Paul R. Bergstresser

A role for NF-κB–dependent gene transactivation in sunburn

Exposure of skin to ultraviolet (UV) radiation is known to induce NF-κB activation, but the functional role for this pathway in UV-induced cutaneous inflammation remains uncertain. In this study, we examined whether experimentally induced sunburn reactions in mice could be prevented by blocking UV-induced, NF-κB-dependent gene transactivation with oligodeoxynucleotides (ODNs) containing the NF-κB cis element (NF-κB decoy ODNs). UV-induced secretion of IL-1, IL-6, TNF-α, and VEGF by skin-derived cell lines was inhibited by the decoy ODNs, but not by the scrambled control ODNs. Systemic or local injection of NF-κB decoy ODNs also inhibited cutaneous swelling responses to UV irradiation. Moreover, local UV-induced inflammatory changes (swelling, leukocyte infiltration, epidermal hyperplasia, and accumulation of proinflammatory cytokines) were all inhibited specifically by topically applied decoy ODNs. Importantly, these ODNs had no effect on alternative types of cutaneous inflammation caused by irritant or allergic chemicals. These results indicate that sunburn reactions culminate from inflammatory events that are triggered by UV-activated transcription of NF-κB target genes, rather than from nonspecific changes associated with tissue damage.

Distinct Autoimmune Syndromes in Morphea: A Review of 245 Adult and Pediatric Cases

OBJECTIVE To determine the prevalence of extracutaneous manifestations and autoimmunity in adult and pediatric patients with morphea. DESIGN A retrospective review of 245 patients with morphea. SETTING University of Texas Southwestern Medical Center-affiliated institutions. Patients Patients with clinical findings consistent with morphea. MAIN OUTCOME MEASURES Prevalence of concomitant autoimmune diseases, prevalence of familial autoimmune disease, prevalence of extracutaneous manifestations, and laboratory evidence of autoimmunity (antinuclear antibody positivity). Secondary outcome measures included demographic features. RESULTS In this group, adults and children were affected nearly equally, and African Americans were affected less frequently than expected. The prevalence of concomitant autoimmunity in the generalized subtype of morphea was statistically significantly greater than that found in all other subtypes combined (P = .01). Frequency of a family history of autoimmune disease showed a trend in favor of generalized and mixed subgroups. The linear subtype showed a significant association with neurologic manifestations, while general systemic manifestations were most common in the generalized subtype. Antinuclear antibody positivity was most frequent in mixed and generalized subtypes. CONCLUSIONS High prevalences of concomitant and familial autoimmune disease, systemic manifestations, and antinuclear antibody positivity in the generalized and possibly mixed subtypes suggest that these are systemic autoimmune syndromes and not skin-only phenomena. This has implications for the management and treatment of patients with morphea.

Conjugated avidin binds to mast cell granules.

The glycoprotein, avidin, conjugated either to the enzyme horseradish peroxidase, or to the fluorochrome dyes, fluorescein or rhodamine, identifies the granules of mast cells in both tissues and cell suspensions. In the absence of prior fixation, mast cells were not identified with conjugated avidin; however, granules released from these cells were stained with this labeled glycoprotein. The specificity of avidin for mast cells was confirmed by the absence of conjugated avidin-positive cells in the skin of mice (S1/S1d) deficient in mature dermal mast cells. Electron microscopic studies confirmed that avidin binds specifically to individual mast cell granules rather than to other cellular structures. Rodent and human mast cells were readily stained with avidin conjugated to horseradish peroxidase or to either of the fluorochrome dyes. The conjugated avidin staining technique is a reliable and simple method for identifying rodent and human mast cells, one that is useful as both an investigative and a clinical tool.

HIV-related skin diseases.

Disorders of the skin and mucous membranes, including various infections, Kaposis sarcoma, and miscellaneous conditions, occur throughout the course of HIV infection, affecting more than 90% of patients at some time. These lesions are often the first manifestations of symptomatic HIV disease. Clinicians need to be aware of these diagnoses and the order of their appearance since correct interpretation is essential for counselling patients about the progression of their illness and for initiating appropriate therapy.

Bacillary epithelioid angiomatosis occurring in an immunocompetent individual.

Within the last several years, a newly characterized condition known as bacillary epithelioid angiomatosis (BEA) has been described in a number of patients with human immunodeficiency virus (HIV) infection. All cases heretofore described have been seen in patients with the HIV infection. We recently evaluated a 37-year-old healthy man who had a localized form of BEA confirmed by biopsy, special strains, electron microscopy, and culture. We conclude that BEA as previously defined may occur in healthy, non-HIV-infected individuals.

Impact of UVB Radiation on the Epidermal Cytokine Network

Chronic exposure to UVB radiation induces and promotes the development of skin cancer via two major mechanisms: (a) somatic mutation and (b) the distortion of immune surveillance ( I ) . The role of epidermal cytokines in the second of these two mechanisms is the focus of this review. Keratinocytes in humans and mice are now known to produce a wide variety of cytokines, including interleukin (1L)la*** (and IL-Ip in humans), IL-3, IL-6, IL-7, IL-8, IL-10, IL-12, 1L15, colony-stimulating factor1 (CSFI ) , granulocyte/ macrophage-CSF (GM-CSF), tumor necrosis factor-a (TNFa), transforming growth factor-a (TGFa), TGFP, platelet-derived growth factor (PDGF), nerve growth factor (NGF), basic fibroblast growth factor (bFGF) and leukemia inhibitory factor (LIF) (Table 5 ; see other reviews (2-4) for more complete lists of references). Langerhans cells, which are skin-specific members of the dendritic cell family of antigen-presenting cells (5,6) have been shown to produce IL1 P, IL-6, TNFa and macrophage inflammatory protein (MIP)-la (Table 5). In addition, melanocytes in humans produce ILldP, IL-6, IL-8, G-CSF and TNFa (see references in Matsue et al. (3)) and dendritic epidermal T cells, which are resident y6 T cells in mouse epidermis (7), secrete IFNy, IL-2, IL-4 and GM-CSF (see references in Matsue et ul. (3)). These cytokines, produced locally within the epidermal microenvironment and termed “epidermal cytokines,” play critical roles during the induction, amplification and resolution of immune responses in skin.

