After centrifugation (14 500 g for 5 min) at 4°C the pellet

was resuspended in 500 µl extraction buffer containing 1 M NaCl, incubated on ice for 20 min and centrifuged (14 500 g for 5 min) at 4°C. The supernatant representing the nuclear protein fraction was collected and stored at −70°C until used. To characterize the NFR further, sera of the 11 patients in group 1 subjected to molecular study were analysed for IgA reactivity with nitrocellulose-blotted Caco2 cell proteins. Total cell protein extract, as well as its cytosolic and nuclear fractions, were boiled for 3 min and submitted to denaturing 10% preparative sodium dodecyl sulphate-polyacrylamide gel electrophoresis ABT-263 cost (SDS-PAGE). Gel-separated proteins were blotted onto nitrocellulose membranes (Protran nitrocellulose transfer membrane; Schleicher & Schuell Whatman CHIR-99021 mw group, Dassel, Germany). Nitrocellulose strips (width 2 cm) were cut from the membranes and were then blocked twice for 5 min and once for 30 min in buffer A [50 mM sodium phosphate buffer at pH 7·4, containing 0·5% Tween 20 and 0·5% bovine serum albumin (BSA)]. Blocked strips were probed overnight at 4°C with sera diluted 1:500 in the same buffer. Thereafter, strips were washed twice for 5 min and once for 15 min with buffer B (50 mM sodium phosphate buffer at pH 7·4, containing 0·5% Tween 20) and incubated overnight at room temperature with a peroxidase-conjugated anti-human IgA polyclonal antibody (Chemicon, Temecula, CA, USA)

diluted 1:8000 in buffer A. Strips were finally washed and dried before exposition to Hyperfilms ECL (Amersham

Pharmacia Biotech, Uppsala, Sweden) for approximately 3–5 s. The purity of nuclear and cytosolic protein fractions Idoxuridine was assessed by exposing the nitrocellulose-blotted total cell protein extract and its fractions to anti-human histone H2B anti-serum (Chemicon). Significant statistical differences between EMA and NFR antibodies, detected as total IgA, IgA1 and IgA2 in sera of the 11 patients in group 1 subjected to NFR characterization, were calculated by χ2 test for qualitative and independent data. The P-values ≤0·05 were considered significant. At baseline, all 20 untreated CD patients in group 1 showed serum IgA EMA-positive and NFR-negative results. Serum EMA disappeared after 76 ± 34 days from starting the GFD while, at the same time, serum NFR antibodies became apparent. The NFR antibodies cleared completely from sera in the following 75 ± 41 days for a total of 151 ± 37 days from starting the GFD (Fig. 2). At the time of monitoring, 24 of 87 treated CD patients in group 2 showed serum IgA EMA-negative and NFR-positive results, while the remaining 63 patients displayed negative results for both circulating antibodies. The combination of three GFD control levels (self-reported, dietetic assessment and serum EMA determination) highlighted that, during the previous months, the 24 patients presenting serum NFR-positive results were introducing small amounts of gluten.

This choice was based on the knowledge that all members of the γc cytokine family signal through the IL-2Rγc (7). Ascending parasitemia following the i.p. injection of 1 × 106 parasitized erythrocytes was similar in both groups of mice, reaching peak values of 20.7 ± 12.5% on day 9 post-inoculation (PI) in knockout MG-132 solubility dmso (KO) mice lacking functional genes for the expression of the IL-2Rγc peptide and 11% on day 7 in control mice. Whereas parasitemia in control mice was suppressed to approximately 0.01% by day 13 PI, parasitemia in IL-2Rγc−/y mice remained at high unremitting levels (8–29%) for >7weeks PI when the experiment was terminated

