Biomedical subjects
Publications and source records attributed to C Abud-Mendoza.
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Dendritic cells (DC) play a dual role in the immune response, participating in its induction, and the maintenance of immune tolerance. The aim of this work was to perform a quantitative and phenotypic analysis of DC generated in vitro in the presence of IL-10 in patients with systemic lupus erythematosus (SLE). Blood samples were obtained from 10 active and untreated patients with SLE and six controls. Monocyte-derived DC were generated in vitro in the presence or absence of IL-10, and a quantitative and phenotypic analysis was performed. We found that freshly isolated monocytes from SLE patients had an increased expression of CD11b. On the other hand, the efficiency of in vitro DC generation was diminished in blood samples from SLE patients for conventional DC, but not for IL-10-treated DC. A diminished expression of HLA-DR, CD9 and CD86 was observed in conventional DC from SLE patients compared with controls. In contrast, enhanced levels of HLA-DR, CD80, CD9 and CD151 tetraspanins, FN1 (a class II MHC-tetraspanin epitope), CD85j/ILT2 and CD69 were detected in IL-10-treated DC from SLE patients. Accordingly, the phenotypic profile of IL-10-treated DC was very different in SLE and controls. However, the synthesis of IL-10 and IL-12 was similar in IL-10-treated and conventional cells in both SLE patients and controls. Our findings on the aberrant phenotype of IL-10-treated DC in SLE and their normal efficiency of in vitro generation may be important for the design of future therapies of this condition based on the administration of DC to induce immune tolerance.
OBJECTIVE: To assess the functional status of the IL-15/IL-15Ralpha cytokine system in different leucocyte subsets from patients with systemic lupus erythematosus (SLE). METHODS: Eighteen patients with SLE (10 with inactive and eight with active disease) and 14 healthy individuals were studied. Serum levels and in vitro production of IL-15 were determined. In addition, the expression of IL-15 receptor alpha (IL-15Ralpha) and membrane-bound IL-15 was assessed and the in vitro effects of IL-15 on CD69 and CD64 expression, interferon-gamma and TNF-alpha synthesis, respiratory burst induction and apoptosis were studied. RESULTS: Serum levels of IL-15 were significantly increased in inactive and active patients with SLE. Accordingly, the in vitro synthesis and release of IL-15 by monocytes in response to IFN-gamma+lipopolysaccharide was significantly enhanced in SLE patients with active disease, as was the percentage of membrane-bound IL-15+ monocytes. On the other hand, enhanced basal expression of IL-15Ralpha was detected in leucocytes from SLE patients, with defective induction upon stimulation with phytohaemagglutinin or phorbol myristate acetate/ionomycin. Furthermore, diminished induction of CD69 expression and interferon-gamma and TNF-alpha synthesis by recombinant human IL-15 was detected in peripheral blood mononuclear cells from SLE, and there was defective induction of CD64 and priming for respiratory burst in neutrophils. The anti-apoptotic effect of IL-15 was diminished in leucocytes from SLE patients. CONCLUSION: Our data indicate that there is enhanced synthesis of IL-15 by immune cells from SLE patients, with a poor response to this cytokine by different leucocyte subsets. This abnormal function of IL-15/IL-15Ralpha may contribute significantly to the pathogenesis of SLE.
The aim of this study was to assess the effect of Adalimumab on different immune parameters in patients with RA. Adalimumab was administered (40 mg every other week for 26 weeks) to eight patients with RA that were refractory to conventional drug therapy. Peripheral blood samples were obtained at days 0, 15 and 180 of Adalimumab therapy, and the following immune parameters were assessed: Number, phenotype, and function of regulatory T lymphocytes. The induction of apoptosis of immune cells and the in vitro and in vivo reactivity towards M. tuberculosis were also analysed. All patients responded to Adalimumab (ACR response 50-70), and a modest but significant increase in the number and function of regulatory T cells was observed at day 15 of anti-TNF-alpha therapy. In addition, an increased percent of apoptotic cells was detected in the peripheral blood at day 15 of Adalimumab therapy. Unexpectedly, most of these effects were not further observed at day 180. However, two patients showed a persistent and marked reduction in the reactivity to M. tuberculosis. Although we have found that Adalimumab affects the number and function of regulatory T lymphocytes, and the apoptosis of immune cells, these effects are transient and its possible causal relationship with the therapeutic activity of this biological agent remains to be determined. Nevertheless, the down-regulatory effect of Adalimumab on the reactivity to M. tuberculosis could be related to an enhanced risk of tuberculosis reactivation.
