Immunologic profiling in schizophrenia and rheumatoid arthritis

Abstract

The negative relationship between schizophrenia (SCZ) and rheumatoid arthritis (RA) has been observed for 85 years, but the mechanisms driving this association are unknown. This study analyzed differences in profiles of cytokines (IL-1β, IL-Ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα), selected genes (HLA-DRB1, IL1RN, HP2), and antibodies related to gluten sensitivity (AGA-IgG, AGA-IgA), celiac disease (tTG), and systemic autoimmunity (ANA, anti-CCP, RF) in 40 subjects with SCZ, 40 with RA, and 40 healthy controls (HC). HLA-DRB1*04:01 alleles were enriched in persons with SCZ and RA compared with HC, and the HP2/HP2 genotype was 2-fold more prevalent in AGA/tTG-positive versus negative SCZ patients. Patients with SCZ demonstrated 52.5% positivity for any of the antibodies tested, compared to 90% of RA patients and 30% of HC. Cluster analysis of the cytokines revealed three clusters: one associated with SCZ marked by high levels of IL-1Ra, one associated with HC, and one associated with both SCZ and RA marked by elevated levels of IFNγ, TNFα, and IL-6. These analyses suggest that stratification of SCZ patients by cytokine profile may identify unique SCZ subgroups and enable the use of currently available cytokine-targeted treatment strategies.

Keywords: Antibodies; Cytokines; Epidemiology; Genes; Immunology.

Fig. 1.

Cytokine levels between the SCZ, RA, and HC groups. The cytokine concentrations found in each patient sera were log10-transformed and plotted. Four patients were removed from the analysis who were found to be outliers (3 HC, 0 RA, and 1 SCZ), as defined by the ROUT calculation, for 2 or more cytokines. The error bars indicate the mean and standard deviation specific to the disease group. The log10-transformed cytokine levels in each group were compared using a one-way AVOVA with Tukey’s test correction for multiple comparisons. HC=healthy control, RA=rheumatoid arthritis, SCZ=schizophrenia. The level of statistical significance is indicated: *p<0.05, **p<0.01, ***p>0.001, and ****p<00,001.

Fig. 2.

Heat map of groups identified by unsupervised hierarchical clustering. Heatmap generated following unsupervised clustering on cytokine levels in healthy controls, RA patients, and SCZ patients. Each individual is represented by a column and each row represents a cytokine. Expression levels are indicated by colors with yellow representing the greatest expression and purple representing the least expression. In total, 116 individuals were analyzed with the 4 individuals excluded from the cytokine analysis in Fig. 1 omitted. Categorical variables displayed at the bottom indicate disease type, and autoantibody and risk allele prevalence for each individual.