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Biomedical subjects

E Toubi

Publications and source records attributed to E Toubi.

At least 19 recordsLinked to original sources
PubMed2007

Protective autoimmunity in cancer (review).

Not all malignant cells progress to invasive cancer, some may even regress, but the early detection of abnormal cells can be crucial for patient survival. Immune surveillance mechanisms are complex and provide continuous efforts for the removal of transformed cells. Naturally occurring antibodies are frontier soldiers that act as the first line of defense in the battle against cancer. During the process of carcinogenesis naturally occurring antibody responses to tumor antigens were found to be associated with improved survival and protection against the spread of cancer. Using the human hybridoma technology, a series of tumor-binding antibodies can be isolated as they have several common features: they are germ-line coded IgM antibodies, they bind to various tumor-antigens, they induce apoptosis of malignant cells, and most importantly they detect not only malignant cells but also the precursor stages (i.e., autoantigens). Natural protective autoantibodies against tumor-antigens were isolated from patients and healthy donors reflecting the development of naturally occurring B-cell responses during the process of cancer evolvement. They fulfill the definition of autoantibodies since they are self-reactive and they also bind altered self-antigens such as tumor cells. In this regard various autoantibodies such as anti-dsDNA and anti-Fas autoantibodies were found to be significantly higher in patients with various carcinomas, thus playing a role for their improved survival. Targeting T-regulatory cells, namely the expression of CTLA-4 was also found to improve survival in cancer patients. Autoimmunity and malignancy frequently coexist and they may share etiological and pathological mechanisms. Therefore, the efficacy of intravenous immunoglobulins or CTLA-4 blockade was also employed as a treatment for prevention of malignancy and metastases spread.

Antigens, CD↗
PubMed2006

Changes in macrophage function after rituximab treatment in patients with rheumatoid arthritis.

OBJECTIVE: To assess changes in macrophage phenotype and function after rituximab-induced B cell depletion in patients with rheumatoid arthritis (RA). METHODS: 10 patients with RA were treated with rituximab, achieving significant B cell depletion 4 months later. Clinical improvement, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, mRNA of B cell activating factor (BAFF), interleukin (IL) 10 and CD86 in human monocyte-derived macrophages (HMDMs) and tumour necrosis factor alpha (TNFalpha) secretion from cultured HMDMs were assessed at baseline and after the depletion. RESULTS: A clinical response of American College of Rheumatology (ACR) 50% improvement was noted in six patients, and another two patients responded with moderate improvement, equivalent to ACR 20-50% improvements. RF and anti-CCP antibodies were positive at baseline in seven of ten patients. RF disappeared or declined in six patients 4 months after treatment, correlating with clinical improvement. By contrast, anti-CCP remained unchanged in six patients. After rituximab treatment, and in association with clinical improvement, BAFF, IL10 and CD86 mRNA expression in HMDM were significantly upregulated compared with values at baseline. A significant decrease in TNFalpha in the supernatant of cultured HMDM was also noted. CONCLUSIONS: In addition to B cell depletion and attenuation in some of the specific autoantibodies, clinical improvement in rituximab-treated patients with RA occurred in association with changes in macrophage function.

Aged↗
PubMed2006

Elevated serum B-Lymphocyte activating factor (BAFF) in chronic hepatitis C virus infection: association with autoimmunity.

In this study we aimed to determine whether serum B-lymphocyte activating factor (BAFF) level is increased in patients with chronic hepatitis C virus (HCV) infection, and to assess its association with HCV-related autoimmunity. Sixty-five patients with chronic HCV infection were compared with two disease control groups [57 patients with systemic lupus erythematosus (SLE) and 15 with chronic hepatitis B virus (HBV) infection] and a healthy control group of 35 individuals. A special attention was given to HCV-related arthralgia and or vasculitis. Serum BAFF was assessed in all studied individuals, whereas rheumatoid factor (RF), anti-cardiolipin antibodies (aCL), and cryoglobulins were determined in HCV and HBV infected patients, and anti-dsDNA antibodies and aCL were assessed in patients with SLE. Mean serum BAFF was increased in patients with HCV infection and SLE (2.4+/-0.8 ng/ml and 3.1+/-1.34 ng/ml respectively) compared to 1.1+/-0.14 ng/ml in patients with HBV; and to 1.1+/-0.27 in healthy controls (all, p<0.0001). The elevation in serum BAFF was associated with HCV-related arthralgia and or vasculitis (p<0.0001), and with the presence of aCL and of cryoglobulins. HBV patients lacked features suggestive of autoimmunity. In SLE patients, elevated serum BAFF was in association with the presence of anti-dsDNA (p=0.002). As in other autoimmune diseases, increased serum BAFF was also found in patients with chronic HCV infection. Elevated serum BAFF levels were associated with clinical and laboratory features of autoimmunity, suggesting that BAFF may play a role in HCV-related autoimmunity.

