Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing.

BACKGROUND: Frontal fibrosing alopecia (FFA) is a scarring alopecia with unclear pathogenesis and a progressive course. The disease has a major impact on patients' quality of life and there is a lack of effective treatment to halt disease progression. METHODS: We profiled lesional and nonlesional scalp biopsies collected in 2017 from patients with FFA (n = 12) compared with scalp biopsies from patients with alopecia areata (AA) (n = 8) and controls (n = 8) to evaluate gene and protein expression, including the primary outcome (CXCL9). We determined significant differences between biomarkers using a two-sided Student's t-test adjusting P-values by false discovery rate. RESULTS: Significant increases were seen in CD8+ cytotoxic T cells, CD11c+ dendritic cells, CD103+ and CD69+ tissue-resident memory T cells in FFA and AA vs. control scalp (P < 0·05), with corresponding significantly upregulated granzyme B mRNA, particularly in FFA (P < 0·01). In AA, cellular infiltrates were primarily concentrated at the bulb, while in FFA these were mainly localized at the bulge. FFA demonstrated significant upregulation of T helper 1/intereferon (IFN) (IFN-γ, CXCL9/CXCL10), the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway (STAT1, JAK3) and fibrosis-related products (vimentin, fibronectin; P < 0·05), with no concomitant downregulation of hair keratins and the T-regulatory marker, forkhead box P3, which were decreased in AA. The stem cell markers CD200 and K15 demonstrated significantly reduced expression only in FFA (P < 0·05). CONCLUSIONS: These data suggest that follicular damage and loss of stem cells in FFA may be mediated through immune attack in the bulge region, with secondary fibrosis and reduced but still detectable stem cells. JAK/STAT-targeting treatments may be able to prevent permanent follicular destruction and fibrosis in early disease stages.

Stem cells in the skin and their role in oncogenesis.

Stem cells generate great interest because they hold the promise for treatment of various incurable diseases. Several distinct stem cell populations have been identified in each organ, including the skin. As the skin is the largest organ in the body and is easily accessible, cutaneous stem cells have raised significant hopes for being a rich source of easily available multipotent stem cells. Genetic alterations and mutations in stem cells are being proposed as initiation step in multiple cancers. Small populations of oncogenic stem cells termed as cancer stem cells or tumour-initiating cells have been identified in multiple tumours, including squamous cell carcinomas, and melanomas that can sustain tumour growth, underlie its malignant behaviour and initiate distant metastases. These cells are controlled and regulated by the same pathways that are also responsible for maintenance and differentiation of normal stem cells. Developing a targeted therapy against the oncogenic stem cells and dysregulated members of the signalling pathways may be the key to understanding and treating skin cancers like melanomas, for which we still do not have an effective treatment.

The Goodpasture antigen is expressed in the human thymus.

BACKGROUND: Autoimmunity to kidney antigens causes membranous nephropathy and Goodpasture's disease and very likely is pivotal in many other glomerular diseases. We investigated the potential for central tolerance to the best-characterized kidney autoantigen, the NC1 domain of the alpha3 chain of type IV collagen [alpha3(IV)NC1], which is the target of autoimmune attack in Goodpasture's disease. METHODS: Indirect immunofluorescence on human thymus and polymerase chain reaction (PCR) and Southern blot analysis of cDNA reverse transcribed from RNA extracted from human thymus and kidney. RESULTS: Indirect immunofluorescence on human thymus demonstrated the presence of alpha3(IV)NC1 in all six thymus samples examined. The homologous collagen IV chain, alpha5(IV)NC1, also was detected with a similar intra-thymic distribution. Strikingly, thymic alpha3 and alpha5 localized around and within Hassall's corpuscles in the thymic medulla, which are structures implicated in T cell apoptosis and possibly negative selection. In contrast, alpha1(IV)NC1 localized to the basement membranes of interlobular septa and blood vessels, as is typical of collagen IV chains situated outside the thymus. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed the presence of mRNA encoding alpha3(IV)NC1 and alpha5(IV)NC1 in thymic tissue establishing that the antigens were likely to have been synthesized locally. CONCLUSIONS: The results demonstrate that alpha3(IV)NC1 is expressed in the human thymus, and therefore should be available for induction of alpha3(IV)NC1-specific tolerance. This observation has the important implication that patients' alpha3(IV)NC1-specific, autoreactive T cells are more likely to recognize cryptic epitopes that are not adequately presented by thymic antigen-presenting cells (APC) than the major antigen-derived epitopes generally identified by conventional approaches.

