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Behçet's disease (BD) is a multisystem disease, which shares some features with other diseases belonging to the autoinflammatory disorders panel. Recent studies have postulated that IL-1β/Caspase-1 may play a cardinal role in autoinflammatory diseases. In this study, we aimed to (i) elucidate the mechanism underlying the involvement of xanthine oxidase (XO) and Uric Acid (UA) in BD (ii) study the direct effects of UA and XO inhibitor "Allopurinol" on nitric oxide (NO) and caspase-1-mediated IL-1β release in peripheral blood mononuclear cells (PBMCs) of BD patients. In this context, plasma of BD patients and healthy controls (HC) were used to measure XO activity, UA, advanced oxidized proteins products (AOPP) and NO levels. In Addition, PBMCs of BD patients and HC were treated or not with either UA or Allopurinol. Then we quantified NO and IL-1β levels, and Caspase-1 Activity in the supernatants and lysates of PBMCs, respectively. We showed that plasma levels of XO activity, UA, AOPP and NO are significantly increased in BD patients compared to those of HC. Interestingly, a significant positive correlation between XO and UA was observed in BD patients. Additionally, while UA has markedly increased NO, IL-1β, and Caspase-1 activity levels in PBMCs of BD patients, Allopurinol has exerted an immunomodulatory effect resulting in reduced NO, IL-1β and Caspase-1 levels in PBMCs of BD patients particularly during the active stages. Collectively, our results indicate a potential clinical use of XO as a tool for assessing BD activity, and suggest that the in-vitro immunomodulatory effect of Allopurinol may have a promising therapeutic value in BD management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Primary Sjögren's syndrome (pSS) represents a chronic, systemic autoimmune disorder, characterized by lymphocytic infiltration of exocrine glands, inducing compromised secretory function and tissue destruction. Increasing evidence had revealed that inflammatory mediators, such as nitric oxide (NO) and pro-inflammatory cytokines, are critical in the development and perpetuation of pSS systemic manifestations. In our current study, we aimed to investigate the ex vivo immunomodulatory effect of interferon (IFN)-β on iNOS expression, as well as on pro-inflammatory (tumor necrosis factor (TNF)-α, interleukin (IL)-6) and immunoregulatory (IL-10) cytokine production. Furthermore, we examined potential associations between the influence of IFN-β treatment on NO production, and pSS clinical and serological manifestations., Methods: In 41 pSS patients documented for their clinical and serological features, NO and cytokines levels were measured by the Griess method and enzyme-linked immunosorbent assay, respectively. Inducible nitric oxide synthase expression was analyzed by fluorescence immunostaining assay, using peripheral blood mononuclear cells (PBMCs) isolated from healthy controls and pSS patients., Results: Our results revealed a strong down-modulating effect of IFN-β in the secretion of pro-inflammatory mediators including TNF-α, IL-6, and NO production. Interestingly, IFN-β exerts an increase in IL-10 levels. The most suppressive effect exerted by IFN-β on NO production was importantly reported for patients with neurological manifestation. This immunomodulatory effect of IFN-β on NO production is highly related to the decrease of inducible nitric oxide synthase (iNOS) expression., Conclusion: Our findings highlight a consistent ex vivo inhibitory effect of IFN-β on pro-inflammatory cytokine production and NO pathway in pSS patients. Our data suggest that IFN-β could represent a potential candidate for targeting inflammation during pSS.

Behçet's disease is a multisystem disease. It stands at the crossroad between the autoimmunity and auto-inflammatory disorders. In this study, we sought to address a relationship that might exist between interleukin-1β (IL-1β) and the oxidants/antioxidants markers in Behçet's patients. Behçet's disease patients (n = 78: active stage, n = 28; inactive stage, n = 50) and 41 healthy controls have been included in our study. In this context, we investigated the plasma levels of IL-1β and the nitrosative/oxidative markers: nitric oxide (NO), advanced oxidative protein products (AOPP) and fatty acids peroxidation-malondialdehyde (MDA). The antioxidant system was assessed by measuring the plasma level of superoxide dismutase (SOD) activity. The Mann-Whitney's U and Pearson's correlation tests were used for statistical analyses. Our case-control study showed that patients in active stage displayed higher plasma levels of IL-1β, NO, AOPP and MDA versus healthy controls and patients in inactive stage. Patients in active stage showed significantly lower SOD levels related to patients in inactive stage and healthy controls respectively, whereas patients in inactive stage showed statistically insignificant SOD level versus healthy controls. Correlation studies showed a significant positive correlation between IL-1β and AOPP, IL-1β and NO, and negative correlation between IL-1β and SOD among Behçet's disease patients. In addition, we showed positive correlation between AOPP and NO, AOPP and MDA and negative correlation between NO and SOD, AOPP and SOD in Behçet's disease patients. Interestingly, our study revealed that IL-1β levels increased and correlated with an imbalance of oxidants/antioxidants system, especially during active stage of Behçet disease. Collectively, our study indicates a possible link between IL-1β production and nitrosative/oxidative markers during Behçet's disease. Exploiting this relationship might provide valuable outputs in the follow-up and prognosis of Behçet's disease with a potential therapeutic value.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder with a complex pathophysiology primarily affecting exocrine glands, leading to compromised secretory function. Recent studies imply that many inflammatory mediators, such as pro-inflammatory cytokines and nitric oxide, are critical in the development and perpetuation of pSS systemic manifestations. In the current study, we aimed to investigate the ex vivo immunomodulatory effect of cardamonin (C 16 H 14 O 4 ), on pro-inflammatory cytokines, TNF-α, IL-6 and inducible nitric oxide synthase (iNOS) expression during pSS. For this purpose, peripheral blood mononuclear cells isolated from pSS patients and healthy controls were cultured with different concentrations of cardamonin. Cytokine levels were measured by ELISA and NO production was assessed using the Griess method. Inducible nitric oxide synthase expression and NF-κB activity were analyzed by immunofluorescence staining. Our results suggest that cardamonin inhibits TNF-α, IL-6 and NO production and downregulates iNOS expression and NF-κB activation. Collectively, our results highlight the ex vivo immunomodulatory effects of cardamonin on pro-inflammatory cytokine production and NO pathway in pSS patients. Therefore, cardamonin is a potential candidate for controlling inflammation during pSS.

CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia (CLL). Important functional properties are associated with CD5 expression in B cells, including signal transducer and activator of transcription 3 activation, IL-10 production and the promotion of B-lymphocyte survival and transformation. However, the pathway(s) by which CD5 influences the biology of B cells and its dependence on B-cell receptor (BCR) co-signaling remain unknown. In this study, we show that CD5 expression activates a number of important signaling pathways, including Erk1/2, leading to IL-10 production through a novel pathway independent of BCR engagement. This pathway is dependent on extracellular calcium (Ca 2+ ) entry facilitated by upregulation of the transient receptor potential channel 1 (TRPC1) protein. We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression. In this subgroup of CLL patients, small inhibitory RNA (siRNA) for CD5 reduces TRPC1 expression. Furthermore, siRNAs for CD5 or for TRPC1 inhibit IL-10 production. These findings provide new insights into the role of CD5 in B-cell biology in health and disease and could pave the way for new treatment strategies for patients with B-CLL.

Background: Follicular helper T (T FH ) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of T FH cell-dependent humoral immune responses is unknown., Objective: We sought to assess the role of Breg cells on T FH cell development and function., Methods: Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate T FH cells. They were cocultured with B cells to induce their terminal differentiation. Breg cells were included in these cultures, and their effects were evaluated by using flow cytometry and ELISA., Results: B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing T FH cell maturation. In cocultures they differentiated B cells into CD138 + plasma and IgD - CD27 + memory cells and triggered immunoglobulin secretions. Breg cells obtained by Toll-like receptor 9 and CD40 activation of B cells prevented T FH cell development. Added to T FH cell and B-cell cocultures, they inhibited B-cell differentiation, impeded immunoglobulin secretions, and expanded Foxp3 + CXCR5 + PD-1 + follicular regulatory T cells. Breg cells modulated IL-21 receptor expressions on T FH cells and B cells, and their suppressive activities involved CD40, CD80, CD86, and intercellular adhesion molecule interactions and required production of IL-10 and TGF-β., Conclusion: Human Breg cells control T FH cell maturation, expand follicular regulatory T cells, and inhibit the T FH cell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the T FH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Sjögren's syndrome (SS) is an autoimmune epithelitis characterized by mononuclear cell (MNC) infiltration of the lacrimal and salivary glands (SG), as well as the presence of serum autoantibodies. This condition is a growing public health concern in Algeria. Herein, we sought to determine if the levels of interleukin (IL)-6, IL-17A, and nitric oxide (NO), were correlated with the extent of MNC infiltration. The expression of inducible NO synthase (NOS2) and CD68 was measured in the SG of all patients, but not in those of the normal controls (NCs). We included 44 primary Sjögren's syndrome (pSS) patients and 15 NCs in this study; we found that the expression of NOS2 and CD68 was elevated in all of the SG of SS patients. Additionally, the serum and saliva levels of IL-6, IL-17A, and NO were higher in the pSS patients, compared with the NCs. Furthermore, the NOS2-induced excess NO was associated with the extent of the MNC infiltration, and thereby with tissue injury. It is also important to note that there were correlations between the levels of IL-6, IL-17A, and NO. Such findings indicate that through the effects of NO, IL-17A participates in the pathophysiology of the disease. With the purpose of improving both the diagnosis and prognosis, IL-6, IL-17A, and NO should be assayed in the serum and saliva of patients suspected of SS., (© The Author(s) 2016.)

Anti-membrane autoantibodies (MbA) have been reported in sera from patients with lupus nephritis (LN) but the targets of the MbA remain to be explored, which is the aim of the current study. Sera were collected from 40 patients with LN determined by renal biopsy, and from 30 systemic lupus erythematosus (SLE) patients without clinical evidence of LN. Thirty autoimmune disease control patients (rheumatoid arthritis, Sjögren's syndrome and systemic sclerosis), and 30 healthy controls were also included. Using flow cytometry, the presence of anti-MbA was explored revealing that IgG anti-MbA positivity was associated with LN (62.5% vs 13.3%) when compared to non-LN SLE patients, autoimmune disease patients (6.7%) and healthy controls (0%). Next, using purified plasma membrane fractions from human embryonic kidney (HEK) cells, the more prominent targets and their occurrence rates were located at 50 kDa, 60/65 kDa, 90 kDa, 110 kDa, 180 kDa and 220 kDa. Alpha-actinin (110 kDa) autoAb was characterized as a major target in LN patients positive for anti-MbA, and anti-MbA binding activity was reduced (36.9 ± 13.7%) in the presence of α-actinin. Laminin (200 kDa) was also characterized as a minor target, which was not the case for annexin A2 (36 kDa). Finally, anti-MbA IgG subclass analysis indicated a predominance of IgG2. In conclusion, IgG anti-MbA were detected at high levels in LN patients supporting a primary pathogenic role for anti-MbA and anti-MbA/α-actinin+ in LN that needs further research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim and Methods. In this study, we evaluated NOS and arginase activities and their regulation during Behçet disease, a systemic chronic inflammatory disorder with uncertain etiology. The peripheral blood mononuclear cells of 36 patients and 15 control samples (PBMC) were cultured in either RPMI 1640, MEM, or DMEM complemented with 10% of FBS and antibiotics. Cultures were performed with or without the control or patients plasma. Subsequent treatment contained anticytokines (IL-6, TGF-β), a mitogenic effector (PHA), or NOS modulators (L-NMMA, BH4). Culture supernatants were harvested after 24 h of incubation. NO and urea measurements were, respectively, performed by modified Griess and Berthelot methods. Results. Higher urea levels were found in patients' plasma compared to the control's (P < 0.05). NOS modulators induced inverted production profiles for NO and urea (P < 0.05). Their results differed depending on the clinical findings (P < 0.05). It was also found that cytokine neutralization induced different response profiles in patients as opposed to control cultures (P < 0.05). Conclusion. Our results suggest that arginases can compete with NOS2 for L-arginine during Behçet disease. Both enzymes are regulated by environmental cytokines and substrate availability. Furthermore, it seems that NOS/arginase balance is dependent on clinical expression.

