Viruses and pemphigus: an intriguing never-ending story.

Virus infections and autoimmunity have long been linked. As to pemphigus, many studies have been directed to prove or rule out the possibility of viral induction. Herpesviruses have often been related to the onset or reactivation of pemphigus. The association may be (i) casual, (ii) due to the iatrogenic immunosuppression facilitating opportunistic viral infections or (iii) based on a pathogenic link between the viral presence and the host's dysregulated immune response leading to autoimmunity. Japanese researchers, using real-time polymerase chain reaction, lately detected herpes simplex virus DNA in the saliva from pemphigus patients at the earliest stage of the disease and with no signs or history of herpetic infection, thus confirming the possible existence of cases of pemphigus induced by herpesviruses. These selected cases could be included into the innovative concept of 'paraviral eruptions', where an inciting role for induction may be played by the concomitant intake of certain drugs.

Wolf's post-herpetic isotopic response: Infections, tumors, and immune disorders arising on the site of healed herpetic infection.

Herpes simplex viruses (HSV-1/HSV-2) and varicella-zoster virus (VZV) have several characteristics in common. Both are epidermoneurotropic, cause skin eruptions accompanied by sensory symptoms (itch, pain), damage peripheral sensory nerve fibers and cutaneous nerve endings, and interfere with neuromediator release, which can alter local mechanisms of immune control. For this reason, herpes-infected areas may become a preferential location for the subsequent onset of immunity-related skin disorders (infections, tumors, and dysimmune reactions), an event first reported by a neurologist and focused on by two brothers, a dermatologist and a pediatrician. The phenomenon therefore named Wolf's post-herpetic isotopic response (PHIR) refers to the occurrence of a new skin disorder at the site of a previous and already healed herpetic eruption (herpes zoster in most cases). Until now, we have been able to gather 189 well-documented cases of PHIR (all reported in the reference section), but our list is far from being complete. Some of the most emblematic cases are briefly described here. In some circumstances, the opposite of PHIR occurs, with diffuse skin disorders or eruptions that selectively spare herpes-infected areas (Wolf's post-herpetic isotopic nonresponse). Experimental investigations with patch testing have been performed in seven patients who were sensitized to nickel and had had herpes zoster in the past years. The tests were carried out bilaterally on the affected dermatomes and on the unaffected contralateral ones. The uneven immune responses we obtained have shown that the immune behavior of an herpes zoster-affected dermatome can be different from that of the corresponding contralateral dermatome, thus supporting the existence of immune dysregulation in herpes-infected areas.

The immunocompromised district in dermatology: A unifying pathogenic view of the regional immune dysregulation.

Besides the systemic immune deficiency, a sectorial default in immune control may occur in immunocompetent subjects. This regional immune defect can appear and remain confined to differently damaged skin areas, lately labeled immunocompromised districts (ICDs). An ICD is a skin area more vulnerable than the rest of the body for genetic or acquired reasons. Its vulnerability mainly consists in a local dysregulation of the immune control, which often facilitates (but sometimes hinders) the local onset of immunity-related eruptions or skin disorders. The factors responsible for localized immune dysregulation are multifarious, being represented by chronic lymphatic stasis, herpetic infections, ionizing or ultraviolet (UV) radiations, burns, all sorts of trauma (especially amputation), tattooing, intradermal vaccinations, and others of disparate nature (eg, paralytic stroke, poliomyelitis). Whatever the cause, in time an ICD may become a vulnerable site, prone to developing opportunistic infections, tumors, or dysimmune reactions (often of granulomatous type), strictly confined to the district itself; however, the opposite may also occur with systemic immune disorders or malignancies that selectively spare the district. In any case, the immunologic behavior of an ICD is different from that of the rest of the body. The pathomechanisms involved in this sectorial immune destabilization may reside in locally hampered lymph drainage that hinders the normal trafficking of immunocompetent cells (eg, chronic lymphedema, posttraumatic lymph stasis) or in a damage to sensory nerve fibers that release immunity-related peptides (eg, herpetic infections, carpal tunnel syndrome), or in both conditions (eg, amputation stump, radiation dermatitis). The ICD is a conceptual entity with no definite shape or dimension. It may take an extremely variable form and extent depending on the causative agent, ranging from a minimal area (eg, intradermal vaccination) or a small area (eg, herpes simplex infection), through a wide area (eg, radiotherapy), a bandlike segment (eg, skin mosaicism, herpes zoster infection), or an acral area (eg, carpal tunnel syndrome), up to a whole limb (eg, Stewart-Treves syndrome) or even an entire half body (eg, brain stroke). Varied newly coined terminology can be used to indicate the specific cause each time that it is responsible for a regional immune dysregulation. The advantage of the umbrella term ICD is that it encompasses all the possible causes involved in a local immune destabilization. An ICD may have a congenital or a postnatal origin, and interesting similarities between the two forms exist. An ICD may also take place in patients with a preexisting systemic immune deficiency, thus creating a more vulnerable site in an already vulnerable patient. Identifying a cutaneous ICD in a given patient is an important standpoint for both diagnostic and prevention purposes. This can be proven by the educative clinical examples that are reported here.