We have explored the therapeutic potential of statins in patients with different inflammatory rheumatic diseases refractory to conventional therapy. We found that simvastatin (80mg o.d. for eight days) induced a rapid and significant reduction in proteinuria levels in three systemic lupus erythematosus (SLE) patients. A similar kind of therapy had a marked beneficial effect in a patient with Wegener's granulomatosis and a patient with erythema nodosum. On the other hand, five patients with rheumatoid arthritis (RA) who received atorvastatin for eight days (20mg/day) showed reduction in C-reactive protein levels and a clinical improvement that was classified as an ACR20 response. Prior to the administration of statins, all these patients had received aggressive conventional therapy with no satisfactory response. A significant reduction in spontaneous apoptosis of peripheral blood lymphocytes and expression of CD69 and HLA-DR was observed in SLE patients after simvastatin therapy. These results prompted us to perform a pilot short-time comparative (simvastatin versus chloroquine) open clinical trial in 15 patients with RA who were receiving methotrexate as a single disease modifying antirheumatic drug with no satisfactory response. Most patients (9/10) who received simvastatin (40mg/day) showed an ACR50 or better response after eight weeks, whereas such a response was not observed in any patient (0/5) treated with chloroquine. Our preliminary results indicate that statins may be an important therapeutic tool for the treatment of inflammatory rheumatic diseases.
Different studies have shown that some autoantibodies are able to penetrate into living cells and that this phenomenon has functional consequences, including apoptosis. We have explored the effect of anti-DNA antibodies (Ab) on the in vitro activation of peripheral blood mononuclear cells (PBMNC) and found that a human polyclonal anti-DNA, IgG, which efficiently penetrated living cells, was able to induce the expression of different cell activation antigens in vitro such as CD69, CD71 or CD98 by PBMNC from normal individuals. However, the cell activation phenotype induced by anti-DNA Ab was considered anomalous since the expression of some activation antigens was not up-regulated, and others showed aberrant behaviour (such as down-regulation of ICAM-1 expression). Similar results were obtained using different murine anti-DNA monoclonal antibodies (mAb). In addition, mAb that showed an efficient ability to penetrate living cells tended to have a greater effect on PBMNC activation. Anti-DNA Ab were also able to induce a noticeable expression of CD95/Fas. These data indicate that penetrating anti-DNA Ab are able to induce an anomalous activation state in vitro in a significant fraction of PBMNC. We believe this effect may occur in vivoand could have an important function in the pathogenesis of the immune dysregulation seen in SLE.
Lymphocytes from patients with systemic lupus erythematosus (SLE) exhibit abnormalities in early cell activation events as well as increased production of IL-10. We explored the possible role of IL-10 on defective cell activation events of SLE lymphocytes and first studied the in vitro effect of IL-10 on peripheral blood mononuclear cells (PBMNC) from healthy subjects. After 5 days of culture in the presence of exogenous IL-10, these cells demonstrated abnormal expression of CD69 as well as high intracellular pH and defective activation of the Na+/H+ anti-porter by PMA. We then investigated the effect of IL-10 blockade on PBMNC from SLE patients. SLE PBMNC cultured for 5 days with a blocking anti-IL-10 monoclonal antibody (mAb) partially corrected abnormalities in CD69 expression and intracellular pH; however, in 1/5 patients studied, no significant positive effect was observed. The effect of the anti-IL-10 mAb was apparently not related to protection against activation-induced cell death. We conclude that IL-10 in normal PBMNC induce some of the defects in early cell activation events seen in SLE lymphocytes. Accordingly, the blockade of IL-10 partially corrects these abnormalities in SLE cells. Our data further support the importance of IL-10 in immune dysfunction seen in SLE.
Several immuno-regulatory abnormalities have been described in SLE patients. T cell dysfunction in SLE includes defective in vitro proliferative responses to several stimuli, reduced IL-2 production and a poor helper function. It has been widely proposed that this defective T cell immunoregulatory function has a key role in the hyperactivity of B cells and auto-antibody production in SLE. However, it has not been elucidated whether or not this cell dysfunction is intrinsic to lymphocytes or is due to other factors such as anti-lymphocyte auto-antibodies. In this study we have evaluated some important early cell activation events in T and non-T lymphocytes from patients with systemic lupus erythematosus (SLE). Peripheral blood lymphocytes from SLE patients and controls were isolated. The intracellular pH (pHi), cytosolic calcium (Ca2+i) and CD69 expression were determined by spectrofluorometry and flow cytometry. Modifications of these parameters in response to protein kinase C (PKC) activators, mitogenic lectins and calcium ionophores were also studied. We found a significant reduction in the increase of pHi in response to PKC activators (PMA) in SLE cells. In addition, the induction of CD69 expression by PMA was significantly lower in T cells from SLE patients. By contrast, freshly isolated non-stimulated SLE cells exhibited a significantly higher pHi, as well as an increased baseline expression of the early cell activation antigen CD69. On the other hand, the increase in Ca2+i in response to a Ca2+ ionophore (4Br-A23187) or thapsigargin in Ca(2+)-free solutions, was smaller in SLE lymphocytes. We concluded that T cells from SLE patients exhibit abnormalities in several key early cell activation events (pHi, Ca2+i and CD69 expression). These abnormalities could have an important role in the T cell dysfunction observed in SLE. The presence of T cells with a preactivated phenotype in the peripheral blood of SLE patients, could be a reflection of the ongoing autoimmune phenomena that is occurring in these patients.
