Conrad Hauser

A Critical Role for p38 Mitogen-Activated Protein Kinase in the Maturation of Human Blood-Derived Dendritic Cells Induced by Lipopolysaccharide, TNF-α, and Contact Sensitizers

We investigated the involvement of mitogen-activated protein kinases (MAPKs) in the maturation of CD83− dendritic cells (DC) derived from human blood monocytes. Maturating agents such as LPS and TNF-α induced the phosphorylation of members of the three families of MAPK (extracellular signal-regulated kinase l/2, p46/54 c-Jun N-terminal kinase, and p38 MAPK). SB203580, an inhibitor of the p38 MAPK, but not the extracellular signal-regulated kinase l/2 pathway blocker PD98059, inhibited the up-regulation of CD1a, CD40, CD80, CD86, HLA-DR, and the DC maturation marker CD83 induced by LPS and TNF-α. In addition, SB203580 inhibited the enhancement of the allostimulatory capacity and partially prevented the down-regulation of FITC-dextran uptake induced by LPS and TNF-α. Likewise, SB203580 partially prevented the up-regulation of IL-1α, IL-1β, IL-lRa, and TNF-α mRNA upon stimulation with LPS and TNF-α, as well as the release of bioactive TNF-α induced by LPS. DC maturation induced by the contact sensitizers 2,4-dinitrofluorobenzene and NiSO4, as seen by the up-regulation of CD80, CD86, and CD83, was also coupled to the phosphorylation of p38 MAPK, and was inhibited by SB203580. The irritants SDS and benzalkonium chloride that do not induce DC maturation did not trigger p38 MAPK phosphorylation. Together, these data indicate that phosphorylation of p38 MAPK is critical for the maturation of immature DC. These results also suggest that p38 MAPK phosphorylation in DC may become useful for the identification of potential skin contact sensitizers.

The Period Length of Fibroblast Circadian Gene Expression Varies Widely among Human Individuals

Mammalian circadian behavior is governed by a central clock in the suprachiasmatic nucleus of the brain hypothalamus, and its intrinsic period length is believed to affect the phase of daily activities. Measurement of this period length, normally accomplished by prolonged subject observation, is difficult and costly in humans. Because a circadian clock similar to that of the suprachiasmatic nucleus is present in most cell types, we were able to engineer a lentiviral circadian reporter that permits characterization of circadian rhythms in single skin biopsies. Using it, we have determined the period lengths of 19 human individuals. The average value from all subjects, 24.5 h, closely matches average values for human circadian physiology obtained in studies in which circadian period was assessed in the absence of the confounding effects of light input and sleep–wake cycle feedback. Nevertheless, the distribution of period lengths measured from biopsies from different individuals was wider than those reported for circadian physiology. A similar trend was observed when comparing wheel-running behavior with fibroblast period length in mouse strains containing circadian gene disruptions. In mice, inter-individual differences in fibroblast period length correlated with the period of running-wheel activity; in humans, fibroblasts from different individuals showed widely variant circadian periods. Given its robustness, the presented procedure should permit quantitative trait mapping of human period length.

Dibutyl Phthalate-Induced Thymic Stromal Lymphopoietin Is Required for Th2 Contact Hypersensitivity Responses

Thymic stromal lymphopoietin (TSLP) is an IL-7–related cytokine, produced by epithelial cells, that has been linked to atopic dermatitis and asthma; however, it remains unclear how TSLP shapes the adaptive immune response that causes these allergic disorders. In this study, we demonstrate a role for TSLP in a Th2 model of contact hypersensitivity in mice. TSLP is required for the development of Th2-type contact hypersensitivity induced by the hapten FITC in combination with the sensitizing agent dibutyl phthalate. TSLPR-deficient mice exhibited a dramatically reduced response, including markedly reduced local infiltration by eosinophils, Th2 cytokine production, and serum IgE levels, following FITC sensitization and challenge. The reduced response by TSLPR-deficient mice is likely due to decreased frequency and reduced T cell stimulatory function of skin-derived Ag-bearing FITC+CD11c+ dendritic cells in draining lymph nodes following FITC sensitization. These data suggest that skin-derived dendritic cells are direct or indirect targets of TSLP in the development of type 2 immune responses in the skin, where TSLP drives their maturation, accumulation in skin draining lymph nodes, and ability to induce proliferation of naive allergen-specific T cells.

