Antibodies to lactoferrin. A possible link between cow's milk intolerance and autoimmune disease.

Lactoferrin is an iron-binding protein present in external secretions and the secondary granules of neutrophils Its function is unknown, although immunomodulatory, antiinfective and nutritional roles have been proposed 11 I. Recently autoantibodies to lactofemn have been found as a component of anti-neutrophil cytoplasmic antibodies (ANCA) in patients with various autoimmune diseases 121. Why lactofemn should be a prominent autoantigen is unknown. We propose that sensitisation by bovine lactoferrin may be responsible. Cow's milk contains bovine lactoferrin, which is 70% homologous to human lactofemn, and could thus prime the immune system, particularly if sensitivity to cow's milk proteins develops in infancy. To provide evidence for this hypothesis, we have examined antibody levels to human and bovine lactoferrin in sera from patients with autoimmune disease and cow's milk intolerance, and healthy infants on different feeding regimes. We have also examined the effect of antibodies on the iron-binding function of lactofenin. Sera were ohtained from 25 infants with cow's milk intoleraece /failure to thrive and 23 normal controls, 25 40-48week old infants from The Gambia who had been exclusively breast-fed, and 10 healthy Swedish infants fed infant formula supplemented with bovine lactoferjn (Img/ml) for 6 months during a study of iron absorption 131. Sera were also obtained from 24 ANCA+ve adults with autoimmune disease and 24 normal adult controls. Antilactoferrin antibodies were determined by ELISA. The effect of anti-lactoferrin antibodies on iron-binding was determined by incubating human lactoferrin with rabbit anti-lactoferrin IgG, and measuring liberation of iron by the bleomycin assay for 'free' iron 141 Antibody levels are shown in table 1. Antibodies to bovine lactoferrin were found in sera of infants with cow's milk intolerance and controls, but titres were significantly higher in the former group (pO.OS). However, the breast-fed Gambian infants had high titres to human lactoferrin but barely-detectable titres against bovine lactofenin. In contrast, the lactofemn-supplemented infants had very high titres to bovine lactoferrin, and titres to human lactofemn were also elevated Titres to human lactoferrin in the ANCA group were as expected higher than in adult controls, and interestingly these patients also had raised titres to bovine lactofemn (p<O.O1 in both cases). Overall there was a signiticant correlation between the titres to bovine and human lactofemn (p<0.05). Antibodies to 6-lactoglobulin, which are known to be associated with cow's milk intolerance were also determined, but were found to be elevated only in the CMI group (not shown). Incubation of iron-saturated lactofenin with antilactofemn IgG resulted in liberation of 'free' iron, as detected by the bleomycin assay. Normal rabbit IgG did not liherate iron, indicating a specific effect The results show that bovine lactofemn is highly antigenic, even in healthy infants when these are exposed to high levels of the protein. The finding that anti-bovine as well as antihuman lactoferrin antibodies are elevated in ANCA patients supports the suggestion that bovine lactoferrin may prime the immune system to react against human lactofenin, as also MCSHARRY, JAMES EG BUNN* and BO LONNERDAL