Deep cutaneous ulcers and sinus formation in an immunocompetent adult

Abstract This report describes a case of unusual deep skin ulcers with tortuous sinus tract formation in an immunocompetent woman. She was initially diagnosed with a Staphylococcus aureus skin infection and histopathologically diagnosed with pyoderma gangrenosum. However, culture from the deep end of ribbon gauze inserted into the subcutaneous sinus tract revealed shiny, light-yellow mucoid colonies, which were identified as Cryptococcus neoformans var. grubii. She was treated with fluconazole for nine months and completely healed. Cryptococcosis is an opportunistic infection caused by variants of C. neoformans species. Cutaneous manifestations of cryptococcosis are quite divergent, rarely occurring as deep skin ulcers with sinus formation.

Methylprednisolone and plasmapheresis are effective for life-threatening diffuse alveolar hemorrhage and gastrointestinal hemorrhage in granulomatosis with polyangiitis: A case report and literature review.

RATIONALE: The treatment of granulomatosis with polyangiitis (GPA) with life-threatening complications, such as diffuse alveolar hemorrhage (DAH) and gastrointestinal hemorrhage (GIH), remains challenging. PATIENT CONCERNS: A 70-year-old female presented with a 6-month history of a productive cough and a 10-day history of arthralgia that progressed to respiratory failure and massive hematochezia. DIAGNOSES: Chest high-resolution computed tomography (HRCT) revealed multiple nodules, masses, and cavities. Urinalysis indicated microscopic hematuria. Test of proteinase3-anti-neutrophil cytoplasmic autoantibody (PR3-ANCA) was positive. INTERVENTIONS: The patient was transferred to the intensive care unit (ICU) and successfully treated with glucocorticoid pulse therapy and plasmapheresis. We combined mycophenolate mofetil (MMF) with glucocorticoid for maintenance treatment. OUTCOMES: The patient survived and is in a stable condition. We report this case that presented with a productive cough, followed by arthralgia, DAH, and GIH. LESSONS: Effective remission-induction therapy is a key to survival, while maintaining a balance between immunosuppression and avoiding infection is another challenge.

Bilateral Morganella Morganii keratitis in a patient with facial topical corticosteroid-induced rosacea-like dermatitis: a case report.

BACKGROUND: Bilateral keratitis rarely occurs in individuals without predisposing factors. Here we describe the clinical course of a patient who developed a bilateral keratitis caused by Morganella. morganii which might be associated with long term using of topical corticosteroids-containing preparations on the face. CASE PRESENTATION: A 52-year-old female patient presented with marked bilateral corneal infiltration and hypopyon without any usual predisposing factors for bilateral infectious keratitis. There was diffuse erythema with itching on face before the onset of eye discomforts. Microbiological culture of materials from both corneas revealed significant growth of Morganella morganii. Topical corticosteroid-induced rosacea-like dermatitis was diagnosed by dermatologist because of the characteristic eruptions and long history of using the corticosteroids-containing cosmetic creams on her face. The corneal ulcers responded well to levofloxacin eye drops and ofloxacin ointment and healed with opacity and neovascularization. CONCLUSION: This case illustrates that bilateral bacterial corneal infection can develop in patients with long term using of topical corticosteroids-containing preparations on the face. To our knowledge, this is the first case of bilateral keratitis caused by Morganella morganii.

Toll-like receptors in human papillomavirus infection.

Infection with human papillomaviruses (HPVs) often causes cutaneous benign lesions, cervical cancer, and a number of other tumors. The mechanisms of host immune system to prevent and control HPV infection still remain poorly understood. Toll-like receptors (TLRs) are specific pattern recognition molecules that bind to microbial components to trigger innate immunity and direct adaptive immunity in the face of immunological danger. TLRs have been established to play an essential role in sensing and initiating antiviral immune responses. Recent accumulating evidence demonstrated that HPVs modulate TLR expression and interfere with TLR signaling pathways, leading to persistent viral infection and carcinogenesis. This review summarizes current knowledge on the roles of TLR during HPV infection, focusing on TLR recognition, modulation of TLR expression and signaling, regulatory receptors involved in TLR signaling, and cross-talk of TLRs with antimicrobial peptides. Immunotherapeutic strategies based on TLR agonists have emerged to be one of the novel promising avenues in treatment of HPV-associated diseases in the future.

