The concept that the pathological hallmark of type 1 diabetes—namely, irreparable damage to β cells—is the result of an autoimmune process has gained sustained credence since it was first intimated in the 1970s. Forty years on, a robust set of criteria can be applied to settle this important question. As a result of numerous, reproducible research findings (Table 13.2.3.1), there is now an overwhelming case to support the assertion that type 1 diabetes is an autoimmune disease.
Perhaps the most persuasive evidence is provided by the case reports of diabetes arising in recipients of bone marrow from patients with type 1 diabetes (1, 2). In these cases, the recipients underwent bone marrow ablation as part of the treatment for their underlying condition (e.g. relapsed haematological cancers) that effectively removed all autologous innate and adaptive immune cells. To reconstitute their immune system, they then received bone marrow from a sibling with type 1 diabetes. They developed the disease themselves some years later. It is hard to argue against the proposal that immune cells transferred in the bone marrow inoculum were responsible for β cell destruction. Indeed, current practice in these circumstances is to ensure immune depletion of any mature T lymphocytes that may be present in the transplanted bone marrow using specific monoclonal antibodies. This successfully circumvents the problem—and also provides clear evidence for the pivotal role for T lymphocytes in causing β cell damage.
It should be noted that the overwhelming majority of patients with type 1 diabetes—especially those inhabiting the Western, developed world—have evidence of the underlying autoimmune processes, as discussed in this chapter. However, there is a recognition that type 1 diabetes may be heterogeneous, as, in some patients, evidence of autoimmunity is lacking (WHO diabetes classification type 1B). In Japan, a fulminant form of diabetes has been described as representing 15–20% of type 1 disease (15). Presentation is characterized by a high prevalence of preceding common cold-like and gastrointestinal symptoms, a near-normal level of HbA1c (despite very high plasma glucose levels and ketoacidosis), raised serum
pancreatic enzyme levels, and absent C-peptide—but only rarely any evidence of autoantibodies against islet cell autoantigens (16). Some cases of type 1 diabetes arising in sub-Saharan Africa have also been described as lacking evidence of autoimmunity against islet cells (see Chapter 13.4.3.4); however, these data require clarification, since it is known that the autoantibodies decline and may disappear from the circulation soon after diagnosis, making retrospective classification of cohorts with established disease highly problematic (17). Future studies in these locations will need to establish evidence of autoimmunity at diagnosis in currently equivocal situations, using the most comprehensive, up-to-date range of serological markers (see Table 13.2.3.2, below), as well as to establish the clinical and immunogenetic features of the disease.
Tet2 Controls β cells Responses to Inflammation in Type 1 Diabetes