Adult↗
PubMed2006

The autoimmune characteristics of progressive or sudden sensorineural hearing loss.

Autoimmune sensorineural hearing loss (ASNHL) is a clinical syndrome that typically produces a bilateral rapidly progressive hearing loss. Autoantibodies and autoreactive T cells have been implicated in the etiopathogenesis of ASNHL. However, the identity of a specific or highly relevant inner-ear self-antigen is still required. In recent years, a role for antiphospholipid antibodies has been also suggested, assuming sudden/progressive hearing loss to be part of the primary antiphospholipid syndrome (APS). In this review, we address the need for specific diagnostic tools in order to establish an autoimmune origin for hearing loss. Moreover, the decision of whether anti-inflammatory drugs or anti-coagulation should be given is also discussed.

Antiphospholipid Syndrome↗
PubMed2006

Increased susceptibility of cord blood B lymphocytes to undergo spontaneous apoptosis.

In this study, we compared the rate of spontaneous apoptosis of B cells from umbilical cord blood with adult B cells and assessed the role of Bcl-2, CD5, interleukin (IL)-4 and B cell-activating factor in B cell spontaneous apoptosis. We found that spontaneous apoptosis of cultured B cells, as assessed by utilizing annexin-V binding, was significantly higher in cord blood than in healthy adult individuals (77.5; 95 CI, 73.5-81.5 versus 59.2; 95 CI, 54-64, respectively, P < 0.0001) and further confirmed by 4' 6-diamidino-2-phenylindole, dihydrochloride (DAPI) staining. Whereas the expression of B cell-activating factor from the tumour necrosis factor family (BAFF) receptor mRNA was similar in B cells from adults and cord blood, we detected lower levels of circulating BAFF in the serum of cord blood (0.68 +/- 0.13 ng versus 1.83 +/- 0.54 ng, P = 0.01). The latter may explain, in part, our observation of lower levels of mean fluorescence intensity of Bcl-2 in cord B cells compared with adults (1.6 +/- 0.9 versus 2.85 +/- 1.3, P = 0.033). CD19(+) CD5(+) B cells from cord blood underwent a lower rate of apoptosis in comparison to CD19(+) CD5(-) B cells (25.1 +/- 9.3%versus 58.5 +/- 12.5%, P < 0.0001). This pattern of sensitivity was comparable in adult blood (15 +/- 5.5%versus 22.7 +/- 9.3%, P = 0.01). Nevertheless, the rate of apoptosis was higher in CD19(+) CD5(+) from cord blood compared to CD19(+) CD5(+) from adults (25.1 +/- 9.3%versus 15 +/- 5.5%, P = 0.0013). The addition of rIL-4 (10 u/ml) to cultured cells decreased B cell apoptosis in a similar fashion in both cord and adults blood. This rescue was strengthened when BAFF (100 microg/ml) was further added. Thus, alterations in Bcl-2 or serum BAFF level may explain the increased rate of cord blood B cell apoptosis.

Adult↗
PubMed2006

The reduction of serum B-lymphocyte activating factor levels following quinacrine add-on therapy in systemic lupus erythematosus.