Update on panniculitis.

There is considerable confusion regarding the pathogenesis, nosology and treatment of panniculitis. This paper examines newer concepts in five types of panniculitis: i.e., histiocytic cytophagic panniculitis, erythema induratum, lipodermatosclerosis, pancreatic panniculitis and alpha-1-antitrypsin deficiency panniculitis. Recent developments in etiology, pathogenesis, molecular techniques, and therapy are discussed.

Cutaneous granulomas masquerading as tuberculoid leprosy in a patient with congenital combined immunodeficiency.

Combined immunodeficiency disorders are characterized by abnormalities in cellular and humoral immunity. This classification includes common variable immunodeficiency (CVI), a primary immunodeficiency disorder characterized by hypogammaglobulinemia, recurrent bacterial infections, and significant T-cell abnormalities. Associated autoimmune diseases include rheumatoid arthritis, pernicious anemia, idiopathic thrombocytopenic purpura, and systemic lupus erythematous. Granulomatous lesions in lymphoid tissues, solid organs, and skin have been reported. We describe a patient with CVI who developed cutaneous granulomas with perineural invasion; to our knowledge, this is a previously undescribed feature.

Childhood longitudinal melanonychia: case reports and review of the literature.

"Longitudinal melanonychia" refers to a brown or brown-black longitudinal band on a fingernail or toenail. A number of conditions can cause longitudinal melanonychia, but its main importance is that, in some patients, it may indicate the presence of a subungual malignant melanoma. Hyperpigmented nail bands are not uncommon in African-American, Latino and Asian patients, especially those over sixty years of age, and are often multiple in these groups. Longitudinal melanonychia is most worrisome when there is a solitary, dark, broad longitudinal band with pigment extending over the proximal nail fold (Hutchinson's sign). Such findings are considered to be a strong indication for biopsy of the nail matrix to rule out melanoma. Since nail matrix biopsy sometimes results in permanent nail deformity, and since the incidence of malignant melanoma is quite small in the pediatric age group, there is some controversy as to whether this procedure should routinely be performed in children. We report two cases of dramatic longitudinal melanonychia in toddlers and review the current literature on the management of this striking condition in the pediatric age group.

Cutaneous polyarteritis nodosa after streptococcal necrotizing fasciitis.

Polyarteritis nodosa (PAN) is a necrotizing arteritis of small and medium-sized vessels. It may present with hypertension and/or renal insufficiency. Peripheral neuropathy, myopathy, joint pains, testicular pain, and ischemic myalgias may also be seen. Gastrointestinal involvement may lead to gangrene of the bowel, peritonitis, perforation, intra-abdominal hemorrhage, and pancreatitis. The cutaneous manifestations include tender subcutaneous nodules grouped along the course of superficial arteries of the lower extremities, with or without an overlying livedo reticularis. Although multisystem involvement is characteristic, sometimes only one organ or system may be involved. Associations with viral hepatitis (both B and C) and streptococcal infection have been established for PAN. Recurrent strep infections of the upper respiratory tract, streptococcal glomerulonephritis and rheumatic fever have previously been linked to PAN. This report extends the spectrum of associated streptococcal infections to include necrotizing fasciitis.

Concurrent chronic lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patient with untreated CLL.

Patients who have chronic lymphocytic leukemia (CLL) are known to have a high frequency of second malignant neoplasms. However, acute myelogenous leukemia (AML) occurring concurrent with or after a diagnosis of CLL is extremely rare. In this article we report a case of AML developing in a 55-year-old male with a 6-year history of untreated CLL. The diagnosis was facilitated by touch preparation of a skin punch biopsy specimen. The patient presented with a two-week history of fever, weakness, anasarca, and a skin rash. Physical examination revealed pink to skin-colored firm papules, which coalesced into indurated plaques on his trunk, upper extremities, and face. The lesions, in combination with generalized edema, produced a leonine facies. Touch prep of the biopsy showed medium to large blasts, large monocytoid cells, and numerous small mature lymphocytes, providing the preliminary diagnosis of a second, previously undiagnosed myelomonocytic malignancy in this patient. The initial diagnosis was subsequently confirmed by histologic, cytochemical, immunohistochemical and flow cytometry studies. This is the first reported case of CLL with concurrent AML in which rapid touch prep of a skin punch biopsy facilitated diagnosis.

