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Background: A new variant of endemic pemphigus foliaceus in El Bagre (El Bagre-EPF), Colombia, South America, shares features with Senear-Usher syndrome and occurs in an endemic fashion. Patients affected by El Bagre-EPF have heterogeneous antigenic reactivity not only to the skin but to other organs, including the heart. Here we test for autoantibodies to the areae compositae of the heart (structure consisting of typical desmosomal amalgamated fascia adherens molecules) and evaluate any possible clinical correlation., Methods: A case-control study comparing 45 patients and 45 controls from the endemic area, matched by demographics including age, gender, weight, work activities, and comorbidities, was performed. Direct and indirect immunofluorescence, immunohistochemistry, confocal microscopic studies, and echocardiogram studies were completed., Results: The main clinical abnormally seen in the El Bagre-EPF patients was left ventricular hypertrophy in 15/45 patients, compared with no such findings in the control population (P < 0.1). Seventy percent of El Bagre-EPF patients and none of the controls displayed polyclonal autoreactivity using different immunoglobulins and complement to the areae compositae of the heart using different methods and antibodies (P < 0.1)., Conclusions: Patients affected by El Bagre-EPF demonstrated autoantibodies to the areae compositae of the heart. This finding was associated with left ventricular hypertrophic cardiomyopathy. The areae compositae may play a role in cell junction tension and the El Bagre-EPF patients' autoantibodies possibly disrupting these junctions and thereby contributing to the left ventricular hypertrophy., Competing Interests: Competing interests: The authors have no conflicts of interest to disclose.

Background: We have described a variant of endemic pemphigus foliaceus (EPF) in El Bagre area known as pemphigus Abreu-Manu. Our previous study suggested that Colombian EPF seemed to react with various plakin family proteins, such as desmoplakins, envoplakin, periplakin BP230, MYZAP, ARVCF, p0071 as well as desmoglein 1., Objectives: To explore whether patients affected by a new variant of endemic pemphigus foliaceus (El Bagre-EPF) demonstrated oral involvement., Materials and Methods: A case-control study was done by searching for oral changes in 45 patients affected by El Bagre-EPF, as well as 45 epidemiologically matched controls from the endemic area matched by demographics, oral hygiene habits, comorbidities, smoking habits, place of residence, age, sex, and work activity. Oral biopsies were taken and evaluated via hematoxylin and eosin staining, direct immunofluorescence, indirect immunofluorescence, confocal microscopy, and immunohistochemistry., Results: Radicular pieces and loss of teeth were seen in in 43 of the 45 El Bagre-EPF patients and 20 of the 45 controls (P < 0.001) (confidence interval [CI] 98%). Hematoxylin and eosin staining showed 23 of 45 El Bagre-EPF patients had corneal/subcorneal blistering and lymphohistiocytic infiltrates under the basement membrane zone and around the salivary glands, the periodontal ligament, and the neurovascular bundles in all cell junction structures in the oral cavity; these findings were not seen in the controls (P < 0.001) (CI 98%). The direct immunofluorescence, indirect immunofluorescence, confocal microscopy, and microarray staining displayed autoantibodies to the salivary glands, including their serous acini and the excretory duct cell junctions, the periodontal ligament, the neurovascular bundles and their cell junctions, striated muscle and their cell junctions, neuroreceptors, and connective tissue cell junctions. The autoantibodies were polyclonal. IgA autoantibodies were found in neuroreceptors in the glands and were positive in 41 of 45 patients and 3 of 45 controls., Conclusions: Patients affected by El Bagre-EPF have some oral anomalies and an immune response, primarily to cell junctions. The intrinsic oral mucosal immune system, including IgA and secretory IgA, play an important role in this autoimmunity. Our data contradict the hypothesis that pemphigus foliaceus does not affect the oral mucosa due to the desmoglein 1-desmoglein 3 compensation., Competing Interests: Competing interests: The authors have no conflicts of interest to disclose.

Background: The majority of the patients affected by a new variant of endemic pemphigus foliaceus in El Bagre, Colombia (El Bagre EPF or pemphigus Abreu-Manu), have experienced vision problems; we have previously reported several ocular abnormalities., Methods: Here, we aimed to investigate reactivity to optic nerves in these patients. We utilized bovine, rat and mouse optic nerves, and performed immunofluorescence and confocal microscopy to test for optical nerve autoreactivity. We tested 45 patients affected by this disease and 45 controls from the endemic area matched by age, sex and work activity., Results: Overall, 37 of the 45 patient sera reacted to the optic nerve envelope that is composed of leptomeninges; the reactivity was polyclonal and present mostly at the cell junctions (P < 0.001). The immune response was directed against optic nerve sheath cell junctions and the vessels inside it, as well as other molecules inside the nerve. No control cases were positive. Of interest, all the patient autoantibodies co-localized with commercial antibodies to desmoplakins I-II, myocardium-enriched zonula occludens-1- associated protein (MYZAP), armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), and plakophilin-4 (p0071) from Progen Biotechnik (P < 0.001)., Conclusion: We conclude that the majority of the patients affected by pemphigus Abreu-Manu have autoantibodies to optic nerve sheath envelope cell junctions. These antibodies also co-localize with armadillo repeat gene deleted in velo-cardio-facial syndrome, p0071 and desmoplakins I-II. The clinical significance of our findings remains unknown., Competing Interests: Competing interests: The authors have no conflicts of interest to disclose.

