Are the B cells cast with the leading part in the Sjogren's syndrome scenario?

The autoimmune exocrinopathy Sjögren's syndrome (SS) is characterized by mononuclear cell (MNC) infiltrates of exocrine glands and overactivity of B lymphocytes. Although T cells have long been perceived as the prime effectors, increasing evidence indicates that the key role is rather served by B cells. Among related abnormalities are rheumatoid factor (RF), anti-SSA/Ro, and anti-SSB/La antibodies (Ab). Also, supporting this view is our finding of an increase in the number of circulating naïve mature B (Bm) cells, with a reciprocal decrease in that of memory B cells. Furthermore, a ratio of Bm2-plus-Bm2' cells to early Bm5-plus-late Bm5 above 5 is diagnostic. This variation partly reflects the migration of active memory B cells into the exocrine glands of the patients, as well as into their skin. More recently, the B-cell-activating factor of the TNF family (BAFF) has been endorsed with a pivotal role in B-cell survival and hence implicated in the pathogenesis of autoimmunity. In practice, B cells have turned quite attractive as a target for biotherapy. For example, treatment with anti-CD20 Ab has afforded some benefits in this disease, while BAFF blockers are still on the way, but should expand our armamentarium for treating SS. With such B-cell-directed biotherapies in mind, we delineate herein the distinguishing traits of B lymphocytes in SS.

Anti-α actinin antibodies as new predictors of response to treatment in autoimmune hepatitis type 1.

BACKGROUND: We reported that combined presence of autoantibodies (Abs) against filamentous-actin (AFA) and α-actinin are specific for autoimmune hepatitis type 1 (AIH-1) diagnosis. AIM: To explore our data and assess whether anti-α-actinin and AFA Abs could be used as indicators of response to treatment and predictors of AIH-1 flares in a large cohort of AIH-1 patients. METHODS: Seven hundred and sixty-four serial serum samples of 86 consecutive AIH-1 patients, 509 pathological and 110 normal controls were tested for the presence of anti-α-actinin and AFA Abs by an in-house IgG-specific ELISA and a standardised commercially available ELISA respectively. Patients sera were divided into baseline group (active disease before treatment initiation, n = 86) and then according to treatment response into group A-responders (n = 40 patients), group B-relapsers/incomplete responders (n = 37 patients) and group C-not-treated (n = 9 patients). RESULTS: Anti-α-actinin and AFA levels were significantly higher at baseline. Double reactivity against α-actinin and AFA was associated with disease activity (OR 4.9; 95% CI: 2.7-9). Anti-α-actinin optical densities (ODs) before treatment decreased significantly at first remission (P < 0.05). Treatment response was associated with anti-α-actinin Abs negativity before treatment (OR 3.4; 95% CI: 1.3-8.9) and absence of double positivity for anti-α-actinin and AFA Abs before treatment (OR 3.8; 95% CI: 1.4-10.4). Responders had lower baseline levels of anti-α-actinin than relapsers and/or incomplete responders (P = 0.002). Binary logistic regression revealed lower levels of anti-α-actinin as the only independent predictors of response (P = 0.05). CONCLUSIONS: Anti-α-actinin Abs at baseline appear to predict treatment response and therefore they might be used for monitoring treatment outcome in AIH-1.

Epigenetic alterations and autoimmune disease.

Recent advances in epigenetics have enhanced our knowledge of how environmental factors (UV radiation, drugs, infections, etc.) contribute to the development of autoimmune diseases (AID) in genetically predisposed individuals. Studies conducted in monozygotic twins discordant for AID and spontaneous autoimmune animal models have highlighted the importance of DNA methylation changes and histone modifications. Alterations in the epigenetic pattern seem to be cell specific, as CD4+ T cells and B cells are dysregulated in systemic lupus erythematosus, synovial fibroblasts in rheumatoid arthritis and cerebral cells in multiple sclerosis. With regard to lymphocytes, the control of tolerance is affected, leading to the development of autoreactive cells. Other epigenetic processes, such as the newly described miRNAs, and post-translational protein modifications may also be suspected. Altogether, a conceptual revolution is in progress, in AID, with potential new therapeutic strategies targeting epigenetic patterns.

Updating the physiology, exploration and disease relevance of complement factor H.

The factor H (FH) protein (also known as beta1H globulin) is the main regulator of the complement alternative pathway. It exhibits multivalent binding sites to the complement component C3b, and polyanions and one binding site to sialic acid and cell surfaces. These multiple binding sites confer to FH a decay-accelerating factor activity in the fluid phase as well as at the cell surface. A defect in FH activity or a FH protein deficiency triggers chronic inflammation and tissue injury, leading to various disorders impacting the kidney or the eye. In contrast, some pathogens, as well as cancer cells, develop various strategies to bind FH and thereby subvert a complement attack. We focus on the functions of FH, and review the main pathological conditions in which FH is involved. Since the pathogenesis is elusive, appropriate FH dosage in biological fluids and FH gene analysis may help in improving understanding of such diseases.

Critical analysis of rituximab-induced serological changes in connective tissue diseases.

A survey of PUBMED and EMBASE supplied 21 articles dealing with the effect of rituximab (RTX) on immunoglobulin (Ig) and autoantibodies (Abs) in nonorgan-systemic autoimmune diseases, and another 12 articles were found by hand search. No statistics could be performed due to the lack of numerical data in the articles. RTX tended to diminish total Ig but still within the normal ranges, more for IgM than IgG and IgA. Rheumatoid factor level decreased by 30 to 60% 3-6 months after RTX, whereas anti-cyclic citrullinated peptide Ab titers declined modestly. In contrast, anti-DNA and anti-C1q Ab levels showed a marked decrease, whereas the other anti-extractable nuclear antigens Ab (anti-SSA, SSB, SM, RNP...) were stable. There are claims for an increase in the BAFF level by approximately 2.5 to 3-fold at 3-4 months, and a return to pre-treatment value at 8-12 months. RTX-induced changes in the serum bring about new insights into mechanisms of action. Therefore, more attention should be paid to such parameters in clinical trials.

