Chronic stimulation desensitizes ß2-adrenergic receptor responses in natural killer cells.

Adrenergic receptors (ARs) are preferentially expressed by innate lymphocytes such as natural killer (NK) cells. Here, we study the effect of epinephrine-mediated stimulation of the ß2-adrenergic receptor (ß2AR) on the function of human NK cells. Epinephrine stimulation inhibited early NK cell signaling events and blocked the function of the integrin LFA-1. This reduced the adhesion of NK cells to ICAM-1, explaining how NK cells are mobilized into the peripheral blood upon epinephrine release during acute stress or exercise. Additionally, epinephrine stimulation transiently reduced NK cell degranulation, serial killing, and cytokine production and affected metabolic changes upon NK cell activation via the cAMP-protein kinase A (PKA) pathway. Repeated exposure to ß2AR agonists resulted in the desensitization of the ß2AR via a PKA feedback loop-initiated G-protein switch. Therefore, acute epinephrine stimulation of chronically ß2AR stimulated NK cells no longer resulted in inhibited signaling and reduced LFA-1 activity. Sustained stimulation by long-acting ß2-agonists (LABA) not only inhibited NK cell functions but also resulted in desensitization of the ß2AR. However, peripheral NK cells from LABA-treated asthma patients still reacted unchanged to epinephrine stimulation, demonstrating that local LABA administration does not result in detectable systemic effects on NK cells.

Additional use of α-IgM antibodies potentiates CpG ODN2006-induced B cell activation by targeting mainly naïve and marginal zone-like B cells.

CpG ODN2006 is widely used as a potent B cell stimulant in vitro and in vivo. However, it shows a deficit in targeting naïve B cells in vitro. In this study, we investigated whether α-IgM can support ODN2006-induced effects on B cells to obtain enhanced activation with focus on different B cell subsets. Our results delineated robust B cell activation, shown by increased activation marker expression and cytokine secretion by each agent alone, and further augmented when used in combination. Interestingly, α-IgM targeted mainly naïve and marginal zone-like B cells, thus complementing the pronounced effects of ODN2006 on memory B cells and achieving optimal activation for all B cell subsets. Taken together, combining ODN2006 and α-IgM is beneficial for in vitro activation including all B cell subsets. Furthermore, our results suggest that α-IgM could enhance efficacy of ODN2006 in vivo with further need of investigation.

Immediate and Delayed Salivary Cytokine Responses during Repeated Exposures to Cold Pressor Stress.

INTRODUCTION: Excessive stress is increasingly recognized as an important trigger of many diseases prevalent in modern societies, and monitoring such stress-related effects could aid prevention. The measurement of salivary markers of inflammation is emerging as a promising tool to non-invasively quantify stress' effects on immune processes in everyday life and thereby detect early aberrations before the manifestation of serious health problems. However, more laboratory-controlled research is needed in order to establish the timescale and determinants of salivary cytokine responses to acute stress. METHODS: We repeatedly exposed participants to Cold Pressor Stress Test (CPT) or a control procedure and measured a wide array of salivary cytokines as well as subjective, cardiovascular, and cortisol stress reactions. CPT exposure was repeated every 15 min, 3 times in total, with a duration of 3 min each. Saliva was sampled immediately after the first two exposures as well as in 15-min intervals until 60 min after the onset of the first intervention. RESULTS: We found that many cytokines were detectable in saliva. Specific stress effects were limited to IL-8 and IL-6, however, which decreased immediately or 15 min after stress onset, respectively. Moreover, IL-8 was negatively correlated to cortisol output in the stress but not in the control group. Significant increases were also observed in salivary TNFα and IFNγ; however, these effects were similar under both stress and control conditions. DISCUSSION: Our results show that particular salivary cytokines may be sensitive to immediate effects of acute CPT-induced stress and also highlight the importance of employing control procedures to discern stress effects from unrelated variations in salivary cytokines.

Modulation of Dopamine Receptors on Osteoblasts as a Possible Therapeutic Strategy for Inducing Bone Formation in Arthritis.

