Relationship of psoriasis severity to obesity using same-gender siblings as controls for obesity.

BACKGROUND: Psoriasis is a multifactorial disease affected by both genetic and environmental factors. Several comorbid conditions, such as smoking, depression and obesity have been found to be associated with psoriasis. This study addressed the association of psoriasis and obesity using same-gender full siblings as controls, correlating between body mass index (BMI) and severity of psoriasis as determined by body surface area (BSA) and the Physician's Global Assessment (PGA). METHODS: In total, 88 patients undergoing outpatient treatment for psoriasis were surveyed for demographic information, psoriasis history, social history, personal and family medical history, whether they had a same-gender full sibling and if so, the age, weight and height of the sibling. Height, weight, PGA scores and percentage of BSA affected by psoriasis, were recorded for each patient. BMI was calculated for each patient and their same-gender full sibling. RESULTS: A positive association between psoriasis severity and BMI was found. PGA score increased with BMI (Spearman's correlation, r(s) = 0.29, P = 0.007). There was also a positive correlation between BMI and BSA%, r(s) = 0.24, P = 0.02. A significant difference in BMI between patients with psoriasis and the same-gender full sibling control was seen for women (mean +/- SD 30.2 +/- 10.2 vs. 27.6 +/- 7.3 kg/m(2), respectively, P = 0.02), but not for men. CONCLUSION: In this study, psoriasis severity was found to be related to the level of obesity. Using same-gender siblings as genetic controls for predisposition to both obesity and psoriasis, patients with psoriasis were more likely to have a higher BMI, particularly for women. This study reinforces the need to treat the whole patient and to encourage healthy living, such as maintaining an appropriate weight, proper eating habits and exercise. Limitations of this study include the relatively small number of patients enrolled, potential inaccuracies in sibling BMIs calculated from information provided by patients, and a lack of information about dietary habits, exercise and lifestyle.

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.

The cutaneous response in humans to Treponema pallidum lipoprotein analogues involves cellular elements of both innate and adaptive immunity.

To extend prior studies implicating treponemal lipoproteins as major proinflammatory agonists of syphilitic infection, we examined the responses induced by intradermal injection of human subjects with synthetic lipoprotein analogues (lipopeptides) corresponding to the N termini of the 17- and 47-kDa lipoproteins of Treponema pallidum. Responses were assessed visually and by flow cytometric analysis of dermal leukocyte populations within fluids aspirated from suction blisters raised over the injection sites. Lipopeptides elicited dose-dependent increases in erythema/induration and cellular infiltrates. Compared with peripheral blood, blister fluids were highly enriched for monocytes/macrophages, cutaneous lymphocyte Ag-positive memory T cells, and dendritic cells. PB and blister fluids contained highly similar ratios of CD123(-)/CD11c(+) (DC1) and CD123(+)/CD11c(-) (DC2) dendritic cells. Staining for maturation/differentiation markers (CD83, CD1a) and costimulatory molecules (CD80/CD86) revealed that blister fluid DC1, but not DC2, cells were more developmentally advanced than their peripheral blood counterparts. Of particular relevance to the ability of syphilitic lesions to facilitate the transmission of M-tropic strains of HIV-1 was a marked enhancement of CCR5 positivity among mononuclear cells in the blister fluids. Treponemal lipopeptides have the capacity to induce an inflammatory milieu reminiscent of that found in early syphilis lesions. In contrast with in vitro studies, which have focused upon the ability of these agonists to stimulate isolated innate immune effector cells, in this study we show that in a complex tissue environment these molecules have the capacity to recruit cellular elements representing the adaptive as well as the innate arm of the cellular immune response.

Derivation of dendritic cell lines from mouse skin.

Dendritic cells (DC) are professional antigen presenting cells characterized morphologically by the extension of numerous dendrites, phenotypically by the expression of relatively large amounts of MHC class II molecules and costimulatory molecules, and functionally by their potent capacity to activate immunologically naive T cells. Members of this family reside not only in lymphoid tissues (e.g., spleen, lymph node, and thymus), but also in epithelial tissues at the environmental interface (e.g., skin). Therefore, external antigens that penetrate into bodies can be readily presented by DC to the immune system.

T cells reactive to keratinocyte antigens are generated during induction of contact hypersensitivity in mice. A model for autoeczematization in humans?

