Patients with recently diagnosed IDDM often have significant abnormalities in cellular and humoral immunity to different cows milk proteins, including BSA (1-9).
R e v i e w s / C o m m e n t a r i e s / P o s i t i o n
Statements
C O M M E N T A R Y
Cow's Milk, Bovine Serum Albumin, and IDDM: Can We Settle the Controversies? DENISE HAMMOND-MCKIBBEN, PHD HANS-MICHAEL DOSCH, MD
formula was RR = 13.1 and that if there was a bias in recall of feeding history, it would map to major histocompatibility complex risk alleles—an unlikely scenario (22). To put this in perspective, theriskdelineated is equal to or larger than widely accepted relaovine serum albumin (BSA) is a con- (20) analyzed physicochemical characteris- tionships between smoking and lung cancer stituent of cows milk whey and meat, tics of BSA that affect its behavior in (RR = - 1 0 [5-15]), smoking and heart disand it is a common additive in immunoassays of anti-BSA antibodies. With ease (RR = 2), and high blood pressure and processed foods because of its high resis- a specific focus on the ABBOS region (21), cholesterol (RR = 2.5-3) (35). tance to degradation. Patients with recently their measurements of the ABBOS accessiIn a different approach to the same diagnosed IDDM often have significant bility to antibody binding in native and question, Norris et al. (24) recently abnormalities in cellular and humoral degraded BSA may explain some of the con- employed a cross-sectional analysis of the immunity to different cows milk proteins, troversy surrounding the presence or DAISY (Diabetes Autoimmunity Study in including BSA (1-9). There is epidemio- absence of an association between abnormal the Young) registry and found that the logical evidence that exposure of genetically immunity to BSA and IDDM and reduce it duration of breast-feeding did not affect diabetes-susceptible infants to intact for- to technical issues. That this would be of the development of (mainly anti-insulin) eign protein such as cow's milk-based for- more than passing interest is evident from autoantibodies in 18 probands with genetic mula before the age of 3 months carries continuing publications of data and editor- risk to develop the disease. This study was with it an elevated risk to develop the dis- ial opinion on these topics in more than a reminiscent of an earlier report of a lack of ease (10-12). dozen papers this year (7,9,18-20,22-29), correlation between anti-cow's milk protein and anti-islet cell antibodies (37), but The relationship between BSA and not counting ours (12,30-34). most cases with diabetes (71%) did have IDDM has engendered much debate elevated BSA antibodies in that study. because elevated, diabetes-associated BSA antibodies were reported in a rather vari- COW'S MILK AND DIABETES — New support for the notion of a speable percentage of diabetic individuals, Four of more than 30 studies analyzing a cific role of cows milk proteins in diabetic including one completely negative report possible link between early cow's milk con- immunity derives from reports of abnormal (Table 1). Abnormal patient T-cell reactivity sumption and diabetes have failed to find T-cell reactivity in newly diabetic children to BSA has been mapped to a single peptide such a relationship (reviewed in 10,26). A (but not control subjects) directed against fragment, the ABBOS epitope, which has consistent cautionary argument in all these the cow's milk protein (3-lactoglobulin (7) structural homology with the Tep69 epi- retrospective, mainly case-control studies and (3-casein (38). A similar conclusion tope of an islet cell antigen, ICA69 (13,14), has been a possible bias in the recall of early derives from a new Swedish study that which was identified as a target of diabetic feeding history of diabetic children. In addi- identified antibodies to the milk protein autoimmunity in four independent labora- tion, and at least as important, a lack of BSA as a significant risk marker for overt tories (15-18). Because of the variability in matching for diabetes-associated histocom- diabetes (27). the detection of abnormal BSA immunity in patibility alleles results in comparing the Reminiscent of the early years of antiIDDM patients, the "BSA hypothesis" (see immunologic effects of foreign antigen smoking campaigns, acknowledgment of below) has generated criticism, and its exposure in cases with controls that most the cow's milk-diabetes link has been far debate became almost synonymous with likely would be unable to mount similar from unanimous, with senior experts warnthat of intact cows milk protein as a dia- immune responses (10,26). In the most ing to stay away from "cows milk phobia" betes risk factor in very young infants (19). recent published study, Perez-Bravo et al. (19,35). The discussion continues to be Here, we will briefly review these issues (22) addressed this issue by comparing dia- lively, with a flurry of editorials and and discuss how data just reported by Alt- betic children with control subjects matched reviews, but on balance, this years crop of ing and van Beresteijn in Diabetes Care (20) for diabetes-associated risk alleles in the new data and the lack of any prospective may explain some of the difficulties sur- HLA region. This study determined that the evidence fall well short of discrediting the rounding the measurement of anti-BSA relative diabetes risk (RR) attributable to diabetogenic effect of early exposure to antibodies in IDDM patients. These authors early weaning with cow's milk-based infant intact cow's milk protein in infant formula (22). Proof or disproof can only come from controlled, prospective trials.
B
From The Hospital For Sick Children, Research Institute, Toronto, Canada. Address correspondence and reprint requests to Hans-Michael Dosch, MD, Department of Immunology, The Hospital For Sick Children, 555 University Ave., Toronto, ON M5G 1X8 Canada Received for publication 6 June 1996 and accepted in revised form 27 November 1996. BSA, bovine serum albumin; 1CA, islet cell antigen; RR, relative risk.
DIABETES CARE, VOLUME 20, NUMBER 5, MAY
1997
BSA AND DIABETES—Do we know the mechanisms, or at least the identity, of culprit proteins in cow's milk-based 897
Cow's milk and IDDM
Table 1—Immune responses to BSA in IDDM Diabetes-associated P Odds ratio Reference
% new IDDM-positive
Comments
Ig
Age (years)
PCFIA PCFIA
IgG IgA
8.4 ±4.3 8.4 ±4.3
8.5 ± 0.2 kfU (142) 3.2±0.1kfU(142)
1.3 ±0.1 kflj (79) 1.8 ±0.1 kflj (79)
100 61