Rheumatoid arthritis (RA) is associated with systemic osteoporosis, which leads to severe disability and low quality of life. Current therapies target osteoclasts to reduce bone degradation, but more treatment options would be required to promote bone protection by acting directly on osteoblasts (OB). Recently, the local production of dopamine in inflamed joints of RA has been observed. Thus, in this project, we aimed to determine the implication of the neurotransmitter dopamine in the bone formation process in RA. Dopamine receptors (DR) in the human bone tissue of RA or osteoarthritis (OA) patients were examined by immunohistochemistry. DR in isolated human osteoblasts (OB) was analyzed by flow cytometry, and dopamine content was evaluated by ELISA. Osteoclasts (OC) were differentiated from the PBMCs of healthy controls (HC) and RA patients. Isolated cells were treated with specific dopamine agonists. The effect of dopamine on mineralization was evaluated by Alizarin red staining. Cytokine release in supernatants was measured by ELISA. Osteoclastogenesis was evaluated with TRAP staining. OC markers were analyzed via real-time PCR and bone resorption via staining of resorption pits with toluidine blue. All DR were observed in bone tissue, especially in the bone remodeling area. Isolated OB maintained DR expression, which allowed their study in vitro. Isolated OB expressed tyrosine hydroxylase, the rate-limiting enzyme for dopamine production, and contained dopamine. The activation of D2-like DR significantly increased bone mineralization in RA osteoblasts and increased osteoclastogenesis but did not alter the expression of OC markers nor bone resorption. DR were found in the bone remodeling area of human bone tissue and dopamine can be produced by osteoblasts themselves, thus suggesting a local autocrine/paracrine pathway of dopamine in the bone. D2-like DRs are responsible for bone mineralization in osteoblasts from RA patients without an increase in bone resorption, thus suggesting the D2-like DR pathway as a possible future therapeutic target to counteract bone resorption in arthritis.

Dopamine receptor 1 expressing B cells exert a proinflammatory role in female patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic rheumatic disease with a clear sex-bias. Recent data indicated a role for dopamine in RA pathogenesis, while dopaminergic pathways can be modulated by estrogens. As defined mechanism of action of dopamine on B cell function in RA are unclear, we aimed to elucidate this, with special focus on sex-differences. Healthy controls (HC, n = 64) and RA patients (n = 61) were recruited. Expression of D1-D5 dopamine receptors (DRs) was investigated by flow cytometry on peripheral blood mononuclear cells (PBMCs). D1-like DRs were stimulated in vitro to assess effects on B cell activation and proliferation. Secretion of cytokines and dopamine content were measured by ELISA. All DRs were expressed on PBMCs of HC and RA patients. Dopamine content in PBMCs, and frequency of D1DR expressing B cells were significantly higher in RA females (p < 0.001). Expression of D1DR on RA B cells correlated positively with disease duration and severity only in women. Combined B cell and D1-like DR stimulation induced higher IL-8 and CCL-3 secretion from PBMCs of female RA patients compared to HC. These results indicate sex-specific differences in dopaminergic pathway in RA, with a proinflammatory feature of the D1DR pathway in women.

Impact of Biological and Lifestyle Factors on Cognitive Aging and Work Ability in the Dortmund Vital Study: Protocol of an Interdisciplinary, Cross-sectional, and Longitudinal Study.

BACKGROUND: Previous research revealed several biological and environmental factors modulating cognitive functioning over a human's lifespan. However, the relationships and interactions between biological factors (eg, genetic polymorphisms, immunological parameters, metabolic products, or infectious diseases) and environmental factors (eg, lifestyle, physical activity, nutrition, and work type or stress at work) as well as their impact on cognitive functions across the lifespan are still poorly understood with respect to their complexity. OBJECTIVE: The goal of the Dortmund Vital Study is to validate previous hypotheses as well as generate and validate new hypotheses about the relationships among aging, working conditions, genetic makeup, stress, metabolic functions, the cardiovascular system, the immune system, and mental performance over the human lifespan with a focus on healthy working adults. The Dortmund Vital Study is a multidisciplinary study involving the Departments of Ergonomics, Immunology, Psychology and Neurosciences, and Toxicology at the Leibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo) in Germany, as well as several national and international partners. METHODS: The Dortmund Vital Study is designed as a combined cross-sectional and longitudinal study. Approximately 600 healthy subjects aged between 20 and 70 years will participate. A wide range of demographic, psychological, behavioral, sensory, cardiovascular, immunological, and biochemical data, a comprehensive electroencephalography (EEG)-based cognitive test battery as well as structural and functional magnetic resonance imaging (MRI) have been included in the study. RESULTS: The study was approved by the Ethics Committee of IfADo in October 2015. The baseline testing was conducted between 2016 and 2021 and will be repeated every 5 years (3 follow-up measures until 2035). As of March 2020 (until the outbreak of the COVID-19 pandemic), 593 participants have been enrolled. Some results from the cross-sectional part of the study were already published, further results will be published soon. Longitudinal data will be analyzed and published by 2025. CONCLUSIONS: We anticipate that the study will shed light on sources of interindividual differences in the alterations of cognitive functioning with increasing age and reveal biological and lifestyle markers contributing to work ability, longevity, and healthy aging on the one hand, and to risk factors for cognitive decline, mild cognitive impairment, or even dementia on the other hand. TRIAL REGISTRATION: ClinicalTrials.gov NCT05155397; https://clinicaltrials.gov/ct2/show/NCT05155397. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32352.

