Increased in vitro apoptosis and altered expression of apoptosis-related molecules have been reported in systemic lupus erythematosus (SLE). It was speculated that autoantigens released from apoptizing cells may contribute to the etiopathogenesis of SLE by both activation of autoreactive lymphocytes and the formation of immune complexes. Conflicting data about the level of cellular apoptosis from animal models for SLE and human SLE indicate different pathomechanisms. In the present study we analysed the count of circulating early apoptotic cells and its correlation with the clinical activity in SLE compared with the amount in primary systemic vasculitis (PSV). The percentage of early apoptotic cells determined by Annexin V-FITC binding cells was significantly increased in peripheral blood of SLE patients compared with normal healthy donors (NHD) and PSV (NHD 5.62%, SLE 13.68%, PSV 8.69%). Analysis of lymphocytes revealed significantly increased counts in the T cell populations (NHD 5.15%, SLE 12.22%, PSV 10.01%), whereas the increase in B cells did not reach significance level (NHD 9.20%, SLE 18.95%, PSV 16.59%). Apoptotic cell count revealed no correlation to SLAM-Score or to immunosuppressive therapy, corticosteroid-dosage or absolute lymphocyte count. The general increase of circulating apoptotic cells may indicate an impaired clearance in SLE patients, independent of clinical activity or therapeutic interventions. Autoantigens from apoptotic cells may contribute to both activation of autoreactive lymphocytes and formation of immune complexes.

Deficiency of CD95 (Apo-1/Fas)-mediated apoptosis has recently been found in some autoimmune lymphoproliferative disorders due to inherited mutations of the CD95 gene. In this study , impairment of CD95 ligand-mediated killing of lymphocytes and eosinophils in Churg-Strauss Syndrome (CSS) , which was a result of variation of CD95 receptor isoform expression , is demonstrated. Compared to those from healthy individuals , peripheral blood lymphocytes from eight CSS patients exhibit a switch from the membrane-bound CD95 receptor expression to its soluble splice variant , which protects from CD95L-mediated apoptosis. In five out of seven CSS patients recurrent oligoclonal T cell expansions were found, all using a V␤-gene from the V␤21 family associated with similar CDR3 motifs , indicating the predominance of T cell clones of a similar specificity in the CSS patients. In two of them , the effect of immunosuppressive therapy was studied. In both cases aberrant overexpression of the soluble CD95 receptor isoform and deviations from normal TCR V␤-gene usage normalized in parallel with the clinical improvement. Furthermore , soluble CD95 was identified as a survival factor for eosinophils rescuing eosinophils from apoptosis in the absence of growth factors in vitro. Churg-Strauss Syndrome (CSS) was for the first time described by Lotte Strauss and Jacob Churg in 1951 in The American Journal of Pathology, 1 defining a new entity with systemic vasculitis, blood and tissue eosinophilia, and a long-term history of asthma. Systemic vasculitis in this rare syndrome mainly affects the lower respiratory tract, kidneys, skin, and nervous system. 2 The gastrointestinal tract is involved in about 35% of the CSS cases. 2 Infiltrating eosinophils are frequently found in granulomatous lesions 3 and the fraction of eosinophils in the peripheral blood correlates with the course of the disease, 3,4 suggestive of a role of eosinophils in the pathogenesis of CSS. 5 On the other hand, T cells were frequently implicated in autoreactivity and inflammatory lesions. 6 However, a potential role of T lymphocytes in CSS and the molecular mechanisms underlying this disease have not yet been studied.One tool to analyze T cell populations in clinical samples at the molecular level is the Immunoscope technique. 5 This approach is based on the hypothesis that the expression of unique, rearranged T cell receptor (TCR) genes reflects the specificity of a given T cell. 7 Each TCR-␤ chain consists of a variable (V), diversity (D), joining (J), and a constant region, the first three determining the antigen specificity in their VDJ-junction, including complementarity-determining region III (CDR3). During T cell differentiation, unique variable region genes are created by recombination of V, D and J segments for the TCR-␤ locus. More than 70 V␤ gene segments have been characterized and are classified into 24 gene families 8 ( Figure 1A).In T cells the CD95/CD95 ligand system is a major pathway of apoptotic cell death and thus essential for prevention of lymp...