Is the blood B-cell subset profile diagnostic for Sjogren syndrome?

OBJECTIVE: To evaluate the relevance of the blood B-cell subset profile for the diagnosis of Sjögren syndrome. METHODS: The distribution of mature blood B cells from Bm1 through Bm5 was determined in 161 patients, of whom 25 fulfilled the American-European Consensus Group criteria for primary SS (pSS), and 136 served as disease controls. RESULTS: The percentage of Bm2 and Bm2' cells was increased in the patients with pSS compared with 54 patients with rheumatoid arthritis (RA) and 18 with systemic lupus erythematosus (SLE) (p<0.001 for the two comparisons). In contrast, those of early Bm5 (eBm5) and Bm5 were decreased in patients with pSS, compared with patients with RA and with SLE (p<0.001 for the two comparisons). The receiver operating characteristic curves allowed for an optimising cut-off value of Bm2+Bm2' cells at 71.1% for 88.0% sensitivity and 83.1% specificity, that of eBm5+Bm5 cells at < or =13.5% for 84.0% sensitivity and 83.1% specificity, and, consequently, that of Bm2+Bm2'/eBm5+Bm5 at > or =5 for 88.0% sensitivity and 84.6% specificity. CONCLUSION: Given its presentation as a signature for pSS, relative to RA and SLE, such a distribution of B-cell subsets might provide a useful diagnostic tool.

[B lymphocytes in Sjögren's syndrome]. / Les lymphocytes B dans le syndrome de Gougerot-Sjögren.

INTRODUCTION: Sjögren's syndrome (SS) is an autoimmune epithelitis hallmarked by a disruption of epithelial cells, the subsequent lymphocytic infiltration of lachrymal and salivary glands (SGs), and their ensuing dryness. One may posit that SS is triggered by viruses, and/or modulated by sex steroid hormones, and there is indeed a consensus that its aetiology is multifactorial, with genetic factors interacting with environmental agents. CURRENT KNOWLEDGE AND KEY POINTS: T-cells have long occupied central stage of the debate on the type of lymphocytes involved in the pathogenesis of SS. The relevance of B cells has, however, been emphasized over the past five years and new insights into their functions revealed. Furthermore, increased levels of the B-cell activating factor (BAFF) may be responsible for quantitative and qualitative anomalies of B-cells found in SS such as emergence of self reactive B-cells. This review reports compelling evidence that B-cells are involved in the pathophysiology of SS. PROSPECTS: Since SS may thus be conceived as a model for B-cell-induced autoimmunity, it is no surprise that B-cell ablative-treatment has proven to be relatively effective in SS.

B-cell: a logical target for treatment of rheumatoid arthritis.

The interest for B-cells in rheumatoid arthritis (RA) is currently being revived. They are involved in the development and activation of lymphoid architecture by regulating dentritic cell and T-cell function through cytokine production. Receptor editing an revising are also essential in B-cells and aid in preventing autoimmunity. Abnormalities in the subset distribution and a default in any task assigned to the B-cells may favor autoimmunity. Beneficied responses to B-cell depletion in RA by anti-CD20 monoclonal antibody rituximab illustrate the importance of B-lymphocytes in the pathogenesis of this disease. A new avenue has thus been opened, whereby B-lymphocytes return as a significant contributor to autoimmune disorders.

BAFF and rheumatic autoimmune disorders: implications for disease management and therapy.

Interest in B-cells has been revived due to the description of new functions. Supporting a role for B-cells in the genesis of autoimmune diseases is the fact that the B-cell activating factor of the TNF ligand family (BAFF) is essential in their physiology. However, in each disease, this is restricted to a subgroup of patients. Based on experiments in mice, and validated in humans, this new cytokine has been highlighted. Excessive production of BAFF alters immune tolerance by rescuing self-binding B-cells. Overexpression in mice leads to autoimmune manifestation, and BAFF levels are elevated in the serum of autoimmune patients. Similar abnormalities occur in chronic lymphocytic leukemia. Recent works suggest that antagonizing the protein (or competing for its receptors) is relevant to the treatment. Advances in our understanding of the BAFF system offers the opportunity to improve our therapeutic approach.

Modulation of autoimmunity by the latest interleukins (with special emphasis on IL-32).

Interleukins (IL) and other cytokines display a number of overlapping abilities to stimulate cells of various lineages and differentiation stages. Most notably, IL-1, tumor necrosis factor (TNF)-alpha, IL-6, IL-15, IL-17, IL-18, IL-21, IL-25, IL-25, IL-31 and IL-32 contribute in concert to pathophysiological events. These include cell death, inflammation, allergy and autoimmunity. Up-regulation of either T helper (TH)1 or TH2 cells is pathogenic, and these subsets downregulate each other. The expression of chemokines/cytokines by endothelial cells is also crucial to autoimmunity by trafficking inflammatory T cells into the central-nervous system. IL-32 (previously termed NK transcript 4), is the newest inflammatory cytokine produced by mitogen-activated lymphocytes, interferon-gamma activated epithelial cells and IL-12, IL-18 and IL-32-activated NK cells. This induces TNF-alpha, IL-1beta, IL-6 and 2 C-X-C chemokine family members involved in several autoimmune diseases. In addition, IL-32 activates arachidonic acid metabolism in peripheral blood mononuclear cells by stimulating the release of prostaglandins. Discovery of this supplementary inflammatory cytokine further complicates the network of inflammation.

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.