GUT IMMUNE SYSTEM TRIGGERED BY COW’S MILK INSULIN?
Outi Vaarala
Department of Molecular and Clinical Medicine, Faculty of Health Sciences, University of Linköping, 58185 Sweden
Abstract: The role of the gut immune system in the development of autoimmunem type 1 diabetes is evaluated in this review with special emphasis in the hypothesis suggesting that dietary cow’s milk insulin could trigger beta- cell autoimmunity when the mechanisms of oral tolerance are disturbed.
Key words: type 1 diabetes; insulin; gut; beta-cell autoimmunity; alpha4beta7- integrin; cytokines; breast milk, microflora, enterovirus
1.
INTRODUCTION
The importance of gut immune system in the development of autoimmune diabetes was suggested by animal studies demonstrating that dietary factors modify the development of autoimmune diabetes in the animal models (Biobreeding (BB)-rats and NOD (non-obese diabetic)-mice). In these animal models autoimmune diabetes develops spontaneously, and the infiltration of pancreatic islets by lymphocytes f (=insulitis) precedes the destruction of insulin-producing beta-cells.
Weaning to the diet of hydrolyzed proteins protects from autoimmune diabetes in NOD-mouse and BB-rat models (Elliot et al., 1999, Kolb et al., 1997). Most importantly this kind of protective diet induces functional changes in the islets infiltrating lymphocytes (Kolb et al., 1997). The cytokine profile in the insulitis from cytotoxic immune response with high IFN-gamma expression is changed to less harmful response characterized by IL-4 and TGF-beta expression. This indicates that an immunological link between diet and autoimmune diabetes exists. t
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More direct evidence suggesting that dietary antigens could cause autoimmune diabetes dietary antigens comes from a transgenic mouse model (Blanas et al., 1996). When ovalbumin was expressed in beta-cells of transgenic mice, oral administration of ovalbumin resulted in the generation of OVA-specific islet-cell infiltrating CD 8 T-cells and development of destructive insulitis.
2. ROLE OF GUT IMMUNE SYSTEM
Accumulating evidence suggests that gut immune system plays a pivotal role in the development of type 1 diabetes. In NOD-mice, islet infiltrating lymphocytes express α4β7-integrin, which is a homing receptor to the gut mucosa (Hänninen et al., 1996 and 1998).
Administration of monoclonal antibodies blocking this receptor or its ligand prevents the development of autoimmune diabetes. Furthermore, mesenterial lymphocytes transfer diabetes from NOD-mice to NOD/scid- mice (Hänninen et al., 1998). These studies indicate that lymphocytes homing to pancreatic islets in the inflammation are also able to home to the gut and this population of lymphocytes may circulate between the gut and the pancreas.
In humans, some reports suggest that autoreactive T-cells may originate from the gut immune system. T-cells derived from pancreas of a patient with type 1 diabetes adhered to mucosal and pancreatic endothelium (Hänninen et al., 1993). Autoreactive T-cells from patients with type 1 diabetes, expressed gut-associated homing receptor α4β7- integrin (Paronen et al., 1996).
Our studies in the intestinal biopsies from children with type 1
diabetes indicate that enhanced intestinal immune activation is associated
with type 1 diabetes, at least in children. Increased expression of HLA
class II-antigen, α4β7-integrin, IL-4 and IL-1β were found in intestinal
mucosa of children with type 1 diabetes without association with celiac
disease or signs of celiac diseases; i.e. antibodies to transglutaminase or
increased number of intraepithelial lymphocytes (Westerholm-Ormio et
al., 2003). In a recent studies, we have also found increased expression
of IL-18 mRNA in intestinal biopsy samples from children with type 1
diabetes (Vaarala et al., unpublished observation). Our results indicate
that primary aberrancies of the intestinal immune system are associated
with type 1 diabetes. It is possible that the intestinal immune activation fundamentally contribute to the development of type 1 diabetes.
3. EFFECT OF COW’S MILK
Epidemiological studies suggest that exposure to cow’s milk (CM) proteins during the first 2 to 4 months of age is associated with about an 1.5-2 fold risk of type 1 diabetes (Gerstein 1994). An association between early CM exposure and risk of type 1 diabetes has not been observed in all epidemiological studies performed. Thus, prospective studies are needed to confirm the possible link between CM exposure and type 1 diabetes. No association of CM exposure with emergence of beta-cell autoimmunity was observed in German and North-American birth-cohort studies (Ziegler et al., 2003 ; Norris et al., 2003). In a Finnish birth-cohort study, exposure to CM formula before 4 months of age implied about five fold risk for the development of multiple autoantibodies and especially autoantibodies against tyrosine phosphatase (IA-2) in children with HLA DQB1*0302 risk allele of type 1 diabetes (Kimpimäki et al., 2001). In some epidemiological studies not only early exposure to CM proteins but also a high dietary intake of CM proteins later in life implied a risk of type 1 diabetes (Verge et al., 1994 ; Virtanen et al., 2000).
4. WHAT ARE THE PUTATIVE DIABETOGENIC FACTORS?
The putative diabetogenic factors in CM are not known, although
several candidates have been identified. Bovine insulin in CM induces ff
primary immunization to insulin in infants exposed to CM formulas
(Vaarala et al., 1999; Paronen et al, 2000). According to our hypothesis,
early immunization to insulin, during the time when gut maturation is
incomplete, may result in aberrant immune response to insulin, which
later could be activated against insulin-producing beta-cells (Vaarala
2002a). The failure of oral tolerance and intestinal immune activation
associated with type 1 diabetes could favour the development of harmful
immune response to insulin. It seems that the regulation of immune
response to dietary insulin is aberrant in children who later develop beta- t
cell autoimmunity. The levels of antibodies to dietary insulin increase during follow-up whereas the antibody levels decrease of remain stable in children without markers of type 1 diabetes related autoimmunity (Vaarala et al., 1999).
Furthermore, increased levels of antibodies binding to insulin are seen in the children with signs of enterovirus infection during the first 6 months of life (Vaarala et al., 2002b). Accordingly, enterovirus infections, which have been connected to the risk of type 1 diabetes, may lead to enhanced immunization to dietary insulin by increasing permeability of the gut or by changing the cytokine environment in the gut. Interestingly, we have found that the concentration of insulin in t mother’s breast milk modifies the humoral immune response to dietary insulin in the infants. The levels of antibodies to dietary insulin were lower in the infants who received breast milk with high insulin content when compared to the infants who received breast milk with low insulin content (Vaarala et al., unpublished observation).
The antigens and cytokines in breast milk may modify the development of immune response to food antigens. Furthermore, the composition of intestinal microflora may be important factor in regulation of immune response to dietary insulin.
5. CONCLUSIONS
Understanding the regulatory mechanisms of the intestinal immune response may reveal means for the prevention of type 1 diabetes and explain the changes in the incidence and etiological factors of type 1 diabetes in different populations.
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