Psoriatic arthritis.
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Arthritis, Psoriatic↗
Biomedical subjects
C Pitzalis
Publications and source records attributed to C Pitzalis.
Modulation of cellular annexin I in human leukocytes infiltrating DTH skin reactions.
Based on our previous studies showing endogenous annexin I being depleted from migrated neutrophils (PMN) in vitro, we have tested whether the levels of this glucocorticoid-regulated protein in PMN and mononuclear cells (PBMC) were modified after adhesion to endothelial monolayers in vitro and extravasation into skin blisters in vivo. In vitro, annexin I levels were depleted more significantly (-70%) in post-adherent PMNs than in monocytes (-25%) and lymphocytes (-50%, only in the positive fraction). In vivo, a significant time-dependent increase (approximately threefold, P < 0.05) in cell-associated annexin I was measured in PBMCs recovered from the blisters, whereas no significant changes were detected in extravasated PMNs. This was associated with annexin I release in the blister fluids (approximately 35 ng/mL), whereas no detectable protein was found in matched-paired plasmas. In conclusion, we report for the first time an activation of the annexin I pathway during an ongoing experimental inflammatory response in humans, which is differently regulated between PMNs and PBMCs.
Adult↗
Neuroendocrine, immunologic, and microvascular systems interactions in rheumatoid arthritis: physiopathogenetic and therapeutic perspectives.
OBJECTIVE: To review the "core" systems interactions in rheumatoid arthritis (RA): neuroendocrine, immunologic, and microvascular, and to interpret an integrated physiopathogenesis of the disease, beginning at a preclinical phase of risk factors to the later stages of manifest clinical inflammation. METHODS: Publications on stress reactions, serum hormonal levels, biological mediators of inflammation and vascular alterations in RA during its preclinical phase, course of active disease, including pregnancy, and hormonal therapy of active disease were retrieved. In addition, experimental reports on biological models of the disease were considered. Levels of adrenal and gonadal steroids (ie, glucocorticosteroids [GCS], dehydroepiandrosterone [DHEA], its sulfate [DHEAS], estradiol [E2], and testosterone [T]), as well as prolactin (PRL) and other hormones, biological mediators, vascular endothelial system (VES) interactions with hormones, and immunologic mediators of inflammation in RA, were reviewed and interpreted. RESULTS: Women with premenopausal onset of RA not previously treated with GCS had lower basal serum levels of adrenal androgens, that is, DHEA or DHEAS, both before and after onset of clinical disease, compared with controls. Risk factors, including hormonal, immunologic, and hereditary indicators, were found to be uniformly present many years before clinical onset in such younger women, as compared with a frequency of circa 15% in matched controls. Also, a history of heavy cigarette smoking significantly predicted the onset of RA in perimenopausal women, and in men, suggesting that vascular endothelial alterations predispose to the disease. In the same prospective study, 1 or more of 4 risk factors were present an average of 12 years before clinical onset of disease in 83% of male RA cases versus 26% in matched controls (ie, sensitivity of 83% and specificity of 74%). Early RA patients may have lower serum cortisol levels than normal controls, and less than expected for the degree of ongoing inflammation, as well as having upregulated PRL levels. CONCLUSION: Among persons genetically prone to RA, the "core" systems are hypothesized to become "remodeled" during a long preclinical phase as a result of chronic imbalances in their interactive homeostasis. This hypothesis needs to be critically assessed in further studies of such physiological precursors of disease as well as stressors in the development and course of RA. Optimal hormonal management of biological mediators of RA is also a priority challenge for disease control in the future. RELEVANCE: Evidence indicates that men and women who are susceptible to premenopausal onset of RA can each be identified long before their clinical onsets of disease, and that productive research in primary prevention is an achievable objective. Disease prevention objectives are central in the public health strategy of the National Arthritis Action Plan and of the US Public Health Service "Healthy People 2000" (and 2010 proposed). Success in such prevention goals can be expected to significantly reduce the enormous burden of this common disease, which affects all segments of the population.
Animals↗
The inhibitory effect of dexamethasone on lymphocyte adhesion molecule expression and intercellular aggregation is not mediated by lipocortin 1.