Subepidermal bullous dermatosis associated with IgA multiple myeloma: a case report.

We describe a case of a 76-year-old man who initially presented with pruritic vesiculobullous eruptions on his trunk and shoulders and was subsequently found to have an immunoglobulin (Ig) A kappa multiple myeloma. Chemotherapy and plasmapheresis led to a dramatic resolution of the skin lesions, which paralleled the fall in serum IgA paraprotein level. However, the myeloma later relapsed, and the resulting paraprotein increase was accompanied by recurrence of vesiculobullous eruptions. The histopathological examinations of both primary and recurrent bullous eruptions demonstrated subepidermal bullae with negative direct immunofluorescence assays. Indirect immunofluorescence test detected neither antibasement membrane nor anti-intercellular circulating antibodies. This is a very rare report of bullous dermatosis with elevated IgA kappa paraprotein that appears before the diagnosis of myeloma, and it is a unique case showing an eosinophil-predominant infiltrate within subepidermal bullae and negative direct and indirect immunofluorescence. As the clinical features and laboratory findings of the bullous eruptions in our patient and the other 2 similar cases were not consistent with the diagnosis of any known bullous disorders, the subepidermal bullous dermatoses might be considered as a novel paraneoplastic entity occurring in association with the underlying IgA multiple myeloma.

Acute monoarthritis in a delayed diagnosis of syphilis patient with persistent rupioid psoriasis-like lesions.

BACKGROUND: The incidence of syphilis is increasing in many parts of the world. Clinicians may have limited experience in the diagnosis when the clinical appearance is unusual. If early diagnosis is not made and prompt treatment not given, then the disease may remain quiescent until more serious symptoms or systemic involvement develops. CASE PRESENTATION: We report the first case of a delayed diagnosis of syphilis with a ten-year history of persistent rupioid psoriasis-like lesions. Acute monoarthritis and high fever together with aggravation of skin lesions led to a careful clinical examination. Skin biopsies demonstrated syphilis spirochetes on immunohistochemical stain, and syphilis serological titers were positive. Standard treatment with benzathine penicillin brought a partial and transient improvement. A complete clinical and serological resolution of the disease was achieved by a prolonged and repeated penicillin treatment combined with methylprednisolone. A 7-year follow-up of the patient proved a full recovery. CONCLUSION: Our case highlights the fact that clinical signs of syphilis can be diverse and complicated. Unusual clinical manifestations can happen in an immunocompetent individual. Treatment strategy may need to be adjusted in a difficult case.

Hemophagocytic syndrome secondary to adult-onset Still's disease but very similar to lymphoma.

Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system. HPS may be primary, or secondary to malignancy, infections, auto-immune diseases and pharmacotherapy. In patients with adult-onset Still's disease (AOSD), HPS is a rare but life-threatening complication. Herein, we described a female patient with HPS secondary to AOSD. During the therapy, giant gastric ulcer similar to lymphoma developed after treatment with corticosteroid and nonsteroidal anti-inflammatory drugs.

Ubiquitination in host immune response to human papillomavirus infection.

Human papillomavirus (HPV) infection with low-risk or high-risk subtypes is very common. Infection with HPVs is often a major causative factor for the development of cutaneous benign lesions, cervical cancer, and a number of other tumors. The mechanisms of host immunity to prevent and control HPV infection still remain unclear. The importance of ubiquitination (or ubiquitylation) as an intracellular proteasomal-mediated protein degradation pathway, and as an important modulator for the regulation of many fundamental cellular processes has been valued over the last decade. Although the molecular and cellular mechanisms are not completely established, the critical role of ubiquitination in host immune response to HPV infection has become increasingly apparent. This review summarizes current knowledge on the possible role that ubiquitination plays in regulating the host immune response during HPV infection. Targeting the components of the ubiquitin system might offer potential therapeutic strategies for HPV-related diseases in the future.