(Figure 1a). This finding that parasitemia was prolonged at high levels in IL-2Rγc−/y mice indicates that signalling through the IL-2R complex is essential for the suppression of P. c. adami parasitemia. Acute blood-stage P. c. adami infections in mice

are suppressed by antibody-mediated immunity (AMI) dependent on CD4+ T cells and B cells (21) and/or cell-mediated immunity (CMI) dependent on CD4+ T cells and γδT cells (22,23). The observation that IL-2Rγc−/y https://www.selleckchem.com/p38-MAPK.html mice failed to clear P. c. adami parasites from their blood indicates that both AMI and CMI against the parasites were defective in these mice lacking a functional IL-2R owing to a mutation of a single gene, the IL-2Rγc gene. IL-2Rγc−/y mice have been reported previously by others to be deficient in αβ T cells, γδT cells and B cells (3,4). As indicated in Table 1, we observed similar deficiencies in Dichloromethane dehalogenase these cell populations. Because IL-2 and IL-15 may have redundant roles in immunity to blood-stage malaria, we determined the time courses of P. c. adami parasitemia in IL-2/15Rβ−/− mice and intact controls following inoculation with 1 × 106 parasitized erythrocytes.

Parasitemia was prolonged in IL-2/15Rβ−/− mice by approximately 3 weeks as compared to control mice (Figure 1b), but the mice eventually cured. Both γδ T cells and B cells were deficient in the spleens of IL-2/15Rβ−/− mice compared with infected control mice (Table 1) with numbers similar to those seen in IL-2Rγc−/y mice. In addition, antibodies reactive with crude malarial antigen were detected in the sera of IL-2/15Rβ−/− mice, following the suppression of parasitemia albeit at approximately half the concentrations seen in control mice (Table 2). This difference was not statistically different. Both IL-2 and IL-15 stimulate through the IL-2/15Rβ (9,13). Whereas IL-2-deficient mice exhibit P. c. adami parasitemia of prolonged duration before spontaneously clearing (11), the effects of IL-15 deficiency on the course of malaria caused by the adami subspecies of the parasite had not yet been determined. To assess whether IL-15 contributes to the suppression of acute parasitemia, we compared time courses of P. c. adami parasitemia initiated with 1 × 106 parasitized erythrocytes in IL-15 KO mice vs. C57BL/6 controls.

“
“Hookworms are one of the most

prevalent parasites of humans in developing countries, but we know relatively little about the immune response generated to hookworm infection. This can be attributed to a lack of permissive animal models and a relatively small research community compared with those of the more high-profile parasitic diseases. However, recently, research has emerged on the development of vaccines to control hookworm infection and the use of hookworm to treat autoimmune and allergic disorders, contributing to a greater understanding of the strategies used by hookworms to modulate the host’s immune response. A substantial body of research on the immunobiology of hookworms originates from Australia, so this review will summarize the current status of the field with a particular emphasis on research carried out ‘down under’. GDC-0941 datasheet Hookworms are one of the most common

parasites of humans, with around 740 million people infected worldwide. Although they cause little mortality, heavy infections can cause iron-deficiency anaemia, growth retardation and low birth weight (1). Hookworms are most prevalent in South America, sub-Saharan Africa and East Asia; however, up until the second half of the 20th century, they were also common in the southern states of USA, Europe (2) and Australia, where they still affect some remote aboriginal communities (3). The two major anthropophilic hookworm species are Necator americanus Rapamycin cell line and Ancylostoma duodenale. The more common parasite, on which the majority of studies have consequently been carried out, is N. americanus. Hookworms are soil-transmitted helminths: infective larvae burrow through the skin and are activated in the process, after which they migrate through the heart and lungs to the gut, where they mature to adults, feed on host blood and produce eggs which are deposited in the faeces. Deposited eggs then develop to infective larvae, completing the life cycle (1). The host see more must therefore mount an immune response against a number of different parasite

stages during a hookworm infection, and the parasite in turn has a number of opportunities to manipulate the host immune system. We will not dwell on the life cycle of the parasite in this review – for more detail, see (4). The immunology of human hookworm infection has not received as much focus as that of other helminth parasites of humans, such as schistosomes and filariae. The reasons for this include the relatively low mortality caused by hookworms, the difficulty/expense in maintaining the life cycle in a suitable animal model and the inability of any of the major species of hookworms to reach maturity in mice. This has especially been a problem in Australia where the best laboratory model, the hamster, is not permitted to be maintained in the country because of quarantine regulations. Consequently, Australian hookworm research has focussed on human immunology, and especially experimental or zoonotic human infections.

