Andreas C. Renkl

Essential Role of Osteopontin in Smoking-Related Interstitial Lung Diseases

Smoking-related interstitial lung diseases are characterized by the accumulation of macrophages and Langerhans cells, and fibrotic remodeling, which are linked to osteopontin (OPN) expression. Therefore, OPN levels were investigated in bronchoalveolar lavage (BAL) cells in 11 patients with pulmonary Langerhans cell histiocytosis (PLCH), 15 patients with desquamative interstitial pneumonitis (DIP), 10 patients with idiopathic pulmonary fibrosis, 5 patients with sarcoidosis, 13 otherwise healthy smokers, and 19 non-smoking controls. Furthermore, OPN overexpression was examined in rat lungs using adenoviral gene transfer. We found that BAL cells from patients with either PLCH or DIP spontaneously produced abundant amounts of OPN. BAL cells from healthy smokers produced 15-fold less OPN, and those cells from non-smoking healthy volunteers produced no OPN. BAL cells from patients with either idiopathic pulmonary fibrosis or sarcoidosis produced significantly less OPN, as compared with patients with PLCH. These data were confirmed by immunochemistry. Nicotine stimulation increased production of both OPN and granulocyte-macrophage colony stimulating factor by alveolar macrophages from smokers. Nicotinic acetylcholine receptor expression resembled the pattern of spontaneous OPN production and was dramatically increased in both PLCH and DIP. OPN overexpression in rat lungs induced lesions similar to PLCH with marked alveolar and interstitial accumulation of Langerhans cells. Our findings suggest a pathogenetic role of increased OPN production in both PLCH and DIP by promoting the accumulation of macrophages and Langerhans cells.

CD44 Variant Isoforms are Essential for the Function of Epidermal Langerhans Cells and Dendritic Cells

Upon antigen encounter epidermal Langerhans cells (LC) and dendritic cells (DC) emigrate from peripheral organs and invade lymph nodes through the afferent lymphatic vessels and then assemble in the paracortical T cell zone and present antigen to T lymphocytes. Part of this process is mimicked by metastasizing tumor cells. Since splice variants of CD44 promote metastasis to lymph nodes we explored the expression of CD44 proteins on migrating LC and DC. We show that following antigen contact, LC and DC upregulate pan CD44 epitopes and epitopes encoded by variant exons v4, v5, v6 and v9. Antibodies against CD44 epitopes arrest LC in the epidermis, prevent the binding of activated LC and DC to the T cell zones of lymph nodes, and severely inhibit their capacity to induce a delayed type hypersensitivity reaction to a skin hapten in vivo. Our results demonstrate that CD44 splice variant expression is obligatory for the migration and function of LC and DC.

The role of CD44 during CD40 ligand-induced dendritic cell clustering and maturation.

The interaction between CD40 on dendritic cells (DC) and its ligand CD154 has been recognized to be an important feature in the maturation of DC. Here, we were interested in the role of CD44 a surface receptor shown to mediate cell‐cell adhesion and binding to Hyaluronic acid (HA). Western blot analysis of human DC stimulated for 3–12 h with CD154 revealed the rapid induction of the 85 kDa standard form of CD44 and an increased HA‐binding affinity. Time‐lapse video‐imaging microscopy of human DC co‐cultured on CD154‐transfected murine fibroblasts showed that the CD44 up‐regulation coincided with the rapid induction of homotypic DC clustering, which did not occur on empty vector‐transfected fibroblasts. In this system, addition of anti‐CD44s mAbs abrogated DC‐cluster formation, thereby inhibiting further maturation, as shown by a reduced TNF‐α production and inhibition of CD154‐induced MHC class II up‐regulation. However, co‐incubation with HA‐degrading enzymes induced no changes in the CD154‐mediated DC clustering and maturation.

Pruritic intertriginous vesiculopustular eruption

A 64-year-old Turkish woman presented with progressive pr -uritic vesicles and erosions in the intertriginous areas, which she first detected during the summer months of the previous year. She reported developing more than 5 new vesicles each week that ruptured promptly after scratching and resolved le -aving hyperpigmentation but no scarring. Her general health was good and she was on no medications.

Zellmigrations- und -adhäsionsprozesse bei Immunreaktionen vom Spättyp

ZusammenfassungDifferenzierte Zellwanderungsmechanismen immunkompetenter Zellen sind von besonderer Bedeutung für den Ablauf von Immunreaktionen. Ein fein abgestimmtes Muster von Zellbindungs und -loslassprozessen, vermittelt durch Adhäsions-moleküle, Proteasen, Zytokine und Chemokine, steuert die gerichtete Wanderung von Immunzellen. In dieser Übersicht wird anhand von Modellen das aktuelle Verständnis von Zellmigrationsprozessen bei Allergien vom Spättyp dargestellt.SummaryCell migration of immunocompetent cells is a central trait of all types of immune responses. A fine-tuned system of adhesion and detachment patterns, mediated by cell adhesion molecules, proteases, cytokines and chemokines, regulates such migration processes. Using current models, the concepts of cell migration in allergic delayed-type hypersensitivity reactions are reviewed.