Low self-reported stress despite immune-physiological changes in paramedics during rescue operations.

Despite the high stress levels, paramedics seem to ignore or even negate the stress. This can be detrimental and lead to stress-related diseases. Therefore, we investigated the divergence between physiological and psychological stress responses of paramedics. Participants were 16 paramedics and 17 white-collar workers. We assessed psychological stress parameters, cortisol awakening response (CAR), and quantified immune parameters. In paramedics, electrocardiogram (ECG) was measured during one complete 24-hour shift. Our results revealed that CAR was higher in paramedics compared to controls. An alteration of immune parameters was observed even during days of free time. Also, ECG recordings showed acute stress in paramedics during rescue situations. Questionnaires revealed that rescue-service specific stressors affect psychological outcomes. However, paramedics reported significantly less mental stress and higher levels of depersonalization than controls. Taken together, our results suggest higher stress in paramedics compared to controls. However, paramedics negate their daily stress. Our findings underline therefore the importance to develop stress-management interventions for paramedics including sensitization for their stress reactions.

Dopamine induces in vitro migration of synovial fibroblast from patients with rheumatoid arthritis.

Preventing synovial fibroblast (SF) migration into the adjacent cartilage is a desirable therapeutic target in rheumatoid arthritis (RA). As previous studies demonstrated that RASF and SF from osteoarthritis (OA) patients express dopamine receptors (DR), aim of the present study was to investigate the impact of dopamine on mobility of fibroblasts from patients with chronic arthritides. Synovial tissue and fibroblasts were obtained from RA and OA patients. Immunohistochemistry was performed for all DR-subtypes in the invasion zone. Migration- and motility-assays were performed under DR-stimulation. Cytokines were evaluated using ELISA. Expression of DRs was evaluated by flow cytometry, and DR activation was measured by xCELLigence real-time analysis. All DRs were expressed in RA invasion zone. Migration and motility of RASF and OASF were increased after DR stimulation in patients ≤ 75 years old. Synovial fibroblasts from older RA patients (> 75 years old) expressed lower levels of D1-, D2- and D4-DR than patients ≤ 75 years old. DR activation was not altered in older patients. Our results suggest a possible involvement of dopamine on migration of fibroblasts from arthritis patients. Therefore, the synovial dopaminergic pathway might represent a potential therapeutic target to interfere with progressive joint damage in RA patients.

Regulation of natural killer cell activity by glucocorticoids, serotonin, dopamine, and epinephrine.

The immune system and the nervous system are highly complex organs composed of various different cells that must interact with each other for proper function of the system. This communication can be mediated by soluble factors. The factors released by the nervous system (neurotransmitters) differ from those released by the immune system (cytokines). Nevertheless, the nervous and immune systems can influence each other's activity because immune cells express neurotransmitter receptors, and neurons express cytokine receptors. Moreover, immune cells can synthesize and release neurotransmitters themselves, thus using neurotransmitter-mediated pathways via autocrine and paracrine mechanisms. Natural killer (NK) cells are innate lymphocytes that are important for early and effective immune reactions against infections and cancer. Many studies have shown the strong influence of stress and the nervous system on NK cell activity. This phenomenon may be one reason why chronic stress leads to a higher incidence of infections and cancer. Here, we review the effects of neuroendocrine factors on the different activities of NK cells. Understanding the effects of neuroendocrine factors on NK cell activities during physiological and pathophysiological conditions may result in novel therapeutic strategies to enhance NK cell functions against tumors.