It has been reported that the immunosuppressive effects of ASC are mediated via soluble factors, and enhanced further if direct cell–cell contact between ASC and immune cells was allowed [14]. Different studies have attributed the immunosuppressive effect of MSC to different immunosuppressive factors. These include indoleamine

2,3-dioxygenase (IDO) [15–17], prostaglandin E2[18], transforming growth factor (TGF)-β and hepatocyte growth factor (HGF) [5], HLA-G [19], nitric oxide [20], interleukin (IL)-10 [21] and haem oxygenase [22]. In addition, there is evidence that cell–membrane interactions between MSC and immune cells via the adhesion molecules intercellular adhesion molecule (ICAM)-1 or vascular cell adhesion molecule (VCAM)-1 play a crucial role in the immunomodulatory Napabucasin price capacity of MSC [14,23]. Thus, the immunomodulatory capacity of MSC is a multi-factorial process. The activity of these processes may depend upon local immunological conditions. It has been demonstrated that in the absence

of inflammation, MSC can stimulate lymphocyte survival and proliferation [24]. Under inflammatory conditions a high production of cytokines, MEK inhibitor such as interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-6, are largely produced and MSC may respond to these factors by changing their immunomodulatory function [25–27]. Exposure of MSC to IFN-γ has been reported to up-regulate the expression of IDO, TGF-β and HGF [25,28] and it was demonstrated recently that IFN-γ-activated MSC are more effective for the treatment of graft-versus-host disease [29]. Effective application of MSC in organ transplantation may require potent and immediate immunosuppressive effects. In vitro activation of MSC could therefore be beneficial for clinical effectiveness of MSC in organ Sitaxentan transplantation. In the present study, we investigated whether different inflammatory conditions affected the gene expression,

phenotype and function of adipose tissue-derived mesenchymal stem cells (ASC). ASC were cultured with alloactivated peripheral blood mononuclear cells (PBMC) (mixed lymphocyte reaction, MLR) or with a cocktail of proinflammatory cytokines containing IFN-γ, TNF-α and IL-6, while their functions and full genome expression were examined. ASC were isolated and expanded from perirenal adipose tissue of four living healthy kidney donors, as described previously [30,31]. These donors (three males, one female, mean age 46 ± 7 years) were approved to donate their kidney after routine screening. They did not use immunosuppressive medication. In brief, perirenal fat was minced and digested with 0·5 mg/ml collagenase type IV (Invitrogen, Paisley, UK) in RPMI-1640 (Invitrogen) for 30 min at 37°C.

The same UVB treatment protocol was used for all patients based on skin type, with initial doses of 130–400 mJ/cm² with subsequent increases of 15–65 mJ/cm² after each treatment session [15]. Both groups

were advised to use moisturizing creams daily. Patients who received combination treatment and NB-UVB therapy alone were comparable regarding age (mean: 36.7 years [range: 19–57] versus find more 33.7 years [range: 27–42]; P = 0.41), gender (five women/one man and five women/one man) and Psoriasis Area and Severity Index (PASI) [14] (18.2 [range: 7.8–32.2) versus 12.3 [range: 8.2–15.1]; P = 0.19). The only difference was that patients receiving combination treatment had a longer duration of the disease compared with patients receiving NB-UVB therapy (mean:

22.3 years [range: 6–36] versus 12.3 years [range: 5–23]; P = 0.036). https://www.selleckchem.com/products/BAY-73-4506.html The control group consisted of 3 anonymous healthy blood donors from the Landspitali University Hospital (Reykjavik, Iceland) blood bank. Heparinized peripheral venous blood was collected at each time point, and peripheral blood mononuclear cells (PBMC) were obtained by gradient centrifugation with Ficoll-Paque PLUS (Healthcare, Uppsala, Sweden), collected at the interface and washed with HBSS medium (Gibco, Carlsbad, CA, USA) prior to staining with such as anti-human CD3, CD4, CLA, CD103 (all from Biolegend, San Diego, CA, USA), CD8, CD45R0, CD54, CCR4 (all from BD Biosciences, San Jose, CA, USA), IL-23R and CCR10 (both from R&D Systems, Abingdon, UK) monoclonal antibodies (mAbs) for T cell analysis and CD14, CD11c, TLR2 (Biolegend) and TLR6 (HyCult Biotechnology, Uden, The Netherlands) mAbs for monocyte analysis. The PBMC (1.0 × 106 cells/ml) were cultured for 16 h in RPMI 1640 medium with penicillin–streptomycin (100 IU/ml and 0.1 mg/ml) (Gibco), in the presence of anti-CD3 (5 μg/ml), anti-CD28 (5.0 μg/ml) mAbs (Biolegend) and brefeldin A (3.0 μg/ml) (eBioscience,

