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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: [email protected] 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 tissues associated with neurological abnormalities and varying degrees of peripheral vascular disease of the lower limb in patients with diabetes.1 Diabetic foot ulceration results from concurrent multiple 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 hyperglycemia-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 Autonomic 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 ª 2013 The International Society of Dermatology

The second major etiological factor in the development of DF concerns both macrovascular and microvascular angiopathy. Macrocirculatory disease in patients with diabetes is identical to the atherosclerotic changes found in non-diabetic subjects; it involves the crural vessels and progresses much faster than in people without diabetes, inducing ulcer formation and gangrene. Microcirculatory 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 control mechanism, increased arteriovenous shunting, impaired postural vasoconstriction, and an impaired cutaneous hyperemic response to injury. Further factors contributing to vascular disease, caused by hyperglycemia, 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 International Journal of Dermatology 2014, 53, 263–266

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Local neuroimmune impairment in diabetic foot

Figure 1 Foot ulceration in a patient with diabetes

The aim of this article is to provide an overview of the etiopathogenetic mechanisms of DF and to propose a unifying view of this topic based on the concept of the immunocompromised district (ICD). The Immunocompromised District In 1955 Wyburn-Mason described a series of 26 patients with malignant tumors that developed at sites previously affected by herpes zoster or simplex lesions.8 He observed that the location of malignancy precisely at the site of an antecedent herpetic infection was not a mere coincidence.8 This phenomenon was subsequently designated an isotopic response by Wolf et al.,9 who described the occurrence of a new, different skin disorder at the site of a previously unrelated and already healed cutaneous disease, in most cases a herpetic infection. In 1982 Ruocco et al.,10 observed an instance of Stewart–Treves syndrome in a lymphedematous limb, demonstrating for the first time, through intradermoreaction to purified protein derivative (PPD), candidin, and phytohemagglutinin (PHA), a local immune impairment in the affected limb and paving the way for the subsequent concept of the immunocompromised district. The ICD is a more extensive novel concept, which includes Wolf’s isotopic response,9 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.11 In International Journal of Dermatology 2014, 53, 263–266

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these loci minoris resistentiae, there is the propensity to develop a secondary disease, which may occur after an extremely variable period of time. Ruocco et al.,11 have recently extended the spectrum of ICD to embrace various conditions that predispose to the harboring of secondary diseases, including chronic lymphedema, herpetic infection (Wolf’s isotopic response9), vaccination, and physical injuries. The term immunocompromised generically indicates an alteration of the immune response, not necessarily a reduction of it.12 Depending on which of the neurotransmitters and immune cells are involved, this destabilization may be either defective, and predispose to infections and tumors, or excessive, and favor the occurrence of some diseases, such as bullous pemphigoid, pemphigus, lichen planus, discoid lupus erythematosus, drug eruptions, and acne.11,13,14 A large body of evidence demonstrates that the skin, nervous system, and immunity are not independent systems but are closely associated in what has been described as the neuroimmunocutaneous system.15,16 When the neuroimmunocutaneous system is destabilized in a given district, whatever the cause (nerve lesion or infection, chronic lymph stasis, amputation trauma, radiodermatitis, thermal burn), the district itself becomes a vulnerable site, prone to harbor a wide range of immunity-related disorders (opportunistic infections, primary or metastatic tumors, immune reactions). The most accepted theory to explain the concept of the ICD refers to an imbalance between immunostimulating and immunosuppressive neuropeptides, favoring the occurrence of opportunistic skin disorders.11,13,17 Regular signaling between sensory fiber-secreted neuropeptides and locally recruited immune cells is a basic requirement for a normal immune response in a given cutaneous district.15,17,18 When either nerve integrity or the normal connection between peripheral nerve fibers and local immune cells is compromised,19,20 the release of neuropeptides is altered, which inevitably destabilizes local immune control. Given that some neuropeptides (e.g. substance P) are immune function stimulators, whereas others (e.g. vasoactive intestinal peptide) are immune suppressors,15 it could be assumed that the ICD can be either reduced or exaggerated, depending on the type of neuropeptide involved in the nerve fiber damage. In support of this theory, our group has recently demonstrated a marked relationship between the occurrence of some skin disorders and underlying neurological impairments. Our first observation concerned a papillomatosis cutis lymphostatica in a paraplegic patient in whom the altered production of neuroimmunomediators, cytokines, and growth factors might explain the genesis of the hyperproliferative stimulus underlying the appearance of a verrucous proliferation (papillomatosis cutis).21 ª 2013 The International Society of Dermatology