B-Lymphocyte-activating factor (BAFF/BLyS) is a survival factor for B cells, belonging to the tumor necrosis ligand super family. Serum BAFF levels have been found to be elevated in patients with systemic lupus erythematosus (SLE). Neutralization of BAFF activity was suggested as an additional therapeutic approach in SLE. To determine the effect of add-on Quinacrine (Qn) treatment on serum BAFF levels and the effect of this treatment on SLE disease activity index (SLEDAI), antidsDNA and anticardiolipin (aCL) antibody levels, we treated 29 stable SLE patients, who were maintained on prednisolone and hydroxychloroquine and in some on azathioprine (AZT), with additional Qn (100 mg/d) with an aim to further reduce disease activity. SLEDAI, antidsDNA, aCL antibodies and serum BAFF levels were assessed before and 3 months after the addition of Qn. Three months following Qn initiation, a reduction in SLEDAI was noticed in 19/29 patients (mean 8.8 +/- 2.3 to 3.3 +/- 1.5, P = 0.009), followed by reduction or discontinuation of prednisolone in all patients and the discontinuation of AZT in five patients. Serum BAFF levels were significantly reduced in 8/12 patients (mean 6.3 +/- 0.5 to 3.0 +/- 0.56 ng/ml P = 0.0001). This reduction was found in correlation with a decrease in aCL titres. However, the decrease in SLEDAI scores and antidsDNA antibody titres was unrelated to the decrease in serum BAFF or aCL levels. We conclude that the addition of Qn to previous therapeutic regimens in active SLE is beneficial and seems to reduce SLEDAI scores, serum BAFF and aCL levels and therefore should be considered in many of our SLE patients before aggressive treatments are given.

Adult↗
PubMed2005

High-dose intravenous immunoglobulins: an option in the treatment of systemic lupus erythematosus.

Despite encouraging reports on the efficacy of intravenous immunoglobulin (IVIG) therapy in systemic lupus erythematosus (SLE), the clinical value of this treatment is not well established, and most of the data are based on case reports and small series of patients. IVIG has been used successfully to treat SLE patients with a broad spectrum of clinical manifestations, such as refractory thrombocytopenia, pancytopenia, central nervous system (CNS) involvement, secondary antiphospholipid syndrome, and lupus nephritis. The beneficial effects of IVIG on overall disease activity are usually prompt, with marked improvement within a few days, but they are often of limited duration. Improvement lasts for several weeks after the last infusion, although clinical response could be maintained by continuous monthly IVIG infusions. IVIG therapy immunomodulates autoimmune diseases by interacting with various Fcgamma receptors in such a way that it downregulates activating FcRIIA and FcRIIC and/or upregulates inhibitory FcRIIB. However, in SLE, additional mechanisms include inhibition of complement-mediated damage, modulation of production of cytokines and cytokine antagonists, modulation of T- and B-lymphocyte function, induction of apoptosis in lymphocytes and monocytes, downregulation of autoantibody production, manipulation of the idiotypic network, and neutralization of pathogenic autoantibodies. At present, IVIG in SLE is indicated either in severe cases that are nonresponsive to other therapeutic modalities, or when SLE can be controlled only with high-dose steroids; in such patients, IVIG thus becomes a useful steroid-sparing agent. However, this needs to be confirmed in double-blind, placebo-controlled studies.

Adjuvants, Immunologic↗
PubMed2005

Increased plasma levels of matrix metalloproteinase-9 are associated with the severity of chronic urticaria.

BACKGROUND: Matrix metalloproteinase (MMP)-9 is produced by many inflammatory cells such as macrophages, neutrophils, mast cells, eosinophils and T lymphocytes. Activated T cells are capable, through cell-cell contact, of inducing MMP-9 expression in human mast cells. OBJECTIVE: To investigate the activation status of peripheral CD4+ T cells and the level of MMP-9 in the plasma of patients with chronic urticaria (CU), and whether MMP-9 levels are in association with CU severity. METHODS: Study subjects included 29 patients with CU and 30 healthy control subjects. At the time of assessment, patients were divided into subgroups according to urticarial severity. Plasma levels of total MMP-9 (free pro-MMP-9 and free MMP-9) were determined by ELISA. CD4+ lymphocytes were positively selected with magnetic microbeads. After 48 h of activation, CD4+ T cells were assayed for both nuclear factor-kappa B (NF-kappa B) expression and proliferation. RESULTS: Plasma levels of MMP-9 were found to be significantly higher in 29 CU patients compared with 18 healthy controls (186 +/- 174 vs. 31 +/- 21 ng/mL, P<0.0001). We also found a significant correlation between MMP-9 levels and urticarial severity (r = 0.92, P<0.001). In addition, CD4+ T cells from CU patients expressed higher levels of NF-kappa B than CD4+ T cells from healthy controls (82 +/- 30 vs. 69 +/- 20 optical density, P = 0.007). Finally, as compared with seven healthy individuals, DNA synthesis in CD4+ T cells from seven CU patients was found to be significantly elevated (1000 +/- 240 vs. 751 +/- 166 counts per minute, P = 0.01). CONCLUSION: Increased levels of MMP-9 are found in CU patients, and particularly among those with severe disease. We also demonstrated that CD4+ T cells from such patients are highly activated.

