Identification of regulatory T cell molecules associated with severity of multiple sclerosis.

BACKGROUND: Regulatory CD4+ T cells (Tregs) exhibit functional alterations in patients with multiple sclerosis (MS). Transforming growth factor (TGF)-ß is a key regulator of Treg development and function. OBJECTIVE: The objective of this study is to determine whether the expression of functionally relevant TGF-ß-regulated molecules is altered in Tregs from patients with MS. METHODS: Expression of nine Treg markers was analyzed by multi-color flow cytometry in CD4+ T cells and Treg subpopulations of 31 untreated MS patients and age- and sex-matched healthy donors (HDs). Correlations between Treg marker expression and clinical variables were sought. RESULTS: Expression of the transcription factor Helios, which defines thymic-derived Tregs, was decreased in this Treg subpopulation. The frequency of peripherally generated Tregs was increased in patients with MS, particularly in patients with progressive MS. Low frequencies of thymic-derived Tregs were associated with magnetic resonance imaging (MRI) lesion-burden and a high relapse rate. Four surface markers associated with TGF-ß signaling (ABCA1, BTLA, DNAM-1, and GARP) were differentially expressed on Tregs from patients with MS and HDs. Expression levels of CD73, CD103, ABCA1, and PAR2 showed strong correlations with disease severity. CONCLUSION: We have identified novel markers abnormally expressed on Tregs from patients with MS that could detect patients with severe disease.

Intrathecal formation of anticardiolipin antibodies in a patient with SLE-related relapsing longitudinal myelitis: a possible pathogenic connection.

BACKGROUND: Nontraumatic acute transverse myelitis (ATM) can occur in response to infectious, inflammatory and vascular triggers; 1% of patients with systemic lupus erythematosus (SLE) develop ATM, but the mechanism remains unknown. OBJECTIVE: The objective of this case report is to describe a case of intrathecal formation of anticardiolipin antibodies (aCL) during SLE-related ATM. METHODS: A single patient analysis was conducted. RESULTS: A 26-year-old housewife was diagnosed with SLE at age 19. Circulating aCL antibodies were positive at diagnosis. At age 21, she developed an episode of severe sepsis. At 23 years of age she developed an episode of ATM that left her paraplegic with a D10 sensory level, from which she recovered partially. Three years later, she developed a clinical relapse of ATM. During that second episode, serum levels of aCL were within normal limits, while cerebrospinal fluid levels were increased, suggesting intrathecal production of aCL. CONCLUSION: Here, we present a case of a woman who developed relapsing SLE-related longitudinally extensive ATM in whom intrathecal formation of aCL was demonstrated, suggesting that local production and cross-recognition of nervous tissue by those autoantibodies may be myelopathic.

Quantitative and functional profiles of CD4+ lymphocyte subsets in systemic lupus erythematosus patients with lymphopenia.

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.

IL-17-producing T cells in lupus nephritis.

Significant evidence implicates interleukin-17 (IL-17) in the pathogenesis of systemic lupus erythematosus (SLE), particularly in the development of tissue damage. IL-17 production and IL-17-producing CD4+ and CD3 + CD4-CD8- cells are increased in patients with SLE. IL-17-producing cells are present in the inflamed kidney tissues from patients with lupus nephritis. In lupus-prone mice, IL-17 production appears to be involved in the expression of disease pathology and pharmacologic or genetic manipulation of its production results in suppression of the disease. It becomes obvious that the use of biologics including humanized anti-IL-17 antibodies or decoy IL-17 receptors deserve clinical consideration. Similarly, the development of drugs that suppress the production of IL-17 is in order.

Interleukin-17 and systemic lupus erythematosus: current concepts.

The emerging role of interleukin (IL)-17 as a hallmark proinflammatory cytokine of the adaptive immune system, produced primarily by a new T helper cell subset termed 'Th17', has received considerable attention. Differentiation of Th17 cells is driven by the simultaneous presence of transforming growth factor-beta and certain inflammatory cytokines (e.g. IL-6, IL-21), and recent studies have shown that inflammation instigated by IL-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. In this review, we focus on the information regarding IL-17 and systemic lupus erythematosus (SLE), a chronic autoimmune disease. The work that has explored the development and behaviour of IL-17-producing cells in SLE is discussed, and different mechanisms by which IL-17 could potentially augment inflammation and autoantibody production in the context of SLE are proposed.

Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance.

Previous reports have suggested that regulatory T cells (Treg) are abnormal in patients with systemic lupus erythematosus (SLE). In the present work, we quantified CD4+FOXP3+ Treg cells in patients with SLE and found no quantitative alterations. However, we found a clear defect in suppression assays. Surprisingly, SLE-derived Treg cells exhibited a normal phenotype and functional capacity. Conversely, SLE-derived CD4+CD25(-) effector T cells resisted suppression by autologous and allogeneic regulatory cells. Our findings strongly suggest that the defect in T-cell suppression observed in SLE is because of effector cell resistance and not because of an abnormal regulatory function.