Dopaminergic Agents in Rheumatoid Arthritis.

Clinical evidences suggest a causal relationship between rheumatoid arthritis (RA) and the dopaminergic system, and several studies described an alteration of the disease in patients treated with dopaminergic agents. Despite these interesting results, potential direct effects of dopamine on RA have not been intensively considered until the last decade. Recent studies confirm a direct effect of dopamine on the systemic immune response as well as on bone remodeling and on joint inflammation, both in humans and in different animal models of arthritis. While more research is necessary to accurately determine the effect of dopamine in RA, these results are encouraging and support a possible use of dopaminergic drugs for the treatment of arthritis in the future. Moreover, they point out that dopaminergic agents use to treat comorbidities, might influence the immune response and the disease progression in RA patients. This review summarizes the current knowledge about the effects of dopaminergic drugs on RA and describes the potential of dopaminergic drugs as future therapeutic strategy in arthritis. Graphical Abstract.

Impairments in the reproductive axis of female mice lacking estrogen receptor ß in GnRH neurons.

The effect of estrogen on the differentiation and maintenance of reproductive tissues is mediated by two nuclear estrogen receptors (ERs), ERα, and ERß. Lack of functional ERα and ERß genes in vivo significantly affects reproductive function; however, the target tissues and signaling pathways in the hypothalamus are not clearly defined. Here, we describe the generation and reproductive characterization of a complete-ERß KO (CERßKO) and a GnRH neuron-specific ERßKO (GERßKO) mouse models. Both ERßKO mouse models displayed a delay in vaginal opening and first estrus. Hypothalamic gonadotropin-releasing hormone (GnRH) mRNA expression levels in both ERßKO mice were similar to control mice; however female CERßKO and GERßKO mice had lower basal and surge serum gonadotropin levels. Although a GnRH stimulation test in both female ERßKO models showed preserved gonadotropic function in the same animals, a kisspeptin stimulation test revealed an attenuated response by GnRH neurons, suggesting a role for ERß in normal GnRH neuron function. No alteration in estrogen-negative feedback was observed in either ERßKO mouse models after ovariectomy and estrogen replacement. Further, abnormal development of ovarian follicles with low serum estradiol levels and impairment of fertility were observed in both ERßKO mouse models. In male ERßKO mice, no differences in the timing of pubertal onset or serum luteinizing hormone and follicle-stimulating hormone levels were observed as compared with controls. Taken together, these data provide in vivo evidence for a role of ERß in GnRH neurons in modulating puberty and reproduction, specifically through kisspeptin responsiveness in the female hypothalamic-pituitary-gonadal axis.

α-MSH modulates cell adhesion and inflammatory responses of synovial fibroblasts from osteoarthritis patients.

INTRODUCTION: The synovium is a target for neuropeptides. Melanocortins have attained particular attention as they elicit antiinflammatory effects. Although synovial fluid from patients with rheumatic diseases contains α-melanocyte-stimulating hormone (α-MSH) it is unknown whether synovial fibroblasts generate α-MSH and respond to melanocortins. METHODS: Synovial tissue was obtained from osteoarthritis (OA) patients. Cells were isolated and prepared either as primary mixed synoviocytes or propagated as synovial fibroblasts (OASFs). Melanocortin receptor (MC) and proopiomelanocortin (POMC) expression were investigated by endpoint RT-PCR, immunofluorescence and Western immunoblotting. Functional coupling of MC1 was assessed by cAMP and Ca(2+) assays. Cell adhesion was monitored by the xCELLigence system. Secretion of α-MSH, tumour necrosis factor (TNF), interleukin (IL)-6 and IL-8 was determined by ELISA. RESULTS: OASFs in vitro expressed MC1. MC1 transcripts were present in synovial tissue and appropriate immunoreactivity was detected in synovial fibroblasts in situ. OASFs contained truncated POMC transcripts but neither full-length POMC mRNA, POMC protein nor α-MSH were detectable. In accordance with this only truncated POMC transcripts were present in synovial tissue. α-MSH increased cAMP dose-dependently but did not alter calcium in OASFs. α-MSH also enhanced adhesion of OASFs to fibronectin and reduced TNF, IL-6 and IL-8 secretion in primary mixed synoviocyte cultures. In OASFs, α-MSH modulated basal and TNF/IL-1ß-mediated secretion of IL-6 and IL-8. CONCLUSION: Synovial fibroblasts express MC1in vitro and in situ. α-MSH elicits biological effects in these cells suggesting an endogenous immunomodulatory role of melanocortins within the synovium. Our results encourage in vivo studies with melanocortins in OA models.