Systemic lupus erythematosus (SLE) disease is an autoimmune disease of unknown aetiology that affects predominantly women of child bearing age. Since previous studies, including ours, have demonstrated that CD4+ T cells and B cells from SLE patients are defective in their ability to methylate their DNA upon antigen stimulation, the aim of this study was to investigate whether DNA demethylation affects the transcription of HRES-1 in B cells. HRES-1 is the prototype of Human Endogenous Retrovirus (HERV) overexpressed in SLE. We have observed that SLE B cells were characterized by their incapacity to methylate the HRES-1 promoter, both in unstimulated and in anti-IgM stimulated B cells. In turn, HRES-1/p28 expression was increased in SLE B cells after B cell receptor engagement, but not in controls. In SLE B cells the Erk/DNMT1 pathway was defective. In addition, blocking the autocrine-loop of IL-6 in SLE B cells with an anti-IL-6 receptor monoclonal antibody restores DNA methylation and control of HRES-1/p28 expression became effective. As a consequence, a better understanding of HERV dysregulation in SLE reinforces our comprehension of the disease and opens new therapeutic perspectives.

Although B cell activating factor (BAFF) and its receptor BR3 are produced and expressed by many cells, their role has been restricted to the lymphocyte lineage. Using various techniques (RT-PCR, indirect immunofluorescence, flow cytometry analysis), we observed the expression of BR3 and the production of BAFF by the human salivary gland cell line, by epithelial cells from biopsies of Sjögren's syndrome patients and their controls, but also by salivary gland epithelial cells in culture. To decipher the role of BAFF and BR3 on epithelial cells, BAFF and BR3 were neutralized by blocking antibodies or RNA specific inhibitor (siBR3) and epithelial cell survival was analyzed. Blocking BR3 promotes epithelial cell apoptosis in vitro. This apoptosis resulted in the nuclear translocation of PKCδ. BAFF neutralization by various anti-BAFF antibodies leads to different effects depending on the antibody used suggesting that only some forms of BAFF are required for epithelial cell survival. Our study demonstrates that BR3 is involved in the survival of cultured epithelial cells due to an autocrine effect of BAFF. It also suggests that epithelial cells produce different forms of BAFF and that only some of them are responsible for this effect., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Toll-like receptors (TLRs) are positioned at the interface between innate and adaptive immunity. Unlike others, those such as TLR9, that recognize nucleic acids, are confined to the endosomal compartment and are scarce on the cell surface. Here, we present evidence for TLR9 expression on the plasma membrane of B cells. In contrast to endosomal TLR9, cell surface TLR9 does not bind CpG-B oligodeoxynucleotides. After B cell-receptor (BCR) stimulation, TLR9 was translocated into lipid rafts with the BCR, suggesting that it could serve as a co-receptor for BCR. Nevertheless, stimulation of B cells with anti-TLR9 antibodies did not modify the BCR-induced responses despite up-regulation of tyrosine phosphorylation of proteins. However, CpG-B activation of B cells, acting synergistically with BCR signals, was inhibited by anti-TLR9 stimulation. Induction of CD25 expression and proliferation of B cells were thus down-regulated by the engagement of cell surface TLR9. Overall, our results indicate that TLR9 expressed on the plasma membrane of B cells might be a negative regulator of endosomal TLR9, and could provide a novel control by which activation of autoreactive B cells is restrained., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Autoimmune neutropenia denotes that the number of circulating polymorphonuclear neutrophils is below 1.5×10(9)/L. This encompasses a wide range of disorders from primary conditions to complications of systemic autoimmune diseases or hematological neoplasms. Antineutrophil autoantibodies are particularly difficult to detect, and their amount does not correlate with the degree of neutropenia. Granulocyte colony-stimulating factor is the first-line therapy, but should be restricted to patients with total absence of neutrophils and/or severe infections., (Copyright © 2014. Published by Elsevier B.V.)

Background: Chronic inflammatory and autoimmune diseases are largely due to inappropriate response of hyperactive or autoreactive B cells. These autoreactive B cells can evade central tolerance checkpoints and migrate to the periphery, where they would be silenced by anergy. Such anergic cells are characterized by B-cell receptor (BCR) desensitization and altered downstream signaling., Objective: We sought to determine whether intravenous immunoglobulin (IVIg) induces a nonresponsive state of B cells and to address the similarities of this mechanism to those described in anergy., Methods: Human B cells were stimulated with anti-IgM antibody, and effects of IVIg on several parameters, such as calcium release, tyrosine phosphorylation, BCR aggregation, BCR internalization, or transcriptional activity, were studied by using flow cytometry, confocal microscopy, Western blotting, and a quantitative PCR array., Results: IVIg-treated B cells show defects in activating coreceptor expression, calcium signaling, and BCR aggregation on engagement by antigen. IVIg also induces suppression of phosphoinositide 3-kinase signaling, which plays a central role in determining B-cell fate. All these events ultimately lead to profound modifications in gene expression, resulting in long-term functional but reversible silencing of IVIg-treated B cells., Conclusion: Our findings provide insights into the effectiveness of IVIg in treating autoimmune or inflammatory pathologies associated with the loss of B-cell tolerance. Furthermore, these data provide a model to explore the complexity of positive versus negative selection in B cells., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Mechanims of peripheral tolerance include molecular controls and the presence of regulatory lymphocytes. Regulatory T lymphocytes (Tregs) correspond to different sub-populations of T cells that control immune responses due to the production of cytokines, such as IL-10 and with direct cell-to-cell contacts. Tregs targets are antigen presenting cells, such as dendritic cells, effector CD4(+) and CD8(+) lymphocytes but also effector antibody-producing B lymphocytes. Regulatory B lymphocytes (Bregs) have been more recently described and likely represent different sub-populations of B cells that control the development of autoimmune and inflammatory diseases due to the production of IL-10 and using intercellular contacts. Bregs targets encompass all the cells involved in the immune responses which are thus under a dual control by regulatory lymphocytes. Development and efficient activity of Tregs appear dependent of Bregs for a better regulation of autoimmune reactions, of anti-infectious reactions, but also of anti-tumor reactions., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Objective: Patients with primary Sjögren's syndrome (SS) are at greater risk of developing lymphoma. This study was undertaken to evaluate whether the Fms-like tyrosine kinase 3 ligand (Flt-3L) might be associated with lymphoma in primary SS., Methods: Serum levels of Flt-3L were measured in 369 patients with primary SS from the French Assessment of Systemic Signs and Evolution of Sjögren's Syndrome study cohort and in 10 patients with primary SS at the time of lymphoma diagnosis in an Italian cohort. Associations between increased levels of Flt-3L and a history of lymphoma, history of previously diagnosed criteria related to a high risk of lymphoma, and greater extent of disease activity were evaluated., Results: Among patients with primary SS, higher levels of Flt-3L were significantly associated with a history of lymphoma (P = 0.0001). Previous markers for risk of lymphoma development, such as presence of purpura, low levels of C4, presence of lymphocytopenia, low levels of IgM, high levels of β2 -microglobulin, and a higher primary SS disease activity score, were all associated with higher levels of Flt-3L. The levels of Flt-3L were also increased in serum obtained from patients with primary SS at the time of lymphoma diagnosis. Furthermore, the Flt-3L levels were elevated in the serum of 6 patients up to 94 months (mean 46 months) prior to the diagnosis of lymphoma. Receiver operating characteristic curve analysis showed that an Flt-3L level of 175 pg/ml was the ideal cutoff value for demonstrating an association with lymphoma (specificity 97.5%, sensitivity 44%, negative predictive value 97%)., Conclusion: Flt-3L is associated with lymphoma in primary SS, and constitutes a good biologic marker. Higher levels of this cytokine are present several years before the diagnosis of lymphoma, and may be useful as a predictive marker of lymphoproliferative disorders in primary SS., (Copyright © 2013 by the American College of Rheumatology.)

