Are phospholipid-binding antibodies implicated in the pathogenesis of diabetic microangiopathy?

Diabetic retinopathy (DR) is a major cause of blindness in the working population of the Western world and there is no doubt that its prevalence is strongly related to the duration of diabetes and the glycemic control. However, although intensive diabetes management, with the goal of achieving near-normal glycemia, has been shown to prevent and/or delay the onset of DR, there is now ample of evidence that the development of this microangiopathy is a multifactorial process in which genetic, metabolic, haemostatic and growth factors play an important role. Moreover, given the suggestions that immunological mechanisms might have a role in the pathogenesis of diabetic microangiopathy via immune complex deposition, it has been hypothesized that antiphospholipid antibodies (A-Ab) directed against endothelial antigens could be responsible for initiating vascular injury. In particular, not only A-Ab production was found to be increased in patients with overt nephropathy or macroangiopathy but also Lupus Anticoagulant positivity, representing an intersection point between immune and haemostatic alterations, has been highlighted as a potential and additional risk factor in the pathogenesis of microangiopathy in type 1 diabetics. Moreover, given the high levels of activated protein C, endothelin-1 and thrombo-modulin that have been observed in normo-albuminuric and uncomplicated patients, it has been concluded that the vascular endothelium shifts pathologically from an antithrombotic to a prothrombotic state even in the early phases of the disease. This condition was found to be more pronounced in subjects with anticardiolipin positivity and/or high circulating immune complexes concentrations, since they possess the ability not only to induce platelet activation and aggregation but also to activate the complement system via the classical pathway. Therefore, a potential synergism between generation of autoantibodies, haemostatic alterations and endothelial stress has been suggested, a stimulating hypothesis that needs further studies to be clarified in its complexity.