Anti-inflammatory effects of cell-based therapy with tyrosine hydroxylase-positive catecholaminergic cells in experimental arthritis.

OBJECTIVES: Studies in rheumatoid arthritis (RA), osteoarthritis (OA) and mice with arthritis demonstrated tyrosine hydroxylase-positive (TH(+)) cells in arthritic synovium and parallel loss of sympathetic nerve fibres. The exact function of TH(+) cells and mode of TH induction are not known. METHODS: Synovial cells of RA/OA were isolated and cultured under normoxic/hypoxic conditions with/without stimulating enzyme cofactors of TH and inhibitors of TH. We studied TH expression and release of cytokines/catecholamines. In vivo function was tested by cell therapy with TH(+) neuronal precursor cells (TH(+) neuronal cells) in DBA/1 mice with collagen type II-induced arthritis (CIA). RESULTS: Compared with normoxic conditions, hypoxia increased TH protein expression and catecholamine synthesis and decreased release of tumour necrosis factor (TNF) in OA/RA synovial cells. This inhibitory effect on TNF was reversed by TH inhibition with α-methyl-para-tyrosine (αMPT), which was particularly evident under hypoxic conditions. Incubation with specific TH cofactors (tetrahydrobiopterin and Fe(2+)) increased hypoxia-induced inhibition of TNF, which was also reversed by αMPT. To address a possible clinical role of TH(+) cells, murine TH(+) neuronal cells were generated from mesenchymal stem cells. TH(+) neuronal cells exhibited a typical catecholaminergic phenotype. Adoptive transfer of TH(+) neuronal cells markedly reduced CIA in mice, and 6-hydroxydopamine, which depletes TH(+) cells, reversed this effect. CONCLUSIONS: The anti-inflammatory effect of TH(+) neuronal cells on experimental arthritis has been presented for the first time. In RA/OA, TH(+) synovial cells have TH-dependent anti-inflammatory capacities, which are augmented under hypoxia. Using generated TH(+) neuronal cells might open new avenues for cell-based therapy.

Increased expression of dopamine receptors in synovial fibroblasts from patients with rheumatoid arthritis: inhibitory effects of dopamine on interleukin-8 and interleukin-6.

OBJECTIVE: Observations in both animal models of arthritis and patients with rheumatoid arthritis (RA) suggest a role for dopamine and its receptors in RA. Because synovial fibroblasts (SFs) contribute to inflammation and joint destruction in RA, the aim of this study was to investigate dopaminergic pathways in SFs obtained from patients with RA and, for comparison, in SFs from patients with osteoarthritis (OA) undergoing knee joint replacement surgery. METHODS: The expression of all dopamine receptors (D1 -D5 ) and dopamine transporter was assessed by immunofluorescence and immunohistochemical staining. The levels of dopamine receptor and tyrosine hydroxylase messenger RNA were measured by real-time polymerase chain reaction. The intracellular content of dopamine, its precursor, and its main metabolites was assayed by high-performance liquid chromatography. The influence of dopamine on proinflammatory interleukin-6 (IL-6) and IL-8, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 (TIMP-1) and TIMP-2 was studied in SFs. RESULTS: SFs possess an intrinsic dopaminergic system, including dopamine receptors, dopamine transporter, and tyrosine hydroxylase, and contain dopamine, its precursor, and its main metabolites. SFs from patients with RA, in comparison with those from patients with OA, showed increased expression of dopamine receptors D1 and D5 , and exogenous dopamine strongly inhibited the production of IL-8 in patients with RA. CONCLUSION: SFs from patients with RA and patients with OA show a dopaminergic phenotype. The expression of D1-like dopamine receptors was higher in RASFs, and this increased expression may lead to antiinflammatory effects, as demonstrated by the expression of IL-8. Studies in animal models and patients with RA are needed to assess the therapeutic potential of endogenous, local production of dopamine in synoviocytes.

Aromatase and regulation of the estrogen-to-androgen ratio in synovial tissue inflammation: common pathway in both sexes.

