Undine Lippert

Mast cells as initiators of immunity and host defense

Abstract: Until recently, mast cells have been viewed primarily as harmful because of their key role as effector cells of allergic and potentially lethal anaphylactic reactions. Their contribution to human health appeared instead to be limited to the elimination of parasites. There is, however, growing evidence for additional beneficial functions of mast cells, particularly regarding the initiation of acquired immune reactions. Thus, mast cells can phagocytize diverse particles, take up antigens, and express a number of receptors, particularly MHC class I and II antigens, ICAM‐1 and ‐3, CD43, CD80, CD86 and CD40L which allow them to interact with T and B lymphocytes. They can also secrete numerous cytokines that induce and enhance recruitment and functions of lymphocytes. Finally, there is good evidence that mast cells present e.g. pollen and bacterial antigens, respond to bacterial superantigens, but fail to react to endogenously produced antigens or superantigens. Mast cells can also activate B cells directly to produce IgE, but this activity and the ability to produce IL‐4 or IL‐13 is restricted primarily to basophil leukocytes and mucosal mast cells. Finally, recent evidence attributes a pivotal role to the cells in natural immunity to bacteria. There is also emerging evidence that mast cells can downmodulate the immune response. While these data require further clarification, the basic ability of mast cells to initiate innate and acquired immune reactions can no longer be questioned.

CD137 ligand reverse signaling has multiple functions in human dendritic cells during an adaptive immune response.

T cell activation via dendritic cells (DC) is an important step in the adaptive immune response, which requires DC maturation, migration to lymph nodes and presentation of antigen to T cells. CD137 receptor expressed on activated T cells is a potent costimulatory molecule. Here, we investigated the functions of CD137 ligand (CD137L) in human monocyte‐derived DC during an immune response. Cross‐linking of CD137L on DC leads to cell maturation in an autocrine fashion, mostly via release of TNF‐α. Reverse signaling of CD137L also mediates migration of DC via up‐regulation of the CCR7 chemokine receptor, demonstrated by an in vivo MIP‐3β‐dependent SCID mouse migration model. Finally, CD137L‐activated DC induce differentiation of human T cells into potent Th1 effectors. Cocultivation of autologous T cells and CD137L‐activated DC in an antigen‐specific reaction leads to T cell proliferation and the release of IL‐12p70 and IFN‐γ. These findings deliver new insights into the multiple effects of reverse signaling of CD137L in human DC during the initiation of an adaptive immune response, including the key features of DC maturation, migration and, ultimately, antigen‐specific T cell differentiation.

LAMP-1 and LAMP-2, but not LAMP-3, are reliable markers for activation-induced secretion of human mast cells

Mast cells are resident tissue cells that induce anaphylactic reactions by rapidly releasing mediators after antigen‐mediated cross‐linking of immunoglobulin E receptors. In the similarly active peripheral blood basophilic leukocyte, lysosome‐associated membrane protein 3 (LAMP‐3; CD63) has been described as an activation marker, but LAMPs have not been investigated in normal tissue mast cells.

H1-antihistamine-refractory chronic spontaneous urticaria: It's worse than we thought – first results of the multicenter real-life AWARE study

Most data on chronic spontaneous urticaria (CSU) originate from highly selected patient populations treated at specialized centres. Little is known about CSU patient characteristics and the burden of CSU in routine clinical practice. AWARE (A World‐wide Antihistamine‐Refractory chronic urticaria patient Evaluation) is an ongoing global study designed to assess chronic urticaria in the real‐life setting.

Fulminant polyarteritis nodosa associated with acute myeloid leukaemia resulted in bilateral lower leg amputation

ARSÈNE MEKINIAN, MARC LAMBERT, JEAN-PAUL BEREGI, SANDRINE MORELL-DUBOIS, DAVID LAUNAY, VIVIANE QUEYREL, MARCO MIDULLA, ERIC HACHULLA, PIERRE-YVES HATRON Internal Medicine Department and Vascular Radiology Department, University Hospital of Lille, Lille, France Accepted 26 May 2009 Correspondence to: Marc Lambert, Internal Medicine Department, University Hospital of Lille, 59037 Lille Cedex, France. E-mail: m-lambert@chru-lille.fr

