Patterns of psoriatic arthritis in Orientals

OBJECTIVE: To determine the clinical features of psoriatic arthritis (PsA) in a multiethnic Oriental population and to study the effect of ethnicity on disease patterns. METHODS: A retrospective study of 80 patients with PsA seen at either a rheumatology or dermatology referral center. Patients and case records were reviewed and data abstracted according to a standard protocol. Eighty consecutive patients with psoriasis without PsA seen at the dermatology center were recruited as controls. RESULTS: Asymmetric polyarthritis developing in the 4th decade with an equal male to female ratio was the commonest pattern of arthritis among Chinese, Indians, and Malays. Clinically apparent lumbar spondylitis was significantly more common in Indians than Chinese (10/11 vs 11/20, respectively; p = 0.046), although the prevalence of lumbar spondylitis was similar in all ethnic groups. Eighty-nine percent of subjects required nonsteroidal antiinflammatory drugs and 51% required disease modifying antirheumatic drugs at some time for control of joint disease. PsA was significantly more common among Indians compared to the ethnic distribution of the Singapore population (p < 0.000001). Multiple logistic regression identified Indian ethnicity as a risk factor for the development of PsA (OR 2.39, 95% confidence interval 1.02 to 5.60). CONCLUSION: The commonest pattern of PsA in all ethnic groups was asymmetric polyarthritis. Ethnicity affected the development and presentation of PsA in our series: Indians with psoriasis had double the risk of developing PsA compared to Chinese with psoriasis, and lumbar spondylitis when present in Chinese subjects was asymptomatic in 45%, being detectable only on radiological examination.     

Inflammatory infiltrate and interleukin-8 expression in the synovium of psoriatic arthritis--an immunohistochemical and mRNA analysis

Psoriatic arthritis is an inflammatory arthropathy that ultimately can lead to joint destruction. In this study, we investigated the immunophenotypes of the inflammatory cells and the expression of interleukin-8 (IL-8), which is the hallmark chemoattractant cytokine of psoriasis in synovial membranes from patients exhibiting active psoriatic synovitis (n = 9). The tissue samples were examined by immunohistochemistry, Western blot analysis and in situ hybridisation. The inflammatory infiltrate consisted predominantly of CD3+ T lymphocytes, with a higher proportion of CD4+ than CD8+ T lymphocytes in six cases. CD3+ T lymphocytes were focally distributed near small blood vessels and the enlarged synovial intima. CD1+ interdigitating reticulum cells were not detected. CD22+ B lymphocytes and plasma cells were found in small aggregates without KiM4+ follicular dendritic cells. KiM8+ macrophages were located in the synovial intima and were distributed in a diffuse pattern near the synovial lining cells. CD15+ neutrophil granulocytes were detected in four cases. They were preferentially located in the vicinity of blood vessels and the synovial intima. IL-8 was found at a high level in the synovial lining cells and to a lesser extent in cells located in the perivascular areas. Immunofluorescence double staining showed IL-8 to be expressed in KiM8+ multinucleated giant cells, KiM8+ macrophages and CD3+ T lymphocytes. IL-8 receptor A was demonstrated in the synovial lining and in macrophages and lymphocytes. IL-8 was detected by immunoblot analysis of the synovial tissue at 8.4 kD. Employing in situ hybridisation, IL-8 mRNA was strongly and preferentially expressed in the synovial intima, as well as in macrophages and lymphocytes. The immunophenotype of the psoriatic arthritis inflammatory cells shows great similarity to the inflammatory infiltrate found in the synovial tissue of patients with rheumatoid arthritis. The preferential expression of IL-8 and IL-8 mRNA in the enlarged synovial intima and in lymphocytes and macrophages suggests that IL-8 exerts its action through activated mononuclear cells and T lymphocytes. It seems to play a role in regulating leucocyte traffic into the enlarged synovial intima and may contribute to the aggressive synovitis of patients with psoriatic arthritis.     

