Flow cytometry study of blood cell subtypes reflects autoimmune and inflammatory processes in autoimmune polyendocrine syndrome type I.

Autoimmune polyendocrine syndrome type I (APS I) is a recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. AIRE is expressed in medullary epithelial cells where it activates transcription of organ-specific proteins in thymus, thereby regulating autoimmunity. Patients with APS I have, in addition to autoimmune manifestations in endocrine organs, also often ectodermal dystrophies and chronic mucocutaneous candidiasis. The aim of this study was to characterize immune cell subpopulations in patients with APS I and their close relatives. Extensive blood mononuclear cell immunophenotyping was carried out on 19 patients with APS I, 18 first grade relatives and corresponding sex- and age-matched healthy controls using flow cytometry. We found a significant relative reduction in T helper cells coexpressing CCR6 and CXCR3 in patients with APS I compared to controls (mean = 4.10% versus 5.94% respectively, P = 0.035). The pools of CD16(+) monocytes and regulatory T cells (Tregs) were also lower in patients compared with healthy individuals (mean = 15.75% versus 26.78%, P = 0.028 and mean = 4.12% versus 6.73%, P = 0.029, respectively). This is the first report describing reduced numbers of CCR6(+)CXCR3(+) T helper cells and CD16(+) monocytes in patients with APS I We further confirm previous findings of reduced numbers of Tregs in these patients.

Heat shock protein 90 - a potential target in the treatment of human acute myelogenous leukemia.

Heat shock proteins (HSPs) are molecular chaperones that stabilize folding and conformation of normal as well as oncogenic proteins. These chaperones thereby prevent the formation of protein aggregates. HSPs are often overexpressed in human malignancies, including AML. HSP90 is the main chaperon required for the stabilization of multiple oncogenic kinases involved in the development of acute myelogenous leukemia (AML). HSP90 client proteins are involved in the regulation of apoptosis, proliferation, autophagy and cell cycle progression; several of these proteins are in addition considered as possible therapeutic targets for the treatment of AML. HSP90 inhibition thereby offers the possibility to modulate several intracellular regulatory pathways through targeting of a single molecule. Several direct inhibitors of HSP90 have been developed, and they are classified into four groups: benzoquinon ansamycines and their derivatives, radicicol and its derivates, small synthetic inhibitors and a final group of other inhibitors. The HSP90 activity is regulated by posttranscriptional modulation; HSP90 inhibition can thereby be indirectly achieved through increased acetylation caused by histone deacetylase inhibitors. Many of these agents have entered phase I/II clinical trials, and the results from these initial studies have documented that HSP90 inhibition can mediate antileukemic effects in vivo. However, one would expect immunosuppressive side effects because HSP90 inhibitors have both direct and indirect inhibitory effects on T cell activation. Thus, future clinical studies are needed to clarify the efficiency and toxicity of HSP90 inhibitors in the treatment of human AML, including studies where HSP90 inhibitors are combined with conventional chemotherapy.

Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell.

Characterization of epigenetic events in carcinogenesis has led to the discovery of a new class of oncogenes and thereby a new class of therapeutic targets. Among the new therapeutic approaches are modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). HDACs deacetylate histones as well as transcription factors and can modulate gene expression through both these mechanisms in normal and malignant cells. Furthermore, acetylation is an important posttranslational modulation of several proteins involved in the regulation of cell proliferation, differentiation and apoptosis in normal as well as cancer cells. Even though several HDAC inhibitors have been characterized in vitro, only a limited number of these agents are in clinical trials. Various HDAC inhibitors differ in their toxicity profile when comparing the side effects described in the available clinical studies of HDAC inhibition in the treatment of cancer. These drugs may also affect normal hematopoiesis; hematologic toxicity is common to many drugs but stimulation of hematopoiesis seems to occur for others. HDAC inhibitors usually affect <10% of the genes in cancer cells. Divergent effects of HDAC inhibition on the global gene expression profiles have been described when testing various cancer cells, and this is further complicated by altered HDAC expression induced by HDAC inhibitors. However, increased p21 expression seems to be a common characteristic for most studies, suggesting an important role of this molecule during HDAC inhibitory treatment. Even though the initial studies are encouraging, additional in vitro and in vivo pharmacological characterization is definitely needed.

Characterization of ribosomal P autoantibodies in relation to cell destruction and autoimmune disease.

Autoantibodies against the ribosomal P proteins are related to cell death and tissue destruction and are frequently exhibited in patients with systemic lupus erythematosus (SLE). In an attempt to explore the effect of tissue destruction on the induction of anti-P autoantibodies, we searched for anti-P autoantibodies by enzyme-linked immunosorbent assay in 201 antinuclear antibody (ANA)-positive individuals, in 10 patients with treated kidney SLE and in 45 acute leukaemia patients undergoing intensive chemotherapy. The autoantibody reactivity was further characterized using one- and two-dimensional immunoblot analysis and immunofluorescence. Anti-P were detected in 5.5% (11/201) of ANA-positive individuals, but not in kidney-affected SLE patients or in patients with leukaemia. Seven of 11 anti-P-positive patients had SLE (3/11), primary Sjögrens's syndrome (1/11) and other autoimmune diseases (3/11). A relation between disease activity and anti-P was suggested by follow-up examinations in one SLE patient, supported by the absence of anti-P autoantibodies in the 10 treated kidney SLE patients. Anti-P autoantibodies were detected by immunoblot in one patient with SLE indicating anti-P2 predominance and in the patient with Sjögrens's syndrome indicating anti-P1 predominance. Diverging humoral responses in these ANA- and anti-P-positive patients were further illustrated by immunofluorescence, elucidating varying nuclear reactivity and anti-P pattern. The observation of anti-P in individuals with active autoimmune disease, but not in patients with chemotherapy-induced cell damage, suggests that anti-P antibodies are part of a specific disease process, and not elicited as a response to cell destruction per se.