The Sjögren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltration of the glands responsible for mouth and eyes dryness. A minority of infiltrating B cells is organized as germinal centers while the majority is aggregated into clusters of transitional and marginal zone B cells. The Toll-like receptor 9 (TLR9) recognizes microbial DNA but also, sometimes, the self DNA. It appears to be a key determinant of the survival and differentiation of B lymphocytes. After laser micro-dissection of B cells from salivary glands, analyses by quantitative RT-PCR showed that transitional B cells express high level of TLR9 mRNA unlike B cells from germinal centers. B lymphocytes from healthy donors were sorted by flow cytometry and stimulated in vitro with their TLR9. It induces survival, activation and proliferation associated with phenotypic changes. Transitional B cells exhibited characteristics of the marginal zone, whereas mature B cells expressed follicular germinal center specificities. Finally, IgM and IgG were secreted by both population, but with elevated production of autoantibodies by the transitional B cells. Increased expression of TLR9 by transitional B cells suggests that they may be highly sensitive to differentiate into autoantibody secreting cells through maturation into the marginal zone into the salivary glands. TLR9 might be a target for forthcoming biotherapies.

Objective: To determine the accuracy of salivary gland ultrasonography (SGUS) for diagnosing primary Sjögren's syndrome (SS) and to suggest modifications of the American-European Consensus Group (AECG) classification criteria., Methods: We conducted a cross-sectional study in a prospective cohort of patients with suspected primary SS that was established between 2006 and 2011. The echostructure of the bilateral parotid and submandibular glands was graded from 0 to 4, and the gland size was measured; blood flow to the parotid gland was assessed using Doppler waveform analysis. The reference standard was a clinical diagnosis of primary SS as determined by a group of experts blinded to the results of SGUS. Receiver operating characteristic (ROC) curve analysis was performed to compare the diagnostic value of the 0-4-point echostructure grade for each of the 4 major salivary glands, the sum of the grades for the 4 glands, and the highest grade among the 4 glands., Results: Of the 158 patients in the study, 78 had a diagnosis of primary SS according to the experts, including 61 patients (78.2%) who met the AECG criteria. Doppler waveform analysis and gland size measurement showed poor diagnostic performance. The results of ROC curve analysis showed that the highest grade among the 4 glands provided the best diagnostic value. The optimal grade cutoff was 2 (62.8% sensitivity and 95.0% specificity). A weighted score was constructed using scores for the 5 variables selected by logistic regression analysis, as follows: (salivary flow×1.5)+(Schirmer's test×1.5)+(salivary gland biopsy×3)+(SSA/SSB×4.5)+(SGUS×2). According to ROC curve analysis, a score of ≥5 of 12.5 had 85.7% sensitivity and 94.9% specificity, compared with 77.9% sensitivity and 98.7% specificity for the AECG criteria. The addition of SGUS to the AECG criteria increased sensitivity to 87.0% but did not change specificity., Conclusion: Modifications of the AECG criteria, including the addition of a SGUS score, notably improved diagnostic performance., (Copyright © 2013 by the American College of Rheumatology.)

Regulatory B cells (Bregs) may act earlier than regulatory T cells (Tregs) and may play as important a role in autoimmune and allergic diseases. Obstacles to the investigation of Bregs are the same as those encountered for Tregs: the regulatory effects are short-lived in some cases, there is no consistent phenotype (C5 expression is neither indispensable nor sufficient), differences exist across species (e.g., between humans and mice), and there are a number of suppression modalities (IL-10, TGF-beta, expression of proapoptotic membrane molecules) that vary across Breg subtypes. The Breg subtypes may be homologous to the Treg subtypes (Br1 cells expressing IL-10, Br3 cells expressing TGF-beta, and B-Foxp3 cells), although the Br1 subtype seems to predominate. Nevertheless, differences with Treg cells may exist: Breg activation may chiefly involve the toll-like receptors rather than the antigen receptor; and Bregs act earlier, facilitating the recruitment of Tregs then disappearing once the Tregs become operational. Bregs make a major contribution to autoimmune disorders associated with several forms of immune deficiency, as well as to the absence of transplant rejection when there is a strong B cell response. Breg deficiencies have been reported in lupus, and the disappointing effects in this disease of treatments designed to inhibit the B cell response may be related to further Breg impairment. In several animal models, Breg stimulation is effective in correcting a variety of autoimmune disorders, most notably those initiated in the mucous membranes. Research into the interactions between the gut microbiota and Bregs holds considerable promise., (Copyright © 2012 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Background: Currently not much is known regarding the environmental factors involved in primary biliary cirrhosis (PBC). It is even more unclear which factors may determine the subgroup (i.e., AMA status) of patients with PBC. We thus tested AMA+and AMA- PBC patients' sera for antibodies (Abs) against multiple infectious agents., Methods: Sera from 69 patients with PBC (49 AMA+and 20 AMA-) and 100 matched controls were screened for IgG-Abs against Toxoplasma gondii, Helicobacter pylori, Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B, and hepatitis C utilizing the BioPlex 2200 and ELISA kits (Bio-Rad Laboratories, USA)., Results: The prevalence of four anti-infectious agents Abs was significantly elevated among PBC patients when compared with controls, namely anti-T. gondii (ATxA; 71% vs. 40%, p<0.0001), EBV early antigen (EA; 44% vs. 12%, p<0.0001), H. pylori (54% vs. 31%, p<0.01), and CMV (90% vs. 75%, p<0.05) Abs, respectively. The co-occurrence of these four anti-infectious agents Abs was highly common in PBC, whereas this infection burden was rare in healthy subjects (20% vs. 3% respectively, p<0.0001). Furthermore, specific infections interactions possibly increasing PBC risk were noted as well. Seropositivity of ATxA was inversely associated with cirrhosis among PBC patients (p<0.05). Finally, no differences were observed between AMA- sera and their AMA+counterparts with regard to seroprevalence of any of the investigated infectious agents., Conclusions: We note the association of ATxA and PBC, with the possibility of a milder disease manifestation. We also suggest that multiple exposures to infectious agents may contribute to PBC risk., (Copyright © 2012 Elsevier Inc. All rights reserved.)