Ichthyosiform mycosis fungoides with alopecia and atypical membranous nephropathy.

We describe here a rare case of variant of mycosis fungoides (MF): ichthyosiform MF with alopecia and atypical membranous nephropathy. The diagnosis was made based on the following findings: generalized ichthyosis-like eruption, alopecia, enlarged superficial lymph nodes, proteinuria, and hematuria, the histological features of the skin biopsy from both ichthyotic and alopecic lesions with immunohistochemical staining, and the renal biopsy examination with immunofluorescence. The histological examination of ichthyotic and alopecic lesions displayed a predominant infiltration of atypical lymphocytes in the upper dermis with the characteristics of epidermotropism and folliculotropism. Immunohistochemical studies demonstrated that most infiltrated atypical lymphocytes were CD3, CD4, and CD45RO positive, whereas negative for CD5, CD7, CD20, CD30, and CD56. A renal biopsy examination revealed atypical membranous nephropathy with deposition of immunoglobulin G (IgG), IgM, IgA, C1q, and C3. In this case atypical membranous nephropathy was involved, which is very uncommon and has never been presented in the literature to date. Although ichthyosiform MF usually features a relatively favorable course, diffuse alopecia and the renal involvement in this case might indicate aggressive disease and poor prognosis.

Toll like receptor agonists augment HPV 11 E7-specific T cell responses by modulating monocyte-derived dendritic cells.

Impaired local cellular immunity is one of the mechanisms responsible for condyloma acuminatum (CA) recurrence. The activation of dendritic cells (DCs) is important in vaccine development. We investigated the effect of different toll like receptor (TLR) agonists including LPS (TLR4 agonist), polyinosinic acid-polycytidylic acid (PIC, TLR3 agonist), CpG oligonucleotide (TLR9 agonist), and imiquimod (TLR7 agonist) on human monocyte-derived dendritic cells (mdDCs) loading of human papillomavirus (HPV) type 11 E7 epitope. As a result, we found that mdDCs loading HLA-A*0201-restricted HPV 11 E7 CTL epitope peptide could respond to the TLR agonists, especially LPS and PIC. This was characterized by an enhanced expression of CD40, CD80, CD86, CD83 and HLA-DR, and a high level of IL-12 production. TLR agonists, especially PIC, enhanced the ability of E7-loaded mdDCs to induce IFN-gamma-secretion CD4(+) naïve T cells. Moreover, E7-loaded mdDCs exposed to TLR agonists augmented autologous T cell responses including effector cytokines production and specific cytotoxic T lymphocyte (CTL) responses. In addition, the inhibitory effect of IL-10 on mdDCs maturation could be partially restored by LPS, PIC or imiquimod. Taken together, these results demonstrate that TLR agonists promoted the maturation of E7-loaded mdDCs and their ability to induce T help type 1 polarization and augment E7-specific T cell responses. These data also indicated that TLR3/4 agonists might be effective adjuvants of mdDC-based vaccines against CA.

Imiquimod inhibits the differentiation but enhances the maturation of human monocyte-derived dendritic cells.

Imiquimod is a topically used immune response modifier effective in the treatment of genital warts caused by HPV. Its therapeutic effects are believed to be the release of proinflammatory cytokines from the monocyte-macrophage lineage resulting in a cascade of events abating the HPV replication. Dendritic cell maturation and activation have also been found to be induced by imiquimod. We hypothesized that imiquimod may promote the development of DC at all levels of their life cycle. In this study, in vitro cultured monocyte-derived dendritic cells (MoDC) were used to evaluate the effect of imiquimod regarding the modulation of DC differentiation, terminal maturation and their function by phenotypic cell surface molecules expression, cytokine secretion and T cell stimulation in allogeneic system. We demonstrate that imiquimod exerts differential effects on DC biology at different stages of DC development. It inhibits the differentiation of DC, which may indicate a more potent antigen uptake activity. DC maturation is induced by imiquimod with an enhanced antigen presenting activity and IL-12 production. These evidence might be relevant with the clinically proven effectiveness of imiquimod in the treatment of genital warts.

[Detection of peripheral blood Th1/Th2 and Tc1/Tc2 subsets in patients with condyloma acuminatum and its significance].

