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Systemic lupus erythematosus (SLE) patients are susceptible to the development of posterior reversible encephalopathy syndrome (PRES). The main theory concerning the physiopathology of PRES suggests that there is brain-blood barrier damage, which is associated with endothelial dysfunction, and characterized by vasogenic oedema. However, current evidence regarding its physiopathogenic mechanisms is quite scant. The aim of this study was to analyse the expression of different serum cytokines, as well as vascular endothelial growth factor (VEGF) and soluble CD40 ligand (sCD40L), in patients with PRES/systemic lupus erythematosus (SLE) and to compare them with levels in SLE patients without PRES and in healthy controls. We performed a transversal study in a tertiary care centre in México City. We included 32 subjects (healthy controls, n = 6; remission SLE, n = 6; active SLE, n = 6 and PRES/SLE patients, n = 14). PRES was defined as reversible neurological manifestations (seizures, visual abnormalities, acute confusional state), associated with compatible changes by magnetic resonance imaging (MRI). Serum samples were obtained during the first 36 h after the PRES episode and were analysed by cytometric bead array, Luminex multiplex assay or enzyme-linked immunosorbent assay (ELISA). Interleukin (IL)-6 and IL-10 levels were significantly higher in PRES/SLE patients (P = 0·013 and 0·025, respectively) when compared to the other groups. Furthermore, IL-6 and IL-10 levels displayed a positive correlation (r = 0·686, P = 0·007). There were no differences among groups regarding other cytokines, sCD40L or VEGF levels. A differential serum cytokine profile was found in PRES/SLE patients, with increased IL-6 and IL-10 levels. Our findings, which are similar to those described in other neurological manifestations of SLE, support the fact that PRES should be considered among the SLE-associated neuropsychiatric syndromes., (© 2017 British Society for Immunology.)

Natural killer (NK) cells participate in the regulation of the immune response. However, the immunomodulatory function of NK cells in systemic lupus erythematosus (SLE) is not well understood. The aim of this study was to evaluate the regulatory function of NK cells in SLE patients and to identify the NK cells involved in the pathogenesis of this complex disease. We analysed the expression of NK receptors and co-stimulatory molecules in peripheral NK cells (CD3 - CD56 + ) from SLE patients, as well as the numbers of human leucocyte antigen D-related (HLA-DR)/CD11c + NK cells. In addition, NK cell regulatory function was assessed by the detection of NK cell-mediated dendritic cell (DC) lysis. We found that SLE patients showed increased numbers of immunoglobulin-like transcript 2 (ILT2) + , CD86 + and CD134 + NK cells. Furthermore, NK cells from SLE patients induced higher levels of DC lysis. We were able to identify a new subset of NK cells co-expressing CD11c and HLA-DR. These atypical NK cells were increased in SLE patients when compared with controls. We have identified an expanded new subset of NK cells in SLE patients. This is the first study, to our knowledge, which demonstrates that NK cells in SLE patients have an altered phenotype with a high expression of receptors characteristic of dendritic cells. Our results suggest that the impairment in the regulatory function of NK cells, together with the increased number of DC-like NK cells, could play an important role in the development of SLE and highlight the importance of NK cells as a future therapeutic target., (© 2017 British Society for Immunology.)

T cells from systemic lupus erythematosus (SLE) patients display a wide array of anomalies in peripheral immune tolerance mechanisms. The role of ubiquitin ligases such as Cbl-b has been described recently in these phenomena. However, its role in resistance to suppression phenotype in SLE has not been characterized, which was the aim of the present study. Thirty SLE patients (20 with active disease and 10 with complete remission) and 30 age- and sex-matched healthy controls were recruited. Effector (CD4 + CD25 - ) and regulatory (CD4 + CD25 + ) T cells (T regs ) were purified from peripheral blood mononuclear cells (PBMCs) by magnetic selection. Suppression assays were performed in autologous and allogeneic co-cultures and analysed by a flow cytometry assay. Cbl-b expression and lysine-63 (K63)-specific polyubiquitination profile were assessed by Western blotting. We found a defective Cbl-b expression in T regs from lupus patients in contrast to healthy controls (1·1 ± 0·9 versus 2·5 ± 1·8, P = 0·003), which was related with resistance to suppression (r = 0·633, P = 0·039). Moreover, this feature was associated with deficient K63 polyubiquitination substrates and enhanced expression of phosphorylated signal transducer and activation of transcription 3 (pSTAT-3) in T regs from lupus patients. Our findings support that Cbl-b modulates resistance to suppression by regulating the K63 polyubiquitination profile in lupus T regs . In addition, defective K63 polyubiquitination of STAT-3 is related to increased pSTAT-3 expression, and might promote the loss of suppressive capacity of T regs in lupus patients., (© 2017 British Society for Immunology.)