Monolesional Kaposi sarcoma at the site of slow healing herpes zoster in an HIV+ patient: immunocompromised district in an immunocompromised patient.

Besides the well-known systemic immune deficiency, also a regional immune deficiency, labeled as "immunocompromised district" (ICD), has been documented and focused in the recent years. The objective of the study is to gain more insights into the mechanisms involved in systemic and local immune destabilization. A 35-year-old, homosexual, and drug-addicted HIV+ man presented with a single nodule of Kaposi sarcoma (KS) located on the penis, where a slow to heal herpes zoster had appeared 2 months before. It has been assumed that the unusual penile location of herpes zoster facilitated the outbreak of KS in the affected dermatome because of a viral damage to sensory nerve fibers of the same dermatome. This damage, by interfering with the immunoregulatory function of neuropeptides released by nerve endings in that area, may have caused a regional alteration of the immune control favoring the local onset of the "opportunistic" angiogenic tumor (KS). In a few words, an ICD took place in an immunocompromised patient, thus introducing a more vulnerable site in an already vulnerable subject. The present case is the second one in the literature to document an ICD in the setting of preexisting systemic immune deficiency.

Pemphigus: associations and management guidelines: facts and controversies.

Pemphigus, a prototypical organ-specific human autoimmune disease, may be associated with other immunity-related disorders, viral infections, and different types of tumors. Coexistence with immune diseases is fairly frequent and, for some of them (eg, myasthenia gravis, Basedow's disease, rheumatoid arthritis, or lupus erythematosus), common pathogenic mechanisms can be considered. The association with viral infections (mainly herpesvirus infections) raises the question of whether the virus triggers the outbreak of the disease or simply complicates its clinical course. Neoplastic proliferations coexisting with pemphigus have a different histogenesis and the pathogenic link may vary according to the associated tumor (thymoma, lymphoma, carcinoma, or sarcoma). A subset of pemphigus-neoplasia association is represented by Anhalt's paraneoplastic pemphigus, with peculiar clinical, histologic, and immunologic features characterizing it. Coexistence of pemphigus with Kaposi's sarcoma, albeit not frequent, offers an intriguing speculative interest. The cornerstone of management in pemphigus is the combination of systemic corticosteroids and immunosuppressants. The conventional treatment used in most cases is based on oral administration of deflazacort and azathioprine. In selected cases, mycophenolate mofetil is preferred to azathioprine. Severe forms of pemphigus require intravenous pulse therapy with dexamethasone (or methylprednisolone) and cyclophosphamide. In the recent years, the use of high-dose intravenous immunoglobulin therapy has gained several consents. Rituximab, a monoclonal anti-CD 20 antibody, which affects both the humoral and cell-mediated responses, has proved to give a good clinical response, often paralleled by decrease of pathogenic autoantibodies. The combination with intravenous immunoglobulin offers the double advantage of better clinical results and a reduced incidence of infection. Interventional treatments, such as plasmapheresis and extracorporeal immunoadsorption, are aimed at patients with life-threatening forms of pemphigus and high levels of circulating autoantibodies, a circumstance where the medical therapy alone risks failing. Second-line treatments include gold salts (which we do not favor because of the acantholytic potential inherent in thiol structure) and the association of oral tetracyclines with nicotinamide, which is rather safe. Local treatments, supplementary to the systemic therapy, are aimed at preventing infections and stimulating reepithelialization of eroded areas. Innovative topical treatments are epidermal growth factor, nicotinamide gel, pimecrolimus, and a proteomics-derived desmoglein peptide. Pemphigus patients should be warned against over-indulging in unnecessary drug intake, prolonged exposure to ultraviolet rays, intense emotional stress, and too spiced or too hot foods. Cigarette smoking is not contraindicated in pemphigus patients because of the nicotine anti-acantholytic properties.

Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies.

Pemphigus includes a group of autoimmune bullous diseases with intraepithelial lesions involving the skin and Malpighian mucous membranes. Pemphigus vulgaris (PV), the most frequent and representative form of the group, is a prototypical organ-specific human autoimmune disorder with a poor prognosis in the absence of medical treatment. The pathomechanism of PV hinges on autoantibodies damaging cell-cell cohesion and leading to cell-cell detachment (acantholysis) of the epidermis and Malpighian mucosae (mainly oral mucosa). A controversy exists about which subset of autoantibodies is primarily pathogenic: the desmoglein-reactive antibodies or those directed against the acetylcholine receptors of the keratinocyte membrane. The onset and course of PV depend on a variable interaction between predisposing and inducing factors. Genetic predisposition has a complex polygenic basis, involving multiple genetic loci; however, the genetic background alone ("the soil"), although essential, is not by itself sufficient to initiate the autoimmune mechanism, as proven by the reports of PV in only one of two monozygotic twins and in only two of three siblings with an identical PV-prone haplotype. The intervention of inducing or triggering environmental factors ("the seed") seems to be crucial to set off the disease. The precipitating factors are many and various, most of them directly originating from the environment (eg, drug intake, viral infections, physical agents, contact allergens, diet), others being endogenous (eg, emotional stress, hormonal disorders) but somehow linked with the subject's lifestyle. As to certain drugs, their potential of provoking acantholysis may be implemented by their interfering with the keratinocyte membrane biochemistry (biochemical acantholysis) and/or with the immune balance (immunologic acantholysis). Viral infections, especially the herpetic ones, may trigger the outbreak of PV or simply complicate its clinical course. The precipitating effect might be due to interferons and other cytokines released by the host as a consequence of the viral attack, which overactivate the immune response. Inductions of PV by physical agents (ultraviolet or ionizing radiation, thermal or electrical burns, surgery and cosmetic procedures), contact allergens (in particular, organophosphate pesticides), dietary factors (eg, garlic, leek, onion, black pepper, red chili pepper, red wine, tea), and emotional stress are rare, but well-documented events. The possible intervention of the environment in the outbreak of PV has been overlooked in the past, but nowadays clinicians perceive it more frequently. The assumption that genetic factors alone are not sufficient to cause the outbreak of the disease, inevitably instills the idea that PV may not occur spontaneously, but always results from an interaction between an individual predisposing genetic background and environmental precipitating factors, often concealed or apparently harmless.

