Читать книгу Clinical Dilemmas in Diabetes - Группа авторов - Страница 37

There are three main categories of factors involved in the pathogenesis of T1D. These are genetic, immunological, and environmental factors (Figure 2.1).

Like other organ‐specific autoimmune diseases, T1D shows specific human leukocyte antigen (HLA) associations. The HLA complex on chromosome 6 comprises the first gene shown to be associated with the disease and it is considered to contribute to almost half of the familial basis of T1D. Two combinations of HLA haplotypes are of particular importance. They are DR4‐DQ8 and DR3‐DQ2, which are present in 90% of children with T1D [5]. A third haplotype, DR15‐DQ6, is found in less than 1% of children with T1D, compared to more than 20% of the general population, and it is considered to be protective. The genotype combining the two susceptibility haplotypes (DR4‐DQ8/DR3‐DQ2) contributes to the greatest risk of the disease and it appears frequently in children with an earlier onset. First‐degree relatives of these children are themselves at greater risk of T1D compared to those of children in whom the disease develops later.

FIG 2.1 Pathogenesis and natural history of Type 1 diabetes. Atkinson MA and Eisenbarth GS Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001;358(9277):221–229.

Candidate gene studies also identified the insulin gene on chromosome 11 as another important genetic susceptibility factor, contributing 10% of the genetic susceptibility to T1D [6]. Similarly, an allele of the gene acting as a negative regulator of T‐cell activation, cytotoxic T lymphocyte antigen 4 (CTLA‐4), found on chromosome 2q33, is considered to be another susceptibility gene for T1D [7]. A variant of PTPN22, the gene encoding Lymphoid Phosphatase (LYP), which is a suppressor of T‐cell activation, has been deemed as another susceptibility gene [8]. Similarly, variation in IL2RA which encodes the α‐chain of the IL‐2 receptor is also associated with T1D [9]. The observation that these susceptibility genes for T1D all play important roles in antigen presentation to T‐cells, emphasizes the potential importance of current therapeutic strategies targeting this interaction [10].

Genetic studies have highlighted the importance of large, well‐characterized populations in the identification of susceptibility genes for T1D. Recruitment of increasingly large populations of patients with T1D and their families is required to provide statistically powerful cohorts in which to identify other disease‐associated genes. Some genes have a relatively minor individual impact on susceptibility to disease but could nevertheless provide more clues to future preventive therapies.

The presence of autoantibodies to β‐cells is the hallmark of T1D (Figure 2.1). Abnormal activation of the T‐cell‐mediated immune system in susceptible individuals leads to an inflammatory response within the islets as well as to a humoral response with production of antibodies to β‐cell antigens. Islet‐cell antibodies (ICA) were the first ones described, followed by more specific autoantibodies to insulin (IAA), glutamic acid decarboxylase (GAD), the protein tyrosine phosphatase (IA‐2), and most recently Zinc Transporter 8 (ZnT8A), all of which can be easily detected by sensitive radioimmunoassay to identify subjects at risk of developing T1D [11]. These autoantibodies are common in both childhood and adult onset T1D, with many subjects being positive for multiple autoantibodies. The type of immune response is age‐dependent, but seroconversion to multiple autoantibody positivity usually occurs tightly clustered in time and is associated with genetic risk.

The presence of one or more type of antibodies can precede the clinical onset of T1D by years or even decades. These autoantibodies are usually persistent, although a small group of individuals may revert to being seronegative without progressing to clinical diabetes. The presence and persistence of positivity to multiple antibodies increases the likelihood of progression to clinical disease.

On that note, recent evidence shows that antibodies specific to oxidative post‐translationally modified insulin (oxPTM‐INS) are present in the majority of newly diagnosed individuals with T1D being significantly more abundant than autoantibodies to native insulin (NT‐INS) [12]. Furthermore, subsequent analysis found that oxPTM‐INS auto‐reactivity is present before diabetes diagnosis in over 90% of individuals, suggesting a potential role for oxPTM‐INS‐Ab as a predictive biomarker of T1D [13].

The progressive reduction of insulin‐secretory reserve leads primarily to the loss of the first phase insulin secretion in response to an intravenous glucose tolerance test, and therefore to a state of absolute insulin deficiency.

Regarding the role of environmental factors, it should be underlined that the increase in incidence of T1D is too rapid to be caused by alterations in the genetic background and is likely to be the result of environmental changes.