UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review

BACKGROUND: Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. METHODS: Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. RESULTS: Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. CONCLUSIONS: Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications

Evidence for an A2_2 adenosine receptor in guinea pig lung

Adenosine receptors in guinea pig lung were characterized by measurement of cyclic AMP formation and radioligand binding. 5'-N-Ethylcarboxamidoadenosine (NECA) increased cyclic AMP Ievels in lung slices about 4-fold over basal values with an EC$_{50}$ of 0.32 $\mu$mol/l. N$^6$ - R-(- )-Phenylisopropyladenosine (R-PIA) was 5-fold less potent than NECA. 5'-N-Methylcarboxamidoadenosine (MECA) and 2-chloroadenosine had EC$_{50}$-values of 0.29 and 2.6 $\mu$mol/l, whereas adenosine and inosine had no effect. The adenosine receptors in guinea pig Iung can therefore be classified as A$_2$ receptors. Several xanthine derivatives antagonized the NECA-induced increase in cyclic AMP levels. 1,3-Diethyl-8-phenylxanthine (DPX; K$_i$ 0.14 $\mu$mol/l) was the most potent analogue, followed by 8-phenyltheophylline (K$_i$ 0.55 $\mu$mol/l), 3-isobutyl-1-methylxanthine (IBMX; K$_i$ 2.9 $\mu$mol/l) and theophylline (K$_i$ 8.1 $\mu$mol/l). In contrast, enprofylline (1 mmol/1) enhanced basal and NECA-stimulated cyclic AMP formation. In addition, we attempted to characterize these receptors in binding studies with [$^3$H]NECA. The K$_D$ for [$^3$H] NECA was 0.25 $\mu$mol/l and the maximal number of binding sites was 12 pmol/mg protein. In competition experiments MECA (K$_i$ 0.14 $\mu$mol/l) was the most potent inhibitor of [$^3$H] NECA binding, followed by NECA (K$_i$ 0.19 $\mu$mol/l) and 2-chloroadenosine (K$_i$ 1.4 $\mu$mol/l). These results correlate well with the EC$_{50}$- values for cyclic AMP formation in lung slices. However, the K$_i$-values of R-PIA and theophylline were 240 and 270 $\mu$mol/l, and DPX and 8-phenyltheophylline did not compete for [$^3$H]NECA binding sites. Therefore, a complete characterization of A$_2$ adenosine receptors by [$^3$H] NECA binding was not achieved. In conclusion, our results show the presence of adenylate cyclase-coupled A$_2$ adenosiile receptors in lung tissue which are antagonized by several xanthines

Lisch nodules. Markers of neurofibromatosis 1 and immunohistochemical references for neuroectodermal differentiation

Iris nodules in neurofibromatosis I have become an important tool in the differential diagnosis of phakomatoses. The clinical appearance and importance of these nodules first recognized by Karl Lisch in Munich in 1937. The diagnosis and differential diagnosis of Lisch nodules are illustrated. The importance of iris nodules in genetic counselling of patients and their relatives is discussed, with emphasis on monosymptomatic cases. Histologically Lisch nodules are formed by aggregations of oval to round cells that form dome-shaped papules on the anterior layer of the iris. Immunohistochemically these cells are characterized by positive staining with antibodies against vimentin and S-100 protein. This proves their ectodermal differentiation. Thus Lisch nodules can be seen as a direct manifestation of neuroectodermal disturbances in neurofibromatosis I

Analysis of T cell activation pathways in patients with liver cirrhosis, impaired delayed hypersensitivity and other T cell-dependent functions

Patients with cirrhosis of the liver frequently demonstrate anergy in intracutaneous tests and fail to respond to vaccination, suggesting impaired delayed hypersensitivity and other T cell-dependent functions in vivo. T cell activation through the coordinated interaction of different cells of the immune system (B cell, antigen-presenting cells (APC)) is an important step in the induction of cellular and humoral immune responses. Impaired T cell-dependent functions in patients with liver cirrhosis may thus be explained by defective T cell activation. We prospectively investigated T cell activation pathways in 12 patients (nine males, three females) with alcoholic liver cirrhosis (seven Child Pugh stage A and B (CP A+B), five Child Pugh stage C (CP C)) and five healthy controls and compared the in vitro results of T cell activation with data obtained in vivo, e.g. intracutaneous tests and vaccination against hepatitis B surface antigen (HBs-Ag). Five out of eight patients who completed vaccination against hepatitis B virus infection were non-responders; one of the three responders had a non-protective anti-HBs titre. Moreover, three of five patients with alcoholic liver cirrhosis CP A+B, and two out of three with CP C were anergic in intracutaneous tests to a set of diverse antigens. All parameters of T cell activation were normal, including proliferation mediated by CD2, CD3–T cell receptor (TCR) complex, and CD28; acquisition of responsiveness to exogenous IL-2 and IL-4; activation of proteinkinase C (PKC) by phorbol ester and calcium influx by addition of ionomycin. The ability of monocytes to deliver costimulatory signals was preserved in patients with alcoholic cirrhosis. In addition, serum of patients with alcoholic liver disease did not inhibit T cell proliferation. We conclude that, although in patients with alcoholic liver cirrhosis T cell-dependent functions are impaired in vivo, T cell activation pathways are not responsible for the observed immune defect