Ziv Paz

The role of T cells in systemic lupus erythematosus: an update.

Purpose of reviewTo describe our current understanding of the role of T cells in the pathophysiology of systemic lupus erythematosus (SLE). Recent findingsOver the last few years, the dominant role of T cells in autoimmunity and SLE was established. Genome-wide-association studies led to the discovery of multiple single-nucleotide polymorphisms associated with SLE. Most of these single-nucleotide polymorphisms fall within the noncoding DNA regions of immune response-related genes and few seem to contribute to the observed abnormal T cell function. The field of epigenetics research developed rapidly and provided us with new insights into the observed generalized hypomethylation in SLE T cells, the abnormal histone modifications and the role of RNA interference. Old observations, such as the decreased interleukin-2 production, are better understood with our evolved knowledge of many signal transduction pathways and the way they converge and regulate the transcription of different genes in T cells. Finally, we are now able to identify subpopulations of T cells, such as Th17 and T regulatory cells, and to define their role in SLE. SummaryT cells are key players in SLE, and over the last few years our understanding of their activation, signal transduction and gene regulation has evolved significantly.

New therapeutics in systemic lupus erythematosus.

Purpose of reviewThe purpose of this review is to discuss new therapeutics in systemic lupus erythematosus (SLE). We will concentrate on both approved and unapproved treatments that were published during the last year. Recent findingsEfforts have focused on the optimization of the use of Belimumab and Rituximab using information generated previously in clinical trials and the development of small new drugs inhibitors of the proteasome and immune cell signaling molecules such as Btk, ROCK and CaMK4. We cannot predict which biologics are going to be effective in humans, as many of the biologics that provide significant benefit in preclinical trials and lupus-prone mice have often proved noneffective in clinical trials. We now realize that lupus-prone mice do not represent human SLE. Yet, genetic or treatments studies in mice are valuable and help us to understand the role of immune or biochemical abnormalities identified in patients in a whole organism. Summary2012 was an exciting year for the field of novel therapeutics in SLE and was signified by the effort to target specific signaling pathways with small molecules and biological agents.

Update on the role of Interleukin 17 in rheumatologic autoimmune diseases.

Interleukin 17 is a proinflammatory cytokine produced by CD4+ T cells when in the presence of a distinct set of cytokines and other cells. Preclinical and clinical studies have assigned a role to IL-17 in tissue inflammation and damage in patients with rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus. Antibodies blocking the action of IL-17 have already been approved to treat patients with psoriasis and it is expected that they may also benefit patients with other rheumatic diseases.

C4d Deposits on the Surface of RBCs in Trauma Patients and Interferes With Their Function

Objective:Complement system is activated in patients with trauma. Although complement activation is presumed to contribute to organ damage and constitutional symptoms, little is known about the involved mechanisms. Because complement components may deposit on RBCs, we asked whether complement deposits on the surface of RBC in trauma and whether such deposition alters RBC function. Design:A prospective experimental study. Setting:Research laboratory. Subjects:Blood samples collected from 42 trauma patients and 21 healthy donors. Intervention:None. Measurements and Main Results:RBC and sera were collected from trauma patients and control donors. RBCs from trauma patients (n = 40) were found to display significantly higher amounts of C4d on their surface by flow cytometry compared with RBCs from control (n = 17) (p < 0.01). Increased amounts of iC3b were found in trauma sera (n = 27) (vs 12 controls, p < 0.01) by enzyme-linked immunosorbent assay. Incubation of RBC from universal donors (type O, Rh negative) with trauma sera (n = 10) promoted C4d deposition on their surface (vs six controls, p< 0.05). Complement-decorated RBC (n = 6) displayed limited their deformability (vs six controls, p < 0.05) in two-dimensional microchannel arrays. Incubation of RBC with trauma sera (n = 10) promoted the phosphorylation of band 3, a cytoskeletal protein important for the function of the RBC membrane (vs eight controls, p < 0.05), and also accelerated calcium influx (n = 9) and enhanced nitric oxide production (n = 12) (vs four and eight controls respectively, p < 0.05) in flow cytometry. Conclusions:Our study found the presence of extensive complement activation in trauma patients and presents new evidence in support of the hypothesis that complement activation products deposit on the surface of RBC. Such deposition could limit RBC deformability and promote the production of nitric oxide. Our findings suggest that RBC in trauma patients malfunctions, which may explain organ damage and constitutional symptoms that is not accounted for otherwise by previously known pathophysiologic mechanisms.

Complement fragment C3d is colocalized within the lipid rafts of T cells and promotes cytokine production.