The presence of anti-Ro52/tripartite motif 21 (Trim21) autoantibodies has been associated with a distinctive clinical profile and has gained value as a prognostic marker in idiopathic inflammatory myopathies (IIM). The aim of the present work was to analyse Ro52/Trim21 expression in different subsets of peripheral blood mononuclear cells (PBMCs) of patients with IIM, as well as the ubiquitination profile and its association with proinflammatory cytokine production. We included 18 patients with recent-onset IIM and 18 age- and gender-matched healthy donors. PBMCs were isolated and different subsets (CD4 + , CD8 + , CD14 + ) were purified by magnetic selection. The expression of Ro52/Trim21 in different PBMC subsets of patients with IIM and healthy donors was analysed by Western blot. We assessed the presence of myositis-specific and associated autoantibodies by enzyme-linked immunosorbent assay (ELISA). Cytokine levels were measured by cytometric bead array. Patients with IIM showed decreased protein expression of Ro52/Trim21 in comparison to healthy controls in PBMC (0·97 ± 0·60 versus 1·84 ± 0·92, P = 0·016), CD4 + lymphocytes (0·79 ± 0·54 versus 2·41 ± 0·78, P = 0·017), and monocytes (0·87 ± 0·35 versus 1·89 ± 0·20, P < 0·001). There were no significant differences among IIM groups. Also, a lower K48-mediated ubiquitination profile was found, predominantly in CD4 + lymphocytes. Furthermore, after mitogenic stimulation, there was a higher synthesis of proinflammatory cytokines by T cells [interleukin (IL)-17A and tumour necrosis factor (TNF)-α] and monocytes [IL-6 and interferon (IFN)-α] from IIM patients compared with healthy controls. Our data suggest that patients with IIM, mainly DM, are characterized by a deficient expression of Ro52/TRIM21 in different PBMC subsets (CD4 + lymphocytes and monocytes), along with lower K48-mediated ubiquitination, which is associated with a proinflammatory cytokine response., (© 2016 British Society for Immunology.)