Background: We previously described a new variant of endemic pemphigus foliaceus in El Bagre, Colombia, South America (El Bagre-EPF, or pemphigus Abreu-Manu). El Bagre-EPF differs from other types of EPF clinically, epidemiologically, immunologically and in its target antigens. We reported the presence of patient autoantibodies colocalizing with armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), a catenin cell junction protein colocalizing with El Bagre-EPF autoantibodies in the heart and within pilosebaceous units along their neurovascular supply routes. Here we investigate the presence of ARVCF in skin and its possibility as a cutaneous El Bagre-EPF antigen., Methods: We used a case-control study, testing sera of 45 patients and 45 controls via direct and indirect immunofluorescence (DIF/IIF), confocal microscopy, immunoelectron microscopy and immunoblotting for the presence of ARVCF and its relationship with El Bagre-EPF autoantibodies in the skin. We also immunoadsorbed samples with desmoglein 1 (Dsg1) ectodomain (El Bagre-EPF antigen) by incubating with the positive ARVCF samples from DIF and IIF., Results: ARVCF was expressed in all the samples from the cases and controls. Immunoadsorption with Dsg1 on positive ARVCF immunofluorescence DIF/IIF cases showed that the immune response was present against non-desmoglein 1 antigen(s). Overall, 40/45 patients showed colocalization of their autoantibodies with ARVCF in the epidermis; no controls from the endemic area displayed colocalization., Conclusions: We demonstrate that ARVCF is expressed in many areas of human skin, and colocalizes with the majority of El Bagre-EPF autoantibodies as a putative antigen., Competing Interests: Competing interests: The authors have no conflicts of interest to disclose.

Background: In many countries and laboratories, techniques such as direct immunofluorescence (DIF) are not available for the diagnosis of skin diseases. Thus, these laboratories are limited in the full diagnoses of autoimmune skin diseases, vasculitis, and rheumatologic diseases. In our experience with these diseases and the patient's skin biopsies, we have noted a positive correlation between periodic acid-Schiff (PAS) staining and immunofluorescence patterns; however, these were just empiric observations. In the current study, we aim to confirm these observations, given the concept that the majority of autoantibodies are glycoproteins and should thus be recognized by PAS staining., Aims: To compare direct immunofluorescent and PAS staining, in multiple autoimmune diseases that are known to exhibit specific direct immunofluorescent patterns., Materials and Methods: We studied multiple autoimmune skin diseases: Five cases of bullous pemphigoid, five cases of pemphigus vulgaris, ten cases of cutaneous lupus, ten cases of autoimmune vasculitis, ten cases of lichen planus (LP), and five cases of cutaneous drug reactions (including one case of erythema multiforme). In addition, we utilized 45 normal skin control specimens from plastic surgery reductions., Results: We found a 98% positive correlation between DIF and PAS staining patterns over all the disease samples., Conclusion: We recommend that laboratories without access to DIF always perform PAS staining in addition to hematoxylin and eosin (H&E) staining, for a review of the reactivity pattern.

Background: Autoimmune vesiculobullous disorders represent a heterogeneous group of dermatoses whose diagnosis is made based on clinical history, histologic features, and immunopathologic features. The most commonly used techniques for the diagnosis of these diseases are direct and indirect immunofluorescence (DIF and IIF), including salt-split processing. NaCl split skin is used to determine the level of blister formation, and the localization of autoantibodies relative to the split. Classically, immunofluorescence has been performed with one fluorochrome in the diagnosis of autoimmune bullous skin diseases., Aims: To compare DIF and IIF of the skin, using a single fluorochrome versus multiple fluorochromes., Materials and Methods: We studied 20 autoimmune skin disease cases using fluorescein isothiocyanate (FITC) alone, in comparison to multiple fluorochromes (with or without DNA counterstaining)., Results: The use of multiple fluorochromes helped to simultaneously visualize reactivity in multiple skin areas, in contrast to using FITC alone., Conclusions: Using multiple fluorochromes allows simultaneous labeling of two or more antigens within the same cell/or tissue section, assists in colocalization of unknown antigens with known molecules, and helps in ruling out "background" staining.