Glucocorticoids exert their anti-inflammatory activity through multiple pathways which include the inhibition of cell adhesion events. The glucocorticoid-induced protein lipocortin 1 (LC1) has reported anti-inflammatory properties and has been proposed as a putative mediator of the anti-inflammatory effects of glucocorticoids. The role of LC1 in mediating the glucocorticoid inhibition of lymphocyte adhesion and cell adhesion molecule (CAM) expression was investigated in vitro using a microaggregation assay, flow cytometry and confocal microscopy. Lymphocytes stimulated for 96 h with plastic-bound OKT3 antibody showed significant increases in LFA-1 and CD2 expression. Dexamethasone (DEX; 10(-6) M) inhibited this increase but the neutralizing anti-LC1 MoAb 1A (5 microg/ml) failed to reverse the DEX effect; neither was purified human LC1 (50 x 10(-9) M) able to inhibit CAM expression. The biological activity of the LC1 was confirmed by its ability to suppress monocyte phagocytosis and respiratory burst in response to bovine serum albumin (BSA)-anti-BSA complexes. OKT3 stimulation of cultured mononuclear cells resulted in intercellular aggregation, scored microscopically using a visual index. This aggregation was completely reversed by 10-6 M DEX but unaffected by LC1 (50 x 10(-9) M). Significant intracellular expression of lymphocyte LC1 was observed using the anti-LC1 MoAb 1B in saponin-permeabilized cells. Distribution of LC1 had a diffuse, cytoplasmic pattern. LC1 expression was reduced following 3 h treatment with 10(-6) M DEX. These findings indicate that the DEX effects on lymphocyte adhesion and CAM expression are not mediated by LC1. Thus the reported in vivo effects of LC1 on leucocyte adhesion and transmigration probably occur through functional/conformation changes of surface CAM, rather than by alteration in expression.
Annexin A1↗
Soluble CD30 in early rheumatoid arthritis as a predictor of good response to second-line therapy.
OBJECTIVE: To evaluate whether serum levels of the soluble form of CD30 (sCD30) correlate with disease activity in early rheumatoid arthritis (RA) and may have prognostic value in predicting the response to disease-modifying anti-rheumatic drugs (DMARDs). METHODS: The levels of sCD30 and C-reactive protein (CRP) were measured in the serum of 14 untreated subjects with early RA, before and during treatment with hydroxychloroquine, for a follow-up period of 8 months. At the end of the study, patients were also evaluated for their response to DMARDs. RESULTS: An inverse correlation between sCD30 and CRP serum values was demonstrated at baseline, but not during the follow-up. Patients who responded to DMARD therapy had higher sCD30 basal levels than non-responders. CONCLUSIONS: The evaluation of sCD30 serum levels in early RA may reflect the attempt by CD30+ T cells to downmodulate inflammation and may be a useful marker to predict a good response to DMARDs.
Adult↗
Extrathymic T cell differentiation in the human intestine early in life.
It is clear from experimental studies in mice that T cell maturation can occur outside the thymus, especially in the intestine. There is little sound evidence so far that extrathymic T cell maturation occurs to any significant extent in human gut, and, postnatally, there is abundant evidence that the gut mucosa is an immune effector organ. Here, we describe a large population of T lymphocytes in human fetal intestinal mucosa that are proliferating (Ki67+) in the absence of foreign Ag (CD3+, Ki67+ lamina propria lymphocytes (LPL) 22 +/- 1.8% and CD3+, Ki67+ intraepithelial lymphocytes (IEL) 9.1 +/- 1.4%), that express the T cell activation markers CD103, HLA-DR, and L-selectin(low), and that express mRNA transcripts for pre-TCR-alpha. There is also a substantial proportion of CD7+ LPLs that do not express CD3 (CD3-7+, 14 +/- 7% of all LPLs) in the fetal gut that may be differentiating into CD3+ cells. Rearranged TCR-beta transcripts of fetal LPLs, IELs, and paired blood lymphocytes were cloned and sequenced, and virtually no overlap of clonality was observed between blood and intestine, suggesting that gut T cells may not be derived from the blood. In addition, 30 days after engraftment of SCID mice with fetal intestine, CD3-7+ cells, proliferating T cells, and pre-TCR-alpha transcripts were abundant, and there is a threefold increase in CD3+ IELs. These data show that in the human intestine before birth a population of precursor T cells exists that may be differentiating into mature T cells in situ.