Objectives: The aim of this study was to recognize risk factors for extrarenal SLE flares in patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT)., Methods: We performed a retrospective, case-control study in a tertiary care hospital in Mexico City from 1993 to 2014. Cases were lupus patients who had any extrarenal flare after RRT. Controls were SLE patients with ESRD but without flares. We recorded demographic features and clinical and immunological parameters. Differences between groups were analysed by Student's t-test. Association was assessed by the odds ratio (OR) and 95% CI. Multivariate analysis was performed by binary logistic regression., Results: Eighty-eight patients were included: 38 cases (50 flares) and 50 controls. The proportion of men was higher in cases (24 vs 8%, P = 0.029). The most common flares were haematologic (42%), mucocutaneous (38%) and articular (30%). Independent risk factors for flares included age at RRT start [OR 0.92 (95% CI 0.88, 0.96), P < 0.001], history of haematologic activity [OR 3.79 (95% CI 1.05, 13.7), P = 0.04], anti-cardiolipin IgM [OR 4.39 (95% CI 1.32, 14.6), P = 0.02] and low C4 levels [OR 9.7 (95% CI 2.49, 39.12), P = 0.001]., Conclusion: SLE patients continue to be at risk for extrarenal activity after RRT. The most common flare was haematologic, which correlated with the history of haematologic activity and anti-cardiolipin positivity as independent risk factors. Lower C4 levels and younger age at the beginning of RRT were also associated. Patients with these characteristics should have a closer follow-up in order to detect and treat SLE flares in a timely manner., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The role of T cells in idiopathic inflammatory myopathies (IIM) is not yet clear. Some alterations in certain subsets have been reported in inflamed muscle cells. However, a broad quantitative assessment of peripheral T cell subsets has not been evaluated. The aim of this study was to address the quantitative profile of potential pathogenic T cell subsets, namely follicular helper T cells (Tfh), T helper type 17 (Th17), CD28(null) and regulatory T cells (Tregs ) in peripheral blood from IIM patients. Thirty IIM patients and 30 age- and gender-matched healthy donors were included. Peripheral blood mononuclear cells were isolated. T cell subsets were evaluated by flow cytometry, as follows: Tfh (CD4(+) CXCR5(+) ) and its subsets Tfh1 (CXCR3(+) CCR6(-) ), Tfh2 (CXCR3(-) CCR6(-) ), Tfh17 (CXCR3(-) CCR6(+) ), Th17 (CD4(+) IL17A(+) ), CD28(null) (CD4(+) CD28(-) CD244(+) ) and Tregs (CD4(+) CD25(high) forkhead box protein 3 (FoxP3(+) ); CD8(+) CD25(high) FoxP3(+) ). Percentage, absolute numbers and mean fluorescence intensity were analysed. We found increased numbers of total Tfh cells (28 ± 8.16 versus 6.64 ± 1.29, P=0.031) in IIM patients when compared to healthy controls. Moreover, this increment was dependent upon Tfh2 and Tfh17 (Tfh2:9.49 ± 2.19 versus 1.66 ± 0.46, P=0.005; Tfh17 9.48 ± 2.83 versus 1.18 ± 0.21, P=0.014). Also, IIM patients showed higher numbers of Th17 cells (30.25 ± 6.49 versus 13.46 ± 2.95, P=0.031) as well as decreased number of Tregs (5.98 ± 1.61 versus 30.82 ± 8.38, P=0.009). We also found an expansion of CD28(null) cells (162.88 ± 32.29 versus 64 ± 17.35, P=0.015). Our data suggest that IIM patients are characterized by an expansion of peripheral proinflammatory T cells, such as Tfh and Th17, as well as pro-apoptotic CD28 null cells and a deficiency of suppressor populations of Tregs (CD4(+) and CD8(+) )., (© 2014 British Society for Immunology.)

Many genetic studies have found an association between interferon regulatory factors (IRF) single nucleotide polymorphisms (SNPs) and systemic lupus erythematosus (SLE); however, specific dendritic cell (DC) alterations have not been assessed. The aim of the present study was to address the expression of IRF3 and IRF5 on different DC subsets from SLE patients, as well as their association with interferon (IFN)-α production and novel SNPs. For the genetic association analyses, 156 SLE patients and 272 healthy controls from the Mexican mestizo population were included. From these, 36 patients and 36 controls were included for functional analysis. Two IRF3 SNPs - rs2304206 and rs2304204 - were determined. We found an increased percentage of circulating pDC in SLE patients in comparison to controls (8.04 ± 1.48 versus 3.35 ± 0.8, P = 0.032). We also observed enhanced expression of IRF3 (64 ± 6.36 versus 36.1 ± 5.57, P = 0.004) and IRF5 (40 ± 5.25 versus 22.5 ± 2.6%, P = 0.010) restricted to this circulating pDC subset from SLE patients versus healthy controls. This finding was associated with higher IFN-α serum levels in SLE (160.2 ± 21 versus 106.1 ± 14 pg/ml, P = 0.036). Moreover, the IRF3 rs2304206 polymorphism was associated with increased susceptibility to SLE [odds ratio (OR), 95% confidence interval (CI) = 2.401 (1.187-4.858), P = 0.021] as well as enhanced levels of serum type I IFN in SLE patients who were positive for dsDNA autoantibodies. The IRF3 rs2304204 GG and AG genotypes conferred decreased risk for SLE. Our findings suggest that the predominant IRF3 expression on circulating pDC is a key element for the increased IFN-α activation based on the interplay between the rs2304206 gene variant and the presence of dsDNA autoantibodies in Mexican mestizo SLE patients., (© 2014 British Society for Immunology.)