BACKGROUND: The role of keratinocytes (KC) in contact hypersensitivity (CH) has been examined more with respect to cytokine secretion and tolerance induction and less as a source of antigenic proteins to which chemical haptens can conjugate. OBJECTIVE: To determine whether KC-derived proteins can serve as antigenic carriers for haptens such as dinitrofluorobenzene (DNFB). METHODS: We examined the capacity of draining lymph node cells from BALB/c mice sensitized to DNFB to proliferate in response to hapten or to hapten-conjugated protein extracts derived from a KC line (DNP-Pam KC extract). Using limiting dilution microculture of these lymph node cells, we established DNP-specific T cell clones as well as DNP-Pam KC extract-reactive T cell clones. We also examined the proliferative responses of the DNP-Pam KC extract-reactive clones and of lymph node cells from mice sensitized to different haptens. RESULTS: Lymph node cells from DNFB-sensitized mice proliferated well to hapten or to DNP-Pam KC extract. Six la(d)-restricted, alphabeta TCR-bearing, CD4+ clones were established: 4 proliferated specifically to soluble hapten (DNBS), whereas 2 proliferated in response to DNP-Pam KC extract. Surprisingly, the DNP-Pam KC extract-reactive clones proliferated as well to Pam KC extract without hapten. Lymph node cells from hapten-sensitized mice not only proliferated specifically in response to the hapten to which they were sensitized, but also proliferated to Pam KC extract without hapten. CONCLUSIONS: T cell clones generated during the induction of (CH) in mice include those reactive to hapten as well as those reactive to KC antigens independent of hapten. Analogous mechanisms in humans might account for autoreactive events such as id reactions associated with CH and angry back syndrome during patch testing.

A role for NF-kappaB-dependent gene transactivation in sunburn.

Exposure of skin to ultraviolet (UV) radiation is known to induce NF-kappaB 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-kappaB-dependent gene transactivation with oligodeoxynucleotides (ODNs) containing the NF-kappaB cis element (NF-kappaB decoy ODNs). UV-induced secretion of IL-1, IL-6, TNF-alpha, 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-kappaB 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-kappaB target genes, rather than from nonspecific changes associated with tissue damage.

Identification of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloning.

Dendritic cells (DC) are special subsets of antigen presenting cells characterized by their potent capacity to activate immunologically naive T cells. By subtracting the mRNAs expressed by the mouse epidermus-derived DC line XS52 with the mRNAs expressed by the J774 macrophage line, we identified five novel genes that were expressed selectively by this DC line. One of these genes encoded a type II membrane-integrated polypeptide of 244 amino acids containing a putative carbohydrate recognition domain motif at the COOH-terminal end. This molecule, termed "dectin-1," was expressed abundantly at both mRNA and protein levels by the XS52 DC line, but not by non-DC lines (including the J774 macrophage line). Dectin-1 mRNA was detected predominantly in spleen and thymus (by Northern blotting) and in skin-resident DC, i.e. Langerhans cells (by reverse transcription-polymerase chain reaction). Affinity-purified antibody against dectin-1 identified a 43-kDa glycoprotein in membrane fractions isolated from the XS52 DC line and from the dectin-1 cDNA-transfected COS-1 cells. His-tagged recombinant proteins containing the extracellular domains of dectin-1 showed marked and specific binding to the surface of T cells and promoted their proliferation in the presence of anti-CD3 monoclonal antibody at suboptimal concentrations. These in vitro results suggest that dectin-1 on DC may bind to as yet undefined ligand(s) on T cells, thereby delivering T cell co-stimulatory signals. Not only do these results document the efficacy of subtractive cDNA cloning for the identification of unique genes expressed by DC, they also provide a framework for studying the physiological function of dectin-1.

Dendritic cells undergo rapid apoptosis in vitro during antigen-specific interaction with CD4+ T cells.