Lack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the interleukin-4R alpha and transforming growth factor-beta genes.

Scleroderma is a disorder characterized by fibrosis of the skin and internal organs and autoimmunity. Whereas the cause is unknown, interleukin-4 and transforming growth factor-beta have been postulated to play a major part in the fibrosis. To investigate the part played by these cytokines, we prepared TSK/+ mice with a targeted mutation in the interleukin-4R alpha or transforming growth factor-beta genes. The breeding failed to produce TSK/+ transforming growth factor-beta -/- mice so analysis of the role of transforming growth factor-beta was limited to TSK/+ transforming growth factor-beta +/- mice. We observed that TSK/+ interleukin-4R alpha -/- did not develop dermal thickening, and deletion of one allele of the transforming growth factor-beta gene resulted in diminished dermal thickness compared with TSK/+ mice; however, the deletion of interleukin-4R alpha or transforming growth factor-beta had no effect on lung emphysema, which is another characteristic of TSK syndrome. Electron microscopic analysis of skin showed that the collagen fibrils in TSK/+ interleukin-4R alpha -/- mice exhibit normal periodicity but have a smaller diameter than the fibers found in C57BL/6 mice. Analysis of skin and serum samples showed that the deletion of interleukin-4R alpha or one allele of transforming growth factor-beta prevented the increase of skin thickness paralleled with a decrease in the dermal hydroxyproline content and development of autoantibodies associated with TSK syndrome. These results demonstrate the importance of interleukin-4 and transforming growth factor-beta for the development of cutaneous fibrosis in vivo and suggest an important part for these cytokines in wound healing and connective tissue maintenance in general.

Arthropod bites manifesting as recurrent bullae in a patient with chronic lymphocytic leukemia.

BACKGROUND: We report a patient with chronic lymphocytic leukemia (CLL) that developed recurrent vesicobullous lesions that histologically demonstrated features of an exaggerated response to an arthropod bite. OBJECTIVE: Patients with CLL can present with many cutaneous manifestations, including specific and nonspecific lesions. Although rare, patients with CLL can develop an exaggerated response to an arthropod bite. CONCLUSION: Emphasis needs to be placed on the clinical recognition of arthropod bites as an unusual cutaneous manifestation of CLL, as they provide the physician with both a diagnostic and a therapeutic challenge. Patients often deny being bitten and, thus, the biopsy results conflict with the patient's history. Additionally, as there is no specific treatment, both the patient and physician are faced with a similar dilemma. Although our patient initially responded well to corticosteroids, his lesions significantly improved while being treated with dapsone.

Induction of skin fibrosis in mice expressing a mutated fibrillin-1 gene.

BACKGROUND: Tight skin mice (TSK) bear a mutated Fibrillin-1 (Fbn-1) gene. Genetic studies show that the TSK mutation is closely associated with the Fbn-1 locus (0-0.7 cM). A previous study showed two recombinants between the Fbn-1 locus and the TSK mutation. TSK mutation and mutated Fbn-1 gene cosegregate in F1 mice. MATERIALS AND METHODS: To elucidate the role of the mutated Fbn-1 gene in occurrence of TSK syndrome, we generated transgenic (Tg) mice expressing mutated Fbn-1 gene. In another set of experiments, we injected normal mice after birth with a plasmid bearing mutated Fbn-1 gene (pdFbn-1). RESULTS: Our results demonstrate that the pdFbn-1 Tg mice developed permanent cutaneous hyperplasia that was permanent. In mice injected as newborns with a plasmid bearing the sense pdFbn-1 gene, cutaneous hyperplasia was transient. In contrast to TSK mice, neither Tg nor mice injected with plasmid developed lung emphysema. The pdFbn-1 Tg and TSK mice spontaneously produced anti-topoisomerase I and anti-Fbn- antibodies, as do humans afflicted by scleroderma; whereas, those injected with a plasmid containing the pdFbn-1 gene produced only anti-Fbn-1 autoantibodies. CONCLUSIONS: The results suggest that, although cutaneous hyperplasia is due to mutated Fbn-1 gene, the TSK syndrome may be multifactorial.

Immunoperoxidase technique for detecting spirochetes in tissue sections: comparison with other methods.