Background: Sebaceoma is a tumor for which the causative oncogenes are not well-understood. Sebaceomas demonstrate some histopathologic features similar to basal cell carcinoma (BCC), such as palisading borders and basaloid cells with additional features, including foamy cytoplasm and indented nuclei., Aims: We examine multiple cell-cycle, oncogene, and tumor suppressor gene markers in sebaceomas, to try to find some suitable biological markers for this tumor, and compare with other published studies., Materials and Methods: We investigated a panel of immunohistochemical (IHC) stains that are important for cellular signaling, including a cell cycle regulator, tumor suppressor gene, oncogene, hormone receptor, and genomic stability markers in our cohort of sebaceomas. We collected 30 sebaceomas from three separate USA dermatopathology laboratories. The following IHC panel: Epithelial membrane antigen (EMA)/CD227, cytokeratin AE1/AE3, cyclin D1, human breast cancer 1 protein (BRCA-1), C-erb-2, Bcl-2, human androgen receptor (AR), cyclin-dependent kinase inhibitor 1B (p27(kip1)), p53, topoisomerase II alpha, proliferating cell nuclear antigen, and Ki-67 were tested in our cases., Results: EMA/CD227 was positive in the well-differentiated sebaceomas (13/30). Cyclin-dependent kinase inhibitor 1B was positive in tumors with intermediate differentiation (22/30). The less well-differentiated tumors failed to stain with EMA and AR. Most of the tumors with well-differentiated palisaded areas demonstrated positive staining for topoisomerase II alpha, p27(kip1), and p53, with positive staining in tumoral basaloid areas (22/30). Numerous tumors were focally positive with multiple markers, indicating a significant degree of variability in the complete group., Conclusions: Oncogenes, tumor suppressor genes, cell cycle regulators, and hormone receptors are variably expressed in sebaceomas. Our results suggest that in these tumors, selected marker staining seems to correlate with tumor differentiation; that is, well-differentiated tumors as a group stained with EMA and AR, and palisaded areas demonstrated consistent p53, topoisomerase II alpha and p27(kip1) staining. In contrast, less well-differentiated areas stained with a different spectrum of markers.

Palmoplantar lichen planus is an uncommon dermatosis. We present a case of 38-year-old Caucasian male with a history of pruritic, scaly lesions on the right plantar foot. Physical examination revealed whitish plaques and numerous spiny hyperkeratotic papules and focal scaling. A biopsy demonstrated orthohyperkeratosis and acanthosis of the epidermis. Immunohistochemical staining revealed positivity within the epidermis and/or lichenoid infiltrate with CD3, CD8, CD45, CD68, myeloid histiod antigen, BCL2, p27, p53, HLA-DPDQDR, metallothionein and tissue inhibitor of metalloproteinases 1. The diagnosis of PPLP was thus confirmed; this case illustrates that PPLP should be considered in the differential diagnosis of uncommon foot dermatoses with a significant junctional inflammatory component.

The cell cycle (or cell-division cycle) is a series of events that take place in a cell, leading to its division and duplication. Cell division requires cell cycle checkpoints (CPs) that are used by the cell to both monitor and regulate the progress of the cell cycle. Tumor-suppressor genes (TSGs) or antioncogenes are genes that protect the cell from a single event or multiple events leading to cancer. When these genes mutate, the cell can progress to a cancerous state. We aimed to perform a narrative review, based on evaluation of the manuscripts published in MEDLINE-indexed journals using the Medical Subject Headings (MeSH) terms "tumor suppressor's genes," "skin," and "cell cycle regulatory checkpoints." We aimed to review the current concepts regarding TSGs, CPs, and their association with selected cutaneous diseases. It is important to take into account that in some cell cycle disorders, multiple genetic abnormalities may occur simultaneously. These abnormalities may include intrachromosomal insertions, unbalanced division products, recombinations, reciprocal deletions, and/or duplication of the inserted segments or genes; thus, these presentations usually involve several genes. Due to their complexity, these disorders require specialized expertise for proper diagnosis, counseling, personal and family support, and genetic studies. Alterations in the TSGs or CP regulators may occur in many benign skin proliferative disorders, neoplastic processes, and genodermatoses.

Background: The in situ signaling transduction within skin biopsies from patients affected by autoimmune skin blistering diseases is not well-characterized., Aim: In autoimmune skin blistering diseases, autoantibodies seem to trigger several intracellular signaling pathways and we investigated the presence of the phosphorylated form of ribosomal protein S6-pS240 within autoimmune skin blistering diseases biopsies., Materials and Methods: We utilized immunohistochemistry to evaluate the presence of S6-pS240 in lesional skin biopsies of patients affected by autoimmune skin blistering diseases including patients with an endemic and nonendemic pemphigus foliaceus (non EPF), with bullous pemphigoid (BP), pemphigus vulgaris (PV), dermatitis herpetiformis (DH), and the respective controls., Results: Most autoimmune bullous skin diseases biopsies stained positive for S6-pS240 around lesional blisters, including adjacent areas of the epidermis; and within upper dermal inflammatory infiltrates, and/or mesenchymal-endothelial cell junctions within the dermis., Conclusions: We document that S6-pS240 is expressed in lesional areas of skin biopsies from patients with autoimmune skin blistering diseases, as well as on eccrine glands and piloerector muscles. Thus, the role of this molecule in autoimmune skin blistering diseases warrants further study.

The immune response in metastatic melanoma is not well established and therefore is of particular interest to test for recruitment of immune cells to the tumor. A 46-year-old Caucasian female was evaluated for an asymptomatic right forearm mass. The lesion had been present for at least 4 years and had become painful 4 months ago. Biopsies for hematoxylin and eosin (H and E) staining, as well as immunohistochemical analysis were performed on the primary tumor and on sentinel lymph nodes. The H and E staining was consistent with metastatic melanoma. Positive staining was noted on the tumor cells with S-100, Mart-1/Melan A/CD63, PNL2, HMB45, and tyrosinase. Peritumoral and intratumoral inflammatory cells stained positive for CD8, CD45, PCNA, myeloid histoid antigen, antihuman plasma cell antibody, and focal BRCA1. The staining patterns of CD8/CD45, myeloid histoid antigen and plasma cell antibody on inflammatory cells around the melanoma cells suggest an unusual type of immune response.