Discoid lupus erythematosus at a site of previous injury.

A 71-year-old man with three patches of discoid lupus erythematosus (DLE) confined to the right preauricular region drew our attention because of the unusual linear arrangement of the lesions. Twenty-five years previously, the patient had suffered a trauma in the same area from falling off his motorcycle. We believe that, despite the great lapse in time, this injury may have facilitated the onset of DLE in the very same area, through long-term destabilization of the local neuroimmune network. The case fits the recently coined concept of the immunocompromised district, a cutaneous region with altered immune control, more susceptible to harbouring opportunistic infections, tumours, and immune disorders.

Beyond zoster: sensory and immune changes in zoster-affected dermatomes: a review*.

Neuroepidermal tropism of varicella-zoster virus accounts for cutaneous and nerve lesions following herpes zoster. Skin lesions heal in a few weeks and may or may not leave visible scars. Nerve lesions involve peripheral sensory fibres, sometimes causing permanent damage that results in partial denervation of the affected dermatome. The effects of the nerve injury involve the sensibility function, thus causing neuralgia, itch, allodynia, hypo- or anaesthesia, as well as the immune function that is related to neuropeptide release, thus altering immune control in the affected dermatome. The neuro-immune destabilization in the zoster-infected site paves the way for the onset of many and various immunity-related disorders along the affected dermatome.

Opportunistic localization of skin lesions on vulnerable areas.

Genetic, developmental, and immune defects can make certain anatomic areas of the body more prone than others to harbor skin lesions. Cutaneous areas with skin barrier dysfunction (eg, atopic dermatitis) are the clearest example of vulnerable sites where opportunistic diseases, mainly infections (eg, herpes simplex), can easily occur. Somatic mosaicism, by giving rise to mutated cell clones with a bandlike arrangement, may form tissue segments prone to developing congenital or acquired skin disorders. Cutaneous districts that have been infected by herpes viruses become sites permissive for a subsequent onset of heterogeneous skin disorders, mainly tumors, further infections, and disimmune reactions (Wolf isotopic response). Regional lymphedema, by impairing lymph circulation and consequently the local immune control, favors the location of immunity-related lesions in the involved district. A vast series of skin injuries, such as ionizing or ultraviolet radiation, burns, traumas, and even vaccinations, can render the affected areas vulnerable to subsequent cutaneous disorders. Lack of immune control, ensuing from locally altered neuroimmune interaction, may be the basic defect responsible for the opportunistic location of skin lesions in herpes-infected, lymphedematous, or otherwise damaged areas, together featuring the novel concept of "immunocompromised district."

Wolf's isotopic response.

The term "isotopic response" was coined by Wolf et al in 1995 to describe the occurrence of a new skin disorder at the site of another unrelated and already healed skin disease. When this term was found to be unsuitable for Medline searches because it generated hundreds of references that were linked with radioactive isotopes, it was changed to "Wolf's isotopic response" and eventually included as such in Stedman's Illustrated Dictionary of Dermatology Eponyms. Our search of the literature yielded 176 cases of Wolf's isotopic response. We describe this entity and present representative clinical examples. Some problems in the definition of Wolf's isotopic response are provided with special emphasis on its overlapping with the Koebner isomorphic response, a similar, but different, phenomenon. Also addressed are a number of issues associated with another term, "isotopic nonresponse," which had been introduced in analogy to the "isomorphic nonresponse" for describing the absence of an eruption at the site of another unrelated and already healed skin disease, or the sparing of the sites of another unrelated and already healed skin disease. In the spirit of the present issue, this contribution discusses only the clinical morphology and not the etiology, pathomechanism, or molecular biology of Wolf's isotopic response.

Vesicular and bullous disorders: pemphigus.

Pemphigus is a chronic, autoimmune disease involving the skin and Malpighian mucous membranes. Pemphigus leads to progressive blistering and subsequent erosions. This article describes the etiology and treatment of pemphigus.