OBJECTIVE: To investigate the role of T-helper (Th) and cytotoxic T (Tc) lymphocyte polarization in the pathogenesis of condyloma acuminatum (CA) and its correlation with recurrence. METHODS: Three-colour immunofluorescent flow cytometry was used to detect the proportion of CD3+ CD8- /IFN-gamma+ (Th1), CD3+ CD8- /IL-4+ (Th2), CD3+ CD8+/IFN-gamma+ (Tc1) and CD3+ CD8+ /IL-4+ (Tc2) cells in the peripheral blood of CA patients and health controls. RESULTS: Compared to health controls, CA patients showed a decreased number of Th1 (P < 0.01) and Tc1 cells (P < 0.05), as well as a decreased Th1/Th2 and Tc1/Tc2 ratio (P < 0.05). Furthermore, in 15 recurrent CA patients the ratio of Th1/Th2 was remarkably decreased (P < 0.01), while the ratio of Tc1/Tc2 had no significant change in comparison with health controls. CONCLUSION: The decrease of Th1 and Tc1 subsets results in relative Th2 and Tc2 predominance, and this tendency is more significant in recurrent CA patients. The Th1 to Th2 and Tc1 to Tc2 shifts in CA patients could be responsible for the fact that human papilloma virus (HPV) is hard to be eliminated.

Mapping of cytotoxic T lymphocytes epitopes in E7 antigen of human papillomavirus type 11.

One of the critical steps in the progression to condyloma acuminatum (CA) is the establishment of a persistent human papillomavirus (HPV) infection, majority of HPV type 6 and 11. Cytotoxic T lymphocytes (CTL), which can be induced by the epitope-based peptides in vitro, are thought to be able to recognize and destroy virus-infected cells. In order to screen and identify HLA-A*0201 restricted HPV-11E7 CTL epitopes, five epitope peptides and tetramers were selected including HPV-11E7 7-15 (TLKDIVLDL), 15-23 (LQPPDPVGL), 47-55 (PLTQHYQIL), 81-89 (DLLLGTLNI) and 82-90 (LLLGTLNIV). Human monocyte-derived dendritic cells (DCs) from HLA-A*0201 healthy individuals were pulsed with these peptides to assess the expression of CD83, CD86, HLA-DR and the secretion of IL-12. The ability of peptide-loaded mature DCs to activate autologous T cells was evaluated by analyzing the frequency of specific tetramer(+) CD8(+) T cells using flow cytometry, and the level of IFN-gamma secretion by ELISA. The ability of the epitope-specific CTLs to kill the target cells was also analysed. It was found that the immature DCs could be fully activated by all the five HPV-11E7 peptides and peptide-loaded mature DCs were able to stimulate the epitope-specific T cells in vitro. There was an increased frequency of CD8(+) T cells specific for the E7 7-15 epitope when compared to other four predicted epitopes of HPV-11E7 (P < 0.05). The epitope-specific CTLs for E7 7-15 induced the strongest cytotoxicity to HPV-11E7 expressing cell line at an E:T ratio of 50:1 (P < 0.05). Taken together, these findings demonstrate that E7 7-15 (TLKDIVLDL) is an HLA-A*0201-restricted CTL epitope of HPV type 11. We propose that this epitope could be more helpful in the characterization of HPV control mechanism and be useful for the development of immunotherapeutic approaches for low-risk HPV infectious diseases such as CA.

[HPV DNA vaccines expressing recombinant CRT/HPV6bE7 fusion protein inhibit tumor growth and angiogenic activity].

