten Sensitivity Antibodies Cascade or INOVA AGA IgG test) may be related to GS and represent antibodies distinct from those seen in CD.
A connection between CD and schizophrenia has been described previously (Eaton et al., 2004). Also the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) data showed the frequency of elevated TG2 to be 5.4%, (Cascella et al., 2011) higher than the 2.5% we observe here (not different from HC). In another previous study, people with schizophrenia and positive TG2 antibodies had higher TG6 IgA (primarily expressed in the brain) than non-schizophrenia controls, (Cascella et al., 2013), suggesting that brain involvement related to TG6 antibodies may be higher in persons with schizophrenia who also have CD. In this study we find similar rates of TG6 IgG and IgA positivity in schizophrenia and HC, although the mean values seen for TG6 IgA were lower in schizophrenia and TG6 IgG higher relative to HC. To our knowledge this is the first population-based prevalence data on TG6 in schizophrenia (no restricted to CD).
This work helps to clearly establish that AGA IgG is elevated in approximately 1/3 of people with schizophrenia and that this group is distinct from the CD group which has only slightly higher prevalence in SZ. More work is needed to understand the mechanisms within this subgroup and to test personalized treatments for these individuals.
Acknowledgements
The authors would like to thank Martin Cihak for his regression analysis.
Funding source
This work was supported by NIMH R34 MH100776-01 (Eaton and Kelly).
Footnotes
Disclosures
All authors declare that they have no conflicts of interest.
Contributor Information
Daniela Čiháková, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
William W. Eaton, Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Haley K. Demyanovich, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA
Katrina Rodriguez, Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
References
- Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, Fasano A, Eaton WW, 2011. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr. Bull 37 (1), 94–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cascella NG, Santora D, Gregory P, Kelly DL, Fasano A, Eaton WW, 2013. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr. Bull 39 (4), 867–871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Demyanovich H, Rowland L, Wijtenburg SA, Eaton W, Rodriquez K, Cihakova D, Vladut M, Jackson J, Feldman S, Carpenter WT, Fasano A, Santora D, Sullivan K, Gaston F, Hong E, Kelly DL, 2017. High antigliadin antibodies (IgG) are linked to peripheral and central measures of inflammation in a subset of people with schizophrenia. Schizophr. Bull 43 (Suppl. 1), S68. [Google Scholar]
- Dickerson F, Stallings C, Origoni A, Schroeder J, Katsafanas E, Schweinfurth L, Savage C, Khushalani S, Yolken R, 2016. Inflammatory markers in recent onset psychosis and chronic schizophrenia. Schizophr. Bull 42 (1), 134–141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H, 2004. Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. BMJ 328 (7437), 438–439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jackson J, Eaton W, Cascella N, Fasano A, Santora D, Sullivan K, Feldman S, Raley H, McMahon RP, Carpenter WT Jr., Demyanovich H, Kelly DL, 2014. Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. Schizophr. Res 159 (2–3), 539–542. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jackson J, Eaton W, Cascella N, Fasano A, Warfel D, Feldman S, Richardson C, Vyas G, Linthicum J, Santora D, Warren KR, Carpenter WT Jr., Kelly DL, 2012a. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophr. Res 140 (1–3), 262–263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jackson JR, Eaton WW, Cascella NG, Fasano A, Kelly DL, 2012b. Neurologic and psychiatric manifestations of celiac disease and gluten sensitivity. Psychiatry Q. 83 (1), 91–102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Okusaga O, Yolken RH, Langenberg P, Sleemi A, Kelly DL, Vaswani D, Giegling I, Hartmann AM, Konte B, Friedl M, Mohyuddin F, Groer MW, Rujescu D, Postolache TT, 2013. Elevated gliadin antibody levels in individuals with schizophrenia. The World Journal of Biological Psychiatry: The Official Journal of the World Federation of Societies of Biological Psychiatry 14 (7), 509–515. [DOI] [PubMed] [Google Scholar]
- Rowland LM, Demyanovich HK, Wijtenburg SA, Eaton WW, Rodriguez K, Gaston F, Cihakova D, Talor MV, Liu F, McMahon RR, Hong LE, Kelly DL, 2017. Antigliadin antibodies (AGA IgG) are related to neurochemistry in schizophrenia. Front. Psych 8, 104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sidhom O, Laadhar L, Zitouni M, Ben Alaya N, Rafrafi R, Kallel-Sellami M, Lahmar H, El Hechmi Z, Makni S, 2012. Spectrum of autoantibodies in Tunisian psychiatric inpatients. Immunol. Investig 41 (5), 538–549. [DOI] [PubMed] [Google Scholar]