Cellular immune responses to β casein: elevated in but not specific for individuals with Type I diabetes mellitus

Abstract

Type I diabetes mellitus appears as the end result of an autoimmune destruction of the insulin secreting pancreatic beta cells [1]. The immunological mechanisms underlying the development of Type I diabetes mellitus as well as the role of environmental agents (e. g. diet, viruses, stress) in the pathogenesis of the disease have been the subject of considerable research. The rationale for investigating environmental agents involves an attempt to explain numerous epidemiological observations including the disease discordance rate amongst twins with Type I diabetes mellitus, a pronounced north-south gradient in the incidence of Type I diabetes mellitus, reports of an increased (e. g. up to fourfold) incidence of Type I diabetes mellitus over the past three decades, and the estimate that more than 80 % of patients with newly-diagnosed Type I diabetes mellitus do not have a firstdegree relative with the disease [2]. Diabetologia (1998) Summary Elevated cellular immune responses against the cows' milk protein b casein have been reported in individuals with Type I diabetes mellitus, a finding supportive of the concept that cows' milk consumption may be causative for the disease. We analysed cellular immune reactivities against b casein in newly-diagnosed Type I diabetic patients, their immediate autoantibody negative relatives, and unrelated healthy individuals in order to further elucidate the role of anti-b casein immunity in the pathogenesis of Type I diabetes mellitus. Peripheral blood mononuclear cells were stimulated in vitro with various concentrations of three different b casein preparations, control antigens (tetanus toxoid, mumps extract) and a mitogen (phytohemagglutinin). The frequency and/or mean simulation index of cellular proliferation against two of the b casein preparations at high antigen concentrations (i. e. 10 or 50 mg/ml) were significantly higher in newly-diagnosed Type I diabetic subjects compared with autoantibody negative healthy control subjects. However, reactivities against b casein in the Type I diabetic probands and their autoantibody negative relatives, individuals with a very low-rate of disease development, were almost identical. Cellular immune reactivities to other antigens were similar between the subject groups. In addition to indicating the need for appropriately matched subject populations (e. g. human leukocyte antigen (HLA) matched relatives) when analysing cellular immune responses, these findings support our previous contention that individuals genetically prone to autoimmunity may be deficient in forming tolerance to dietary antigens. However, the significance of anti-b casein immunity as a specific causative factor in the pathogenesis of Type I diabetes mellitus remains unclear.

Establishment of T cell lines to bovine beta-casein and beta-casein-derived epitopes in patients with type 1 diabetes

“…We previously reported enhanced cellular immune response to bovine -casein in patients with type 1 diabetes (Cavallo et al 1996b) and this was confirmed by other authors (Ellis et al 1998). However, a similar increase was noticed also in first degree relatives of type 1 diabetes probands (Ellis et al 1998), pointing out the role of genetic susceptibility in this response.…”

“…However, a similar increase was noticed also in first degree relatives of type 1 diabetes probands (Ellis et al 1998), pointing out the role of genetic susceptibility in this response.…”

“…Increased cellular and humoral immune responses to different cow's milk proteins including BSA, -lactoglobulin and -casein have been reported in patients with type 1 diabetes (Karjalainen et al 1992, Cavallo et al 1996b, Vaarala et al 1996, Ellis et al 1998, but these results have not always been confirmed (Atkinson et al 1992, Roep et al 1999, Sarugeri et al 1999.…”

Autoreactive T cell Responses in Insulin-dependent (Type 1) Diabetes Mellitus. Report of the First International Workshop for Standardization of T cell assays

“…Nonetheless, the majority of studies published to date have not reported differences in response rates to antigens unrelated to -cells between diabetic and control subjects, which is consistent with the results of most participants in the workshop. It may be important to extend the number of control stimuli tested in order to assess specificity of the proliferative response, for instance by inclusion of cocktails of vaccine antigens (PPD, tetanus toxoid, candida albicans) [66]. This may provide a standard reference value as positive control, which is more constant than the results obtained with individual antigens.…”

Environmental factors in the etiology of type 1 diabetes

“…Increased T cell immunity to beta casein has been reported in patients with newly diagnosed type 1 diabetes [Cavallo et al, 1996] but also in their unaffected relatives [Ellis et al, 1998]. This indicates that a genetic failure in the regulation of the immune response to this dietary protein may be related to type 1 diabetes.…”