San Diego, CA, USA) at 37 °C. The T cells were first stained for CD4 and CD8, then fixed and permeabilized and stained intracellularly with anti-human Fluorouracil mw tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-17A (all from Biolegend) and IL-22 (R&D Systems) mAbs. The cells were washed with phosphate-buffered saline (PBS) prior to fluorescence-activated cell sorting (FACS) analysis. Serum samples were collected at each time point and frozen at −70 °C until used. At the end of the study period, the levels of IL-22, IL-17, IL-23, CCL20, IL-1β and TNF-α were determined by enzyme-linked immunosorbent assays (ELISAs), using commercially available kits (R&D Systems), according to the manufacturer’s instructions. A 3-mm punch biopsy was taken from the arm of each patient at every evaluation. The biopsy was taken from the edge of the thickest lesion on the forearm, then fixed in formaldehyde and stained using HE for histologic evaluation.

pylori infection (Sayi et al., 2009). Conversely, IFN-γ can lower the colonization of H. pylori and is critical for H. pylori clearance (Yamamoto et al., 2004; Sayi et al., 2009). Most evidence indicates that IFN-γ plays a protective role in H. pylori infection (Sawai et al., 1999; Hasegawa et al., 2004; Yamamoto et al., 2004; Cinque et al., 2006; Sayi et al., 2009); furthermore, this occurs principally between IFN-γ and the bacteria. Our results provide further evidence that IFN-γ may help control H. pylori infection indirectly by controlling its virulence factor, CagA. Previous studies suggested that IFN-γ is a key

antimicrobial factor, against, in particular, intracellular pathogens such as viruses and Mycobacterium tuberculosis (Young et al., 2007). We too showed that buy KPT-330 IFN-γ can downregulate the expression of the major virulent factor CagA in the extracellular bacterium H. pylori for an indirect effect on such pathogens. IFN-γ

is a well-known immune active factor (Wu et al., 2005), and its production is accompanied by host immunity change in response to H. pylori (Shimizu et al., 2004; Pellicanòet al., 2007). In turn, IFN-γ can downregulate CagA expression. We found that H. pylori SS1 had the same effect as H. pylori 26695 (data not shown), but this needs to be confirmed by animal models. Hence, immune responses to H. pylori play an important role in the defense MEK inhibitor against bacterial infection. In conclusion, we found that INF-γ can bind to the surface of H. pylori, which results in the downregulated expression of CagA, the major virulent factor in H. pylori. These findings provide insights into understanding the effect of a high level of IFN-γ on gastric mucosa infected with H. pylori and how IFN-γ can Tau-protein kinase contribute to control H. pylori infection. The mechanism by which IFN-γ causes downregulation of CagA needs further investigation. This work was supported by the National Natural Science

Foundation of China (Nos 30770118, 30972775, 30800406, 30800037, 30971151 and 30800614), the National Basic Research Program of China (973 Program 2007CB512001) and the Science Foundation of Shandong Province, China (Nos ZR2009CZ001 and ZR2009CM002). Yinghui Zhao and Yabin Zhou contributed equally to this work. Fig. S1. Effect of IFN-γ on the growth of Helicobacter pylori. Fig. S2. Binding of IFN-γ to Helicobacter pylori. Please note: Wiley-Blackwell is not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. “
“The adenosine monophosphate-activated protein kinase (AMPK) is activated by antigen receptor signals and energy stress in T cells. In many cell types, AMPK can maintain energy homeostasis and can enforce quiescence to limit energy demands.