This paper was to study the angiogenic inhibitory effect and the potential antitumor effect of the constructed recombinant DNA vaccine CRT/HPV6bE7 in vivo. The C57BL/6 mice were vaccinated respectively with recombinant CRT/HPV6bE7 DNA plamids. The inhibitory effects on angiogenesis of generated vaccines in vivo were evaluated by a bFGF-induced angiogenesis assay using the Matrigel kit. To investigate the potential antitumor effect, the mean tumor weights, sizes and tumor appearing times were measured in C57BL/6 mice treated with HPV6bE7-expressing B16 cells. The results indicated that the recombinants CRT180/HPV6bE7 and CRT180 showed strong anti-angiogenic effects in bFGF-induced angiogenesis in vivo. Moreover, CRT180/HPV6bE7 and CRT180 DNA vaccines could significantly inhibit the tumor growth in tumor challenge experiment, and CRT180/HPV6bE7 was superior to other vaccines in delaying tumor formation time, limiting tumor size and weight in tumor protection experiment. In conclusion, recombinant CRT180/HPV6bE7 DNA could elicit a most efficient anti-angiogenic effect and inhibit tumor growth in mice inoculated with DNA vaccines. The antiangiogenic activity of CRT were suggested residing in a domain between CRT 120-180 aa.

[The construction and immune response of fusion DNA vaccine CRT180/HPV6E7].

OBJECTIVE: To investigate the immune response, in particular, the anti-virus cellular immune response induced by the constructed fusion DNA vaccine CRT (Calreticulin) 180/HPV6E7 in vivo and vitro. METHODS: The HPV6E7 open reading frame was amplified by polymerase chain reaction from pUC/HPV6 plasmid. The CRT180 gene was cloned by reverse transcription from human muscle tissues. The PCR products of CRT180 and HPV6E7 were subcloned into pcDNA3. 1-GFP eukaryotic vector. The recombinant plasmids CRT180/ HPV6E7 was authenticated by restrict enzyme digestion and confirmed by DNA sequencing. The DNA plasmid HPV6E7 with report gene GFP was transfected to murine B16 cells by lipofectamine kit to establish the target cells. The HPV6E7-expressing cell line was selected by G418 and identified by RT-PCR. The C57BL/6 mice were vaccinated via intramuscular injection in the right legs with 100 microg plasmid encoding CRT180-HPV6E7, CRT180 or HPV6E7, empty plasmid without insert, and PBS group respectively. The changes of the T lymphocyte subsets in the peripheral blood of the mice were evaluated by flow cytometric analysis. The lymphocytes from the spleen and lymph nodes were harvested and co-cultured with HPV6E7-expressing cell lines. The CTLs kill activity and the cytokines IL-2, IFN-gamma secretion levels of the lymphocytes were assessed by LDH and ELISA respectively. RESULTS: The constructed recombinant plasmids pcDNA3. 1-CRT180/HPV6E7, pcDNA3. 1-CRT180 and pcDNA3. 1-HPV6E7 were authenticated by restrict enzyme digestion and confirmed by DNA sequencing. Green fluorescence located in the cellular nucleus and plasma could be detected by fluorescent microscope after transfection with plasmids. The results of RT-PCR from the selected positive cell line showed the expected fragments of HPV6E7 mRNA. After immunization, the percentage of CD8+ or TCRgamma delta tau cells in the peripheral blood, the CTLs kill activity of the spleen cells and lymphocytes against HPV6E7-expressing cells, and the secretion levels of IL-2, IFN-gamma in CRT180/HPV6E7 vaccinated group increased significantly compared with the control groups (P < 0.05). CONCLUSION: Vaccination with fusion DNA vaccine CRT180/HPV6E7 could elicit a more efficient HPV6E7-specific immune response than with HPV6E7 plasmid, indicating the potential of CRT180/HPV6E7 vaccine to enhance the antigen presentation. The recombinant CRT180/HPV6E7 might help the elimination of virus in animal models and accordingly be used as a vaccine candidate in the therapy of CA.

[Effects of drugs known to trigger psoriasis on HaCaT keratinocytes].