Interleukin-2 is found in the synovium of psoriatic arthritis and spondyloarthritis, not in rheumatoid arthritis

Many factors have been reported to stimulate the release of brain natriuretic peptide (BNP) as well as atrial natriuretic peptide (ANP). In hypertensive patients, however, little is known about whether these factors differ from those in normotensive subjects or if they are influenced by antihypertensive treatment. We measured the plasma concentrations of BNP and ANP in 12 hypertensive patients and examined the chronic effects of beta-adrenoceptor blockade on BNP secretion during exercise with a bicycle ergometer. The exercise raised both plasma BNP and ANP with concomitant increases in systolic blood pressure, heart rate (HR) and plasma norepinephrine (NE) and epinephrine (Epi) before and after treatment. Before treatment, the changes in ANP and BNP correlated with that in HR (p < 0.05). After treatment 4 wk of treatment, the change in ANP correlated with those in NE and Epi as well as HR. Multivariate regression analysis indicated that only NE was a significant stimulus for ANP secretion during the treatment period. As for BNP, HR was the only significant stimulant for its secretion both before and after treatment. In essential hypertension, beta-adrenergic receptor blockade affected the factors stimulating exercise-induced ANP release but not those stimulating BNP release. BNP release, therefore, seems to be stimulated by similar but distinct factors from those that stimulate ANP release.     

The chronobiology of human cytokine production

Cytokine production in human whole blood exhibits diurnal rhythmicity. Peak production of the pro-inflammatory cytokines IFN-gamma, TNF-alpha, IL-1 and IL-12 occurs during the night and early morning at a time when plasma cortisol is lowest. The existence of a causal relationship between plasma cortisol and production is suggested by the finding that elevation of plasma cortisol within the physiological range by the administration of cortisone acetate results in a corresponding fall in pro-inflammatory cytokine production. Cortisol may not be the only neuroendocrine hormone that entrains cytokine rhythms; other candidates include 17-hydroxy progesterone, melatonin and dihydroepiandrostene dione (DHEAS). The finding of diurnal cytokine rhythms may be relevant to understanding why immuno-inflammatory disorders such as rheumatoid arthritis or asthma exhibit night-time or early morning exacerbations and to the optimisation of treatment for these disorders. Diurnal rhythmicity of cytokine production also has implications for the timing of blood samples drawn for diagnostic T-cell assays. Finally, diurnal rhythmicity of immune function suggests that the nature of an immune response, for example in response to vaccination, may be modified by the time of day of antigen administration and raises the possibility that immune responses could be therapeutically manipulated by co-administration of immuno-regulatory hormones such as glucocorticoids.     

Expression of N-acetyl-D-galactosamine associated epitope in synovium: a potential marker of glycoprotein production

OBJECTIVE: To investigate synovial glycoprotein production in situ, a novel monoclonal antibody (Mab), A13D8, was used to evaluate the expression of an epitope containing N-acetyl-D-galactosamine (GalNAc) in normal and pathological synovium. METHODS: Immunohistological and cytochemical analysis of synovial tissue samples was undertaken with single and double staining techniques using the A13D8 Mab, anti-CD68, vascular cell adhesion molecule-1 (VCAM-1), the hyaluronan associated enzyme uridine diphosphoglucose dehydrogenase (UDPGD), and the anti-Golgi Mab SSN/HR-1992. The specificity of the A13D8 Mab was established through blocking studies using carbohydrate residues, including GalNAc and N-acetylglucosamine (GlcNAc). RESULTS: A13D8 is expressed intensely in the cytoplasm of normal type B lining cells, which coexpress VCAM-1 and UDPGD, and is not expressed by CD68+ type A lining cells. In the lining layer of RA synovium, there is a negative correlation between A13D8 expression and the level of lymphocytic infiltration in the sublining areas (r = -0.43, p < 0.001). The endothelium of a subset of venules, typically in lymphocyte-rich aggregates, also stains intensely for A13D8. Pretreatment of the Mab with GalNAc completely eliminates the tissue staining, as well as the 110 kDa band seen on immunoblot, whereas pretreatment of A13D8 with GlcNAc and lactose has no effect. Double staining of HEp-2 cells with A13D8 and the anti-Golgi Mab SSN/HR-1992 reveals co-localization of the A13D8 epitope to the Golgi apparatus. CONCLUSION: Type B synovial lining cells and selected synovial endothelium express GalNAc containing epitope identified by Mab A13D8. Marked reduction in the expression of this epitope in the lining layer of inflamed RA synovium suggests that the synovial production of GalNAc containing glycoproteins, such as mucins, may be altered in this disorder.     