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Most recently, we observed a patient who developed recurrent hemorrhagic blistering of the fingertips on only the first three fingers of the left hand.22 This patient was affected by carpal tunnel syndrome in the left hand only; we considered the area innervated by the median nerve to be an ICD, in which the compression of nerve fibers dysregulated the release of neuropeptides and thus facilitated the blistering.22 The last example in support of this theory refers to a hemiplegic patient affected by unilateral bullous pemphigoid.13 With reference to this patient, we proposed that hemiplegia might cause a local imbalance between immunosuppressive and immunostimulating neuropeptides that facilitates the development of bullous pemphigoid in the hemiplegic side only and not elsewhere on the skin.13 Hemiplegia, which represents a triggering factor, may induce opportunistic localized bullous pemphigoid in a genetically predisposed subject. These three examples demonstrate the gradually expanding spectrum of the relatively new pathogenic concept of the ICD, which is likely to become applicable in a growing group of skin disorders. The ICD in DF Diabetic foot is known to result from different concurrent pathophysiological mechanisms.2 The major underlying causes are peripheral neuropathy (PN) and lower extremity arterial disease (LEAD).2 Other important contributing factors include infections, foot deformity, and ulceration.2 The role of each of these factors in the pathogenesis of DF is quite clear, but there is a lack of consensus on the connections between them and on how each factor might play a role in a common pathway leading to the development of DF. Referring to the model of ICD, we propose a pathogenic mechanism which might represent a unifying concept able to explain the occurrence of DF. We will consider separately three different pathophysiological factors implicated in the pathogenesis of DF: PN, LEAD, and infections. Peripheral neuropathy affects all the fibers of the nervous system, including the sensory, motor, and autonomic fibers. The most common pathway to ulceration is thought to involve peripheral sensorimotor and autonomic neuropathy and to lead to a loss of sensitivity which might favor the occurrence of foot ulcers.2 We think that, although this theory is quite interesting, DF aligns with the concept of the ICD. Peripheral neuropathy damages nerve fibers, thereby inducing a dysregulation in the local release of neuropeptides. In analogy with the recurrent blistering that occurs in carpal tunnel syndrome, an imbalance between immunosuppressive and immunostimulating neuropeptides would alter local immune response and favor the development of DF. ª 2013 The International Society of Dermatology

Local neuroimmune impairment in diabetic foot

Updates in medicine

It has been hypothesized that peptides normally secreted from the terminal nerve are also important in the pathophysiology of Charcot foot in diabetes.23 Among these substances, calcitonin gene-related peptide (CGRP) is a likely candidate because it is known to antagonize the synthesis of the receptor activator of nuclear factor-kB ligand (RANKL).23–25 Hence, any reduction of CGRP through nerve damage will result in an increase in RANKL expression.23–25 Another element in favor of our hypothesis is LEAD.2 Angiopathy may be both macrovascular and microvascular. In particular, diabetes mellitus is a disorder that primarily affects the microvascular circulation. In the extremities, microvascular disease caused by sugar-coated capillaries limits the blood supply to the superficial and deep structures. Pressure caused by ill-fitting shoes or trauma further compromises the local blood supply at the microvascular level, predisposing the patient to infections, which may involve the skin, soft tissues, bone, or all of these in combination. Vascular flow alterations resulting in lymphedema26 are included among the major factors responsible for the development of an ICD because they impede the normal trafficking of immunocompetent cells through lymphatic channels. Recently, phlebolymphedema has been added to this growing list of causes of an ICD.27 As in lymphedema, the impaired microvascular circulation favors a local anomaly in immune control because it hinders white blood cell migration into the area of interest, predisposing to infections. Both PN and LEAD, along with diabetic impaired immune function, such as the lower efficiency of glycosylated immune proteins and, importantly, neutrophil dysfunction, predispose to the occurrence of infections that occur in the principal locally immunocompromised area, the foot. The destabilization of immune control in the ICD may result in a local reduction in immunity that favors the local onset of opportunistic infections or a locally exaggerated activation of immunity, which accounts for the outbreak of dysimmune reactions (ulcers in DF) that are restricted to the district itself. In conclusion, we think that the concept of the ICD could be considered as representative of the hitherto missing link between the various factors and outcomes in DF and might lead to the development of a coherent basis upon which the foundations for further research on this topic and its potential prevention and treatment can be laid. References 1 Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 1999; 22: 157–162. International Journal of Dermatology 2014, 53, 263–266