Adolescent↗
PubMed2005

Predictive and protective autoimmunity in cardiovascular diseases: is vaccination therapy a reality?

The role of the immune system in modulating atherosclerosis has recently been well documented. Studies have revealed that cellular and humoral immunity plays crucial roles in atherogenic plaque formation. This includes macrophages, CD4+ T cells and dendritic cells as well as autoantigens such as oxidized low density lipoprotein (oxLDL), heat shock proteins and beta2-glycoprotein I. Given these recent advances, various modifications of the immune system in experimental models have been proposed as therapeutic strategies, with the potential of inhibiting atherosclerosis progression. These modifications are switching the immune system (CD4+ T cells) from Th1 towards a Th2 anti-inflammatory cytokine secretion, and the induction of protective antibodies both of which may be induced by specific vaccination. Recent identification of specific immunoreactive antigenic epitopes on modified LDL, their successful implementation for immunization and the induction of atheroprotection, supports the idea that active vaccination may emerge as a novel immuno-modulating atheroprotective strategy.

Atherosclerosis↗
PubMed2005

Increased spontaneous apoptosis of CD4+CD25+ T cells in patients with active rheumatoid arthritis is reduced by infliximab.

Increased secretion of tumor necrosis factor-alpha (TNF-alpha), along with interleukin-1 (IL-1) and interleukin-6 (IL-6), is important in the pathogenesis of rheumatoid arthritis (RA). T regulatory CD4(+)CD25(+) cells play a role in maintaining self-tolerance by downregulating Th1-induced proinflammation. This function has been found to be altered in active RA, whereas anti-TNF-alpha therapy has been found to improve the suppressive abilities of these cells. Our objectives were to investigate whether T regulatory cells in patients with active RA display a higher sensitivity to spontaneous apoptosis than in normals, and to look into the potential of infliximab (anti-TNF-alpha therapy) to reduce the sensitivity of these cells to spontaneous apoptosis. Seventeen patients suffering from active RA, having failed multiple disease-modifying antirheumatic drug (DMARD) therapies, were treated with infliximab. Spontaneous apoptosis (as detected by annexin V binding) was determined in all patients and compared with a group of normal individuals at baseline and after three months on infliximab treatment. Peripheral blood mononuclear cells were incubated in 24-well plates at 1 x 10(6) cells/mL for 48 hours. Annexin V binding on CD4(+)CD25(+) was assessed using three-color assay by flow cytometry. Prior to infliximab initiation, spontaneous apoptosis of T regulatory cells from active RA patients was found to be increased in comparison with controls (26 +/- 4.2% vs. 19.8 +/- 4.8%, respectively; P = 0.01). Three months later (while still on infliximab) spontaneous apoptosis was comparable in the two groups (20.7 +/- 5.2% vs. 20.9 +/- 3.4%; P 5 0.8). The absolute number of CD4(+)CD25(+) cells/mL in the peripheral blood at baseline was reduced in 11 out of 17 active RA patients when compared with that of the control group (24 +/- 7 vs. 32 +/- 11, respectively; P = 0.02). Following anti-TNF-alpha therapy, CD4(+)CD25(+) cell counts of patients were equivalent to those of normals. The alteration and reversal in both spontaneous apoptosis and cell count of T regulatory cells was found to correlate with RA disease activity. CD4(+)CD25(+) T regulatory cells display increased proclivity to undergo spontaneous apoptosis in active RA. Alterations in CD4(+)CD25(+) cell apoptosis and cell count were found to correlate with RA disease activity. Reversal of these deviations from normal was documented in association with the beneficial outcome of infliximab therapy.