Acute pancreatitis induces cytokine production in endotoxin-resistant mice

PURPOSE: An automated contour detection algorithm was developed for the objective and reproducible quantitative analysis of velocity-encoded MR studies of the ascending aorta. METHOD: The only user interaction required is the manual definition of a center point inside the cross-section of the aorta in one of the available images. The automated contour detection algorithm detects an initial model contour in this image and subsequently corrects for motion and deformation of the aortic cross-section in each of the acquired images over the complete cardiac cycle using dynamic programming techniques. Integrating the flow velocity values for each pixel within the detected contour results in an instantaneous flow value. Next, by integrating the instantaneous flow values for each acquired phase over the complete cardiac cycle, left ventricular stroke volume measurement could be obtained. The results of the automated method were compared with results derived from manually traced contours in MR studies from 11 healthy volunteers. RESULTS: An excellent agreement in stroke volume measurements was observed: signed difference 0.61+/-1.15%. Inter- and intraobserver variabilities were <2% for both manual and automated image analysis methods. Manual tracing of contours required on the order of 10 min; the analysis time for automated contour detection was <6 s/study. CONCLUSION: The present contour detection allows fast and reliable left ventricular stroke volume measurements from aortic flow studies using velocity-encoded MR studies in healthy volunteers. Further study is required to assess the accuracy and reproducibility of the algorithm in patients with aortic and aortic valve disease.     

Characterization of cytokine production in murine Trypanosoma cruzi infection by in situ immunocytochemistry: lack of association between susceptibility and type 2 cytokine production

The ability of subcutaneous pretreatment with an immunogenic peptide derived from Fel d I, the major cat protein, to suppress the development of allergic responses was examined in a mouse model of antigen-induced sensitization. BALB/c mice exposed to aerosolized Fel d I chain 1 peptide developed antigen-specific IgE responses, immediate cutaneous reactivity to the peptide, and increased airway responsiveness (AR). Both subcutaneous and intraperitoneal administration of the peptide prior to sensitization caused a 50% reduction in cutaneous reactivity which was associated with a decrease in serum anti-Fel d I chain 1 IgE and IgG1 antibody responses and an increase in specific IgG. Pretreatment with the peptide also suppressed spleen and lymph node proliferative responses to the peptide. However, only subcutaneous peptide injections could prevent the development of increased AR. Transfer of spleen cells from subcutaneously peptide-treated mice to sensitized recipients reduced serum antigen-specific IgE and IgG1 antibody responses and skin test reactivity, and prevented alterations in AR. These data suggest that IgE (and IgG1) responses and airway hyperresponsiveness induced by allergen sensitization via the airways can be modulated by subcutaneous administration of peptide. Further, the results define a model for investigating the modulatory effects of subcutaneous administration of immunogenic peptides or protein on an ongoing allergic response.     

Differential regulation of cytokine production by nitric oxide

Nitric oxide (NO) has recently been identified as a potent and pleiotropic intracellular mediator produced by and acting on many cells of the body. Although considerable attention has been devoted to the regulation of NO by inflammatory cytokines, and also to the role of NO as an important effector molecule in immune function, there is very little information on the role of this mediator in modulating T-cell-dependent cytokine production. In this study we show that physiological levels of NO (either produced by activated macrophages or by the addition of exogenous NO donors) can selectively down-regulate interleukin-3 (IL-3) production by spleen cells from contact-sensitized mice, while leaving IL-2 activity unaffected. Thus NO may have an important role as an immunomodulatory as well as effector molecule in the immune system.     

Lead differentially modifies cytokine production in vitro and in vivo

An imbalance between helper T cell type 1 (Th1) and helper T cell type 2 (Th2) activation can result in immunodysregulations leading to impaired cell-mediated immunity with an increased incidence of infectious disease or cancer and/or aberrant humoral immunity that may culminate with an autoimmune disease. Mercury, a heavy-metal toxicant, is known to induce renal autoimmunity characterized by a predominant Th2 response. Lead, another metal toxicant, causes enhanced B cell activities and impairs host resistance to several bacterial and viral infections. In addition, Pb was reported to enhance Th2 proliferation and inhibit Th1 proliferation. The differential effects of Pb on Th subset activation have been further investigated. In vitro IL-4 production by a Th2 clone was significantly increased by the addition of PbCl2, whereas IFN gamma production by a Th1 clone was decreased by the addition of PbCl2. When BALB/c mice were subcutaneously exposed to PbCl2, ex vivo Il-4 production by anti-CD3-stimulated splenic T cells was enhanced, but IFN gamma production was inhibited. Additionally, the plasma IL-4 and IgE levels of Pb-exposed mice were increased, and the plasma IFN gamma levels were significantly lowered in the absence of any additional exogenous antigen. In vitro, ex vivo, and in vivo treatment with HgCl2 produced similar findings. This study is the first report of the preferential activation of a Th2 response by Pb in vivo and suggests that PB, like Hg, may induce autoimmune responses by upsetting the balance between Th1- and Th2-like cells, which could enhance production of antibodies to self antigens.     

