BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjögren's syndrome

OBJECTIVE: Treatment with rituximab depletes B cells from the peripheral blood (PB) and salivary glands (SGs) of patients with primary Sj?gren's syndrome (SS). The purpose of this study was to track the repopulation of B cell subsets in PB as well as their subsequent homing into SGs in patients with primary SS treated with rituximab. METHODS: A series of 4-color flow cytometry experiments delineated B cell subsets in 15 patients with primary SS. All were tested on days 8 and 15 of treatment. Nine of the patients were followed up monthly for 10 months, and the remaining 6 patients were followed up monthly for 24 months. Enzyme-linked immunosorbent assays were developed to measure serum levels of BAFF and rituximab. SGs were biopsied at the start of the study and 4 months after treatment in 15 patients, 12 months after treatment in 3 patients, and 24 months after treatment in 2 patients. RESULTS: Baseline serum levels of BAFF correlated inversely (r = -0.92, P < 5 x 10(-4)) with the duration of B cell depletion: the higher the BAFF levels, the shorter the duration of B cell depletion. Four B cell subsets repopulated the PB: plasmablasts (CD19+, CD5-,IgD-,CD38++), transitional type 1 (T1) B cells (CD19+,CD5+,IgD+,CD38++), mature Bm2 cells (CD19+,CD5+/-,IgD+,CD38+/-), and memory B cells (CD19+,CD5-,IgD-,CD38-). Increased numbers of Bm2 cells and decreased memory B cells reappeared with time. Sequential SG biopsies revealed that B cells were absent in these glands for 12 months: they were detected 24 months after rituximab treatment. Memory and T1 B cells were the first B cells identified locally. CONCLUSION: The timing of B cell repopulation is modulated by BAFF and is followed by reconstitution of the preexisting abnormalities.     

B cell-ablative therapy: where are we now?

Based on their multifaceted functions, B cells participate in several pathological settings such as lymphoproliferative disorders, autoimmune diseases and graft rejection. B cell-ablative therapy has thus emerged as a mainstay in these diseases. A number of anti-B cell antibodies (Abs) have been generated, among which anti-CD20 Abs appear to be efficient. Rituximab (RTX) is one of these anti-CD20 monoclonal Abs. Originally approved for the treatment of non-Hodgkin lymphoma, RTX is now being administered in other malignant proliferations, applied to an increasing number of autoimmune diseases and required to prevent rejection of a graft. Although this medication is remarkably safe, a handful of laboratory tests have been proposed to monitor RTX-treated patients. The efficacy in different diseases, and the emergence of new anti-CD20 Abs raise many questions. Thus, their detailed understanding can lead to a better issue for inhibition of immune responses.     

Non-invasive positive pressure ventilation in acute respiratory failure: providing competent care

Non-invasive positive pressure ventilation (NPPV) has been used as an alternative strategy to provide ventilatory support for patients with acute respiratory failure. Most studies demonstrate that the use of NPPV in acute respiratory failure results in a reduction in the need for endotracheal intubation and an overall survival advantage. However, current evidence, in the form of randomized controlled trials, suggests that these benefits may be restricted to patients suffering from acute exacerbation of chronic obstructive pulmonary disease (COPD).

The clinical application of NPPV involves the development of competence in delivering the particular intervention. Clinical outcomes and thus valid comparisons with alternate methods of ventilatory support can only be made if attention is paid to the clinical indications for the application of NPPV and patient subgroups it is used to treat and the level of competence of care givers in its application and delivery. One essential element of competence is the establishment of an appropriate knowledge base and the development of clinical practice guidelines. This literature review identifies the current indications for NPPV and the relevant information for developing clinical practice guidelines for the management of this form of ventilatory support.     

Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: Is there a link?