Background: A characteristic feature of early active psoriatic lesions is the intraepidermal penetration of neutrophils, with attendant formation of Munro-Saboureau microabscesses. Previous immunofluorescence studies have shown reactivity of in vivo binding of stratum corneum antibodies (SCAs) within the Munro-Saboreau microabscesses in cases of psoriasis., Aims: In our study, we aimed to investigate any correlation between the SCAs and the Munro-Saboureau microabscesses., Materials and Methods: We investigated 50 archival biopsies of psoriasis with Munro-Saboureau microabscesses, and attempted to confirm antibody colocalization within these microabcesses via immunohistochemistry staining. As controls, we utilized 50 skin biopsies from healthy patients undergoing esthetic plastic surgery procedures., Results: Within the Munro-Saboureau microabscesses, the following markers were statistically significantly positive relative to controls: CD1a, CD8, CD23, cyclooxygenase-2, myeloid histoid antigen, albumin, fibrinogen, kappa, lambda, von Willebrand factor, IgG, IgM, IgD, complement/C3c, C3d, myeloperoxidase, and carcinoembryonic antigen (P < 0.05). Autoreactivity to blood vessels was also detected, with multiple immunoglobulins and complement factors., Conclusions: We document important correlations between the Munro-Saboureau microabscesses, SCAs, and other immunoreactants.

Context: Type IV collagen is a type of collagen found primarily in the skin within the basement membrane zone. The type IV collagen C4 domain at the C-terminus is not removed in post-translational processing, and the fibers are thus link head-to-head, rather than in a parallel fashion. Also, type IV collagen lacks a glycine in every third amino-acid residue necessary for the tight collagen helix. Thus, the overall collagen-IV conformation is structurally more pliable and kinked, relative to other collagen subtypes. These structural features allow collagen IV to form sheets, which is the primary structural form found in the cutaneous basal lamina. There are six human genes associated with collagen IV, specifically COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6. The aim of this review is to highlight the significance of this protein in normal skin, and in selected diseases., Results: The alpha 3 protein constituent of type IV collagen is thought to be the antigen implicated in Goodpasture's syndrome, wherein the immune system attacks the basement membranes of the renal glomeruli and pulmonary alveoli. In addition, mutations to the genes coding for type IV collagen lead to the Alport syndrome. Furthermore, autoantibodies directed against denatured human type IV collagen have been described in rheumatoid arthritis, scleroderma, and SLE. Structural studies of collagen IV have been utilized to differentiate between subepidermal blistering diseases, including bullous pemphigoid, acquired epidermolysis bullosa, anti-epiligrin cicatricial pemphigoid, and bullous lupus erythematosus. Collagen IV is also of importance in wound healing and in embryogenesis., Conclusions: Pathological studies have demonstrated that minor structural differences in collagen IV can lead to distinct, clinically different diseases.

Context: Tattoos are produced by introducing colorants of various compositions into the skin, either accidentally or for cosmetic purposes., Case Report: A 62-year-old male presented with a cosmetic tattoo and requested a total excision of the lesion. Dermatopathologic analysis of the excised tissue with hematoxylin and eosin examination, as well as immunohistochemistry was performed. H&E staining demonstrated classic histologic features of a tattoo. Utilizing immunohistochemistry, dermal histiocytic antigen presenting cells stained with HAM56 and CD68 antibodies; the staining was present surrounding the tattoo pigment., Conclusions: We identified two macrophage markers (HAM56 and CD68) surrounding dermal tattoo pigment. A minimal dermal inflammatory immune was noted to the tattoo pigment. Moreover, the immune response and/or tolerance to tattoos is not well characterized. We suggest that tattoo materials and techniques could be utilized in therapeutic delivery for diseases such recessive dystrophic epidermolysis bullosa, potentially preventing immune rejection of gene therapy agents.

Context: Trichilemmal (pilar) cysts are common skin lesions that often present on the scalps of mature men and women. These cysts often become inflamed when the wall of the cyst ruptures, but few reports have addressed the immunologic features of this process., Case Report: A 22-year-old female presented with rapidly growing nodule on her left cheek, with evidence of acute inflammation. Skin tissue for hematoxylin and eosin examination, as well as for immunohistochemical analysis was taken and reviewed. As controls, we utilized two archival, non-inflamed trichilemmal cysts. Hematoxylin and eosin staining demonstrated classic features of an inflamed trichilemmal cyst. No cytologic atypia was noted, and no significant number of mitotic figures was identified. Immunohistochemistry stains revealed that several cell cycle/tumor suppressor/apoptotic markers, antigen presenting cell markers, metalloproteinases and T cell response markers were highly expressed inside and around the disrupted cyst. The control, non-inflamed cysts were negative for the same markers. CD1a was also appreciated within the epidermis, suprajacent to the inflamed cyst., Conclusions: Upregulation and/or downregulation of selected cell cycle regulator and/or tumor suppressor/apoptotic markers, as well as antigen presenting cells and some protein kinases could recruit and activate T lymphocytes and other inflammatory cells to the non-disrupted cyst for unknown reasons. The immune response may be involved in the initial cyst rupture, or induced by an unknown alteration in the cyst. Larger studies are needed to address these questions.