The complement system plays an important role in tissue inflammation and damage in SLE patients. High levels of C3d were detected on the surface of erythrocytes and lymphocytes of SLE patients. The objective of this study was to assess the functional consequences of C3d fragments deposited on the surface membrane of SLE T cells. Methods: 46 SLE patients, 43 patients with other autoimmune diseases (OAD) and 33 healthy individuals (N) were enrolled in this study. T cells were isolated from peripheral blood and flow cytometry studies were conducted to assess the levels of C3d fragments, Ca++ influx responses and cytokine production. Confocal microscopy was used to study co-localized molecules. Student’s t-test was performed to determine statistical significance among study groups. Results: A significant percentage of the SLE T cells were found to be positive for C3d (13.58 ± 3.92%) when compared with normal T cells (4.52 ± 2.92%) (p < 0.0000547) and T cells from patients with other autoimmune diseases (6.31 ± 4.57%) (p < 0.00513). Peak Ca++ influx responses were significantly higher in C3d− SLE T cells compared with C3d+ SLE T cells (p < 0.011). C3d+ T cells produced significantly more IL-2, IFN-gamma, IL-4 and IL-17. In contrast to the increased production of IL-2 by the C3d+ T cells, the overall SLE T cell population produced less IL-2 when compared with T cells from normal individuals or patients with other autoimmune disease. The C3d fragments were found to be localized within the lipid rafts. Conclusion: C3d fragments are localized in the lipid rafts of SLE T cells and contribute to abnormal T cell function by modulating Ca++ influx responses and increased cytokine production.

Nephritic Factor Autoantibodies

“C3 nephritic factor” or C3NeF is an autoantibody that reacts with a neoantigen exposed on the Bb portion of the C3 convertase (C3bBb). C3NeF was first described in patients with membranoproliferative glomerulonephritis (MPGN) and originally was thought to be responsible for the persistent hypocomplementemia seen in MPGN via persistent activation of the alternative pathway of complement. The ability to produce C3NeF is present in everyone from the time of birth, and C3NeF can also be found in the sera of healthy individuals and in other pathological conditions except for MPGN, specifically in acquired lipodystrophy. C3NeF are heterogeneous between and even within individuals, and some assays may detect only subsets of C3NeF. Despite strong disease association with MPGN and its effects on C3 convertase stability, the pathogenic significance of C3NeF is uncertain because C3NeF activity correlates poorly with C3 consumption and disease progression. The detection of C3NeF can be utilized clinically to support the diagnosis of MPGN and acquired lipodystrophy. However, since we lack data about its real sensitivity and specificity and due to its high detection rates in healthy individuals and other medical conditions, positive and negative results should not be over interpreted.

Value of Antimalarial Drugs in the Treatment of Lupus

Abstract Antimalarial agents are now used as the standard of care for the treatment of systemic lupus erythematosus (SLE). The first documented use of antimalarial medications dates back to the sixteenth century. However, it was not until 1951 when Page, extrapolating from the observations he made during the Second World War, demonstrated clear success in treating 18 patients with cutaneous lupus. This was the beginning of a new era. Hydroxychloroquine came on the market in 1955 and, over the course of a few decades. became the cornerstone of SLE treatment.

C4d Deposits on the Surface of Red Blood Cells in Trauma Patients and Interferes with their Function

Objective:Complement system is activated in patients with trauma. Although complement activation is presumed to contribute to organ damage and constitutional symptoms, little is known about the involved mechanisms. Because complement components may deposit on RBCs, we asked whether complement deposits on the surface of RBC in trauma and whether such deposition alters RBC function. Design:A prospective experimental study. Setting:Research laboratory. Subjects:Blood samples collected from 42 trauma patients and 21 healthy donors. Intervention:None. Measurements and Main Results:RBC and sera were collected from trauma patients and control donors. RBCs from trauma patients (n = 40) were found to display significantly higher amounts of C4d on their surface by flow cytometry compared with RBCs from control (n = 17) (p < 0.01). Increased amounts of iC3b were found in trauma sera (n = 27) (vs 12 controls, p < 0.01) by enzyme-linked immunosorbent assay. Incubation of RBC from universal donors (type O, Rh negative) with trauma sera (n = 10) promoted C4d deposition on their surface (vs six controls, p< 0.05). Complement-decorated RBC (n = 6) displayed limited their deformability (vs six controls, p < 0.05) in two-dimensional microchannel arrays. Incubation of RBC with trauma sera (n = 10) promoted the phosphorylation of band 3, a cytoskeletal protein important for the function of the RBC membrane (vs eight controls, p < 0.05), and also accelerated calcium influx (n = 9) and enhanced nitric oxide production (n = 12) (vs four and eight controls respectively, p < 0.05) in flow cytometry. Conclusions:Our study found the presence of extensive complement activation in trauma patients and presents new evidence in support of the hypothesis that complement activation products deposit on the surface of RBC. Such deposition could limit RBC deformability and promote the production of nitric oxide. Our findings suggest that RBC in trauma patients malfunctions, which may explain organ damage and constitutional symptoms that is not accounted for otherwise by previously known pathophysiologic mechanisms.