Updates in medicine Relationship between local neuroimmune impairment and diabetic foot: the immunocompromised district theory Adone Baroni, MD, PhD, Teresa Russo, MD, and Vincenzo Piccolo, MD Department of Dermatology and Venereology, Faculty of Medicine, Second University of Naples, Naples, Italy Correspondence Teresa Russo, MD c/o II Policlinico Edificio 9 Primo Piano Via Pansini 5 Napoli 80131 Italy E-mail: russo.teresa87@gmail.com Funding sources: none. Conflicts of interest: none Abstract Background Diabetic foot (DF) can be defined as an infection and/or an ulceration with or without destruction of deep tissues associated with neurological abnormalities and varying degrees of peripheral vascular disease of the lower limb in patients with diabetes. Both neuropathy and vascular disease, along with the well-known impairment of immune function in patients with diabetes, contribute to polymicrobial foot infections, which further aggravate the already severe clinical manifestations of diabetes. Discussion The immunocompromised district (ICD) is a novel pathogenic concept referring to a site in which there is an obstacle to the normal trafficking of immunocompetent cells through lymphatic channels, and/or interference with the signals that neuropeptides and neurotransmitters, released by peripheral nerves, send to cell membrane receptors of immunocompetent cells. These loci minoris resistentiae have the propensity to develop a secondary disease, which may occur after an extremely variable length of time. Conclusions In this work, we provide an overview of etiopathogenetic mechanisms of DF and propose a unifying view of this topic based on the concept of the ICD. Diabetic Foot: Definition and Current Etiopathogenesis Diabetic foot (DF; Fig. 1) can be defined as an infection and/or ulceration with or without destruction of deep tis- sues associated with neurological abnormalities and vary- ing degrees of peripheral vascular disease of the lower limb in patients with diabetes. 1 Diabetic foot ulceration results from concurrent multi- ple contributing causes, such as peripheral neuropathy, foot trauma, foot deformity, peripheral vascular disease, foot edema, and callus formation. 1,2 Diabetic neuropathy develops as a result of hypergly- cemia-induced metabolic abnormalities that lead to nerve dysfunction and ischemia. 3 Motor neuropathy of the foot causes the weakening and wasting of small intrinsic muscles, leading to the instability of joints and consequent deformities that favor foot ulceration. 4 Auto- nomic neuropathy is a common finding in patients with longstanding diabetes. The involvement of vasomotor nerves induces the opening of the arteriovenous shunts, leading to a neuropathic edema. Autonomic neuropathy is also responsible for the decreased activity of sweat glands in the feet, which causes dryness of the skin and results in fissures that predispose the patient to risk for infection. 5 The second major etiological factor in the develop- ment of DF concerns both macrovascular and microvas- cular angiopathy. Macrocirculatory disease in patients with diabetes is identical to the atherosclerotic changes found in non-diabetic subjects; it involves the crural ves- sels and progresses much faster than in people without diabetes, inducing ulcer formation and gangrene. Micro- circulatory disease, by contrast, is unique in patients with diabetes; it involves peripheral small vessels and is thought to be provoked by functional abnormalities of microcirculation favored by an altered neurogenic con- trol mechanism, increased arteriovenous shunting, impaired postural vasoconstriction, and an impaired cutaneous hyperemic response to injury. Further factors contributing to vascular disease, caused by hyperglyce- mia, include endothelial cell dysfunctions, smooth cell abnormalities, and an increase in thromboxane A2, which induces plasma hypercoagulability. Cumulatively, each of these factors contributes to ischemia in the lower extremity and to an increased risk for ulceration in patients with diabetes. 3,6,7 Both neuropathy and vascular disease, along with the well-noted impaired immune function in patients with diabetes, contribute to the occurrence of polymicrobial foot infections, which further aggravate the already severe clinical manifestations of diabetes. 2 ª 2013 The International Society of Dermatology International Journal of Dermatology 2014, 53, 263–266 263