Unlabelled: Subcorneal pustular dermatosis (SPD) represents a chronic, relapsing sterile pustular eruption, involving the trunk and flexoral proximal extremities. A 54-year-old female presented with recurrent, flaccid pustules measuring several millimeters in diameter, on normal and mildly erythematous skin of the groin and submammary areas. Biopsies for hematoxylin and eosin (H&E) examination, direct immunofluorescence (DIF) and immunohistochemistry (IHC) analysis were performed. The H&E staining demonstrated typical features of SPD, including some damage within dermal pilosebaceous units subjacent to the subcorneal blistering process. DIF revealed strong deposits of immunoreactants IgG, IgM, fibrinogen and complement/C3, present in a shaggy pattern within the subcorneal disease areas; in focal, areas of the basement membrane junction and in focal pericytoplasmic areas of epidermal keratinocytes. IHC revealed strong positivity to HLA-DPDQDR, mast cell tryptase, CD68, and ZAP-70 in the subcorneal inflammatory infiltrate, and surrounding dermal blood vessels. Myeloperoxidase was also positive. Positive staining with the anti-ribosomal protein S6-pS240 at the edges of hair follicles and sebaceous glands subjacent to the subcorneal blisters was also noted., Conclusions: We conclude that this disorder may have several components in its etiopathology, including a possible restricted immune response and a possible genetic component; these possibilities warrant further investigation.

Context: Central centrifugal cicatricial alopecia (CCCA; originally entitled follicular degeneration syndrome, or hot comb alopecia) was first described in African American women utilizing hot combs and/or strong chemical hair care products., Case Report: A 67 year old African American female was evaluated for the presence of alopecic areas occurring on the scalp vertex, and spreading centrifugally. The alopecic lesions appeared as diffuse patches, including atrophic small areas surrounding individual hair follicles., Patients and Methods: Skin biopsies for hematoxylin and eosin examination, as well as for direct immunofluorescence and immunohistochemistry analyses were performed., Results: hematoxylin and eosin staining demonstrated histopathologic findings of premature desquamation of the inner root sheath and eccentric thinning of the follicular epithelium, supporting the diagnosis of CCCA. Direct immunofluorescence revealed strong depositions of Complement/C3, fibrinogen and kappa light chains around the hair follicles. Immunohistochemistry demonstrated increased expressions of HLA-ABC (as in African American patients with insulin independent diabetes mellitus). We also detected positive p53, bcl-2 and MAC staining in the hair follicle areas., Conclusions: Follicular degeneration syndrome may have an important immunological component previously not described, and multicolor immunofluorescence may be useful in establishing an early diagnosis.

Context: Discoid lupus erythematosus is a chronic inflammatory skin disorder presenting with scarring lesions that occur predominately on sun exposed areas of the face and scalp., Case Report: A 22-year-old male was evaluated after presenting with reddish-purple, atrophic and erythematous plaques on the scalp, with loss of hair within the plaques. Biopsies for hematoxylin and eosin examination, direct immunofluorescence and immunohistochemistry analysis were performed. The hematoxylin and eosin staining demonstrated classic features of cutaneous lupus. Direct immunofluorescence revealed strong deposits of immunoglobulins IgG and IgM, fibrinogen and Complement/C3, present in 1) a shaggy pattern at the epidermal basement membrane zone, and 2) focal pericytoplasmic and perinuclear staining within epidermal keratynocytes. Immunohistochemisty staining revealed strongly positive staining with antibodies to cyclooxygenase-2, Zeta-chain-associated protein kinase 70, and HLA-DPDQDR in areas where the inflammatory infiltrate was predominant, as well as around dermal blood vessels and within the dermal extracellular matrix., Conclusions: Noting the autoimmune nature of lupus and its strong inflammatory component, we present a patient with active discoid lupus erythematosus and strong expression of Zeta-chain-associated protein kinase 70, cyclo-oxygenase-2, and HLA-DPDQDR in the inflammatory areas. We suggest that these molecules may play a significant role in the immune response of discoid cutaneous lupus, possibly including 1) the biosynthesis of the prostanoids and 2) activation of the signaling cascade in response to T-lymphocyte receptor stimulation.

Context: Inflamed seborrheic keratoses are generally associated with the accumulation of variable numbers of lymphocytes and histiocytes in the superficial dermis. The precise immunologic mechanism of this histologic phenomenon is not known, Case Report: A 62-year-old male presented with a patch on the right neck with additional features of inflammation. Skin biopsies for hematoxylin and eosin examination, as well as for immunohistochemistry analysis were performed., Results: H&E staining demonstrated classic features of an inflamed seborrheic keratosis. Overexpression of LAT, COX-2, CD1a, and CD68 was noticed in the inflammatory infiltrate. A strong presence of CD1a was also seen in the epidermis suprajacent to the inflammation. Myeloid/histiocyte antigen was strongly expressed by the keratinocytes, Conclusion: A complex immune response seems to be involved in the pathophysiology of an inflamed seborrheic keratosis.