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2 Dinh TL, Veves A. A review of the mechanisms implicated in the pathogenesis of the diabetic foot. Int J Low Extrem Wounds 2005; 4: 154–159. 3 Simmons Z, Feldman EL. Update on diabetic neuropathy. Curr Opin Neurol 2002; 15: 595–603. 4 Andersen H. Motor dysfunction in diabetes. Diabetes Metab Res Rev 2012; 28: 89–92. 5 Vinik AI, Maser RE, Mitchell BD, et al. Diabetic autonomic neuropathy. Diabetes Care 2003; 26: 1553– 1579. 6 Veves A, Akbari CM, Primavera J, et al. Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes 1998; 47: 457–463. 7 Caballero AE, Arora S, Saouaf R, et al. Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 1999; 48: 1856–1862. 8 Wyburn-Mason R. Malignant change arising in tissues affected by herpes. Br Med J 1955; 2: 1106–1109. 9 Wolf R, Brenner S, Ruocco V, et al. Isotopic response. Int J Dermatol 1995; 34: 341–348. 10 Ruocco V, Pisani M, Astarita C. Syndrome de Stewart– Treves avec deficit regional de limmunite cellulare possibile: hypothese pathogenique. Ann Dermatol Venereol 1982; 109: 489–492. 11 Ruocco V, Brunetti G, Puca RV, et al. The immunocompromised district: a unifying concept for lymphedematous, herpes-infected and otherwise damaged sites. J Eur Acad Dermatol Venereol 2009; 23: 1364– 1373. 12 Ruocco V, Ruocco E, Brunetti G, et al. The correct meaning of the term immunocompromised: a necessary explanation. J Eur Acad Dermatol Venereol 2011; 25: 1242. 13 Piccolo V, Russo T, Baroni A. Unilateral bullous pemphigoid in hemiplegic patients: an instance of immunocompromised district. J Dermatol 2012; 40: 64– 65. 14 Sardana K, Relhan V, Sehgal VN, et al. Occurrence of acne comedones over healed linear scar of herpes zoster: a neurogenic perception. J Eur Acad Dermatol Venereol 2007; 21: 431–432.

15 Misery L. Skin, immunity and the nervous system. Br J Dermatol 1997; 137: 843–850. 16 Lotti T, Bianchi B, Panconesi E. Neuropeptides and skin disorders. The new frontiers of neuro-endocrine-cutaneous immunology. Int J Dermatol 1999; 38: 673–675. 17 Ruocco V, Sangiuliano S, Brunetti G, et al. Beyond zoster: sensory and immune changes in zoster-affected dermatomes: a review. Acta Derm Venereol 2012; 92: 378–382. 18 Ruocco V, Ruocco E, Brunetti G, et al. Achilles heel in dermatology. J Eur Acad Dermatol Venereol 2010; 24: 1119–1120. 19 Muller SA, Winkelmann RK. Cutaneous nerve changes in zoster. J Invest Dermatol 1969; 52: 71–77. 20 Oaklander AL. The density of remaining nerve endings in human skin with and without post-herpetic neuralgia after shingles. Pain 2001; 92: 139–145. 21 Baroni A, Ruocco V, Di Maio R, et al. Papillomatosis cutis arising on an immuno-compromised district due to paraplegia. Br J Dermatol 2010; 163: 646–648. 22 Baroni A, Piccolo V, Russo T, et al. Recurrent blistering of the fingertips as a sign of carpal tunnel syndrome: an effect of nerve compression. Arch Dermatol 2012; 148: 545–546. 23 Rogers LC, Frykberg RG, Armstrong DJ, et al. The Charcot foot in diabetes. Diabetes Care 2011; 34: 2123– 2129. 24 Jeffcoate WJ, Game F, Cavanagh PR. The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes. Lancet 2005; 366: 2058–2061. 25 Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 2008; 473: 139–146. 26 Ruocco V, Schwartz RA, Ruocco E. Lymphedema: an immunologically vulnerable site for development of neoplasms. J Am Acad Dermatol 2002; 47: 124–127. 27 Ruocco E, Brunetti G, Brancaccio G, et al. Phlebolymphedema: disregarded cause of immunocompromised district. Clin Dermatol 2012; 30: 541–543.

Updates in medicine

International Journal of Dermatology 2014, 53, 263–266

ª 2013 The International Society of Dermatology

Relationship between local neuroimmune impairment and diabetic foot: the immunocompromised district theory.

Diabetic foot (DF) can be defined as an infection and/or an ulceration with or without destruction of deep tissues associated with neurological abnorm...
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