Sex hormones play an active role in inflammatory responses, with androgens being anti-inflammatory, whereas estrogens have both pro- and anti-inflammatory effects. In rheumatoid arthritis (RA) patients, low levels of androgens and high levels of estrone are found in the synovial fluid. Aromatase is the key enzyme for the conversion of androgens into estrogens. Proinflammatory cytokines stimulate aromatase activity so that the inflammatory milieu can induce conversion of androgens to estrogens. Moreover, testosterone inhibits aromatase activity. As local androgen levels are low in RA, this can contribute to high aromatase activity in the synovium. Importantly, aromatase-converted estrogens are converted into proproliferative and proinflammatory 16-hydroxylated estrogens. A hormone involved in aromatase activity is vitamin D, which downregulates aromatase in human RA macrophages. Collectively, evidence suggests a key role of aromatase in sex hormone balance during chronic inflammation and points to the importance of vitamin D as a possible new tool for aromatase modulation.

Intra-articular glucocorticoid injections decrease the number of steroid hormone receptor positive cells in synovial tissue of patients with persistent knee arthritis.

OBJECTIVES: To explore changes in the number of steroid hormone receptor positive cells in synovial tissue (ST) after intra-articular glucocorticoid injection, to correlate these changes with changes in clinical variables, and to evaluate whether the number of steroid hormone receptor positive cells predicted the clinical response to glucocorticoid injection. METHODS: Fourteen patients with persistent knee arthritis despite at least two previous injections in an outpatient setting received an intra-articular injection with glucocorticoids, followed by 3 days of admission with bed rest. Clinical efficacy was assessed at 6 and 12 weeks. ST biopsies were performed 2 weeks before and 12 weeks after the injection. The presence of different cell types (T cells, macrophages, fibroblast-like synoviocytes) and numbers of glucocorticoid, androgen and oestrogen α and ß receptor positive cells were evaluated by histochemistry. RESULTS: Patients showed, despite previous failures, good clinical response to glucocorticoid injection, with significant improvement in erythrocyte sedimentation rate, visual analogue scale (VAS) for pain, and joint disability score. The number of steroid hormone receptor positive cells decreased markedly (p<0.05 for all four receptors). The decrease in oestrogen receptor α positive cells correlated significantly with the improvement in VAS for pain and joint disability score. The number of glucocorticoid, androgen and oestrogen α and ß receptor positive cells before injection did not predict the effect of treatment. CONCLUSIONS: Intra-articular glucocorticoid injections followed by bed rest for persistent arthritis are clinically effective and significantly decrease the number of steroid hormone receptor positive cells in ST. The relevance of the latter needs further study.

Relationship between placenta growth factor 1 and vascularization, dehydroepiandrosterone sulfate to dehydroepiandrosterone conversion, or aromatase expression in patients with rheumatoid arthritis and patients with osteoarthritis.

OBJECTIVE: Proliferating pannus is in many aspects similar to placental tissue. Both fibroblast-rich tissues have high vascularity, and tissue from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA) demonstrates conversion of androgenic prehormones to downstream estrogens. We undertook this study to investigate similarities between proliferating pannus and placental tissue by focusing on angiogenic placenta growth factor 1 (PlGF-1) in patients with OA and patients with RA. METHODS: We used immunohistochemistry to study the presence of PlGF-1, its synovial distribution, and the PlGF-1-expressing synovial cell type. The relationship between PlGF-1 and conversion of the biologically inactive placental prehormone dehydroepiandrosterone sulfate (DHEAS) to the biologically active dehydroepiandrosterone (DHEA) was investigated in mixed synovial cells. The effects of DHEA on PlGF-1 expression were studied by intracellular fluorescence-activated cell sorting analysis. RESULTS: PlGF-1-positive cells were detected in the lining and sublining areas in patients with RA and patients with OA, and cellular density was similar. Double staining revealed that PlGF-1-positive cells were macrophages. In RA and OA, the density of PlGF-1-positive cells correlated positively with the density of macrophages and the density of type IV collagen-positive vessels. The supernatant concentration of (3) H-DHEA after conversion from (3) H-DHEAS and the density of aromatase-positive cells were positively correlated with the density of PlGF-1-positive cells only in OA. Low DHEA concentrations (≤10(-9) M) had stimulatory effects on PlGF-1 when compared to serum concentrations (10(-8) M to 10(-7) M) in the monocytic cell line THP-1 and in primary mixed synovial cells. CONCLUSION: PlGF-1 functions similarly in inflamed synovium and in the placenta. It is related to vessel formation and, in OA patients, to androgen/estrogen conversion. Evolutionarily conserved functions of PlGF-1 for placental phenomena are obviously also present in synovial inflammation.

