Healthy First‐Degree Relatives of Patients with Type 1 Diabetes Exhibit Significant Differences in Basal Gene Expression Pattern of Immunocompetent Cells Compared to Controls: Expression Pattern as Predeterminant of Autoimmune Diabetes

Abstract

Expression features of genetic landscape which predispose an individual to the type 1 diabetes are poorly understood. We addressed this question by comparing gene expression profile of freshly isolated peripheral blood mononuclear cells isolated from either patients with type 1 diabetes (T1D), or their first‐degree relatives or healthy controls. Our aim was to establish whether a distinct type of ‘prodiabetogenic’ gene expression pattern in the group of relatives of patients with T1D could be identified. Whole‐genome expression profile of nine patients with T1D, their ten first‐degree relatives and ten healthy controls was analysed using the human high‐density expression microarray chip. Functional aspects of candidate genes were assessed using the MetaCore software. The highest number of differentially expressed genes (547) was found between the autoantibody‐negative healthy relatives and the healthy controls. Some of them represent genes critically involved in the regulation of innate immune responses such as TLR signalling and CCR3 signalling in eosinophiles, humoral immune reactions such as BCR pathway, costimulation and cytokine responses mediated by CD137, CD40 and CD28 signalling and IL‐1 proinflammatory pathway. Our data demonstrate that expression profile of healthy relatives of patients with T1D is clearly distinct from the pattern found in the healthy controls. That especially concerns differential activation status of genes and signalling pathways involved in proinflammatory processes and those of innate immunity and humoral reactivity. Thus, we posit that the study of the healthy relative’s gene expression pattern is instrumental for the identification of novel markers associated with the development of diabetes.

Gene/environment interactions in the pathogenesis of autoimmunity: New insights on the role of Toll-like receptors

“…First-degree relatives of T1D patients, independently by the presence or not of autoantibodies, showed up-regulation of TLR2, TLR6 and TIRAP in respect with healthy controls. This observation supports the idea that autoantibody-negative healthy relatives showed however a different regulation of several immune-related signaling pathways [62], accordingly with the presence of proinflammatory islet-selective T cell responses observed in these subjects by the group of de Marquesini [102].…”

“…These cells begin the infiltration of the pancreas and, through the release of cytokines, support cytotoxic T lymphocytes (Tc) which are responsible for the progressive destruction of  cells [62]. Although the etiology must be yet elucidated, a combination of environmental, genetic and stochastic factors contributes to its pathogenesis [87,88,90].…”

“…The whole-genome expression profile of peripheral blood mononuclear cells (PBMCs) isolated from 9 T1D patients, their 10 firstdegree relatives and 10 healthy controls has been analyzed by using the human highdensity expression microarray chip [62]. T1D subjects showed a significant different expression of 9 genes with respect to controls.…”

Case report: type 1 diabetes in monozygotic quadruplets

“…Thus, although a pre-diabetic stage of the quadruplet C correlates with a more recent occurrence of enteroviral infection, its positivity for anti-islet autoantibodies GAD65 and IA-2A indicates that this infection might not be a primary cause of the antiislet autoimmunity, which rather results from a genetic predisposition of quadruplets to diabetes. 44 This line of arguments is further supported by a recent study suggesting that the progression from islet autoimmunity to fully blown T1D may increase after an enterovirus infection. 15 In this respect, the timing of infection and its periodic recurrence as well as a dose of the virus are certainly important parameters when considering the effect of viral infection on the same diabetes-susceptible genetic background.…”

Perfis de Expressão Gênica e Possíveis Interações entre microRNAs e mRNAs em Diabetes Mellitus Tipo 1 com Enfoque em Resposta ao Estresse Oxidativo e Reparo do DNA

“…Moreover, the highest number of differentially activated cell signalling processes (99 pathways) was reported in the comparison between the relatives, regardless of autoantibody status, and the control group. Interestingly, DNA damage and oxidative stress were among those pathways (Stechova et al 2011). Thus, these findings showed that non-diabetic relatives of T1DM patients also present alterations in the expression of genes.…”