Genetic basis of ultraviolet-B effects on contact hypersensitivity

The genetic basis of the effects of ultraviolet B(UVB) radiation on the induction of contact hypersensitivity (CH) to dinitrofluorobenzene (DNFB) has been explored in genetically defined mice. It was found that acute, low-dose UVB radiation produced profound depletion of epidermal Langerhans cells (LC) at UVB-treated sites in all strains of mice tested. However, when DNFB was applied to UVB radiation sites, unresponsiveness developed in some strains of mice, but vigorous contact hypersensitivity was induced in others. The UVB-susceptible phenotype proved dominant or codominant in F1 hybrids derived from parental strains of the susceptible and UVB-resistant phenotypes. Experiments conducted in one set of F1 hybrids derived from two UVB-susceptible parental strains displayed UVB resistance, suggesting gene complementation, and showed that more than one genetic locus was involved. Segregant backcross populations, analyzed for the capacity to develop CH after UVB treatment and skin painting with DNFB, revealed that at least two, and probably three, independent genetic loci participate in determining UVB resistance. Results of experiments with H-2 congenic and recombinant mice derived from the B10 background implicated class I genes of the major histocompatibility complex as relevant genetic factors. These results indicate that there is a dissociation between the effects of UVB radiation on epidermal Langerhans cells and the capacity of a cutaneous surface to support the induction of contact hypersensitivity. The data indicate that the induction of CH to haptens is dependent on normal numbers of functional LC at the skin painting site only in some strains of mice. The data imply that in the so-called UVB-resistant strains of mice, alternative (non-Langerhans cell-dependent) mechanisms allow for the induction of CH. Several independent genetic loci, one of which appears to be H-2, govern this UVB-related effect.

Identification of a human homologue of the dendritic cell-associated C-type lectin-1, dectin-1

Previously we identified the novel type II lectin receptor, dectin-1, that is expressed preferentially by murine antigen presenting dendritic cells (DC) and is involved in co-stimulation of T cells by DC. To identify the human homologue (DECTIN-1), we employed degenerative PCR amplification of mRNA isolated from DC and subsequent cDNA cloning. DECTIN-1 is a type II lectin receptor with high homology to type II lectin receptors expressed by natural killer (NK) cells. It contains an immunoreceptor tyrosine-based activation motif within the cytoplasmic domain. Human DECTIN-1 mRNA is expressed predominantly by peripheral blood leukocytes and preferentially by DC. The mRNA likely encodes a 33 kDa glycoprotein. In human epidermis, the protein is expressed selectively by Langerhans cells, which are an epidermal subset of DC. A truncated form of DECTIN-1 RNA (termed T beta) encodes for a polypeptide lacking almost the entire neck domain, which is required for accessibility of the carbohydrate recognition domain to ligands. Genome analysis showed the deleted amino acid sequence in T beta to be encoded by an exon, indicating that T beta RNA is produced by alternative splicing. DECTIN-1 gene maps to chromosome 12, between p13.2 and p12.3, close to the NK gene complex (12p13.1 to p13.2) which contains genes for NK lectin receptors. Our results indicate that human DECTIN-1 shares many features with mouse dectin-1, including the generation of neck domain-lacking isoforms, which may down-regulate the co-stimulatory function of dectin-1.

Acanthosis nigricans: A cutaneous marker of tissue resistance to insulin

Tissue resistance to insulin is a major feature underlying the development of acanthosis nigricans in many patients. We report two unusual cases of acanthosis nigricans with contrasting forms of insulin resistance and propose an algorithm for the evaluation of patients with acanthosis nigricans. Further, we present a schematic framework that emphasizes the role of insulin and insulin growth factors in the pathogenesis of acanthosis nigricans.

Idiopathic atro hie blanche

Idiopathic atrophie blanche (segmental hyalinizing vasculitis; livedo reticularis with summer ulceration) is a chronic cutaneous disorder of young to middle-aged women that is characterized by persistent painful leg ulcerations. Primary lesions consist of purpuric macules and papules which undergo superficial ulceration, followed eventually by the development of irregular, atrophic, porcelain white scars with fine borders of ectatic vessels. We have studied twelve patients with idiopathic atrophie blanche by immunofluorescence, thin section light microscopy, and electron microscopy. All patients were examined extensively in order to rule out primary immunologic and vaso-occlusive disorders that may result in a similar clinical appearance. Subsequently, ten patients were treated for 1 to 12 years with combinations of phenformin and ethylestrenol. Each treated patient noted rapid improvement in existing lesions, significantly less pain, and a decrease in the development of new lesions. Side effects in all but two patients were minimal and well tolerated. Light and electron microscopic examination of early and well-developed lesions revealed fibrin plugs which first occlude superficial dermal vessels, followed by necrosis and obliteration of the affected vessel walls. Eventually, new vessel formation occurs in some areas of fibrin deposition. Polymorphonuclear leukocytes and mononuclear cells only rarely participate in this process. Although this disorder has previously been considered a localized form of cutaneous vasculitis, the absence of both leukocytes and nuclear fragmentation from the neighborhood of vascular structures in early lesions differentiates this disorder from immune complex-mediated necrotizing vasculitis. Thus the term vasculopathy describes this disorder more appropriately than the term vasculitis.