Context: Bullous allergic reactions are inflammatory skin disorders, presenting usually as a result of some type of reaction to medication., Case Report: A 67-year-old female was evaluated for the presence of diffuse patches of erythema, microvesiculation, vesicles, crusts, and oozing of sudden appearance on the extremities and on the rest of the body after taking sulfamethoxazole in combination with trimethoprim. Skin biopsies for hematoxylin and eosin examination, as well as for direct immunofluorescence and immunohistochemistry analysis were performed. H&E staining demonstrated classic features. Direct immunofluorescence revealed strong deposits of fibrinogen in the vessels of the skin. The immunohistochemistry stain showed strong positivity of myeloperoxidase within the blister cavity. The distribution of the vessels around the inflammatory process were noticed by using antibodies to CD34 as well to collagen IV., Conclusions: sulfamethoxazole is catalysed by CYP2C9 and/or myeloperoxidase. Thus, myeloperoxidase appears to be of importance in this disorder.

Context: Bullous pemphigoid (BP), the most common autoimmune blistering disease, is mediated by autoantibodies. BP primarily affects the elderly and is characterized by the development of urticarial plaques surmounted by subepidermal blisters, and the deposition of immunoglobulins and complement at the basement membrane zone (BMZ) of the skin. BP is immunologically characterized by the development of autoantibodies targeting two structural proteins of the hemidesmosomes, BP180 (collagen XVII) and BP230 (BPAG1)., Case Report: A 63 -year-old Caucasian female patient was evaluated for a 4 day history of several itching, erythematous blisters on her extremities. Biopsies for hematoxylin and eosin (H&E) examination, as well as Periodic acid-Schiff (PAS), immunohistochemistry (IHC) and direct immunofluorescence (DIF) analysis were performed., Results: H&E demonstrated a subepidermal blister, with partial re-epithelialization of the blister floor. Within the blister lumen, numerous neutrophils were present, with occasional eosinophils and lymphocytes also noted. Within the dermis, a mild, superficial, perivascular and periadnexal infiltrate of lymphocytes, histiocytes and occasional eosinophils was identified, with mild perivascular leukocytoclastic debris. The PAS stain was positive at the BMZ, and around selected blood vessels, nerves and sweat glands. DIF revealed linear deposits of IgG and Complement/C3 and fibrinogen at the BMZ, and around selected dermal nerves, blood vessels and sweat glands. Strong granular deposits of IgE were also observed, colocalizing with monoclonal antibodies to Collagen IV (CIV). By IHC, positive CD45 staining of lymphocytes was seen surrounding selected dermal blood vessels, eccrine sweat glands, and nerves., Conclusion: The patient displayed IgG, IgE, and fibrinogen autoantibodies against the BMZ, as well as around some dermal nerves and sweat glands; their binding in the skin could trigger complement activation. In addition, the role of the dermal CD45 positive lymphocytes warrants further investigation.

Context: Herpes simplex virus (HSV) infection of the skin represents a common challenge in dermatology; however, currently the port of viral entry remains obscure. HSV is known to induce an immunoglobulin-binding cell surface receptor in infected cells that utilizes a non-immune mechanism. The replication of HSV in cultured cells is accompanied by the appearance of surface receptors with an affinity for the Fc region of immunoglobulin G., Case Report: We describe a 43 year old African American male who presented with a generalized rash, including intense pruritus and umbilicated vesiculopustules. The patient had been previously diagnosed and treated for psoriasis with methotrexate and prednisone. Hematoxylin and eosin demonstrated keratinocytes with ballooning degeneration within the epidermis. Direct immunofluorescence (DIF) results resembled the pattern of paraneoplastic pemphigus, with negative indirect immunofluorescence (IIF) results on rat bladder. Immunohistochemistry revealed deposits of the complement membrane attack complex within dermal sweat glands, as well as the presence of herpes simplex virus 1 on the skin. We report a case of Kaposi varicelliform eruption, a cutaneous eruption caused by a virus infecting patients with pre-existing dermatoses., Conclusion: HSV virus infection with over-expression of the junctional adhesion molecule close to herpetic infection sites may preferentially increase viral entry through the skin, possibly triggering a Kaposi varicelliform eruption.

Context: Atopic dermatitis is a chronic inflammatory skin disease resulting from interactions between environmental and genetic factors. Recent studies link atopic dermatitis with asthma and with eosinophilic esophagitis., Case Report: Based on this association, we investigated by indirect immunofluorescence the immunoreactivity patterns on monkey esophagus substrate utilizing the serum of a patient with severe atopic dermatitis. We also examined the patient's skin biopsy by H&E histology and immunohistochemistry. We detected strong deposits of albumin, IgE, IgG, IgD, IgA, Complement/C1q and mast cell tryptase in multiples structures of the skin, as well as a broad pattern of intraepithelial staining on monkey esophagus. Strong staining positivity was also detected within the inflammatory infiltrate around the upper dermal vessels, as well as additional positive staining for the human leukocyte antigen system antigens DR DP and DQ., Conclusion: Our findings demonstrate that there could be an indication for testing patients with severe atopic dermatitis for autoreactivity to filaggrin (anti-keratin antibodies) utilizing monkey esophagus. Larger studies are needed to clarify any immunologic interaction between the reactivity to albumin and food allergens that may sensitize patients via the esophageal mucosa.