BACKGROUND: The pathogenesis of autoeczematization (AE) is not well understood; however, previous studies suggest that AE is an autoimmune condition. OBJECTIVE: Our purpose was to assess whether AE is associated with an abnormal immune recognition of autologous skin antigens. METHODS: Eight patients with AE, six healthy control subjects, and three patients with localized contact dermatitis (LCD) were studied. Activation markers were detected on peripheral blood T lymphocytes. Autologous mixed epidermal cell-lymphocyte reaction (AMECLR) was performed for each subject and cell proliferation was assessed by tritiated thymidine incorporation. RESULTS: Many activated T cells were detected in patients with AE (5.2% +/- 4.5% vs 0.2% +/- 0.4% in control subjects, p < 0.05). AMECLR showed a significantly higher cell proliferation in AE compared with both healthy subjects and patients with LCD (6372 +/- 3217 cpm vs 2638 +/- 1788 cpm, and 2471 +/- 1389 cpm, respectively; p < 0.05). Peripheral blood mononuclear cells cultured in the presence of an autologous skin homogenate also showed a significantly increased cell proliferation in patients with AE than in control subjects. CONCLUSION: Our results suggest that an abnormal immune response against autologous skin antigens occurs in AE that could be related to the pathogenesis of this disease.
We evaluated the therapeutic potential of methotrexate (MTX) in patients with systemic lupus erythematosus (SLE). Their serious disease ruled out further treatment with prednisone or prednisone plus cyclophosphamide. Low dose oral MTX (5-10 mg/week) was added to the therapy (prednisone or prednisone plus cyclophosphamide) of 10 selected patients with SLE. Eight of them showed marked improvement and we were able to taper prednisone and completely discontinue cyclophosphamide therapy. Our results suggest that the use of oral MTX in low, weekly doses can be useful as adjunctive therapy for selected cases of childhood SLE.
To get further insight into the pathogenesis of polymorphous light eruption, we studied nine patients with polymorphous light eruption and six healthy persons. Two skin biopsy specimens were obtained from each person, one from previously ultraviolet light-irradiated skin and another one from unirradiated skin. An epidermal cell suspension, skin homogenate, or both were prepared from each specimen. Autologous cultures were made with peripheral blood mononuclear cells combined with irradiated or unirradiated skin homogenate and peripheral blood mononuclear cells combined with irradiated or unirradiated epidermal cell suspension. Cell proliferation was assessed by 3H-thymidine incorporation assay. The response of peripheral blood mononuclear cells to unirradiated epidermal cells or unirradiated skin homogenate was similar in both patients and controls. However, peripheral blood mononuclear cells from patients with polymorphous light eruption showed a significantly increased proliferative response to both irradiated epidermal cells and irradiated skin homogenate. Our results indicate that ultraviolet light increases the stimulatory capability of polymorphous light eruption epidermal cells in a unidirectional mixed culture with autologous peripheral blood mononuclear cells. This suggests that an immune sensitization against autologous ultraviolet light-modified skin antigens occurs in polymorphous light eruption.
Synovial fluid mononuclear cells from 5 patients with active Behçet's syndrome who were receiving no treatment were observed to have: decreased proportions of CD4+ and CD8+ cells, decreased proliferative responses of T cells in AMLR, poor capacity of non-T cells to stimulate in AMLR, decreased production of IL-2 upon PHA stimulation as compared both to their own peripheral blood mononuclear cells and to synovial fluid and peripheral blood mononuclear cells from 6 patients with RA and 6 patients with synovial effusions due to noninflammatory conditions. These findings provide further evidence of an immunoregulatory disturbance in Behçet's syndrome and indicate that synovial fluid, may be an important site where this derangement occurs in the active stage of the disease.
Some lepromatous leprosy (LL) patients are characterized by the presence of activated suppressor T cells that specifically inhibit the immune response to Mycobacterium leprae antigens. Immune contrasuppressor (CS) cell activity antagonize suppressor function. Whereas the former function has been extensively studied in leprosy, the latter has not been explored. We studied the peripheral blood mononuclear cells (PBMNC) of 20 patients with leprosy (10 lepromatous and 10 tuberculoid) and six healthy contacts. We found CS-like activity in the PBMNC from some LL patients when assayed in vitro using lepromin as antigen. This CS-like function was found in CD8+, vicia villosa adherent (VV+) T cells. CS-like activity was not detected in PBMNC from either tuberculoid patients or healthy contacts. Pre-treatment of CD8+, VV+ cells with either recombinant IL-2 (5 u/ml) or recombinant interferon-gamma (1,000 u/ml) did not modify significantly their putative CS function. However, in 50% of lepromatous patients the pre-incubation of CD8+, VV+ cells with both lymphokines together increased significantly the CS-like activity. These data suggest that the in vitro immune response to M. leprae in some LL patients can be augmented by either modifying numerically the contrasuppressor T cells or activating them with lymphokines.