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Only limited data have been published about the therapeutic use of anakinra in patients with psoriatic arthritis. We undertook this study to evaluate the efficacy and safety of anakinra in patients with active psoriatic arthritis. In a prospective open-label single-center study, 20 patients were treated with 100 mg anakinra everyday either alone or in combination with ongoing methotrexate over 6 months. Safety and efficacy was evaluated using Psoriasis Arthritis Response Criteria (PsARC), Disease Activity Score (DAS) 28, American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), Psoriasis Area and Severity Index Score, Dactylitis Score and Health Assessment Questionnaire (HAQ), and the C-reactive protein, and erythrocyte sedimentation rate. Of the 20 patients enrolled, six completed 24 weeks, 18 completed 12 weeks, and 19 completed 4 weeks of treatment. Early-treatment termination was mainly due to inefficacy (13 patients) and only one drop-out occurred because of an unrelated adverse event. Six patients fulfilled continuously the PsARC until week 24. A moderate EULAR response was achieved by four patients and a good EULAR response by three patients in week 24. Five patients reached ACR 20, four patients ACR 50, and two patients ACR 70 in week 24. HAQ improved slightly throughout the study (n = 19, mean (SD); baseline, 1.127 (0.671); week 24, 1.055 (0.812)) just as DAS 28 (n = 16; baseline, 4.7(1.5); week 24, 4.0(2.0)). Only nine patients showed skin manifestations affecting >3% of their body surface area which improved in two, worsened in four, stabilized in two patients, and newly evolved in one patient. Adverse events were mainly mild (95%). Fifteen (75%) patients showed injection site reactions. No serious infections occurred. Anakinra was well tolerated with no occurrence of serious drug-associated adverse events and lead to improvement of signs and symptoms in nine out of 19 patients, therefore providing a potential therapeutic option in patients with active psoriatic arthritis.

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Our findings suggest that the described ocular findings of VKH disease may represent a component of a syndrome consisting also of melanoma-associated hypopigmentation. Within the framework of current concepts of immunity in patients with MM and VKH, the long recurrence-free interval might support the hypothesis of an autoimmune or hypersensitivity process against melanocytes. The use of immunosuppressive therapy in the treatment of VKH and its potential influence on the development of metastatic disease should be carefully reconsidered.

Programmed cell death (apoptosis) can be found in normal thyroid tissue and in various diseases affecting the thyroid gland. The Fas/Fas ligand (FasL) system is involved in the induction of apoptosis in human thyrocytes. Cross-linking the Fas receptor with its own ligand or with an antibody capable of oligomerizing with the receptor induces programmed cell death. We investigated the role of Fas-induced apoptosis in primary human thyrocytes in vitro. Cell cultures of normal human thyrocytes were prepared from specimens obtained during surgery for uninodular goiter. Apoptosis was induced by incubation of the cells with a monoclonal IgM anti-Fas antibody. The presence of apoptosis was determined by FACS analysis of FITC-labelled annexin V binding combined with dye exclusion of propidium iodide. We found a significant rate of Fas-induced apoptosis in normal thyrocytes after activation with a monoclonal anti-Fas antibody. TSH was able to inhibit Fas-mediated apoptosis in a dose-dependent manner. This effect was more pronounced when thyrocytes were incubated in the presence of interferon-gamma. Low concentrations of iodine were able to inhibit apoptosis, while high concentrations of iodine increased the rate of Fas-induced apoptosis. Our results show that Fas-mediated apoptosis is inducible in normal human thyrocytes in vitro and is influenced by TSH and iodine. The Fas/FasL system may play an important role in the regulation of cell number within the thyroid gland, and may be involved in the processes leading to goiter in iodine deficiency.

1alpha,25(OH)2-vitamin D3 is a hormone which potentially stimulates bone cell growth and differentiation. TNFalpha is one possible inductor for apoptosis; apoptosis being an important regulatoring factor for bone modelling and remodelling. We examined the influence of physiological levels (0.1 nM) 1alpha,25(OH)2-vitamin D3 on TNFalpha-mediated apoptosis in human osteoblast-like cells. These human cells were obtained from bone fragments obtained during orthopedic operations on patients without systemic bone disease. Treatment with 1alpha,25(OH)2-vitamin D3 for 8 weeks resulted in a significant reduction (30%) of viable cell number compared to untreated cells. Incubation with TNFalpha (100 ng/ml for 4 hours) only had limited effects on the rate of apoptosis in control cells. After pretreatment with 1alpha,25(OH)2-vitamin D3, induction of apoptosis increased up to 10% in human osteoblast-like cells. In parallel to the induction of apoptosis, 1alpha,25(OH)2-vitamin D3 stimulated osteocalcin and alkaline phosphatase as markers of mature osteoblasts. Our data suggest that 1alpha,25(OH)2-vitamin D3 has a stimulatory effect on TNFalpha-induced apoptosis in human osteoblast-like cells as a result of 1alpha,25(OH)2-vitamin D3-induced cell differentiation.