Endotoxin release and cytokine production in acute and chronic meningococcaemia

Muscle activity produces an electrical signal termed the myo-electric signal (MES). The MES is a useful clinical tool, used in diagnostics and rehabilitation. This signal is typically stored in 2 bytes as 12-bit data, sampled at 3 kHz, resulting in a 6 kbyte s-1 storage requirement. Processing MES data requires large bit manipulations and heavy memory storage requirements. Adaptive differential pulse code modulation (ADPCM) is a popular and successful compression technique for speech. Its application to MES would reduce 12-bit data to a 4-bit representation, providing a 3:1 compression. As, in most practical applications, memory is organised in bytes, the realisable compression is 4:1, as pairs of data can be stored in a single byte. The performance of the ADPCM compression technique, using a real-time system at 1 kHz, 2 kHz and 4 kHz sampling rates, is evaluated. The data used include MES from both isometric and dynamic contractions. The percent residual difference (PRD) between an unprocessed and processed MES is used as a performance measure. Errors in computed parameters, such as median frequency and variance, which are used in clinical diagnostics, and waveform features employed in prosthetic control are also used to evaluate the system. The results of the study demonstrate that the ADPCM compression technique is an excellent solution for relieving the data storage requirements of MES both in isometric and dynamic situations.     

Staphylococcal enterotoxin-A directly stimulates signal transduction and interferon-gamma production in psoriatic T-cell lines

MRI has gained an undisputed place in the evaluation of malignant bone tumors, not only for verifying results of conventional radiographs and clarifying differential diagnoses; it has also become increasingly important for the assessment of the malignant/benign nature of the tumor, its growth rate, definition of adequate sites for biopsy, local preoperative staging, and evaluation of the response to chemotherapy. However, several pitfalls have to be observed regarding choice of technical parameters (coils, sequences, imaging planes), tissue differentiation, and tumor staging. When staging malignant tumors, critical aspects which have to be observed are tumor extension, integrity of the cortical bone, soft tissue components, infiltration of a joint or neurovascular bundle. The use of contrast agents provides important additional information but can also give rise to misinterpretations. Thus, all features of a tumor have to be observed in order to establish a final diagnosis. Particular difficulties can occur with the interpretation of MR images of osteomyelitis, osteoid osteoma, stress and insufficiency fractures, bone infarcts, myositis ossificans, hemangiomas, and aneurysmal bone cysts.     

Inflammatory cytokine production in whole blood modified by liposome-encapsulated hemoglobin

The effect of Neo Red Cells (NRC), liposome-encapsulated hemoglobin, on production of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) were studied in whole blood preparations ex vivo. Venous blood was collected with heparin and incubated in a CO2 incubator. Treatment of blood samples with NRC reduced the constitutive levels of TNF-alpha and IL-6. Lipopolysaccharide (LPS) treatment for 24 h increased production of TNF-alpha and IL-6 in a dose-dependent manner. Pretreatment with NRC (5%) for 24 h markedly potentiated the LPS-induced TNF-alpha production and, that of IL-6 to a lesser extent. Northern blotting analysis of total RNA in whole blood showed that pretreatment with NRC caused a marked increase in TNF-alpha mRNA expression in response to LPS. It is concluded that NRC potentiates LPS-induced TNF-alpha and IL-6 production in whole blood ex vivo, and that the potentiating effect of NRC on LPS-induced TNF-alpha production can be attributed, at least in part, to an increase in its mRNA expression.     

Regulation of cytokine production by eicosanoids and nitric oxide

Cytokines are widely regarded as regulatory molecules of inflammatory and immune reactions. Nevertheless, the details of functioning of the complex cytokine network are not yet fully understood. Recent data indicate that eicosanoids, primarily the products of the inducible form of cyclooxygenase (COX-2), are involved in the regulation of cytokine production. We have shown that prostaglandins of E series are no longer only suppressor molecules but they selectively up- or down-regulate the cytokine production. Similarly, nitric oxide (NO) generated in activated immune cells by inducible isoform of nitric oxide synthase (iNOS), is considered to be an immunoregulatory molecule. In this article we present a new concept of interactions between cytokines, eicosanoids (prostaglandins and leukotrienes) and NO. Finally, the impact of these molecules on the regulation of the immune system is discussed.     