Aging↗
Skin and joint disease in psoriatic arthritis: what is the link?
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Arthritis, Psoriatic↗
The pharmacokinetics and human anti-mouse antibody response in rheumatoid arthritis patients treated with a chimeric anti-CD4 monoclonal antibody.
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Animals↗
Fourth International Symposium on the Immunotherapy of the Rheumatic Diseases. 21-25 May 1997, Cyprus.
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Cyprus↗
Corticosteroids inhibit lymphocyte binding to endothelium and intercellular adhesion: an additional mechanism for their anti-inflammatory and immunosuppressive effect.
Glucocorticosteroids (GCS) are potent anti-inflammatory and immunosuppressive agents widely used in the treatment of many medical conditions, but their mechanism of action is not yet fully understood. Some of the anti-inflammatory effects of GCS have been attributed to the synthesis of lipocortins, whereas the immunosuppressive effects are thought to be mediated through the inhibition of several immune functions through a down-regulation of cytokine gene expression. Another important mechanism of action of GCS may relate to their ability to interfere with the phenomena of adhesion and migration of inflammatory cells. In this study, the direct effects of GCS on lymphocyte adhesion capacity in vitro were investigated. We demonstrate that GCS inhibit lymphocyte adhesion to endothelium through the down-modulation of lymphocyte adhesion molecules. We also provide evidence that GCS inhibit cell aggregate formation induced by TCR ligation, which directly correlates with the down-modulation of LFA-1 and CD2, but not LFA-3 or ICAM-1. Such down-modulation was paralleled by a decrease in the steady state mRNA level of LFA-1 and CD2 gene products, which suggests a direct GCS control of the expression of these genes. Finally, we show that GCS effects are mediated through the GCS receptor, since they can be completely reversed by the GCS-R antagonist RU-486. This study supports the concept that some of the immunosuppressive and anti-inflammatory effects of GCS are likely to be exerted by the inhibition of adhesion-dependent lymphocyte functions.
Adrenal Cortex Hormones↗
Comparison of the effects of oral versus intravenous methylprednisolone regimens on peripheral blood T lymphocyte adhesion molecule expression, T cell subsets distribution and TNF alpha concentrations in multiple sclerosis.
We investigated in multiple sclerosis the difference between two commonly used oral and intravenous steroid regimens on the level of adhesion molecule expression on blood T lymphocytes, the distribution of circulating T cell subsets, and the concentration of serum tumour necrosis factor alpha. Venous blood samples were collected from a cohort of 22 patients with acute relapses who were participating in a randomised trial comparing intravenous methylprednisolone 1000 mg daily for 3 days with oral methylprednisolone 48 mg daily for one week, 24 mg daily for one week, and finally 12 mg daily for one week. There was a similar significant reduction of T cell LFA-1 surface expression and serum TNF alpha concentrations after 4 days of treatment with each regimen. There was no change in other lymphocyte adhesion molecules expression (ICAM-1, LFA-3 or CD2) at day 4, although LFA-3 and CD2 expression was moderately decreased at day 28 and day 90 respectively; nor was there any change in the distribution of lymphocyte subsets (CD4, CD8, and CD45RA, CD45RO), although a small decrease in CD45RO circulatory T cells was noted at day 28. This study suggests that some of the beneficial effects of glucocorticosteroids may be related to the inhibition of lymphocyte adhesion as well as the modulation of proinflammatory cytokines.
Administration, Oral↗
[Monoclonal antibody therapy].
Monoclonal antibodies (mAb) are antibodies, produced by cell clones, directed against specific antigens (Ag), which act by binding specifically to the target Ag. Depending on the mAb used, this binding may have different effects on the target (neutralizing, lytic, opsonizing or antibody dependent cytotoxicity, ADCC). In clinical practice, mAb are used as immunosuppressants, antineoplastic agents, or for diagnostic purposes. mAb are given i.v. by slow infusion; the dosage depends on the mAb used. Contraindications include allergic, neoplastic, infective diseases, but also hypertension, cardiac failure and pregnancy. Infusions are usually well tolerated, headache and skin rashes being recorded only rarely; however, little is known about long-term effects (possible derangement of the immune response and/or increase in neoplasms). mAb are potentially a powerful tool in medicine, but more studies are required to define their role and establish their possible adverse effects in humans.