CD5(+) B lymphocytes have distinct functional properties compared with B lymphocytes that lack CD5. However, it remains unclear if and how the CD5 molecule modulates B lymphocyte biology and responses. Our recent studies have revealed that CD5 promotes constitutive activation of multiple signaling pathways including extracellular signal-regulated kinases (ERK1/2), phosphatidylinositol 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) and calcineurin-NFAT signaling pathways. Further, changes in cytokine production including the production of IL-10 are related to the activation of the transcription factors NFAT2 and STAT3. All in all, these studies provide a framework for understanding how CD5 impacts B lymphocyte biology and responses., (Copyright © 2012. Published by Elsevier B.V.)

Maturation of B cells depends on environmental stimuli. Peripheral immature B cells develop into follicular pathway when antigenic stimulation is combined with T cell signals. Here, we wished to identify stimuli contributing to the development into marginal zone B cells known to be involved in autoimmune response. We found that TLR9 stimulation of transitional B cells induces proliferation and specific maturation into CD24(-) CD38(+) CD21(high) CD23(low) IgM(high) IgD(low) and Notch2(high) B cells characteristics of marginal zone B cells. Terminal differentiation into antibody-secreting cell associated with isotype switch commitment is also triggered which leads to a striking production of autoantibodies. Interestingly, mature B cells do not differentiate into marginal zone pathway following TLR9 stimulation, nor do transitional B cells under antigenic and T cell combined signals. These results suggest that transitional B cells are specifically sensitive to TLR9 stimulation to produce autoreactive marginal zone B cells., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The continuing progress in discovering lymphocyte subsets and the lengthening list of cytokines involved, together with how they are affected in primary Sjögren's syndrome (pSS), has further fuelled the debate on pSS pathogenesis. In this review the "interferon signature" observed in the salivary glands and the role of T-cell derived cytokines (Th1/Th2 polarization, Th17 and regulatory T cells) will be discussed. A particular emphasis has been placed on the B-cell derived cytokines and especially on FLT3-Ligand, a cytokine associated with lymphoma in pSS, and B-cell activating factor (BAFF) that prevents apoptosis of autoreactive B cells. It has indeed become a challenge to understand how the interaction between several interconnected networks of cytokines impact so different cell population in the immunopathogenesis of pSS., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The B-cell activating factor belonging to the tumor-necrosis factor family BAFF contributes to autoimmune disorders. As such, BAFF might become a therapeutic target. However, this molecule has pleiotropic effects that are as numerous as they are varied. The real effect of each form (spliced, glycosylated, membrane bound, soluble, homotrimerized, heterotrimerized, multimerized) has not been well characterized yet. Consequently, conflicting results, regarding the serum concentrations of BAFF or its functional effect, exist in literature. BAFF quantification based on ELISA commercial kits was indeed found to be inaccurate. The complexity of the various forms of BAFF will be reviewed by focusing on the different structural aspects of the molecule. These data have particular implications for autoimmunity, not only because of the role of these factors on B cell growth and survival, but also their influence on the onset and severity of several autoimmune diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background/purpose: Primary Sjögren's syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. Environmental and hormonal factors, such as vitamin-D may play a role in the pathogenic process and disease expression. Thus, we aimed to evaluate levels of vitamin-D and their association with manifestations of SS., Methods: Vitamin-D levels were determined in 176 primary SS patients and 163 matched healthy volunteers utilizing the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). A correlation between vitamin-D levels and clinical and serological manifestations of SS was performed., Results: Mean vitamin-D levels were comparable between SS patients and control 21.2 ± 9.4 ng/ml and 22.4 ± 10 ng/ml, respectively. Peripheral neuropathy was diagnosed in 23% of SS patients and associated with lower vitamin-D levels (18.6 ± 5.5 ng/ml vs. 22.6±8 ng/ml (p = 0.04)). Lymphoma was diagnosed in 4.3% of SS patients, who had lower levels of vitamin-D (13.2 ± 6.25 ng/ml), compared to SS patients without lymphoma (22 ± 8 ng/ml), (p = 0.03). Other clinical and serological manifestations did not correlate with vitamin-D status., Conclusions: In this study, low levels of vitamin-D correlated with the presence of peripheral neuropathy and lymphoma among SS patients. The link between vitamin-D and neuropathy or lymphoma was reported in other conditions, and may support a role for vitamin-D in the pathogenesis of these processes. Plausible beneficial effect for vitamin-D supplementation may thus be suggested., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

T cells have originally occupied central stage of the debate on the type of lymphocytes governing the pathogenesis of Sjögren's syndrome (SS). However, B cells has since been substituted for T cells, and insights into their functions have revealed that they accomplish various tasks. Beyond the paradigm that T lymphocytes maintain strict control over B lymphocytes, these latter cells solicit their own help from the former, release a flurry of cytokines, and act as antigen- presenting cells. In SS, excessive of the B cell-activating factor (BAFF) may cause B-cell quantitative anomalies, such as inflation of mature B (Bm)2/Bm2' cells in the circulation, or accumulation of transitional type 2, marginal zone (MZ) and memory B cells within the exocrine gland infiltrates. These excesses are also associated with B-cell qualitative anomalies, such as the internal synthesis of BAFF, and a default mechanism that promotes the autoantibody production in ectopic germinal centers or MZ equivalents. Thus, SS should rather be conceived as a quintessential model for B cell-induced autoimmunity. Such a view opens novel prospects for treatment, and indeed B cell-ablative therapy has already been shown to be beneficial to these patients.