The terminal fate of dendritic cells (DC) remains relatively uncertain. In this study, we tested the hypothesis that DC undergo apoptosis after Ag-specific interaction with T cells. When splenic DC isolated from BALB/c mice were cocultured with HDK-1 T cells (a keyhole limpet hemocyanin (KLH)-specific CD4+ Th1 clone) in the presence of KLH, they showed conspicuous cell death as measured by propidium iodide (PI) uptake and chromatin condensation, whereas they remained relatively intact when incubated with either T cells or KLH alone. Likewise, the long term DC line XS52, which was established from BALB/c mouse epidermis, also died rapidly (within 2 h), and they exhibited characteristic DNA laddering when cocultured with HDK-1 T cells in the presence of KLH. RT-PCR and FACS analyses revealed the expression of CD95 (Fas) by XS52 DC and of CD95 ligand (CD95L) (Fas ligand) by activated HDK-1 T cells, suggesting a functional role for these molecules. In fact, anti-CD95L mAb inhibited partially (50%) T cell-mediated XS52 cell death, and coupling of surface CD95 with anti-CD95 mAb triggered significant XS52 cell death, but only in the presence of cycloheximide. Thus, ligation of CD95 (on DC) with CD95L (on T cells) is one, but not the only, mechanism by which T cells induce DC death. Finally, DC isolated from the CD95-deficient mice were found to be significantly more efficient than DC from control mice in their capacity to induce delayed type hypersensitivity responses in vivo. We propose that T cell-induced DC apoptosis serves as a unique down-regulatory mechanism that prevents the interminable activation of T cells by Ag-bearing DC.

Fatal scleromyxedema: report of a case and review of the literature.

Scleromyxedema is a rare fibromucinous connective tissue that can be associated with systemic changes, such as myopathy, neurologic defects, esophageal dysmotility, paraproteinemia, and restrictive lung disease. We describe a fatal case of scleromyxedema in which neurologic, cardiac, gastrointestinal, and muscle changes were present. At autopsy, mucin was found in the papillary dermis of skin and in coronary and pulmonary vessels, but was absent from the brain, kidneys, heart, gastrointestinal tract, esophagus, liver, thyroid, lymph nodes, bone marrow, and pancreas. Because the pathogenesis of scleromyxedema may not always be attributable to mucin deposition, the role of circulating factors in the development of systemic manifestations warrants further investigation.

MHC class I expression on dendritic cells is sufficient to sensitize for transplantation immunity.

The immunogenicity of an allograft correlates with the number of MHC class II+ antigen-presenting cells (dendritic cells) that it contains. To determine whether these antigen-presenting cells induce not only MHC class II-mediated immune responses, but also physiologically relevant levels of MHC class I immunity, we took advantage of a unique MHC class I+/class II-/CD80+ dendritic cell line (80/1 DC) derived from murine (C3H, H-2k) fetal skin. The 80/1 DC sensitized H-2-disparate recipients for specific transplantation immunity, as evidenced by significantly accelerated rejection (second set) of skin allografts from C3H mice, but not of third-party allografts. As few as 10(2) 80/1 DC, administered by the subcutaneous route, were effective, indicating their high potency as stimulator cells. Several lines of evidence support the hypothesis that the immunization observed was mediated primarily by direct presentation of allo-class I: (i) Blockage of the co-stimulatory molecule CD80 on 80/1 DC abrogated their sensitizing capacity; (ii) equal numbers of a nonprofessional antigen-presenting cell line (L929, C3H origin) as well as dead 80/1 DC failed to accelerate graft rejection; and (iii) injection of syngeneic (BALB/c) Langerhans cells pulsed with 80/1 DC fragments induced a delayed-type hypersensitivity reaction to these fragments but failed to accelerate rejection of C3H skin grafts. We conclude that direct allo-class I immunity can occur in the absence of class II expression when induced by a professional antigen-presenting cell and that this mechanism has biologic relevance in transplantation immunity.

Cytokine-mediated communication by keratinocytes and Langerhans cells with dendritic epidermal T cells.

Dendritic epidermal T cells (DETC) are skin-specific members of the epithelial gamma delta T-cell family that reside normally in murine epidermis. Recent studies indicate that certain cytokines (e.g. IL-2, IL-7 and IL-15) secreted by neighboring cells promote their residence and regulate their immune function. Conversely, DETC regulate the function of neighboring keratinocytes and Langerhans cells by elaborating other cytokines (e.g. interferon-gamma, keratinocyte growth factor and colony-stimulating factors). This reciprocal interaction represents a unique model of cytokine-mediated intercellular communication by tissue-specific gamma delta T cells with nearby epithelial and antigen presenting cells.

Functional roles for granzymes in murine epidermal gamma(delta) T-cell-mediated killing of tumor targets.

