title: Enhanced levels of cow's milk antibodies in infancy in children who develop type 1 diabetes later in childhood.
abstract: BACKGROUND
  Early exposure to cow's milk (CM) proteins have been implicated in the pathogenesis of type 1 diabetes (T1D).
  
  
  OBJECTIVE
  We analyzed the development of the humoral immune response to dietary CM proteins in early childhood and its relation to later T1D.
  
  
  METHODS
  We studied a subgroup of 94 children randomized to be weaned to a CM-based infant formula in the trial to reduce insulin-dependent diabetes mellitus in the genetically at risk (TRIGR) pilot study. All subjects carried human leukocyte antigen-conferred T1D susceptibility and had an affected first-degree relative. After 7 years of follow-up, 8 subjects had progressed to T1D, 15 had at least one disease-associated autoantibody, and 71 remained autoantibody negative (controls). Immunoglobulin (Ig) G and IgA class antibodies to whole CM formula, beta-lactoglobulin (BLG), bovine serum albumin, and alpha-casein and IgG antibodies to bovine insulin (BI) were measured with enzyme-linked immunosorbent assays from sequential samples.
  
  
  RESULTS
  The children with later T1D showed increased IgG levels to BLG from 3 to 18 months of age (p = 0.028) and enhanced IgA levels to CM formula at the age of 9 months (p = 0.022) compared with controls. In the children with an affected father or sibling, IgG antibodies to BI were higher in autoantibody-positive subjects than in autoantibody-negative subjects at 18 months of age (p = 0.022).
  
  
  CONCLUSIONS
  An enhanced humoral immune response to various CM proteins in infancy is seen in a subgroup of those children who later progress to T1D. Accordingly, a dysregulated immune response to oral antigens is an early event in the pathogenesis of T1D.
authors.affiliation: Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland. kristiina.luopajarvi@hus.fi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Luopajärvi
authors.forename: Erkki
authors.initials: E
authors.lastname: Savilahti
authors.forename: Suvi M
authors.initials: SM
authors.lastname: Virtanen
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Hans K
authors.initials: HK
authors.lastname: Akerblom
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000032:analysis*; D001942:Breast Feeding; D002417:Cattle; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006801:Humans; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007223:Infant; D041943:Infant Formula; D007330:Insulin Antibodies / Q000032:analysis; D008297:Male; D008892:Milk / Q000276:immunology*; D008894:Milk Proteins / Q000276:immunology*; D012307:Risk Factors; D013745:Tetanus Toxoid / Q000276:immunology
chemical_list: D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007330:Insulin Antibodies; D008894:Milk Proteins; D013745:Tetanus Toxoid