Be they follicular cells within the germinal centers (GCs) or marginal zone (MZ), all naïve mature B lymphocytes need tonic signaling to stay alive. We reasoned that the same holds true for those B lymphocytes that proliferate in the salivary glands (SGs) of patients with primary Sjögren's syndrome. Based on B cell infiltration, 11 SGs and three tonsil samples were selected for further examination. Tissue sections were stained using CD20 combined with CD10, CD21, CD27, CD38 or IgD. They were also laser-microdissected for quantitative RT-PCR of transcription factors, GC-specific activation-induced cytidine deaminase (AID) and TLR9. Some B cell aggregates proved to be real GCs according to their membrane markers, whereas others were clusters of transitional type II B cells. These contained mRNAs for Notch-2 and Blimp-1, but not for Pax-5, Bcl-6 and AID. Unanticipated was the finding of mRNAs for TLR9 in these clusters of MZ B-cells, but not in the real GCs. Not only do TLR9 deliver sufficiency of tonic signaling to keep B cells alive, but they also confer autoreactive B cells with an MZ-like phenotype. Thus, TLRs might be targets for forthcoming biotherapies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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 Sjögren'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.

The potential predictive value of tumor bulk, genetic, and immunological variants in patients with low-grade non-Hodgkin's lymphoma to respond to treatment with rituximab (RTX) monotherapy was evaluated. Thus, the value of assessing the effect of 18-fluoro-desoxy-D-glucose (FDG) uptake on PET scan, polymorphisms in Fc gamma receptor (FcγR) IIIa-158, FcγRIIa-131, and C1qA-276 genes in predicting the response to treatment were evaluated in 50 low-grade non-Hodgkin's lymphoma patients. The influence of RTX pharmacokinetics, plasma levels of the B cell-activating factor (BAFF), and human antichimeric antibodies was also investigated. The therapeutic response was evaluated 10 weeks after treatment using revised Cheson's criteria. Lower maximal standardized uptake values (SUV(max)) at baseline were predictive of complete response. FcγRIIIa-158 polymorphism was also associated with complete response to RTX confirming previous findings, whereas polymorphisms in the FcγRIIa-131 and C1qA-276 genes were not. Lower blood levels of RTX were observed in males, but the effectiveness of RTX in males and females was the same. BAFF was not detectable in plasma before or after treatment, and no patients developed human antichimeric antibodies. Low-grade non-Hodgkin's lymphoma patients with a low SUV(max) at baseline and an FcγRIIIa-158 V/V genotype generally had a complete response to RTX.

Background: Chronic lymphocytic leukemia remains incurable, despite the addition of rituximab to chemotherapy as an available means of treatment. The resistance of certain patients to this monoclonal antibody prompted us to set up in vitro studies of another CD20-specific monoclonal antibody, B1 (later termed tositumomab). We hypothesized that the membrane lipid organization of leukemic B cells might be instrumental in the cells' sensitivity to the B1 monoclonal antibody., Design and Methods: B lymphocytes from 36 patients with chronic lymphocytic leukemia and 13 patients with non-Hodgkin's lymphoma were investigated for B1-triggered cell death. Membrane components, such as sphingomyelin and ganglioside M1, were investigated by flow cytometry, immunofluorescence and co-immunoprecipitation, together with the Csk-binding protein., Results: Chronic lymphocytic leukemia patients segregated into two groups: B cells from one group were sensitive to B1, whereas those from the second group were not. Further results ascribed the resistance of these latter cases to a defective recruitment of Csk-binding protein, resulting in a lack of sphingomyelin and ganglioside M1 at the outer leaflet of the plasma membrane of their malignant B cells. Sphingolipids were indeed retained in the cytoplasm, because of lowered activity of P-glycoprotein. Supporting this mechanism, rifampicin, an inducer of P-glycoprotein, improved the activity of this transmembrane efflux pump, normalized the quantity of sphingomyelin within the membrane, and thereby restored the efficacy of the B1 monoclonal antibody in the formerly B1-resistant cases of chronic lymphocytic leukemia., Conclusions: The lipid organization of membranes of B cells from patients with chronic lymphocytic leukemia differs from one patient to another. In practice, given the relevance of the membrane lipid distribution to the efficacy of biotherapies, this observation is of potential importance.

Autoimmune diseases are complex diseases resulting of the interaction between both genetics and environmental factors over time. Different phases in the development of autoimmune diseases are characterized by the detection of serum autoantibodies several months or years before the onset of clinical manifestations and subsequent diagnosis. In addition to serum antibodies, genetic susceptibility factors may predict the future development of the disease. Currently, prediction in type 1 diabetes is the most accurate, with the analysis of genetic susceptibility factors in first-degree relatives of patients and several autoantibody tests. In the future, multiple antibodies test, in combination with the analysis of genetics, epigenetics and immunological anomalies in fine models may allow the precise prediction in autoimmune diseases. Prevention measures might thus be introduced as an attempt to avoid or delay the disease., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Sjögren'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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Mature dendritic cells (DCs) are stimulators of T-cell immune response, whereas immature DCs support T-cell tolerance. Murine B cells can inhibit the production of IL-12 by DCs and thereby hinder the inflammatory response. Notwithstanding the importance of this modulation, only a few studies are available in humans. Here, we have developed an in vitro model of cocultures to assess its significance. We establish that human activated B cells restrained the development of monocytes into immature DCs and their differentiation into mature DCs. In addition, they decreased the density of HLA-DR from mature DCs, the expression of CD80 and CD86 coactivation molecules, the production of IL-12p70 required for antigen presentation and Th1 differentiation, and inhibited the DC-induced T-cell proliferation. These modulations were mediated by CD19(+)IgD(low)CD38(+)CD24(low)CD27(-) B cells and needed direct cell-to-cell contacts that involved CD62L for the control of CD80 and CD86 expression and a soluble factor for the control of IL-12 production. Moreover, mature DCs from patients with systemic lupus erythematosus displayed insensitivity to the regulation of IL-12. Overall, it appears that human B cells can regulate DC maturation and function and that inefficient B-cell regulation may influence an improper balance between an effector inflammatory response and tolerance induction.