Moderate and severe neutropenia in patients with systemic lupus erythematosus.

OBJECTIVES: Neutropenia is an uncommon albeit relevant finding in patients with systemic lupus erythematosus (SLE). It has been ascribed to several aetiologies and represents a challenging dilemma in which clinical findings, laboratory data and medication history must be carefully evaluated. The aim of this work was to review the cases of moderate and severe neutropenia in our cohort of SLE patients in order to identify predisposing factors, clinical outcomes and related prognostic implications. METHODS: Thirty-three cases of neutropenia (neutrophil count <1000/microl) in patients with SLE were included. Sixty-five age- and sex-matched patients with SLE served as controls. Information was obtained by medical chart review. Statistical analyses included descriptive statistics, Student's t-test, paired t-test, chi 2 or Fisher's exact test, and logistic regression. RESULTS: Baseline characteristics did not differ between groups. Use of concomitant medications and immunosuppressive drugs, as well as history of thrombocytopenia and central nervous system involvement, were associated with an increased risk for developing neutropenia. Along with neutropenia, cases had lower haemoglobin and platelet values and higher levels of liver enzymes. Moreover, disease activity was lower than in controls. One month after the neutropenia event, leucocyte and total granulocyte counts were still lower in patients than in controls. Mortality did not differ between patients with neutropenia and controls. CONCLUSIONS: Most episodes of severe granulocytopenia in SLE patients occur as part of drug toxicity-induced medullar hypoplasia.

Interleukin-2 and systemic lupus erythematosus--fifteen years later.

Systemic lupus erythematosus (SLE) is a highly heterogeneous disorder in which multiple immunologic abnormalities have been described. In this review, we thoroughly analyse the impaired T cell production of, and response to, interleukin-2 (IL-2) characteristic of patients with SLE. Since it was first reported, several articles have provided us with enlightening, but somewhat confusing, data that reveal the complexity of the subject. The IL-2 production by T cells is part of a complex network in which a discrete alteration is capable of disrupting the whole system. On the other hand, regulatory mechanisms exist that, in an attempt to compensate the primary alteration, provoke secondary defects. Evidence indicates that this defect is not intrinsic, but rather, results from multiple microenvironmental influences that act on the T cell and modify its activation state and its cytokine production. Abnormalities in co-stimulatory mechanisms and in cytokines that may be related to the IL-2 production deficiency, have been described in patients with SLE. We also consider the information derived from murine SLE models, IL-2 knockout models and reports concerning the immune dysregulation present in patients with SLE.

Participation of the CD69 antigen in the T-cell activation process of patients with systemic lupus erythematosus.

Accumulating evidence has implicated T cells in the pathogenesis of systemic lupus erythematosus (SLE). The CD69 antigen is an integral membrane protein rapidly induced on the surface of activated lymphocytes. We obtained CD4+ and CD8+ T cells from normal subjects and patients with SLE. The percentage of CD69 expression in freshly isolated cells and after in-vitro incubation with mitogens was quantified by three-colour immunofluorescent staining. Expression of this protein was increased in both CD4+ and CD8+ T-cell subsets from SLE patients when compared with normal cells, although the difference was significant only in the CD8+ T-cell subset (P = 0.05). Cellular activation increased CD69 expression. When stimulated with anti-CD2/CD2R or phytohaemagglutinin (PHA), the percentage and absolute numbers of CD69+ cells were lower in patients than in controls. Addition of anti-interleukin (IL)-10 monoclonal antibody (MoAb) increased the percentage of in-vitro CD69 expression in SLE cells. These results suggest that the peripheral blood lymphocytes from patients with SLE have an intrinsic defect that alters their activation process, including the expression of CD69, and might explain some of the T immunoregulatory abnormalities observed in these patients.

Immunoregulatory defects in patients with systemic lupus erythematosus in clinical remission.

Little is known about the immune system of patients with systemic lupus erythematosus (SLE) during periods of silent disease. To address this issue we analysed lymphoid populations andcytokine production of mononuclear cells obtained from SLE patients in remission. We studied 43 patients with inactive disease, 10 with active disease and 30 controls. Remission was defined as at least 1 year during which lack of clinical disease activity permitted withdrawal of all treatment. Remission length ranged from 1 to 30 years. Flow cytometry and ELISA were used to study lymphoid populations (CD4, CD8 and CD19) and cytokine production (IL-2, 4, 10, 12 and 18). Patients with short remission periods (up to 15 years) exhibited an increased percentage of B cells; production of IL-2, IL-10 and IL-12 was decreased; production of IL-18 was increased. Interestingly, patients from groups with long time of inactive disease had corrected most alterations, but had an impaired IL-18 expression. IL-12 production correlated strongly with the length of the remission period (r = 0.7565). The immune system of patients with inactive lupus has partially corrected the disturbances present during disease activity. This is accomplished gradually, sometimes until counter-regulatory alterations are developed. This may allow patients to remain without disease activity.