The reflection of medicine in the universal arts has motivated several rheumatologists to discover features of rheumatic diseases depicted by the artist's eyes long before they were defined as specific pathologic entities. The result has been the identification of several pieces of art dating from the Middle Ages, the Renaissance, the Baroque and Post-Impressionist periods that depict clear features of several rheumatic diseases such as RA, OA, camptodactyly and temporal arteritis, among others. On the other hand, great artists such as Pierre-Auguste Renoir, Antoni Gaudí, Raoul Dufy, Paul Klee, Frida Kahlo and Niki de Saint Phalle are good examples of how rheumatic diseases such as RA, scleroderma and chronic pain can influence the artist's perspective, the technique used and the content of their work. Art can serve as a powerful resource to understand the natural course of diseases. By learning through the artist's eyes the way illnesses behave and evolve in time, rheumatologists can trace the history of several conditions., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Lymphopenia is a common clinical manifestation in patients with systemic lupus erythematosus (SLE). However, its physiopathogenic role and the contribution of different T cell subsets in this setting have not been addressed fully. The aim of this study was to characterize T cell subsets quantitatively and functionally and their association with lymphopenia and azathioprine treatment in SLE. We included 84 SLE patients and 84 healthy controls and selected 20 patients for a 6-month longitudinal analysis. Peripheral blood mononuclear cells were isolated, and T cell subsets were analysed by flow cytometry. Functional analyses included autologous and allogeneic co-cultures of T cells. Our data show persistently lower absolute numbers of CD4(+) CD25(high) T cells [regulatory T cells (T(regs) )] (1·9 versus 5·2, P < 0·01) and CD4(+) CD69(+) T cells (3·2 versus 9·3, P = 0·02) and higher activity scores (4·1 versus 1·5, P = 0·01) in SLE patients with lymphopenia compared with those without lymphopenia. Lymphopenia increased the risk for decreased numbers of CD4(+) CD25(high) cells (relative risk 1·80, 95% confidence interval 1·10-2·93; P = 0·003). In addition, azathioprine-associated lymphopenia was characterized by decreased absolute numbers of CD4(+) CD69(+) and CD4(+) interleukin (IL)-17(+) cells compared to disease activity-associated lymphopenia. Functional assays revealed that SLE effector T cells were highly proliferative and resistant to suppression by autologous T(regs) . In summary, lymphopenia was associated with deficient numbers of CD4(+) CD25(high) and CD4(+) CD69(+) cells and resistance of effector T cells to suppression by T(regs) , which could contribute to the altered immune responses characteristic of SLE. Furthermore, azathioprine treatment was associated with decreased numbers of CD4(+) CD69(+) and CD4(+) IL-17(+) cells and diminished T(reg) suppressive activity., (© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.)

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.

Objective: To compare the utility of anti-chromatin antibodies for the diagnosis of systemic lupus erythematosus (SLE) and as markers of disease activity., Methods: We included 73 consecutive patients (62 female) with SLE (four or more ACR criteria) of recent onset (<1 yr since diagnosis). As control groups we included 130 healthy blood donors and 261 patients with 11 systemic autoimmune diseases (SAD). Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). A venous blood sample was drawn to measure three anti-chromatin antibodies [anti-nucleosome (anti-NCS), anti-double-stranded DNA (anti-dsDNA) and anti-histones (anti-HST)] by enzyme-linked immunosorbent assay., Results: The prevalence of anti-chromatin antibodies in SLE patients and healthy controls was 100 and 3% respectively for anti-NCS, 63 and 5% for anti-dsDNA, and 15 and 3% for anti-HST. Anti-NCS had a sensitivity of 100% and specificity of 97% for SLE diagnosis. When SLE and SAD patients were compared [excluding mixed connective tissue disease (MCTD)], the sensitivity of anti-NCS, anti-dsDNA and anti-HST antibodies for SLE diagnosis was 93, 71 and 40% respectively and the specificity was 97, 98 and 98%. Anti-chromatin antibodies were not useful in differentiating between SLE and MCTD patients. Anti-NCS antibodies showed the highest correlation with disease activity (r = 0.45, P < 0.0001), especially in patients negative for anti-dsDNA antibodies (r = 0.58, P = 0.001). Anti-NCS antibodies also showed strong association with renal damage (odds ratio 4.1, 95% confidence interval 1.2-13.6, P = 0.01)., Conclusion: Anti-NCS antibodies could be a useful tool in the diagnosis and assessment of disease activity in SLE patients, especially in patients who are negative for anti-dsDNA antibodies.

