IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia

Abstract

Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R2=0.34–0.55, p≤0.0001; controls R2=0.05–0.06, p>0.33). A gauge of blood-CSF barrier permeability and CSF flow rate, the CSF-to-serum albumin ratio, was significantly elevated in cases compared to controls (p≤0.001–0.003). Indicators of intrathecal IgG production, the CSF IgG index and the specific Antibody Index, were not significantly altered in schizophrenia compared to controls. Thus, the selective diffusion of bovine milk casein and wheat gluten antibodies between serum and CSF in schizophrenia may be the function of a low-level anatomical barrier dysfunction or altered CSF flow rate, which may be transient in nature.

Gastroenterology issues in schizophrenia: Why the gut matters

“…Studies of cerebrospinal fluid can lend some insight regarding how exogenous or gut-produced factors might gain proximity to the brain in schizophrenia [80, 89-91, 18, 56]. Toward this end, we found that antibodies directed against food antigens in the CSF are highly correlated with serum levels in samples from antipsychotic-naïve people with schizophrenia, a pattern not found in control individuals [18]. These data in conjunction with measurements of relative serum to CSF albumin and total IgG support the possibility of either an anatomical barrier abnormality or reduced CSF flow associated with schizophrenia [89,92].…”

“…Further propagating this connection are the technological advances that have fueled the burgeoning field of microbiome research. In a series of research reports, we have united conceptually and experimentally a number of risk factors for the development of schizophrenia through a common origin in the gut [13][14][15][16][17][18]. The disease-associated interaction of such biological variables as humoral immunity to food antigens, intestinal inflammation, exposure to the parasite Toxoplasma gondii, endothelial barrier defects and microbial dysbiosis is consistent with a physiological model whereby gut-based processes can create a systemic state of immune dysregulation.…”

“…It is currently not known whether the pathological brain effect of these food-based antigens are due to direct effects of the foodderived peptides on the brain or of an associated immune activation in response to an antigenic peptide. We discuss in the next section, our findings of antibodies against gluten and casein in CSF samples and suggest that the food-related immune response in the presence of compromised epithelial and endothelial barriers may be a possible pathological mechanism in psychiatric disorders [18]. Others hypothesize that these food-derived opioid peptides may be relevant epigenetically to brain disorders due to their ability to modulate cysteine uptake in neuronal and GI epithelial cells and thus influence the DNA methylation profile of affected cells [65].…”

Review paper. Gluten-related disorders and schizophrenia - potential linking mechanisms, diagnostic and therapeutic challenge

“…However, when blood-brain barrier is damaged, exorphins can pass from the intestinal lumen into the bloodstream (where they stimulate the immune system), and then pass into the CSF. It has been shown that in patients with schizophrenia, the higher the level of anti-gluten antibodies was detected in blood, the higher level of them was determined in the CSF [104]. This relationship suggests that in patients the spread of antibodies occurs on a larger scale than in healthy subjects, indicating some subtle, transient disorders of bloodbrain barrier.…”

“…Jednkaże, gdy bariera krew-mózg jest uszkodzona, egzorfiny mogą przedostawać się ze światła jelit do krwioobiegu (gdzie pobudzają układ immunologiczny), a następnie do CSF. Wykazano, że u chorych na schizofrenię, im wyższy poziom przeciwciał przeciwglutenowych wykrywano we krwi, tym wyższy ich poziom oznaczano w CSF [104]. Ta zależność sugeruje, że u osób chorych rozprzestrzenienie się przeciwciał zachodzi na szerszą skalę niż u osób zdrowych, co wskazuje na pewne subtelne, przemijające zaburzenia bariery krew-mózg.…”