Context: Smoot muscle (SM) is a muscle tissue that contracts without conscious control, made up of spindle-shaped, untreated cells with single nuclei and found in the walls of the internal organs, such us the stomach, intestine, bladder, and blood vessels, excluding the heart and in the (arrector pili) muscle in the skin., Case Report: A 59 Caucasian woman was evaluated for pruritic rash and violaceous plaques mostly in the upper extremities with some with ulcers in her mouth. Biopsies for hematoxylin and eosin and immunohistochemistry examination, as well as for direct immunofluorescence analysis were performed. The hematoxylin and eosin staining demonstrated mild epidermal atrophy with focal follicular plugging. A mild interface infiltrate of lymphocytes and histiocytes and a superficial and deep, perivascular and periadnexal dermal infiltrate of lymphocytes, histiocytes and plasma cells was observed. Was difficult to diagnose as either lichen planus or lupus erythematosus. The histological studies from two places showed features of both lupus erythematosus and lichen planus. The direct immunofluorescence revealed focal deposits of immunoglobulins IgG, present at the basement membrane junction of the skin as well as in the sweat glands of IgM, fibrinogen and complement/C3. In addition, deposits of IgE surrounding the superficial dermal blood vessels and ecrine glands. Antibodies to piloerector muscle using several immunoglobulins, corroborated by immunohistochemistry stains., Conclusions: This is the first case reporting autoantibodies to the piloerector muscle in a patient having mixed clinical and histopathological diagnoses of lupus/lichen planus overlapping syndrome with strong IgE immune response.

Context: Discoid lupus erythematosus (DLE) is a chronic skin condition, often presenting inflammatory, scarring lesions predominating on sun exposed areas of the face and scalp., Case Report: A 46-year-old black female was evaluated for possible DLE. Biopsies for hematoxylin and eosin (H&E) and immunohistochemistry (IHC) examination, as well as for direct immunofluorescence (DIF) analysis were performed. The H&E staining demonstrated mild epidermal atrophy with focal follicular plugging. A mild interface infiltrate of lymphocytes and histiocytes and a superficial and deep, perivascular and periadnexal dermal infiltrate of lymphocytes, histiocytes and plasma cells was observed The DIF revealed strong deposits of immunoglobulins IgG, IgM, fibrinogen and Complement/C3, present in a granular pattern at the basement membrane junction (BMZ) of the skin as well as in the BMZ of the sebaceous glands. In addition, deposits of IgA surrounding the superficial dermal blood vessels were appreciated. The IHC displayed compartmentalization of vimentin around the BMZ of both the superrficial skin and sebaceous gland BMZs, as well as similar patterns of deposits of the same immunoglobulins, complement, and fibrinogen as visualized by DIF., Conclusions: Minimal attention has been given to the process of compartmentalization of the dermis in inflammatory skin conditions, including DLE. However, it seems that in addition to the classical immunoglobulin and complement "lupus band" deposits at the BMZ, an additional, orchestrated immunologic reorganization of the dermis surrounding the inflammatory process is also present. Such an immunologic reorganization of the dermis could play a significant role in the pathophysiology of this disorder.

Context: Skin changes in pregnancy can be categorized as 1) physiological/hormonal, 2) alterations in pre-existing skin diseases, or 3) represent development of new dermatoses, some of which may be pregnancy specific., Case Report: We describe a 19 years old female at 27 weeks gestation who presented with a rash on the face and breast, with intense pruritis. Hematoxylin and eosin demonstrated Scabies mites within the epidermis, with an intense perivascular infiltrate of lymphohistiocytic cells around the superficial dermal blood vessels. By direct immunofluorescence (DIF), human fibrinogen was also detected in the perivascular areas. DIF also revealed deposits of human IgG and complement C5-9/MAC deposits in the sweat glands, as well as in nerves surrounding the sweat glands subjacent to the mites. Overexpression of ezrin and junctional adhesion molecule antibodies close to the scabies infection sites were also seen., Conclusion: Given that the hallmark of clinical scabies is intense pruritus and that very limited information is available regarding the pathophysiology of this symptom, we suggest that the itching sensation may be exacerbated by nerves and eccrine sweat glands in close proximity to the sites of infection.

Context: Anti-neutrophil p-ANCA antibodies are directed against antigens in the peripheral cytoplasm of both neutrophilic granulocytes and monocytes. They are detected in several autoimmune disorders and are particularly associated with systemic vasculitis., Case Report: We report a case of a 54-year-old female presenting with a pruritic rash, including purpura and diffuse erythema. A biopsy with hematoxylin and eosin (H & E) analysis, direct immunofluorescence (DIF), immunohistochemistry (IHC) and enzyme-linked immunosorbent assays for ANCAs were performed. The H & E staining demonstrated leukocytoclastic vasculitis, with focal vascular fibrinoid necrosis. The DIF revealed evidence of vasculitis, the presence of p-ANCAs and neutrophil extracellular traps (NETs). The IHC displayed autoreactivity to myeloperoxidase within the vessels. The IHC aided in ruling out any intrinsic autofluorescence of the vessels., Conclusions: By observing the deposition of neutrophil extracellular traps and myeloperoxidase in inflamed skin vessels, biopsy analysis may alert physicians for rapid therapeutic intervention in patients presenting with possible vasculitides.