Objective: To determine the prevalence of antineutrophil cytoplasmic autoantibodies (ANCA) in sera of patients with tuberculosis compared with healthy control subjects and a group of patients with atopic asthma., Methods: The presence of ANCA was examined in patients with tuberculosis, and in asthmatic patients and healthy subjects as control groups, by means of indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) to detect anti-proteinase 3 (PR3-ANCA) and antimyeloperoxidase (MPO-ANCA) antibodies., Results: ANCA were present in 20 (44.4%) of 45 tuberculosis patients by IIF (16 c-ANCA, four p-ANCA) and in 18 (40%) patients by ELISA (15 PR3-ANCA, three MPO-ANCA). High odds ratios for ANCA positivity were observed for tuberculosis patients when compared with both control groups. ANCA results were not related to the category of tuberculosis, stage of disease, presence of concomitant diseases or pharmacotherapy., Conclusions: As many clinical similarities between tuberculosis and Wegener's granulomatosis exist, we propose that a positive ANCA test in patients living in countries with a high prevalence of tuberculosis must be carefully interpreted as indicative of systemic vasculitis, especially when no signs of extrapulmonary involvement occur.

The aim of the study was to determine whether collagen-polyvinylpyrrolidone (collagen-PVP) modifies some proinflammatory responses in synovium cultures from rheumatoid arthritis (RA) patients. Synovium from 10 RA patients were cultured with or without 1% collagen-PVP. Tissues on the 3rd, 5th and 7th culture day were sectioned and stained by the Herovici technique. Total collagen and type I/III collagen ratios were evaluated by the Woessner micromethod and by interrupted gel electrophoresis, respectively. Collagenolytic activity was assessed by degradation of [3H]-collagen in supernatants. TIMP-1, IL-1beta and TNF-alpha were determined in supernatants by ELISA, and the results were normalized by DNA concentration. IL-1beta, TNF-alpha, IL-6, IL-8, MMP-1, TIMP-1, Cox-1, VCAM-1, ICAM-1 and Fas/APO95 expression was evaluated by immunohistochemistry. Apoptosis was detected by TUNEL technique. The histological analysis and electrophoresis revealed a 1.7-fold increase of type III collagen in a time-dependent fashion in collagen-PVP-treated cultures. Proinflammatory cytokines (IL-1beta: 58 +/- 9 versus 22 +/- 10; TNF-alpha: 41 +/- 6 versus 11 +/- 3; IL-8: 59 +/- 12 versus 29 +/- 9; treated versus untreated), adhesion molecule (ICAM-1: 57 +/- 11 versus 29 +/- 15; VCAM-1: 49 +/- 7 versus 21 +/- 13; treated versus untreated) as well as Cox-1 (59 +/- 10 versus 20 +/- 3) expression was down-regulated in RA synovium treated. Meanwhile, TIMP-1 (36 +/- 7 versus 57 +/- 11) and Fas expression (20 +/- 10 versus 55 +/- 13) and apoptosis (14 +/- 3 versus 55 +/- 5) were up-regulated in treated cultures compared with controls. In supernatants, the collagenolytic activity, as well as IL-1beta and TNF-alpha, levels were all down-regulated in treated cultures (two, three, fourfold, respectively). The addition of collagen-PVP to synovium-induced down-modulation of some inflammatory parameters and an increase in apoptosis of synovial cells. Perhaps this mechanism could contribute to inhibit outgrowth of pannus formation and to down-regulate inflammation of joints in patients with RA.

We have evaluated the production of PRL by human peripheral mononuclear cells (PBMNC) from normal subjects and patients with systemic lupus erythematosus (SLE). Conditioned medium prepared from basal and Con-A-stimulated PBMNC was assessed for the presence of PRL-like by its ability to stimulate growth of PRL-responsive Nb2 rat lymphoma cells. In the presence or absence of Con-A, SLE PBMNC secrete significantly higher (P < 0.001) amounts of bioactive PRL-like species than normal cells. Growth of Nb2 cells by conditioned medium was inhibited with specific antiserum to human PRL. Western blotting using a polyclonal antibody to human PRL revealed a single 60-kDa PRL-like species in both normal and SLE PBMNC extracts, the immunoreactivity of which was preferentially found in SLE subjects. With the use of reverse transcription-PCR an expected 633-bp band was observed, and its similarity to pituitary PRL was further confirmed by Southern blot analysis with human PRL complementary DNA as a probe. We conclude that a high molecular mass PRL-like species is synthesized and secreted by PBMNC, and patients with SLE have an increased secretion of lymphocyte-derived PRL-like material.