Not only is nephritis a common complaint in systemic lupus erythematosus, but it is also the most life-threatening complication of the disease. Anti-double-stranded DNA antibodies (Abs), which are found in up to 80% of these patients, might be nephritogenic per se. That is, they may cross-react with mesangial cell (MC) surface proteins, such as alpha-actinin and annexin A2, they may cross-react with mesangial matrix protein such as laminine and fibronectin, or they may recognize chromatin material previously deposited in the glomeruli. The consequence of the binding of anti-MC Abs may be their internalization, which results in activation and proliferation of these MCs. In turn, these activated MCs are suspected of promoting immune complex formation by sequestering and thereby protecting chromatin from degradation. The present paper will explain the mechanisms through which such autoAbs may initiate nephritis.

Sjögren's syndrome is an autoimmune disease characterized by an autoimmune exocrinopathy involving mainly salivary and lacrimal glands. The histopathological hallmark is periductal lymphocytic infiltration of the exocrine glands, resulting in loss of their secretory function. Several systemic manifestations may be found in patients with Sjögren's syndrome including neurological disorders. Neurological involvement ranges from 0 to 70% among various series and may present with central nervous system and/or peripheral nervous system involvement. This paper endeavors to review the main clinical neurological manifestations in Sjögren syndrome, the physiopathology, and their therapeutic response.

Background: Adamantiades-Behçet's disease (ABD) is a chronic multisystemic inflammation with unknown pathophysiology. This disorder is associated with a dysregulation of the cytokine network that hyperactivates neutrophils and macrophages. In this study, we investigate the modulatory effects of flavonoïd compounds extracted from Algerian medicinal plant Artemisia herba alba on Th1 and Th2 cytokines and nitric oxide production., Methods: The modulatory effects of flavonoïds extracted from Artemisia herba alba on cytokines and nitric oxide production by peripheral blood mononuclear cells isolated from Algerian ABD patients and healthy controls were respectively measured by means of ELISA assays and Griess modified method., Results: Our results show that flavonoïds significantly reduce the production of interleukin-12, the key effector of T helper 1 (Th1) cells and nitric oxide in a dose-dependent manner in Adamantiades-Behçet's disease. In contrast, the production of IL-4, the key marker of Th2 cells was increased., Conclusion: This study suggests that in vitro supplementation with flavonoïds extracted from Artemisia herba alba could have potential immuno-modulatory effects characterised by a down-regulation and up-regulation of Th1 and Th2 cytokines, respectively. Moreover, flavonoïds may prevent nitric oxide induced damages.

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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The difficulty in predicting the consequences of interactions between different cytokine networks has increased with the expansion of the T helper (Th) cell universe and the discovery of numerous B lymphocyte-derived cytokines. Consequently, it is now difficult to conceptualize a straightforward view of the contribution of these disturbances to the pathogenesis of primary Sjögren's syndrome (SS). Th1 cells, which produce interferon-γ and IL-2, and Th17 cells, which make IL-17 and TNF-α, have been cast in the leading roles of the play. However, the complex role of T-cell subsets in SS is accentuated by the reciprocal effects of Th17 cells and regulatory T cells found in salivary glands of SS patients. Furthermore, B lymphocyte polarization into type-1 B effector (Be1) and Be2 cells and B-cell modulating factors of the TNF family, most notably the B-cell-activating factor (BAFF), and their prominent role in SS are additional complicating factors. Whereas Th17 cells orchestrate autoreactive germinal centers, local BAFF would repress the generation of Th17 cells. Such new insights into interconnected cytokines in primary SS may lead to new treatments for these patients.

Objective: To determine whether a proliferation-inducing ligand (APRIL) has a role in the survival of plasma cells infiltrating salivary glands from SS patients., Methods: We performed immunological staining for APRIL in minor salivary glands from SS with a pair of antibodies specifically recognizing APRIL-producing cells and secreted APRIL., Results: Despite high leucocyte infiltration, APRIL-producing cells, identified as neutrophils, were rare in SS salivary glands. Keratinocytes from the adjacent oral epithelium also produced APRIL, but we never detected significant levels of secreted APRIL in SS salivary glands. We obtained similar results with B-cell lymphomas associated with SS. In fact, there was no significant difference in APRIL production and the level of secreted APRIL in these pathological samples compared with normal corresponding tissues., Conclusion: The combined observation that APRIL production is not up-regulated in lesions from SS patients, and that secreted APRIL is not retained in these lesions, indicates that plasma cells frequently present in SS lesions may not rely on APRIL for survival, as they do in other rheumatic diseases.

Objective: To evaluate the diagnostic accuracy of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) and 1987 ACR criteria for rheumatoid arthritis (RA), and the respective role of the algorithm and scoring of the ACR/EULAR., Methods: In total, 270 patients with recent-onset arthritis of < 1 year duration were included prospectively between 1995 and 1997 and followed for 2 years. RA was defined as the combination, at completion of followup, of RA diagnosed by an office-based rheumatologist and treatment with a disease-modifying antirheumatic drug or glucocorticoid. We compared the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the criteria sets in the overall population, in the subgroup meeting the tree condition for ACR/EULAR scoring, and in the overall population classified according the full tree., Results: At baseline, 111 of the 270 patients had better alternative diagnoses and 16 had erosions typical for RA; of the 143 remaining patients, 52 had more than 6 ACR/EULAR 2010 points (indicating definite RA) and 91 had fewer than 6 points. After 2 years, 11/16 patients with erosions and 40/52 with more than 6 points had RA. 100 of the 270 patients met the reference standard for RA. Sensitivity, specificity, PPV, and NPV of the ACR/EULAR (full tree) were 51/100 (51%), 153/170 (90%), 51/68 (75.4%), and 153/202 (75.7%), respectively. Diagnostic accuracies of the ACR/EULAR score and ACR 1987 criteria were not statistically different., Conclusion: Much of the improvement of the ACR/EULAR criteria was ascribable to the use of exclusion criteria in the algorithm.