First appearance and location of catecholaminergic cells during experimental arthritis and elimination by chemical sympathectomy.

OBJECTIVE: The sympathetic nervous system is proinflammatory in early collagen-induced arthritis (CIA) and antiinflammatory in late disease. In late arthritis, sympathetic innervation of synovial and lymphoid tissue is markedly reduced. Thus, its suggested antiinflammatory role is difficult to explain. We hypothesized that newly discovered catecholamine-producing (catecholaminergic) cells are targets of chemical sympathectomy. However, in CIA, the time point of appearance, the location, and the possible chemical elimination of catecholaminergic cells have not been studied. The purpose of this study was to investigate the emergence and location of catecholamine-producing and -storing cells in different organs and joints of mice after induction of CIA and to determine whether catecholamine-producing cells can be depleted by 6-hydroxydopamine (6-OHDA) during the early and late phases of CIA in vivo. METHODS: The presence of cells positive for tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT-2) was evaluated immunohistologically in the lymph nodes, thymus, bone marrow, spleen, and joints of control and arthritic mice. Density was evaluated at different time points after early and late chemical sympathectomy. (131)I-metaiodobenzylguanidine ((131)I-MIBG) scintigraphy demonstrated functional activity of these cells in joint inflammation. RESULTS: The density of TH+ and VMAT-2+ cells was highest after arthritis onset (from day 28 onward) and was observed to occur in the following sequence: lymph nodes, thymus, joints, bone marrow, and spleen. Even before arthritis onset (days 5-21), these cells were already more numerous, particularly in the draining lymph nodes, thymus, and joints. (131)I-MIBG scintigraphy demonstrated catecholamine-storing cells in inflammatory hot spots in the paw. Chemical sympathectomy strongly reduced the density of catecholaminergic cells in vitro and in vivo. CONCLUSION: After disease onset, catecholaminergic cells are particularly present in primary and secondary lymphoid organs and joints. Since catecholaminergic cells have been reported to have antiinflammatory properties in arthritis, the proinflammatory role played by chemical sympathectomy in late arthritis, as we previously determined, is probably dependent on catecholaminergic cell elimination.

Loss of sympathetic nerve fibers in intestinal endometriosis.

This study analyzed by immunofluorescence staining the sympathetic innervation in the bowel adjacent to the endometriotic lesion and in the healthy tissue at the border of the resected specimen. Sympathetic nerve fibers are significantly reduced in the mucosal and muscular layer near the endometriotic lesions; in contrast, sensory nerve fiber density is not altered in the area near the endometriotic lesions.

Cryptococcosis mimicking cutaneous cellulitis in a patient suffering from rheumatoid arthritis: a case report.

BACKGROUND: Cryptococcus neoformans is an encapsulated yeast and the most frequent cryptococcal species found in humans. Cryptococcosis is considered an opportunistic infection as it affects mainly immunosuppressed individuals. In humans, C. neoformans causes three types of infections: pulmonary cryptococcosis, cryptococcal meningitis and wound or cutaneous cryptococcosis. CASE PRESENTATION: An 81-year-old woman developed severe necrotizing cellulitis on her left arm without any preceding injury. The patient had been treated with systemic corticosteroids over twenty years for rheumatoid arthritis (RA). Skin biopsies of the wound area were initially interpreted as cutaneous vasculitis of unknown etiology. However, periodic acid Schiff staining and smear analysis later revealed structures consistent with Cryptococcus neoformans, and the infection was subsequently confirmed by culture. After the initiation of therapy with fluconazole 400 mg per day the general condition and the skin ulcers improved rapidly and the patient was discharged to a rehabilitation facility. Subsequently surgical debridement and skin grafting were performed. CONCLUSIONS: Opportunistic infections such as cryptococcosis can clinically and histologically mimic cutaneous vasculitis and have to be investigated rigorously as a differential diagnosis in immunosuppressed patients.