Animals↗
Percentage of anti-CD4 monoclonal antibody-coated lymphocytes in the rheumatoid joint is associated with clinical improvement. Implications for the development of immunotherapeutic dosing regimens.
OBJECTIVE: We assessed the effect of a daily dosing schedule of the chimeric anti-CD4 monoclonal antibody (MAb), cM-T412, in rheumatoid arthritis (RA) patients, and compared lymphocyte changes in the peripheral blood (PB) and synovial fluid (SF) of these patients. METHODS: Twelve patients received 50 mg/day of cM-T412 for 5 days, followed by a maintenance treatment of 50 mg/week for 5 weeks (6 patients), or a retreatment course of 50 mg/day for 5 days after 5 weeks (6 patients). Paired PB and SF samples were obtained during treatment for analysis. RESULTS: Changes in lymphocyte count and coating with the MAb in PB did not reflect changes in the SF. After 5 daily treatments, the percentage of cM-T412-coated CD4+ lymphocytes in SF correlated with the degree of clinical improvement seen in patients at 2 weeks after the initiation of therapy (r = 0.75, P < 0.05). CONCLUSION: These results demonstrate the importance of antibody dosage and treatment regimen in determining clinical benefit. Our findings suggest that the percentage of cM-T412-coated CD4+ lymphocytes in SF may be a predictor of clinical outcome.
Adult↗
Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis.
OBJECTIVE: To investigate whether T cell migration into different sites of inflammation (skin and synovium) within the same individual is principally regulated by tissue-specific homing or by more general mechanisms related to inflammation. METHODS: Expression of cutaneous lymphocyte antigen (CLA) and its ligand, E-selectin, was analyzed by immunohistochemistry and immunofluorescence using paired skin and synovial membrane (SM) samples from patients with psoriatic arthritis (PsA). To investigate disease specificity, delayed-type hypersensitivity (DTH) skin lesions, induced by tuberculin purified protein derivative, and SM from patients with rheumatoid arthritis (RA), were studied as controls. To directly examine cell migration in in vivo, the proportion of CLA+ T lymphocytes migrating into suction-induced skin blisters was assessed by flow cytometry. Using the same technique, levels of paired peripheral blood and synovial fluid (SF) T cells were also analyzed. RESULTS: CLA+ T cells preferentially accumulated in the skin, but not in the joint, of patients with PsA. Similarly, CLA+ T lymphocytes predominated in the DTH skin lesions of RA patients, but were very rare in the SM of RA patients, and were scarcely represented in the SF of patients with several chronic inflammatory arthropathies. In addition, CLA+ T lymphocytes preferentially migrated into epidermal skin blisters. This preferential pattern of CLA+ T cell accumulation was not related to the selective expression of E-selectin, since this was similar in the skin and SM of both PsA and RA patients. CONCLUSION: The distinct pattern of T cell infiltration into sites of inflammation within the skin and synovium is regulated by both organ-specific homing and general inflammation-related mechanisms.
Adult↗
The Michael Mason Prize Essay 1996. Role of adhesion mechanisms in the pathogenesis of chronic synovitis.
The hallmark of many rheumatic conditions, including rheumatoid arthritis (RA) and other seronegative inflammatory arthropathies (OIA), is a persistent inflammatory process that mainly affects synovial joints. Although the aetiology of the synovitis remains elusive, the pathogenesis is thought to be immune mediated. There are several reasons to believe that synovial T lymphocytes (S-TL) play a central role both as regulatory and effector cells in the initiation and perpetuation of the inflammatory process. In early studies, we demonstrated that the majority of S-TL are of the CD45RO 'memory' phenotype, while CD45RA 'naive' T cells are virtually absent. Various mechanisms can be responsible for such preferential accumulation. In this dissertation, I will present a number of studies, carried out over several years, investigating the relative role of adhesion and migration in the pathogenesis of the CD45RO accumulation in inflamed tissues. Since the first step in lymphocyte extravasation is adhesion to endothelium, the ability of purified CD45RO vs CD45RA T cells to adhere to human umbilical vein endothelial cells (HUVEC) in vitro was analysed. Second, to examine the migration process itself, an in vivo model of cell migration into suction-induced skin blisters raised over delayed-type hypersensitivity reactions was developed. Third, the role of tissue-specific homing mechanisms in the regulation of T-cell migration into different inflammatory sites was investigated. Finally, the adhesion of T cells to extracellular matrix (ECM) components, as a mechanism for preferential cell retention in inflamed tissues, was examined. These studies demonstrate that the critical mechanisms leading to CD45RO lymphocyte accumulation in chronic inflammatory foci include (a) an increased adhesion to endothelium, (b) an increased migratory capacity and (c) an increased adhesion to ECM components. I also present evidence to suggest that besides these general mechanisms, organ-specific homing may be of relevance in determining the selective accumulation of distinct CD45RO T cells in different inflamed tissues.
