title: Immune activation by casein dietary antigens in bipolar disorder.
abstract: OBJECTIVE
  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 (R(2) =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/χ(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.
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD 21287, USA. eseverance@jhmi.edu
authors.forename: Emily G
authors.initials: EG
authors.lastname: Severance
authors.forename: Didier
authors.initials: D
authors.lastname: Dupont
authors.forename: Faith B
authors.initials: FB
authors.lastname: Dickerson
authors.forename: Cassie R
authors.initials: CR
authors.lastname: Stallings
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Origoni
authors.forename: Bogdana
authors.initials: B
authors.lastname: Krivogorsky
authors.forename: Shuojia
authors.initials: S
authors.lastname: Yang
authors.forename: Willem
authors.initials: W
authors.lastname: Haasnoot
authors.forename: Robert H
authors.initials: RH
authors.lastname: Yolken
mesh_terms: D000328:Adult; D000818:Animals; D000941:Antigens / Q000276:immunology; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D002364:Caseins / Q000008:administration & dosage / Q000276:immunology*; D002417:Cattle; D003863:Depression / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D018020:Lithium Compounds / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment
chemical_list: D000941:Antigens; D014150:Antipsychotic Agents; D002364:Caseins; D007074:Immunoglobulin G; D018020:Lithium Compounds