Adult↗
PubMed2004

Clinical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients.

BACKGROUND: Despite the disabling nature of chronic urticaria (CU), little is known about the disease's duration or the efficacy of adopting aggressive therapeutic regimens such as cyclosporine A. OBJECTIVES: The aim of this study was to evaluate whether parameters such as angioedema, autologous serum test, anti-thyroid antibodies, and total IgE could predict both CU duration and severity. PATIENTS AND METHODS: One hundred and thirty-nine patients suffering from CU were prospectively followed over a 5-year period for disease duration, severity and the presence of angioedema. Also investigated was the association between these clinical parameters and the subsequent detection of autologous serum test, anti-thyroid antibodies, and total IgE. RESULTS: CU lasted over 1 year in more than 70% of cases and in 14% it still existed after 5 years. Angioedema co-existed or appeared during the course of CU in 40% of patients and was associated with disease duration. Autologous serum test and anti-thyroid antibodies were found positive in 28 and 12% of patients, respectively, compared to none of normal individuals, P = 0.001. CU duration was associated with the presence of both autologous serum test and anti-thyroid antibodies; however, autologous serum test and not anti-thyroid antibodies was found in association with CU severity. CONCLUSION: We demonstrate for the first time that CU duration is associated with clinical parameters such as severity and angioedema, and with laboratory parameters such as autologous serum test and anti-thyroid antibodies. The ability to predict CU duration may facilitate decisions regarding the possible early initiation of cyclosporine A as a means by which to reduce disease severity and duration.

Adolescent↗
PubMed2003

Quinacrine added to ongoing therapeutic regimens attenuates anticardiolipin antibody production in SLE.

The benefit of combining quinacrine (Qn) with hydroxychloroquine (HCQ) in the treatment of systemic lupus erythematosus (SLE) was previously re-evaluated by us. In our current study we observed that, in 11 active SLE patients (SLEDAI score 5-12), the addition of Qn (100 mg/day) to their existing ongoing therapeutic regimens resulted in a significant attenuation of their previously persistent anticardiolipin antibody (aCL) response. This was in comparison with a matched non-Qn treated control group composed of 14 randomly chosen aCL-positive SLE patients with a similar SLEDAI score 6-10. Prior to Qn treatment the therapeutic regimens of 12 months' duration, included in all cases HCQ (400 mg/day), in many cases prednisone (P, 10-20 mg/day) and in some additional cases immunosuppressive drugs. SLEDAI scores and aCL levels were monitored during the entire follow-up period which totaled 24 months in the study group and 15-18 months in the controls. Along with the beneficial effect of the added Qn on SLEDAI scores, aCL disappearance was documented in eight of 11 patients and remained negative during 8-12 months of follow-up (P = 0.004), compared with such a change in only three of 14 non-Qn treated aCL-positive patients (P = 0.18). We conclude that the added Qn treatment to former established therapeutic protocols may eliminate aCL response in SLE patients. Whether this agent's effect is permanent needs further elucidation.

Adult↗
PubMed2002

Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection is associated with immune-mediated abnormalities and B-cell lymphoproliferation evolving to an overt lymphoma. Recently, CD81 was identified as an HCV receptor on B-lymphocytes, providing a mechanism by which B cells are infected and activated by the virus. In addition, expansion of CD5+ B lymphocytes was described to be associated with various non-HCV related autoimmune disorders. Therefore, we studied the possible role of peripheral B cells CD81 and CD5 over-expression in the development of HCV-related autoimmunity and their association with disease severity in chronic HCV infection. Peripheral B cells CD5 expression and mean fluorescence intensity (MFI) of CD81 were determined in 30 HCV-infected patients, 30 healthy controls and 15 patients with hepatitis B virus infection using fluorescence-activated cell scan (FACS). We have also investigated the association between peripheral CD5 and CD81 B-cell over-expression and markers of autoimmunity and disease severity in patients chronically infected by HCV. CD5+ B-cells were increased in chronic HCV infection (23.2 +/- 7.2%) compared with those of healthy controls (15 +/- 5.5%) (P < 0.0001) and chronic HBV infection (19 +/- 3.7%) (P = 0.08). CD81 MFI was significantly higher in HCV-infected compared to HBV-infected patients and healthy controls. Both increased CD81 MFI and CD5+ B-cell expansion were associated with the production of rheumatoid factor and mixed cryoglobulins and positively correlated with HCV viral load and histological activity index. The overexpression of CD81 and the expansion of CD5+ peripheral B-cells in HCV-infected patients may possibly play a role in the development of HCV-associated autoimmunity and lymphoproliferation.