The prominent feature of immunological defects in systemic lupus erythematosus (SLE) is the production of autoantibodies (auto-Abs) to nuclear antigens including DNA, histones and RNP. In addition, there is growing evidence that epigenetic changes play a key role in the pathogenesis of SLE. Autoreactive CD4(+) T cells and B cells in patients with SLE have evidence of altered patterns of DNA methylation as well as post-translational modifications of histones and ribonucleoproteins (RNP). A key question that has emerged from these two characteristic features of SLE is whether the two processes are linked. New data provide support for such a link. For example, there is evidence that hypomethylated DNA is immunogenic, that anti-histone auto-Abs in patients with SLE bind epigenetic-sensitive hot spots and that epigenetically-modified RNP-derived peptides can modulate lupus disease. All in all, the available evidence indicates that a better understanding of dysregulation in epigenetics in SLE may offer opportunities to develop new biomarkers and novel therapeutic strategies.     

Epigenetics and Sjögren's syndrome

There is growing evidence that epigenetics, the study of heritable changes in gene expression that do not involve mutations in the DNA itself, may play an essential role in autoimmune diseases (AID). In Sj?gren's syndrome (SS), a chronic AID characterized by an epithelis of the exocrine glands, epigenetic studies have focused on three mechanisms: DNA methylation and its consequences including human endogenous retrovirus (HERV) expression; microRNA expression; and protein post-translational modifications associated with autoantibody production. Although in its infancy, comprehension of the epigenetic (dys)regulation in SS may help us to understand: why SS affects predominantly middle-aged women; why genetically predisposed individuals develop SS but not others; why flare-ups occur; why treatment responses differ between patients; and why some patients develop lymphoma. From these studies will arise a better comprehension of the pathophysiology of SS as well as development of new diagnostic and prognostic biomarkers, and novel therapeutics for prevention and perhaps early intervention.     

TLR9 responses of B cells are repressed by intravenous immunoglobulin through the recruitment of phosphatase

One way for intravenous Ig (IVIg) to affect responses of the B cells might be to operate through their TLR7 and TLR9. We confirm the ability of TLR agonists to induce CD25 expression in B cells. For this to occur, sialylated Fc-gamma of IgG included in the IVIg preparation are required. As a result, IVIg suppresses TLR-induced production of the proinflammatory IL-6, but not that of the anti-inflammatory IL-10. That is, IVIg mimics the effects of the MyD88 inhibitor. Finally, as we previously showed that IVIg induces CD22 to recruit the inhibitory SHP-1, we established that this enzyme was also involved in IVIg-induced inhibition of TLR9 signaling. This is the first report to demonstrate such a mechanism underlying the negative impact of IVIg on B lymphocytes.     

In Sjögren's syndrome, B lymphocytes induce epithelial cells of salivary glands into apoptosis through protein kinase C delta activation

Sj?gren's syndrome (SS) is a chronic autoimmune epithelitis associated with diffuse lymphocytic infiltration that varies in composition and differs according to lesion severity. T lymphocytes have been viewed as competent in their own right in the destruction of epithelial cells, whereas B lymphocytes that predominate in severe lesions have never been implicated in direct tissue damage. Using co-culture experiments with human salivary gland (HSG) cell line cells and tonsilar B lymphocytes, we observed that direct HSG cell-B lymphocyte contacts were able to induce apoptosis in epithelial cells. This B lymphocyte-mediated cell death could not be ascribed to Fas-Fas ligand interactions but required translocation of protein kinase C delta (PKC δ) into the nucleus of epithelial cells. Ultimately, activation of PKCδ resulted in histone H2B phosphorylation on serine 14 and poly (ADP-ribose) polymerase cleavage. Our results suggest that B lymphocytes infiltrating the SGs of patients with SS could evoke epithelial cell apoptosis.     

A case for the graft-versus-host disease as a model for B cell-mediated autoimmunity

Following allogenic hematopoietic stem cell transplantation (HSCT), patients with autoimmune disease or hematopoietic malignancy may develop acute or chronic graft-versus-host (GvH) disease. B lymphocytes, from the recipient as well as from the donor, have recently been implicated in the pathogenesis of such disturbances. Their deleterious effects are accounted for by other tasks B lymphocytes accomplish than the antibody production. We highlight herein some recent observations in the context of B cells in the GvH disease.