Granzymes, a family of serine proteases contained in cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells, play a critical role in killing tumor targets by triggering rapid breakdown of DNA and subsequent apoptosis. We have reported previously that dendritic epidermal T cells, which are skin-specific members of the tissue-type gamma(delta) T-cell family in mice, are capable of killing selected tumor cell lines. Here we report that short-term cultured dendritic epidermal T-cell lines contain significant N-alpha-benzyloxycarbonyl-L-Lys-thiobenzyl esterase activity, produce granzyme A protein, and express constitutively mRNA for granzymes A and B. Messenger RNA expression for granzyme B was also confirmed in freshly procured Thy-1+ epidermal cells (i.e., dendritic epidermal T cells). Finally, preincubation of dendritic epidermal T cell lines with a granzyme inhibitor, dichloroisocoumarin, but not with a cysteine protease inhibitor, E-64, abrogated completely their capacity to trigger DNA breakdown in YAC-1 target cells. These results reinforce the concept that dendritic epidermal T cells represent skin-resident killer cells that share several functional properties with conventional killer leukocytes, thereby playing a local immunosurveillance role against tumor development.

Ultraviolet B radiation sensitizes a murine epidermal dendritic cell line (XS52) to undergo apoptosis upon antigen presentation to T cells.

Ultraviolet B irradiation of skin leads to immunologic tolerance, rather than immunity against newly introduced Ag, by altering the function of Langerhans cells, skin-specific members of the dendritic cell (DC) family. Using the murine epidermal-derived DC line, XS52, which retains important features of resident Langerhans cells, we have tested the hypothesis that UV radiation delivers a signal leading to apoptosis. XS52 cells, when exposed to modest fluences (25-100 J/m2) of radiation, underwent apoptosis during a subsequent 6-h incubation with LPS or upon 6-h coculture with the keyhole limpet hemocyanin-specific Th1 clone HDK-1 in the presence of Ag. Specifically, XS52 cells treated in this way exhibited diminished cell viability, DNA laddering, and condensed staining of DNA. By contrast, none of these changes was induced by radiation alone, LPS alone, or coculture with T cells and Ag. Likewise, neither UV radiation plus T cells nor radiation plus Ag were sufficient to induce apoptosis, indicating that both T cells and Ag are required to induce apoptosis in the UV-sensitized cells. XS52 cells remained fully susceptible to T cell-mediated apoptosis even 16 h after irradiation, indicating the persistence of the sensitized state. These observations establish a model in which UV radiation induces a first event in which DC become sensitive to a second, apoptotic signal that is delivered by Ag-specific interaction with T cells or by LPS. We suggest that DC undergoing apoptosis deliver unusual activation signals to T cells during Ag presentation, signals that lead to cellular unresponsiveness rather than to effective immunity.

T cell-mediated terminal maturation of dendritic cells: loss of adhesive and phagocytotic capacities.

Dendritic cells (DC) are a specific subset of APC characterized by the potent ability to activate immunologically naive T cells. We have observed previously that the murine epidermis-derived DC line XS52 undergoes a set of profound changes upon Ag-specific interaction with T cells, including IL-1 beta secretion acquired expression of CD86, and lost expression of CD115 (CSF-1 receptor) and proliferative responsiveness to CSF-1. These changes, which appear to reflect a critical transition during Ag presentation, have been termed T cell-mediated "terminal maturation" of DC, Here we report that XS52 cells also lose their adhesive and phagocytotic capacities during this event. XS52 cells, ordinarily adhere to petri dishes and phagocytose latex heads, as has been reported for DC freshly procured from spleen and skin. Importantly, XS52 cells lose both capacities after 3 to 24 h of incubation with HDK-1 T cells (keyhole limpet hemocyanin-specific TH1 clone) or with 5S8 T cells (dinitrobenzene sulfonate specific Th0 clone) in the presence of Ag. By contrast, incubation with T cells alone or with Ag alone has minimal effects, indicating that this regulation required both T cells and Ag. With respect to mechanisms, several lines of evidence suggest this IFN-gamma, which is secreted by T cells, serves as the primary mediator in down-regulating both capacities. Our observations illustrate a unique mechanism by which responding T cells upon Ag-specific activation by DC, suppress the machinery of Ag uptake through the elaboration of IFN-gamma.

HIV-related skin diseases.

Disorders of the skin and mucous membranes, including various infections, Kaposi's 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.