To investigate whether lithium carbonate, propranolol or chloroquine aggravate psoriasis through influencing cytokines of the psoriatic cytokine network, HaCaT keratinocytes were stimulated with TNF-a after treatment with these drugs. Protein secretion of a set of multiple different cytokines and growth factors in culture supernatants were measured by using a cytokine antibody array technology. Expression of IL-8 and IL-6 mRNA was determined by real-time PCR. In culture supernatants of TNF-alpha-stimulated HaCaT cells, production of IL-6 and TNF-alpha could be enhanced by lithium carbonate; production of IL-6 and a panel of cytokines and growth factors could be enhanced by propranolol hydrochloride; and IL-6 was up-regulated by chloroquine diphosphate as well. Real-time PCR analysis showed a significantly dose-dependent increase of IL-8 and IL-6 mRNA expression in HaCaT cells stimulated with TNF-a as compared to cells without TNF-alpha-stimulation, the mRNA expression of IL-8 was higher than that of IL-6 with the same concentration of TNF-alpha (P < 0.01). Compared with HaCaT cells cultured with medium alone, propranolol hydrochloride at the concentration of 1 x 10(-6) mol x L(-1) could stimulate HaCaT cells to express higher level of IL-6 mRNA (P < 0.05). The drugs investigated show a modulatory effect on certain cytokines and growth factors which are able to modulate inflammatory type of immune reaction present in psoriatic lesions.

Recombined DNA vaccines encoding calreticulin linked to HPV6bE7 enhance immune response and inhibit angiogenic activity in B16 melanoma mouse model expressing HPV 6bE7 antigen.

Calreticulin (CRT) has been reported to have an effect of upregulating MHC class I presentation as well as inhibiting angiogenesis in vitro and in vivo. Combination of dual mechanisms of enhanced immunogenicity of human papillomavirus (HPV) 6bE7 antigen and antiangiogenesis may be introduced in the strategy of vaccines against condyloma acuminatum (CA) resulting from HPV infection. Therefore, we constructed DNA vaccines by employing different lengths of CRT chimerically linked to a model antigen HPV6bE7 and investigated the immunological and antiangiogenic effects of these vaccines in a B16 melanoma model that express HPV6bE7 antigen. Our results showed that vaccination with CRT180/HPV6bE7 or CRT120/HPV6bE7 enhanced the presence of CD8(+) T cells and TCRgammadelta T cells in vivo, increased the specific lysis activity against E7-expressing cells and secretion levels of IL-2 and IFN-gamma by activating T cells in vitro significantly. Moreover, recombined CRT180 or CRT120 with HPV6bE7 vaccines could elicit a more efficient E7-specific immune response than HPV6bE7 alone. The similarity of immunological enhancement of CRT180/HPV6bE7 and CRT120/HPV6bE7 implies that the immunologically active region mainly exist in fragment 1-120 aa. Furthermore, CRT180/HPV6bE7 and CRT180 displayed remarkable superiority over CRT120/HPV6bE7 in vivo angiogenesis assay, suggesting that the antiangiogenic activity of CRT resides in a domain between aa 120 and 180. Vaccination with CRT180/HPV6bE7 generated the best protective effect of delaying tumor formation and reduction of tumor size in tumor growth inhibition experiment among all DNA constructs. Therefore, CRT180/HPV6bE7 vaccine may enhance the immunological response to HPV6bE7 and inhibit angiogenesis. This construct may be useful in preventing HPV-associated dermatosis and may be developed as a promising strategy to control CA.

Increased endocytic activity in monocyte-derived dendritic cells in patients with psoriasis vulgaris.

BACKGROUND & OBJECTIVE: The understanding of the pathogenesis of psoriasis vulgaris has focused on T cell mediated immune disorder for many years. Recent studies provide evidence that dendritic cells may be of major importance as regulatory cells driving the psoriasis tissue reaction, and they are one of the therapeutic targets. In order to further characterize the role of dendritic cells in psoriasis, this study was designed to assess the differentiation of dendritic cells from monocytes (MoDC), the expression of phagocytosis related receptors by MoDC, their endocytic activity for fluorescent beads and lucifer yellow as well as their superoxide generation in patients with psoriasis. METHODS: Twenty eight patients with psoriasis vulgaris and 12 healthy controls were included in the study. MoDC were obtained by culturing monocytes with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 5 days. Cell surface expression of CD1a, CD14, CD40, CD80, CD83, CD86, HLA-DR, mannose receptor (MR) and Fcg receptors by MoDC and their endocytosis of dextran and lucifer yellow were analyzed by flow cytometry. Zymosan ingestion was measured to access the phagocytosis of MoDC. RESULTS: Differentiation of monocytes to dendritic cells was upregulated in patients manifested as significantly increased expression of CD40, CD80, CD86 and HLA-DR compared with that in healthy controls (P<0.01). Expression of MR and Fcg receptor II (CD32) by MoDC was significantly increased in patients with psoriasis as well (P<0.01). Endocytosis of dextran but not lucifer yellow in patients was significantly higher than controls (P<0.01), and significantly enhanced phagocytosis by increasing zymosan ingestion was also observed (P<0.01) in patients. Taken together, endocytic and phagocytic activity of MoDC in psoriasis was increased than normal persons. INTERPRETATION & CONCLUSION: Enhanced activity of dendritic cells binding and capturing foreign antigens for subsequent antigen presentation and the initiation of immune responses in psoriasis may contribute to the pathogenesis of the disease. The upregulated expression of MR and the enhanced endocytic activity of DC might be an explanation for the absence of skin infection observed in psoriasis.