BACKGROUND: With the increasing incidence of human immunodeficiency virus (HIV) infection and immunosuppressive therapy, the incidence of syphilis has been increasing. Given the fact that the above conditions may mask or obscure the usual clinical signs and symptoms of syphilis, a means of enhanced detection is essential. AIMS METHODS: The purpose of this study was to determine whether an immunoperoxidase method using an antibody against treponemes would increase the sensitivity and specificity of diagnosis in biopsies of patients with secondary syphilis. This was compared to serology and silver stain in cases of known syphilis. RESULTS: Immunoperoxidase for treponemes was at least as sensitive (9/10) as pathology (9/10), and more sensitive than conventional silver stain (6/10) or serology (7/10). CONCLUSIONS: In those equivocal cases of secondary syphilis, where confirmation is essential, immunoperoxidase for treponemes may be a useful adjunct.

Properties of HLA class II molecules divergently associated with Goodpasture's disease.

Goodpasture's disease provides an opportunity to analyse molecular mechanisms that may underlie MHC class II associations with autoimmune disease because it is caused by autoimmunity to a defined antigen [the 230 amino acid NC1 domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1)] and has strong HLA class II associations. We compared the alpha3(IV)NC1 peptide binding of class II molecules with strong positive (DR15) and dominant negative (DR7/1) associations using an inhibition binding assay and short synthetic peptides spanning the sequence of alpha3(IV)NC1. DR15 in general bound the peptides with low affinity (three of 23 < 100 nM) compared to DR1 and DR7 (12 and 10 < 100 nM respectively), and no peptide bound DR15 with much higher affinity (>10-fold) than both DR1 and DR7. Thus DR15 molecules are unlikely to increase susceptibility to Goodpasture's disease by presenting a particular alpha3(IV)NC1-derived peptide uniquely well and DR1/7 are unlikely to protect by their inability to present particular peptides. However DR1/7 could protect by capturing alpha3(IV)NC1 peptides and preventing their display bound to DR15; the binding data suggest that all the major (biochemically detectable) alpha3(IV)NC1 peptides presented bound to DR15 by DR15 homozygous antigen-presenting cells (APC) would bind preferentially to DR1/7 in DR15, 1/7 heterozygote APC.

Immune recognition of glomerular antigens.

Autoimmunity is thought to cause most varieties of glomerulonephritis including membranous nephropathy, minimal-change nephropathy, Goodpasture's disease and possibly IgA nephropathy. Much effort has been and is directed at understanding the mechanisms of immune system driven inflammation and of the consequent renal injury and repair or scarring. The purpose of this article is to focus attention on the way the immune system recognizes kidney autoantigens, a process that must be a pivotal in the initiation of autoimmune kidney disease.

Dermatofibrosarcoma protuberans in two patients with acquired immunodeficiency syndrome.

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive cutaneous tumor of intermediate malignancy. Most commonly, it arises as an asymptomatic, indurated plaque on the trunk within which protuberant nodules develop over time. We describe its occurrence in two patients with human immunodeficiency virus, a previously unreported association. The first patient, a 41-year-old woman, complained of painful lesions around the left shoulder that developed within a scar from previous trauma to the area. The second patient, a 50-year-old man, developed a recurrent DFSP within the scar from a previous surgical procedure. Dermatofibrosarcoma protuberans was confirmed in both cases by the histopathologic and immunohistochemical findings.

The HLA complex in Goodpasture's disease: a model for analyzing susceptibility to autoimmunity.

Human lymphocyte antigen (HLA) associations are recognized for many autoimmune diseases, but the mechanisms are not clear. Goodpasture's disease provides a unique opportunity to investigate possible mechanisms because strong HLA associations are known, the autoantigen is well defined, and major antigen-derived peptides presented bound to HLA molecules have been identified. Therefore, it may be possible to directly analyze interactions between the antigen and HLA molecules associated with the disease, and to examine influences on antigen presentation to T cells. Towards this goal, we present a detailed analysis of HLA associations with the disease and examine molecular mechanisms that could account for them.

p53 mutations in basal cell carcinomas arising in routine users of sunscreens.

Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC). The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5-9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these p53 exons. All of the mutations were located at dipyrimidine sites, five of the six were C-->T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P = 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers. These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations. It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53-independent pathway. Alternatively, solar UVA wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/or a tumor suppressor gene, other than p53, for these patients.