Adult↗
PubMed2001

Accelerated Fas-mediated apoptosis of monocytes and maturing macrophages from patients with systemic lupus erythematosus: relevance to in vitro impairment of interaction with iC3b-opsonized apoptotic cells.

Impaired handling of apoptotic cells has been suggested as an important factor in the development of systemic lupus erythematosus (SLE), and a role for complement in the removal of apoptotic cells was shown recently. We studied the in vitro function of macrophages from 40 patients with SLE and their matched controls in the removal of heterologous apoptotic cells opsonized by iC3b. Interaction index of apoptotic cells opsonized by iC3b was significantly lower in patients with SLE and averaged 71% +/- 37 of that of healthy individuals (p < 0.002) and 69% +/- 35 of patients with rheumatoid arthritis (p < 0.007). SLE patients had increased apoptosis of both freshly isolated monocytes (p < 0.001) and maturing macrophages (p < 0.04) that led to decreased density of monocyte-derived macrophages. Apoptosis was inhibited by adding soluble Fas receptor indicating Fas-mediated apoptosis. As demonstrated in both healthy controls and patients with SLE, decreased macrophage density by itself caused significant decreased uptake of apoptotic cells by the remaining macrophages. Maintaining normal density in SLE patients either by an increased initial density or by using soluble Fas restored the interaction capacity of the individual macrophages in the majority of patients. We concluded that impaired in vitro interaction of iC3b-opsonized apoptotic cells with macrophages from patients with SLE was mainly associated with Fas-dependent accelerated apoptosis of the monocytes/macrophages. Accelerated apoptosis of phagocytes may represent a novel in vitro mechanism of impairment of interaction with apoptotic cells that, apart from reducing the number of professional phagocytes, alters the function of the remaining macrophages.

Apoptosis↗
PubMed2001

Enhanced peripheral T-cell apoptosis in chronic hepatitis C virus infection: association with liver disease severity.

BACKGROUND/AIMS: It has been suggested that enhanced T-cell apoptosis in hepatitis C virus (HCV) infection may lead to down-regulation of their cellular immune response, thus contributing to the persistency of HCV infection. In the present study we have investigated the role of bcl-2 and nuclear factor kappa B (NFkappaB) in dexamethasone-induced apoptosis of peripheral T cells in chronic HCV infection. METHODS: The expression of bcl-2 and NFkappaB in peripheral T cells as well as spontaneous and dexamethasone-induced T-cell apoptosis were studied in HCV-infected patients (n=21), hepatitis B virus (HBV)-infected patients (n=14) and healthy individuals (n=19). These parameters were correlated with markers of autoimmunity and disease severity. RESULTS: NFkappaB, but not bcl-2 expression, was significantly decreased in the HCV-infected patients. This decrease was associated with the presence of mixed cryoglobulins (MC) and rheumatoid factor and was positively correlated with alanine aminotransferase (ALT) levels and histological activity index (HAI). Both spontaneous and dexamethasone-induced T-cell apoptosis were enhanced in HCV-infected patients; however, only the latter was correlated with the presence of MC, ALT levels and HAI. CONCLUSIONS: We confirm previous reports that enhanced T-cell apoptosis in HCV infection may play an important role in disease severity. Decreased expression of NFkappaB is important in the development of peripheral T-cell apoptosis, thus contributing to viral persistence and autoimmunity in these patients.

Adult↗