Evidence suggesting involvement of interleukin-4 (IL-4) production in spontaneous in vitro IgE synthesis in patients with atopic dermatitis

To investigate the regulatory role of interleukin-4 (IL-4) and interferon-gamma (INF-gamma) and their involvement in the abnormality of IgE synthesis in patients with atopic dermatitis (AD), we studied the effect of recombinant human IL-4 and INF-gamma, as well as blocking antibodies (Abs) to these lymphokines on spontaneous IgE synthesis by peripheral blood lymphocytes (PBLs) from patients with AD and from healthy control subjects. PBLs from patients with AD demonstrated elevated spontaneous IgE production that was not stimulated further by the addition of recombinant IL-4, whereas for the healthy control subjects, recombinant IL-4 increased spontaneous IgE production by PBLs. INF-gamma that has been previously demonstrated to antagonize the effect of IL-4 on IgE synthesis, decreased IgE production of patients with AD. Addition of Abs to INF-gamma did not change spontaneous IgE production for patients with AD or for healthy control subjects. Together with our observation that IL-4 Abs lowered the high spontaneous IgE production by PBLs from patients with AD, these results suggest that in AD, IL-4 production by lymphocytes, together with a lack of INF-gamma production, is at least partially responsible for the increased spontaneous IgE production.

High sensitization rate to emulsifiers in patients with chronic leg ulcers

Emulsifiers are common constituents of most topical preparations. To study the sensitization rate in a population with frequent use of these agents, we selected 47 patients with chronic or recurrent (> 1 year) inflammatory skin disease (leg ulcers, contact dermatitis, atopic dermatitis, psoriasis) for patch testing with the following emulsifiers: Tween 40 (polyoxyethylene sorbitan monopalmitate), Tween 80 (polyoxyethylene sorbitan monooleate), Span 60 (sorbitan monostearate), Span 80 (sorbitan monooelate), Ariacel 83 (sorbitan sesquioleate), Atlas G 2162 (polyoxyethylene oxypropylene stearate), Atlas G 1441 (polyoxyethylene sorbitol lanolin derivative), triethanolamine, Lanette O (cetylstearyl alcohol), Lanette N. 12 patients had at least 1 positive reaction (25.5%) at 3 or 4 days. Among them, 10 had leg ulcers (43.4% of the leg ulcer group), and 2 had contact dermatitis (13.3% of the contact dermatitis group). No positive reaction was observed in the other patients. When the patients were tested with their own topical preparations or wound dressings, 6 of them, all with leg ulcers, had positive reactions. These results show a surprisingly high prevalence of sensitization to emulsifiers in patients with chronic leg ulcers, in contrast to patients with other inflammatory skin diseases.

Lentiviral Transduction of Dendritic Cells Confers Protective Antiviral Immunity In Vivo

ABSTRACT Control of a viral infection in vivo requires a rapid and efficient cytotoxic-T-lymphocyte response. We demonstrate that lentivirus-mediated introduction of antigen in dendritic cells confers a protective antiviral immunity in vivo in a lymphocytic choriomeningitis virus model. Therefore, lentiviral vectors may be excellent vaccine candidates for viral infections.

Surgical pitfalls in a patient with type IV Ehlers-Danlos syndrome and spontaneous colonic rupture: Report of a case

PURPOSE: This paper intends to stress the importance of early diagnosis and discuss surgical treatment of Type IV Ehlers-Danlos syndrome (EDS-4), an autosomal dominant connective tissue disease characterized by typical features of the face and extremities, inappropriate and easy bruising, and extreme tissue fragility, which may lead to dramatic and often fatal complications, mostly spontaneous arterial or intestinal rupture. METHODS: We report the case of a 41-year-old female who presented with spontaneous perforation of the sigmoid colon. RESULTS: The patient was seen over a nine-year period, during which time she required six operations and presented with a great number of surgical complications including stenosis of an end-colostomy, repeated subocclusive episodes caused by intraperitoneal adhesions, and enterocutaneous fistulas, finally ending with an ileostomy and short bowel syndrome. It is only after a difficult laparotomy for ovarian cyst excision, marked by numerous adhesions and friable bowel, that the diagnosis of EDS-4 was considered and established. CONCLUSIONS: In case of “idiopathic” spontaneous perforation of the colon in a young adult, features of EDS-4 should be thoroughly looked into and, if found, skin fibroblast culture with collagen Type III analysis performed. The surgical treatment of choice consists of subtotal colectomy and permanent endileostomy. In case of patient refusal, a second-stage ileorectal anastomosis can be performed but carries the high risk of anastomotic leakage.