We studied the in vitro production of interleukin-2 (IL-2), the expression of IL-2 receptors, the absorption of IL-2, and spontaneously expanded suppressor cell function by mononuclear cells from 15 patients with systemic lupus erythematosus (SLE) and 15 healthy control subjects. These functions were studied in the presence or absence of AS-101, a recently described organotellurium compound with immunoregulatory properties. AS-101 was found to be non-toxic to cells from both patient and control groups; it increased the production of IL-2, elevated the percentage of Tac-positive cells even among cells that had been pre-treated with pronase, and ameliorated the absorption of IL-2. It also enhanced the suppressor cell function in cells from SLE patients. Since these functions are known to be defective in vitro in cells of SLE patients, and since preliminary testing of AS-101 in humans indicates that it is a safe drug, this immunoregulatory compound holds promise for a novel and effective treatment of SLE.

T cells from 18 untreated SLE patients produced significantly more B cell growth factor (BCGF) than did those from normal subjects. Those from SLE patients with active disease produced significantly more than did those from patients with inactive disease. The response to BCGF of SAC-stimulated B lymphocytes from SLE patients was higher than that of B lymphocytes from normal individuals. Similarly preactivated B cells from five of seven SLE patients also proliferated upon the addition of interleukin 1 (IL-1) whereas those of normal subjects did not. Simultaneous addition of IL-1 and BCGF had a synergistic proliferative effect on B cells from two of seven SLE patients but not on any of the controls. Interleukin 2 (IL-2) had no proliferative effect in either SLE or normal B cells. Supernatant fractions from T cells of seven of 10 patients with active SLE and three of 10 with inactive SLE induced more IgG production by CESS cells than did those of normal subjects indicating a higher production of B cell differentiation factor by SLE T cells than by those of controls. Our findings may explain the reported preactivation and predifferentiation of peripheral blood B cells from SLE patients and give insight into the mechanisms leading to the production of autoantibodies in this disease.

Interleukin-1 (IL-1) is a monocyte product with diverse amplifying effects on immune cell reactions. We have studied 16 untreated SLE patients to determine the production of IL-1 by their monocytes under the stimulus of E. Coli lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) and measured by the capacity of their supernatants to augment normal autologous mixed lymphocyte cultures (AMLR) or to replace accessory cells in Con A-induced proliferation of T lymphocytes. Concurrently, we studied the response of T lymphocytes from these same patients to IL-1 by its capacity to increase the percentage of stable E rosette forming cells and by the enhancement of T cell proliferation in AMLR. Monocytes from SLE patients produced significantly less IL-1 activity than those of age matched controls, regardless of the stimulus (LPS or PMA), as well as of the indicator system. All patients with active disease and seven of the 10 patients with inactive disease had decreased production of IL-1 activity as determined by at least one method. Response of T lymphocytes from SLE patients to IL-1 produced by normal monocytes was also found decreased as compared to normals. This defect was more marked in the T cells from patients with active than in those of patients with inactive disease. These findings indicate that the immunoregulatory disturbance that SLE patients have encompasses monocytes as well as T and B lymphocytes and suggest that the defect is either multicentric or originates in the stem cell.

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.

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.

Interleukin-1 (IL-1) is a monocyte derived factor that participates in immune regulation and in the regulation of fibroblast proliferation and collagen deposition. It therefore, seems particularly pertinent to study in scleroderma, a disorder of immune regulation where increased collagen deposition is a hallmark. The production of IL-1 by lipopolysaccharide stimulated monocytes from 18 untreated scleroderma patients was akin to that of their normal matched controls. However, the unstimulated monocytes from six of the 18 scleroderma patients released IL-1 activity spontaneously into their supernatants. All six patients with spontaneous IL-1 release had less than 5 years disease duration. The response to IL-1 by T lymphocytes from patients with scleroderma was low as compared to those from controls. The presence of spontaneous IL-1 production with decreased response to IL-1 in scleroderma may indicate an in vivo pre-activation of monocytes to produce this factor that might have a bearing in the pathogenesis of collagen deposition in scleroderma.