Dimethylfumarate is a potent inducer of apoptosis in human T cells.

Fumaric acid esters (FAE) have been used for the systemic treatment of psoriasis in Germany for almost 50 years. Recently, it has been shown that dimethylfumarate (DMF) as the main ingredient of the marketed FAE mixture is a potent inhibitor of the nuclear transcription factor NF-kappaB. DMF was also shown to induce apoptosis in various cells. Because T cells play a crucial role in psoriasis pathogenesis, we asked whether DMF and its main metabolite methylhydrogenfumarate (MHF) were able to induce apoptosis in these cells. Purified human T cells were treated with DMF and MHF (1-20 microg/mL) and stimulated with interleukin 2, anti-CD3 antibodies or both for 48 h, and apoptosis was subsequently determined by the expression of Apo2.7 as well as by terminal deoxynucleotide transferase nick end labeling. The expression of antiapoptotic protein Bcl-2 was simultaneously determined. The results showed a dose-and-time dependent up-regulation of Apo2.7 expression and DNA fragmentation by DMF preferable in stimulated T cells. MHF and the solvent dimethyl sulfoxide were without effect. DMF, but not MHF, led to a concentration-dependent decrease of Bcl-2 expression in interleukin-2-stimulated T cells. The data provide evidence that the effect of FAE treatment of psoriasis may at least in part be due to induction of apoptosis in activated T cells.

Vitamin D(3) and analogues modulate the expression of CSF-1 and its receptor in human dendritic cells.

The active vitamin D(3)-metabolite 1,25(OH)(2)D(3) inhibits the interleukin 4/granulocyte-macrophage colony-stimulating factor (IL-4/GM-CSF)-induced differentiation of human monocytes into dendritic cells without altering survival. Colony-stimulating factor 1 (CSF-1) is an important survival factor for cells of the monocytic lineage. We therefore investigated whether the inhibitory activity of 1,25(OH)(2)D(3) is paralleled by a regulation of CSF-1 and its receptor. Purified human monocytes were cultured together with IL-4/GM-CSF in the presence of 1,25(OH)(2)D(3), its analogue tacalcitol, the low-affinity vitamin D receptor ligand 24,25(OH)(2)D(3), or the solvent ethanol for up to 5 days. Expression of CSF-1, CSF-1R, and GM-CSF mRNA was measured by RT-PCR. Protein secretion for CSF-1 was measured by ELISA, expression of CSF-1R by flow cytometry. The results showed that 1,25(OH)(2)D(3) and tacalcitol significantly up-regulated CSF-1 mRNA-expression and protein secretion in a dose-dependent manner. The effect of 1,25(OH)(2)D(3) occurred already after 1h of pre-treatment. In contrast, CSF-1R mRNA- and cell surface-expression was down-regulated simultaneously. The solvent ethanol and 24,25(OH)(2)D(3) were without effect. GM-CSF mRNA expression was not modulated in 1,25(OH)(2)D(3)-treated cells. These data point towards a distinct and specific regulation of CSF-1 and its receptor by 1,25(OH)(2)D(3) and its analogue tacalcitol in human monocytes which parallels the inhibition of differentiation into dendritic cells without altering survival.