Forty-one of 858 patients with systemic lupus erythematosus (SLE) developed clinical deformity of their hands. This deformity was clinically and radiologically different from that found in 40 patients with classical or definite rheumatoid arthritis (RA), and tended to appear early in the course of disease. Characteristics of this arthropathy included nonerosive carpal collapse; exceptional erosion of the styloid processes; Z deformity of the thumb; nonerosive ulnar deviation and subluxation of MCP joints; parametacarpophalangeal joint hook formation; scant and asymmetric joint erosions; and swan neck deformity of the fingers. Most of these changes seemed to be due to involvement of the ligaments rather than to the destructive effect of synovitis. Patients with SLE with deforming arthropathy had a higher frequency of rheumatoid factor positivity, sicca symptoms and antibodies to native DNA, whereas they had lower incidence of facial rash and photosensitivity than did those without. Other manifestations did not differ. We propose that most patients with SLE with deforming arthropathy belong to a subset of SLE rather than representing the coexistence of SLE and RA.
Lepromatous leprosy is characterized by immune anergy and abnormal suppressor T-cell function. Contrasuppressor cells are a subset of CD8+, vicia villosa-adherent T lymphocytes. T-contrasuppressor (Tcs) cells act on T-helper cells to cause them to become unresponsive to the action of T-suppressor cells. In 8 lepromatous (LL) and 7 tuberculoid (TT) patients, and 6 healthy contacts we studied the percent of the following lymphocyte subsets: CD3+, CD4+, CD8+, Ia+, vicia villosa+ (VV+), CD8, VV+, VV, Ia+, and Ia, Tac+. This was done in baseline status as well as post-stimulation with recombinant gamma interferon (rIFN-gamma). We found that peripheral blood mononuclear cells from LL and TT patients and controls exhibit a similar number of putative contrasuppressor lymphocytes (CD8, VV+ cells). However, in the contrasuppressor subset from LL patients we found a low percent of Ia+ (p less than 0.05 compared to controls or TT). In the three groups studied, the rIFN-gamma enhanced the percent of Ia+ lymphocytes in the CD8, VV+ cell subpopulation. However, the CD8, VV+ lymphocytes from LL patients, despite the effect of rIFN-gamma, continue to have a low percent of Ia+ cells (p less than 0.05 compared to controls or TT). These findings suggest that LL patients might have abnormalities in the contrasuppressor immune circuit. Future functional studies on the role of Tcs cells in the anergy seen in LL will be required in order to define the apparent dysfunction occurring in this disease.
The production of the T cell lymphokine interleukin-2 (IL-2) was found to impaired in all of seven male patients with AIDS or homosexuals with persistent generalized lymphadenopathy (AIDS related complex, AIDS-RC) whom we studied. Conversely the T cell response to IL-2 was found unimpaired as was the production of the monocyte factor interleukin-1 (IL-1). The response of T cells to IL-1 was found markedly decreased in two of the four patients with AIDS and in two of the three patients with AIDS-RC. Five of six patients had flat curves in autologous mixed lymphocyte cultures with no significant proliferative response throughout 7 days. The exception was a Haitian heterosexual patient with AIDS. Natural killer cell function was decreased in three of four patients with AIDS and two of three patients with AIDS-RC but it augmented normally in the presence of IL-2 in four, including the two who had it normal basally. Responses to pokeweed mitogen were within normal limits in all seven patients despite decreased responses to concanavalin A and phytohaemagglutinin. These findings help pinpoint the defect in AIDS to the T4+ cell, and perhaps even to one of its subpopulations, and suggest a role for IL-2 in the treatment of AIDS.
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We describe 12 patients with systemic lupus erythematosus (SLE) who developed massive pulmonary hemorrhage with very active disease. Other causes of pulmonary bleeding were excluded. Eleven of the 12 patients died, but only 4 had hemoptysis. Massive pulmonary hemorrhage should be suspected, even in the absence of hemoptysis, in severely ill patients with lupus who develop acute respiratory distress with bilateral pulmonary infiltrates and a drop in hemoglobin of 3 or more g/dl. Because of the deadly nature of this complication of SLE, when it is suspected, intensive corticosteroid and immunosuppressive treatment should be instituted.