Lupus nephritis (LN) remains the most common severe manifestation of systemic lupus erythematosus (SLE) characterized by the presence of autoantibodies (Abs) that are believed to play a central role in the pathogenesis of LN. Among more than 100 Abs reported in SLE, only a few display a direct glomerular binding capacity. Such antiglomerular Abs are detected at the onset of the disease before antinuclear Abs detection and proteinuria, this detection is associated with the related autoantigen overexpression. Antiglomerular Abs are able to interfere with cell metabolism, to penetrate living cells, and to induce glomerular cell proliferation. In addition, antiglomerular Abs could be nephritogenic causing proteinuria, particularly when they cross-react with anti-dsDNA Abs. Antiglomerular Abs encompass anti-α-actinin, anti-laminin-1, antifibronectin, antimyosin, and anticollagen Abs. The pathogenic activity of anti-α-actinin Abs has been demonstrated in non-autoimmune mice after immunization with α-actinin, but not with dsDNA, leading to a SLE-like disease with proteinuria and glomerular immune complex deposition. Similarly, extracorporeal immunoabsorption to remove anti-laminin-1 Abs reduces kidney-Abs deposition and proteinuria in mice and humans proving their pathogenic effect. Altogether this suggests that antiglomerular Abs participate, at least at the beginning, in the glomerular immune complex deposition and in the kidney damage.

Regulatory functions for B lymphocytes have been reported in murine models of autoimmune diseases in which B-cell deficient mice were shown to exhibit exacerbated disease. The B cells responsible for the immune regulations were identified as a subpopulation of interleukin 10-secreting cells. However, the mechanism of induction and the characteristics of regulatory B cells in humans have been hardly studied. This study reports that regulation of T cell responses can be induced by B cells following CD40-dependent cognate interaction. T cell proliferation and cytokine production were differentially regulated. Thus, CD40-induced regulatory B cells partially inhibited T cell proliferation following CD40 interaction without requirement of soluble factor. In contrast, modulation of Th1 differentiation resulted from CD80- and CD86-dependent interactions and from IL-10 production. The suppressive effects were mediated by CD19(high)IgD+CD38(high)CD24(high)CD5(high) B cells and appeared to be indirect, through the induction of regulatory T cells as indicated by the appearance of Foxp3+CD4+CD25+T cells. These data suggest that activation signals from T cells initiate regulatory properties in B cells that modulate T cell responses involving regulatory T cells. Finally, studies in autoimmune patients revealed that regulation of T cell proliferation was defective in systemic lupus erythematosus but efficient in other diseases. Restoration of efficient B-cell regulatory activity could provide innovative B-cell based treatment of autoimmune diseases., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 containing the known exon 1 (E1A) and other CD5 transcripts containing the new exon 1 (E1B). These malignant B cells, as well as B cell lines transfected with cDNA for E1A-cd5 or with cDNA for E1B-cd5 produce IL-10, raising the possibility that CD5 participates in the secretion of IL-10. We identified transcription factors involved in this production in CD5(+) B lymphocytes from CLL patients and in E1A-cd5-transfected or E1B-cd5-transfected Jok cells. STAT3 is activated via phosphorylation of serine 727 but also NFAT2 through its translocation into the nucleus. Chromatin immunoprecipitation experiments confirmed the role of STAT3 and allowed the discovery of a role for NFAT2 in IL-10 production. Both transcription factors bind not only to the enhancer of the Il-10 gene but also to the promoter of the Il-5 and Il-13 genes. Furthermore, transfection of B cell lines with E1A-cd5 or E1B-cd5 established that activation of STAT3 and NFAT2 is regulated by CD5. The same holds true for the production of IL-10, IL-5, and IL-13 and the expression of the receptors for these cytokines. This interpretation was confirmed by two experiments. In the first, downregulation of CD5 by small interfering RNAs lowered the production of IL-10. In the second experiment, transfection of the GFP-NFAT2 gene into B lymphocytes induced nuclear translocation of NFAT2 in CD5(+) but not in CD5(-) B cells. Thus, CD5 expression is associated with NFAT2 activity (and mildly STAT3 activity), indicating that CD5 controls IL-10 secretion.

Background: Heat shock protein (hsp) 60 that provides "danger signal" binds to the surface of resting endothelial cells (EC) but its receptor has not yet been characterized. In mitochondria, hsp60 specifically associates with adenosine triphosphate (ATP) synthase. We therefore examined the possible interaction between hsp60 and ATP synthase on EC surface., Methodology/principal Findings: Using Far Western blot approach, co-immunoprecipitation studies and surface plasmon resonance analyses, we demonstrated that hsp60 binds to the β-subunit of ATP synthase. As a cell surface-expressed molecule, ATP synthase is potentially targeted by anti-EC-antibodies (AECAs) found in the sera of patients suffering vasculitides. Based on enzyme-linked immunosorbent assay and Western blotting techniques with F1-ATP synthase as substrate, we established the presence of anti-ATP synthase antibodies at higher frequency in patients with primary vasculitides (group I) compared with secondary vasculitides (group II). Anti-ATP synthase reactivity from group I patients was restricted to the β-subunit of ATP synthase, whereas those from group II was directed to the α-, β- and γ-subunits. Cell surface ATP synthase regulates intracellular pH (pHi). In low extracellular pH medium, we detected abnormal decreased of EC pHi in the presence of anti-ATP synthase antibodies, irrespective of their fine reactivities. Interestingly, soluble hsp60 abrogated the anti-ATP synthase-induced pHi down-regulation., Conclusions/significance: Our results indicate that ATP synthase is targeted by AECAs on the surface of EC that induce intracellular acidification. Such pathogenic effect in vasculitides can be modulated by hsp60 binding on ATP synthase which preserves ATP synthase activity.

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., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The recently recognized importance of B cells in systemic lupus erythematosus (SLE) raises the question as to whether those expressing CD5 predominate over the remaining B lymphocytes in the pathophysiology of this disease. Owing to their B B-cell receptor (BCR) polyspecificity, autoantibody production has been originally ascribed to CD5-positive B1 lymphocytes. Instead, it has since been established that high-affinity autoantibodies derive from CD5-negative B2 cells. Even worse, in the light of current findings, CD5-positive B cells have been considered to play a paradoxical role in preventing, rather than inducing, autoimmunity. In this context, there is evidence that the membrane expression of CD5 is regulated, and, to this end, a genetic mechanism has been described, based on the selection between exon 1A (E1A) and exon 1B (E1B). The full-length protein variant, encoded by E1A-cd5, translocates the phosphatase SHP-1 to the vicinity of the BCR, raises its threshold, and thereby limits the response of autoreactive B cells. In contrast, the truncated variant, encoded by E1B-cd5, remains in the cytoplasm, along with SHP1. Normally, EIB E1B is silenced by methylation and its product degraded in the proteosomes. Hence, a defect in the DNA methyl transfer favors the development of SLE, by preventing the effects of SHP-1.