Context: The analysis of allergic drug reaction pathology may be difficult, especially if multiple histological reaction patterns are detected on review of hematoxylin and eosin (H&E) stained sections. In this case, we emphasize the value of adding immunohistochemistry (IHC) and multicolor direct immunofluorescence (DIF) as tools to improve the diagnosis of these complex disorders., Patient and Methods: Our patient is a twenty-year-old Caucasian female, who presented with a sudden onset of erythematous macules on the skin following administration of amoxicillin. Lesional tissue was examined by H & E and IHC, and perilesional tissue by DIF and IHC., Results: The H&E findings revealed diffuse dermal edema, and a mild, superficial, perivascular dermatitis with a mixed inflammatory infiltrate, consistent with an allergic drug eruption. The IHC and DIF studies revealed autoreactivity to sweat glands, nerves and dermal blood vessels, as well as dermal deposits of immune reactants such as fibrinogen and complement around the inflamed areas., Conclusions: Fibrin-fibrinogen degradation products have been shown in some cases of allergic disorders; thus, we encourage the effect further testing for these immunoreactants in biopsies from patients with possible allergic drug reactions.

Context: Hair loss is one of the most striking clinical features of active systemic lupus erythematosus (SLE), however, very few studies have investigated the immunological features of this process., Case Report: We describe a 33 years old female who presented with scalp hair loss and arthralgias. Physical examination revealed erythematous plaques on the nose and scalp, with bitemporal hair loss. Scalp biopsies revealed epidermal hyperkeratosis, with a mild interface infiltrate of lymphocytes and histiocytes and a superficial and deep, perivascular and periadnexal infiltrate of mostly CD4 positive cells. Antibodies to HAM 56, CD68, CD1a, S-100, mast cell tryptase and c-kit/CD117 were strongly positive around the hair follicles, and in the adjacent sebaceous glands., Conclusion: We present the first report showing a significant presence of several antigen presenting cells around the hair follicular units in a patient with alopecia in active SLE. Today, antigen presenting cells and dendritic cells (DC) are modeled as the master regulators of human immunity. One aspect that has become clearly appreciated is the great diversity of DC subtypes, each with considerable functional differences. Thus, we suggest that APC and DCs are equipped with Pattern Recognition Receptors (PRRs) to some hair follicular unit antigens; that these innate sensors recognize conserved molecular patterns on self- tissue, and play a significant role in the pathophysiology of alopecia in SLE patients.

Background: We reported a new variant of endemic pemphigus foliaceus in El Bagre, Colombia., Aims: Our study performed Complex Segregation Analysis (CSA) and short tandem repeats to discriminate between environmental and/or genetic factors in this disorder., Materials and Methods: The CSA analysis was carried out according to the unified model, implemented using the transmission probabilities implemented in the computer program POINTER, and evaluated by using a software package for population genetic data analysis (GDA), Arlequin. We performed pedigree analyses by using Cyrillic 2.1 software, with a total of 30 families with 50 probands (47 males and 3 females) tested. In parallel to the CSA, we tested for the presence of short tandem repeats from HLA class II, DQ alpha 1, involving the gene locus D6S291 by using the Hardy-Weinberg- Castle law., Results: Our results indicate that the best model of inheritance in this disease is a mixed model, with multifactorial effects within a recessive genotype. Two types of possible segregation patterns were found; one with strong recessive penetrance in families whose phenotype is more Amerindian-like, and another of possible somatic mutations., Conclusion: The penetrance of 10% or less in female patients 60 years of age or older indicates that hormones could protect younger females. The greatest risk factor for men being affected by the disorder was the NN genotype. These findings are only possible due to somatic mutations, and/or strong environmental effects. We also found a protective role for two genetic loci (D6S1019 AND D6S439) in the control group.

Context: Pompholyx (called dyshidrosis by some) is one of the most common conditions and its immune response is presently poorly understood., Case Report: We describe a 58 year old African American female with a clinical history of rheumatoid arthritis and type II diabetes who presented a chronic five-year, itchy vesicular/blistering rash involving her hands and feet. A lesional skin biopsy was taken for hematoxylin and eosin (H & E) analysis. In addition, a multicolor direct immunofluorescence (MDIF) and immunohistochemistry (IHC) studies were performed. The major findings to be reported were: the H & E examination revealed spongiotic dermatitis and pompholix. IHC and MDIF studies demonstrated focally deposits of positive CD45, CD3, CD8, anti myeloperoxidase (MPO), and anti-human IgE, C3C, C3D and anti-human-fibrinogen within the epidermal spongiotic process, as well as around the blood vessels surrounding the inflammatory process especially at the sweat glands and respective ductus. The patient began mycophenolate mofetil therapy, with successful clearing of the palms and soles., Conclusion: The significance of our findings indicates a complex immunological process including complement, MPO and T-cell immune response. In addition, possibly a secondary allergic process for the presence of IgE immune response and possibly aggravation by application of other medicines. Further immunological studies on pompholyx are needed. (Abreu-Velez AM, Pinto FJ, Howard MS. North Am J Med Sci 2009; 1: 117-120).