Facial dermatitis, contact urticaria, rhinoconjunctivitis, and asthma induced by potato.

BACKGROUND Potato contains multiple heat-labile proteins which can induce immediate hypersensitivity reactions. Rhino-conjunctivitis, asthma, contact urticaria and protein contact dermatitis have been described in association with potato exposure. OBJECTIVE A patient with possible airborne facial dermatitis to potato is described. RESULTS A middle-aged atopic housewife with pre-existent atopic dermatitis suffered from rhino-conjunctivitis, asthma, and contact urticaria when pealing raw potatoes, but her main complaint was intense, treatment-resistant dermatitis of the face. The investigations showed a positive prick test, a positive patch test, and positive specific serum IgE to raw potato. Potato avoidance led not only to the resolution of the immediate symptoms, but also of the facial dermatitis, suggesting she had dermatitis due to this vegetable. CONCLUSIONS Potato may induce contact dermatitis with positive immediate and delayed hypersensitivity tests.

Nephrogenic Fibrosing Dermopathy in a Renal Transplant Recipient with Tubulointerstitial Nephritis and Uveitis

We report a patient with nephrogenic fibrosing dermopathy. He had chronic renal failure with arthritis, uveitis and histologically severe tubulointerstitial nephritis for which he received a renal transplant from a family relative. After an episode of acute renal failure with the transplant he developed painful, erythematous, firm papules and plaques with geographic borders on the legs, anterior thorax and elbow. A skin biopsy revealed increased fibroblast and collagen fiber content of the dermis and subcutaneous septae. Mucin deposition, sparse smooth-muscle-actin-positive cells and an increased number of CD34-positive cells in the deep dermis were found. After several weeks of hemodialysis, the lesions changed from an inflammatory to a purely sclerotic phase. The fibrocyte, a recently described circulating cell type, that is deposited in scar tissue may be involved in the pathogenesis of this novel pseudosclerodermatous skin disorder.

Oral carrageenan induces antigen-dependent oral tolerance: prevention of anaphylaxis and induction of lymphocyte anergy in a murine model of food allergy.

Immunosuppressive effects of carrageenan, a high-molecular-weight polysaccharide, on antibody and T cell responses have been previously demonstrated. However, its effect on anaphylaxis is unknown. Our objectives were to test carrageenan-mediated oral tolerance induction in young mice subsequently sensitized to a common cows milk antigen. C3H/HeJ mice were fed or not λ-carrageenan (0.5 g/L) and/or 0.01 mg/mL β-lactoglobulin (BLG) for 5 d before oral sensitization with BLG and cholera toxin. Subsequently, the mice were challenged with BLG and symptom scores of anaphylaxis were recorded. Mesenteric lymph node cells, spleen cells, Peyers patches cells, intraepithelial lymphocytes, and lamina propria lymphocytes were isolated and stimulated in vitro with BLG, IL-2, or left unstimulated. BLG-specific IgG, IgG1, and IgG2a antibodies were measured. Pretreatment with carrageenan and BLG, but not pretreatment with either carrageenan or BLG alone or omission of pretreatment, diminished significantly the number of anaphylactic mice after BLG challenge (6.3%versus 53% in mice without pretreatment, p = 0.006). Mesenteric lymph nodes and spleen cells from pretreated mice proliferated less in presence of BLG or IL-2 than cells from sensitized control mice. Antigen-specific antibody production and passive cutaneous anaphylaxis was not suppressed by carrageenan and BLG pretreatment. In conclusion, carrageenan administered to young mice in conjunction with low doses of allergen before sensitization efficiently prevents anaphylaxis.