Control of the synovium in haemophilia

The method of administration of alteplase has evolved since its introduction to clinical practice in the late 1980s. The initial dosage regimen of a graded administration of 100 mg was replaced by the front-loaded weight adjusted regimen, the efficacy of which was demonstrated in the GUSTO 1 trial. Double bolus administration was shown to achieve superior TIMI 3 patency of the infarct related artery in a small angiographic study, but the COBALT trial failed to show equivalence and indeed showed a slightly higher mortality and incidence of stroke, so cannot be recommended. Reteplase, a deletion mutant of alteplase, also showed superior efficacy in achieving coronary patency but no clinical superiority in outcomes in the 15,000 patient GUSTO 3 trial. The case of administration of reteplase, however, has some attraction as an alternative to alteplase. Trials of newer agents based on further modifications of alteplase are ongoing, but at present the front-loaded alteplase regimen remains the standard for clinical practice.     

Mechanisms associated with defective TH1 cytokine production in HIV infection

Qualitative and quantitative changes in immune functions of different T-cell subsets associated with infection by human immunodeficiency virus type 1 (HIV-1) were analyzed by flow cytometric assessment of intracytoplasmic cytokines. The T(H)1 cytokines, interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), were produced by both CD4 and CD8 T-cell subsets. When normal peripheral blood mononuclear cells (PBMC) were activated in culture, both cytokines were produced predominantly by CD4 (CD4) cell and only a minor fraction of normal CD8 cells produced these cytokines. In the cultures of PBMC from HIV-1-infected individuals (HIV+PBMC), more HIV+CD8 cells produced IL-2 and IFN-gamma. Production of IFN-gamma by HIV+CD4 cells was markedly reduced, while IL-2nd tumor necrosis factor-alpha (TNF-alpha) production by HIV+CD4 remained relatively intact until the disease progressed further. Normal CD4 cells which were isolated by using a cell sorter, FACSCalibur was still able to produce IL-2 and TNF-alpha. But for full production of IFN-gamma, normal CD4 required some accessory cells, the identity of which could not yet be established.     

Langerhans cells may trigger the psoriatic disease process via production of nitric oxide

Psoriasis is a skin disease that appears to result from a dysfunction in the normal mechanism(s) that regulates wound healing. The Langerhans cell is a specialized epidermal macrophage that may instigate wound healing via production of nitric oxide and epidermal growth factor. Here, Vera Morhenn suggests that, whereas precise coordination of the synthesis of these two substances regulates normal wound healing, a disturbance of this regulation could lead to psoriasis.     

Altered cytokine production and impaired antimycobacterial immunity in protein-malnourished guinea pigs

Protein malnutrition leads to multiple detrimental alterations of host immune responses to mycobacterial infection. In this study, we demonstrated that splenocytes from low-protein (LP) guinea pigs vaccinated 6 weeks previously with attenuated Mycobacterium tuberculosis H37Ra failed to control the accumulation of virulent M. tuberculosis H37Rv in cocultured autologous peritoneal macrophages, despite the fact that they were able to control the accumulation of virulent tubercle bacilli in cocultured syngeneic peritoneal macrophages from normally nourished guinea pigs as successfully as did those from high-protein (HP) counterparts. Vaccine-induced growth control of virulent M. tuberculosis H37Rv in these cocultures appeared to be mediated by CD4 lymphocytes but not CD8 cells. Tuberculin (purified protein derivative [PPD])-induced lymphoproliferation was markedly impaired in vaccinated LP guinea pigs, and the depletion of CD4 lymphocytes significantly decreased lymphocyte proliferation whereas CD8 cell depletion did not. Protein malnutrition also impaired the abilities of cells from vaccinated LP guinea pigs to produce cytokines, including interferon, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta), in response to PPD, despite the demonstration of higher serum levels of TNF-alpha and TGF-beta after an intravenous injection of PPD into LP guinea pigs. In contrast, peritoneal macrophages from protein-malnourished guinea pigs produced a higher level of TGF-beta 4 days after infection in vitro with M. tuberculosis H37Rv than did those from protein adequate controls. These results suggest that dietary protein malnutrition impairs vaccine-induced resistance to M. tuberculosis, in part, by altering the cytokine profile to favor macrophage deactivation.