Update on the cutaneous neurobiology of pruritus

ZusammenfassungDie Pathogenese des chronischen und akuten Pruritus ist bislang noch nicht vollständig geklärt. Interaktionen von Neuronen mit transienten und residenten Zellen der Haut scheinen jedoch eine wichtige Rolle in der Regulation des Pruritus einzunehmen. Neuronale Zellen, die spezifische Rezeptoren exprimieren und Neuromediatoren ausschütten, sind dabei aktiv beteiligt. Durch die freigesetzten Mediatoren können Immunzellen wie Mastzellen und eosinophile Granulozyten aktiviert werden, die bei vielen Hauterkrankungen mit chronischem Pruritus im entzündlichen Infiltrat in der Haut vorliegen. Mastzellen und eosinophile Granulozyten exprimieren Rezeptoren für Neuromediatoren und setzen selbst Neuromediatoren und Zytokine frei, die wiederum zu einer Aktivierung von peripheren Nervenfasern führen. Beispielsweise können Mastzellen und eosinophile Granulozyten Neurotrophine wie „nerve growth factor“ (NGF) und „brain-derived neurotrophic factor“ (BDNF) sowie Zytokine wie IL-31 freisetzen. NGF, BDNF und IL-31 korrelieren bei Patienten mit chronisch entzündlichen Hauterkrankungen wie der atopischen Dermatitis mit der Krankheitsschwere und teilweise mit dem Pruritus der Patienten. Ferner führen NGF, BDNF und IL-31 zu einem vermehrten Nervenfaserwachstum. Es scheint also, dass das Zusammenspiel zwischen transienten und residenten Zellen in der Haut mit peripheren Nervenfasern, Mastzellen und eosinophilen Granulozyten eine wichtige Rolle in der gegenseitigen Aktivierung spielt, wobei noch nicht gänzlich klar ist, wie diese neurobiologischen Zusammenhänge zu einer Induktion von Pruritus führen können.AbstractThe pathogenesis of chronic and acute pruritus is not yet completely understood. Interactions of neurons with resident and nonresident skin cells seem to play an important role in the regulation of pruritus. Neuronal cells which express specific receptors and are capable of releasing neuromediators play an active role in this interaction. Furthermore, released neuromediators can activate immune cells including mast cells and eosinophils, which are increased in the inflammatory infiltrate of many pruritic skin diseases. Mast cells and eosinophils express receptors for neuromediators themselves. In addition, they can release neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and cytokines including interleukin (IL)-31 which correlate with disease activity in patients with inflammatory skin diseases including atopic dermatitis and induce neuronal outgrowth. In part, a correlation of these mediators has also been described with pruritus. Although the interplay between transient and resident cells in the skin with peripheral nerves, mast cells, and eosinophils plays an important role in the mutual activation, the neurobiological mechanisms that lead to pruritus are not completely clear yet.The pathogenesis of chronic and acute pruritus is not yet completely understood. Interactions of neurons with resident and nonresident skin cells seem to play an important role in the regulation of pruritus. Neuronal cells which express specific receptors and are capable of releasing neuromediators play an active role in this interaction. Furthermore, released neuromediators can activate immune cells including mast cells and eosinophils, which are increased in the inflammatory infiltrate of many pruritic skin diseases. Mast cells and eosinophils express receptors for neuromediators themselves. In addition, they can release neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and cytokines including interleukin (IL)-31 which correlate with disease activity in patients with inflammatory skin diseases including atopic dermatitis and induce neuronal outgrowth. In part, a correlation of these mediators has also been described with pruritus. Although the interplay between transient and resident cells in the skin with peripheral nerves, mast cells, and eosinophils plays an important role in the mutual activation, the neurobiological mechanisms that lead to pruritus are not completely clear yet.

A rare case of a sclerodermoid chronic graft versus host disease. Successful treatment with extracorporeal photopheresis (ECP)

A 31-year-old woman presented with progressive deep linear induration on her lower abdomen, forearms and thighs. These symptoms developed three years after allogenic stem cell transplantation. Furthermore, the patient showed multiple hypopigmented lichenoid papules on the extensor surfaces of the forearms consistent with lichen sclerosus. Histological analysis of a biopsy specimen from her left thigh showed dermal sclerosis extending into the fascia, thus establishing the diagnosis of a rare combination of superficial and deep sclerodermoid chronic graft-versus-host disease. After 7 cycles of extracorporeal photopheresis, a marked resolution of the indurations and a reduction of the modified Rodnan skin score from 12 to 7 were noted.

Ungewöhnliche chronische sklerodermiforme Graft-versus-Host-Erkrankung@@@A rare case of a sclerodermoid chronic graft versus host disease: Erfolgreiche Therapie mittels extrakorporaler Photopherese (ECP)@@@Successful treatment with extracorporeal photopheresis (ECP)

A 31-year-old woman presented with progressive deep linear induration on her lower abdomen, forearms and thighs. These symptoms developed three years after allogenic stem cell transplantation. Furthermore, the patient showed multiple hypopigmented lichenoid papules on the extensor surfaces of the forearms consistent with lichen sclerosus. Histological analysis of a biopsy specimen from her left thigh showed dermal sclerosis extending into the fascia, thus establishing the diagnosis of a rare combination of superficial and deep sclerodermoid chronic graft-versus-host disease. After 7 cycles of extracorporeal photopheresis, a marked resolution of the indurations and a reduction of the modified Rodnan skin score from 12 to 7 were noted.

Ungewöhnliche chronische sklerodermiforme Graft-versus-Host-Erkrankung

A 31-year-old woman presented with progressive deep linear induration on her lower abdomen, forearms and thighs. These symptoms developed three years after allogenic stem cell transplantation. Furthermore, the patient showed multiple hypopigmented lichenoid papules on the extensor surfaces of the forearms consistent with lichen sclerosus. Histological analysis of a biopsy specimen from her left thigh showed dermal sclerosis extending into the fascia, thus establishing the diagnosis of a rare combination of superficial and deep sclerodermoid chronic graft-versus-host disease. After 7 cycles of extracorporeal photopheresis, a marked resolution of the indurations and a reduction of the modified Rodnan skin score from 12 to 7 were noted.