Immune activation by casein dietary antigens in bipolar disorder

Objectives: Inflammation and other immune processes are increasingly linked to psychiatric diseases. Antigenic triggers specific to bipolar disorder are not yet defined. We tested whether antibodies to bovine milk caseins were associated with bipolar disorder, and whether patients recognized different epitopes of the casein protein than control individuals. Methods: Anti-bovine casein immunoglobulin G (IgG) levels were measured with solid-phase immunoassays in 75 individuals with bipolar disorder and 65 controls. Epitope recognition was evaluated in immunoassays by cross neutralization with anti-bovine casein polyclonal antibodies of defined reactivity. Group-specific reactivity and associations with symptom severity scores were detected with age-, gender-, and race-controlled regression models. Results: Individuals with bipolar disorder had significantly elevated anti-casein IgG (t-test, p = 0.001) compared to controls. Casein IgG seropositivity conferred odds ratios of 3.97 for bipolar disorder [n = 75, 95% confidence interval (CI): 1.31–12.08, p = 0.015], 5.26 for the bipolar I subtype (n = 56, 95% CI: 1.66–16.64, p = 0.005), and 3.98 for bipolar disorder with psychosis (n = 54, 95% CI: 1.32–12.00, p = 0.014). Lithium and/or antipsychotic medication did not significantly affect anti-casein IgG levels. Casein IgG measures correlated with severity of manic (R2 = 0.15, 95% CI: 0.05–0.24, p = 0.02) but not depressive symptoms. Unlike controls, sera from individuals with bipolar disorder did not inhibit binding of casein-reactive animal sera (t-test/¿2, p = 0.0001). Conclusions: Anti-casein IgG associations with bipolar I diagnoses, psychotic symptom history, and mania severity scores suggest that casein-related immune activation may relate to the psychosis and mania components of this mood disorder. Case-control differences in epitope recognition implicate disease-related alterations in how the casein molecule is digested and/or how resulting casein-derived structures are rendered immunogenic

Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia

Previous studies show increased antibody levels to bovine casein in some individuals with schizophrenia. The immunogenicity of specific domains of bovine casein varies among people with milk sensitivities and thus could vary among different neuropsychiatric disorders. Using ELISAs and immunoblotting, we characterized IgG class antibody specificity to whole bovine casein and to the as, ß, and ¿ subunits in individuals with recent onset psychosis (n = 95), long-term schizophrenia (n = 103), and non-psychiatric controls (n = 65). In both patient groups, we found elevated IgG to casein proteins, particularly to whole casein and the as subunit (p = 0.0001). Odds ratios of casein seroprevalence for recent onset psychosis (age-, gender-, race-, smoking-adjusted) were significant for whole casein (8.13, p = 0.0001), and the as (7.89, p = 0.0001), ß (5.23, p = 0.001) and ¿ (5.70, p = 0.0001) subunits. Odds ratios for long-term schizophrenia were significant for whole casein (7.85, p = 0.0001), and the as (4.78, p = 0.003) and ¿ (4.92, p = 0.004) subunits. Within the recent onset group, odds ratios were particularly significant for a subgroup of people with psychotic disorders that included major depressive disorders (8.22–16.48, p = 0.0001). In a different recent onset subgroup (schizophrenia-spectrum disorders), PANSS scores for negative symptoms were correlated with casein antibody levels for the as and ¿ subunits (p = 0.001–0.01). Immunoblotting patterns also exhibited group specificity, with ¿ predominant in recent onset and as in schizophrenia (Fisher's Exact Test, p = 0.001). The elevated IgG and unique patterns of antibody specificity to bovine casein among diagnostic groups provide a rationale for clinical trials to evaluate efficacies of dietary modifications in individuals with neuropsychiatric diseases