Arthritis, Rheumatoid↗
Cytokine and adhesion molecule expression in the minor salivary glands of patients with Sjögren's syndrome and chronic sialoadenitis.
OBJECTIVE: To investigate the role of cytokines and cell adhesion molecules in the pathogenesis of Sjögren's syndrome (SS). METHODS: Using an indirect immunoperoxidase technique we assessed the expression of the cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8), transforming growth factor beta (TGF beta) and granulocyte macrophage colony stimulating factor (GM-CSF), of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), lymphocyte function associated antigen-1 (LFA-1), the activated molecular form of LFA-1 (NKI-L16), CD2, and LFA-3, and of a panel of cellular markers in the minor salivary glands. RESULTS: In SS and chronic sialoadenitis (CS), the ductal epithelial cells and acini expressed all the cytokines examined. The percentage of glandular mononuclear cells which stained positive for cytokines did not differ significantly between SS and CS. NKI-L16 was detected on 33.6 (SD 10.1)% and 15.3 (4.3)% of LFA-1 cells in SS and CS, respectively (p < 0.002). CONCLUSION: SS and CS did not differ in the pattern of cytokines examined. The characteristic cell clustering seen in the salivary glands in SS may be caused by the upregulation of NKI-L16.
Adult↗
Monoclonal antibody therapy in rheumatic disease.
In rheumatic disease, monoclonal antibodies have been used for the treatment of refractory rheumatoid arthritis, systemic lupus erythematosus, unresponsive vasculitis and relapsing polychondritis. Our greatest experience has however been with rheumatoid arthritis. After molecular engineering, hybrid monoclonal antibodies constructed from animal sources become largely human, and thus well tolerated, and highly specific. They can be focused selectively to particular targets, but the problem is to identify the causative antibody. In rheumatoid arthritis, we do know a great deal about the pathogenesis of the disease and rational targets can be selected. The major histocompatibility complex class II molecules would theoretically be the most effective target, but no specific antigen has been identified. Total blockade of all class II molecules would probably result in unacceptable immunosuppression. Despite this handicap, anti-HLA-DR4 monoclonal antibodies have been used in humans in an attempt to generate an anti-idiotypic response against DR4. T lymphocytes are known to play a major role in the pathogenesis of rheumatoid arthritis, thus targeting their surface markers would be a reasonable approach to monoclonal antibody therapy. Trials have been conducted using antibodies against the surface markers CD7, CD5, CDw52 and CD4. Further work has centered on differentiation antigens. Preliminary evidence suggests anti-interleukin-2-receptor monoclonal antibodies may be effective in rheumatoid arthritis. There have also been reports of attempts at anti-cytokine immunotherapy. Adhesion molecules would be another potential target. The ongoing trials have given us much insight into the pathogenesis of rheumatoid diseases and led us to the stage where we are now attempting to identify appropriate therapeutic regimes and combinations to maximise patient benefit. At present, we must continue our research for the causative antigen.
Antibodies, Monoclonal↗
Adhesion molecules in rheumatoid arthritis: role in the pathogenesis and prospects for therapy.
The essential role played by cell adhesion and migration in the generation of chronic synovitis is now beyond doubt. Some of the beneficial effects of currently used drugs may be related to their ability to interfere with these mechanisms. The complexity of the process, however, means that there are many potential targets for therapeutic intervention and therefore further studies of the basic mechanisms are necessary to identify those which are most important.
Arthritis, Rheumatoid↗