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Etiopathology of Atherosclerosis and Type 1 Juvenile Diabetes: Towards a Unifying Hypothesis?
Petru Liuba, Ph.D., M.D.1 and Sture Sjöblad, M.D., Ph.D.2, Divisions of Pediatric 1Cardiology and 2Diabetes, Metabolism and Endocrinology, Lund University Hospital, Lund, Sweden
Please address correspondence to:
Petru Liuba, Ph.D., M.D.
Pediatric Cardiology
Lund University Hospital
SE-22185 Lund, Sweden
Email: petru.liuba@med.lu.se
Type 1 diabetes (T1D) results from destruction of insulin-producing (β) cells in the pancreas. It typically occurs in previously healthy children being one of the most common childhood diseases. Intriguingly, the diabetes morbidity continues to rise especially in Europe and
The precise pathophysiology of T1D is not yet clarified. There is a general consensus that accumulation of autoreactive T cells into the islets and their subsequent attack on β-cells is a crucial step in the early development of T1D. This early event, probably triggered by an infectious disease, is in part mediated by human leukocyte antigen (HLA) molecules via their ability to process and present relevant epitopes of islet autoantigens to autoreactive T cells [1]. Postmortem studies near the onset of T1D have shown that class II HLA molecules may be abundantly expressed on vascular endothelial cells lining the capillaries and capillary sinusoids in the islets [2]. The upregulation of HLA is paralleled by strong expression of adhesion molecules (i.e. ICAM-1) in the same endothelial areas [3]. These events, seemingly induced by circulating proinflammatory mediators, facilitate the homing and migration of inflammatory cells such as T cells across the dysfunctional endothelium. Recent evidence suggests that similar changes may be found on the surface of endothelial cells of other vascular beds [4]. This fits well with the clinical observation that T1D is often comorbid with chronic autoimmune diseases in other organs such as gut (celiac disease) and thyroid gland (autoimmune thyroiditis). These disorders share some of the HLA DQ diabetes risk alleles with T1D. An activated endothelium could be the link. In children with diabetes risk HLA, signs of systemic endothelial cell activation can be seen already before the clinical onset of diabetes suggesting this to be an early phase of the disease process [5].
The genetic HLA-related susceptibility is recognized in more than 80% of young patients with T1D [6]. Two HLA haplotypes, DQB1*0302-A1*0301 (DQ8) and DQB1*0201-A1*0501 (DQ2), appear to confer the highest risk for developing T1D, especially when both are present in the genotype (i.e. HLA-DQ2/8). This genotype is present in nearly 30% of type 1 diabetics compared to 1% in nondiabetic population. There is some epidemiological evidence suggesting that diabetic microvascular retinopathy is more frequently encountered in patients with HLA-DQ [7]. In atherosclerotic plaque, class II HLA molecules on the surface of endothelial and smooth muscle cells colocalize with activated inflammatory cells [8]. By inhibiting regulatory T cells, autoimmunity-risk HLA may promote alternative pathways to damage endothelial cells given the importance of these cells in controlling the pathological activity of autoreactive T lymphocytes and hence their binding to activated endothelium. Importantly, similar changes in T cell phenotype have been linked to atherosclerosis [9]. We have recently demonstrated that children and young adults with T1D and HLA-DQ 2/8 have a significantly greater risk of atherogenic changes in the brachial artery and systemic microvascular dysfunction than those without this genotype, irrespective of age, diabetes duration, body mass index, and glycozylated hemoglobin [10,11]. These findings might be important since T1D remains an important source of cardiovascular morbidity at the adult age despite significant advancements in diabetes therapy and monitoring. Indeed, in almost 50% of diabetics, their cardiovascular complications cannot be explained by their glycemic levels.
Theoretically, given the upregulatory effects exerted by systemic inflammation on both vascular adhesion molecules and HLA molecules, their putative detrimental influences on the vascular wall would gain further consistency in an inflammatory environment. In patients with rheumatoid arthritis (RA), another cardiovascular risk factor with important genetic susceptibility, the mortality from cardiovascular disease was found to be most increased in patients with RA-risk HLA and inflammatory activity [12]. In our afore-mentioned study of children and adolescents with T1D [10], we observed further decrease in brachial artery’s endothelium-dependent reactivity in HLA DQ2/8 patients with low-grade inflammatory activity, i.e. C-reactive protein > 1 mg/l. However, no such interplay could be observed in microcirculation, which was assessed by laser Doppler flowmetry [11]. The meaning and causes of this discrepancy remain be determined in future studies. We did however observe a moderate correlation between blood pressure and CRP in HLA DQ2/8 patients, which was not present in those without this genotype. It is well known that microvascular endothelium is an important regulator of arterial blood pressure.
One intriguing epidemiological observation is that the risk of developing T1D seems to increase with the number of infections experienced by an individual during the year preceding the onset of T1D [1]. Although we currently lack the knowledge of the precise underlying mechanisms, there are other reports on similar associations between infectious recurrence and chronic diseases such as multiple sclerosis or rheumatoid arthritis. In some animal studies, the development of atherosclerotic plaque was accelerated by repeated infection [13]. One possible mechanistic link between these chronic inflammatory diseases (e.g. atherosclerosis and T1D) and infection might be endothelial injury. Infections cause vascular endothelial dysfunction, which may persist for up to 1 year after the infectious illness [14]. Mild respiratory infections (“common cold”) seem to aggravate arterial endothelial dysfunction in young patients with T1D [15]. Those with increased recurrence of infections of this type are more susceptible to decreased carotid artery elasticity [16]. The latter was earlier shown to be in part dependent on the functional integrity of endothelial cells. In atherosclerosis-susceptible mice, the degree of endothelial vasomotor dysfunction in skin microcirculation correlates with the number of pathogen inoculations (Odermarsky M, Liuba P unpublished data).
Although appealing, there is no evidence to date of a direct interplay between infections and HLA in the causation of T1D or atherosclerosis. Since infection promotes the inflammatory milieu needed for endothelial cell activation and upregulation of HLA, and since certain HLA seem to exacerbate endothelial dysfunction of both large and small vessels [10,11], these changes could in individuals with disease-susceptible genotypes contribute to more specific steps in which homing, transmigration, and accumulation of inflammatory cells to certain tissues occur. In arteries, this process could provide an important ground for further development of changes typical to atherosclerosis, such as lipid oxidation, smooth muscle cell proliferation, and formation of fatty streaks. Diabetes may in this context not be an exclusive prerequisite for accelerated atherosclerosis. At microcirculatory level, transendothelial migration of autoreactive T cells would create the premises for tissue inflammation and destruction. In pancreas, for instance, these microcirculatory changes could perhaps contribute to diabetes immunity by facilitating local presentation to the immune system of antigenic peptides of processed islet proteins.
Should vascular endothelial dysfunction prove to play a pivotal role in the pathogenesis of both T1D and its associated atherosclerotic disease, it is then conceivable that combined endothelium-targeting and immunoregulatory strategies already in diabetes-risk individuals without overt T1D (i.e. diabetes HLA-risk individuals) might reduce not only the cardiovascular burden but also the prevalence of T1D later in life. Further studies are needed to provide additional mechanistic insights into the gene-environment interaction on vascular endothelium and the timing and role of endothelial dysfunction in the development of T1D and atherosclerosis.
Acknowledgements
Dr Liuba received a clinical investigator award from FAMRI, USA, for clinical studies on the role of genetics and environmental factors on the development of atherosclerosis in children with diabetes-risk HLA.
References