The PRM has a branched structure and contains α-Rhap-(13)-α-Rhap- side-chain epitope linked (13) to a (16)-linked α-Manp core.8 The cell wall structure of carbohydrates present in peptidopolysaccharides isolated from mycelia of P. boydii8 and S. apiospermum12 are therefore structurally different. This supports the more recent finding of Gilgado et al. Selumetinib manufacturer [3] that they are not respective teleomorph and anamorph of the same species. However, of

the many different carbohydrate epitopes present in glycocomplexes of opportunistic, fungal pathogens P. boydii,8S. prolificans,10 and now S. apiospermum,12 an α-Rhap-(13)-α-Manp-(12)-α-Manp-(1 structural component is conserved. The carbohydrate epitopes of mycelial S. prolificans peptidorhamnomannan (PRM-Sp) differ from those of the PRM glycopeptides of P. boydii, a related opportunistic pathogen. The 13C NMR examination, as did methylation analysis, showed PRM-Sp to be different from PRM-Pb which indicated that PRM-Sp11 contained a high proportion of 2-O-substituted Rhap units, absent in PRM-Pb. The α-L-Rhap-(12)-α-L-Rhap-(13)-α-L-Rhap-(13)-α-D-Manp- groups present in PRM-Sp resemble those of the rhamnomannans from the pathogen Sporothrix schenckii,15 but with the latter lacking one of the internal, 3-O-substituted α-L-Rhap units. Consequently,

immunological tests could be interesting in terms of their comparison. The glycopeptide extracted from conidia of S. prolificans contained the same monosaccharide units as those of its mycelium, but with a trace of 2-O-methylrhamnose residues.10 The O-linked oligosaccharides (Fig. 2) CHIR-99021 supplier were isolated from the PRMs of P. boydii, S. apiospermum and S. prolificans mycelium. They were obtained in their non-reducing forms via reductive β-elimination and found to be, based on a combination of techniques including gas chromatography, ESI-MS, 1H COSY and TOCSY and 1H (obs.), 13C HMQC NMR spectroscopy and methylation analysis (Fig. 3a and

b).8,10 All of these oligosaccharides had a terminal mannitol unit, corresponding to the Manp unit Dimethyl sulfoxide formerly O-linked to the peptide moiety. This finding agrees with all reports to date concerning fungal protein O-glycosylation, referred to as protein O-mannosylation by Strahl-Bolsinger et al. [16]. Of particular interest is the presence of terminal 2-O-methylrhamnose residues in the O-linked oligosaccharides of conidia of S. prolificans. Mild reductive β-elimination of its PRM cleaved O-linked structures to give a mixture of oligosaccharides which was fractionated by Bio-Gel P-2 column chromatography. Two predominant isolates were β-D-Galp-(16)-[2Me-α-L-Rhap-(13)-α-L-Rhap-(13)-Manp-(12)]-D-Man-ol and another lacking the β-Galp unit. Neither was formed from mycelial glycoprotein, although β-D-Galp-(16)-[α-L-Rhap-(13)-α-L-Rhap-(13)-Manp-(12)]-D-Man-ol was a common component (see Fig. 2). These results are significant, since 2-O-methylrhamnose has not yet been detected in fungi, although it has been widely encountered elsewhere.

Many Māori will prefer to die at home and whānau often prefer to take their terminally ill relative home, although, as with other groups in DMXAA order society, the pressures of urbanization and geographical spread of modern whānau mean that this should not be assumed. When an individual prefers to die on their tūrangawaewae (tribal land) this may be geographically distant from their

current place of residence and/or rural. Good palliative care is likely to be facilitated by a heath care professional assisting the patient and whānau with finding appropriate health care services in their chosen place of death, for example identifying a local general practitioner and referring to local palliative care services. Community palliative care services may be more acceptable than inpatient hospice care to many Māori. In hospital or hospice, whānau and patients should

be offered a single room and access to appropriate spiritual and cultural support. As autopsy can be particularly distressing to Māori it is appropriate to prepare whānau in advance if referral to the coroner and/or autopsy is likely to be necessary and explain PD98059 why.[9] Care of the tūpāpaku (deceased) can be a particularly sensitive area as it is generally highly ritualized in Māori culture. Whānau may have specific cultural and spiritual practices they wish to observe around handling of the body, including washing and dressing and staying with the tūpāpaku as they progress from the ward, to the mortuary and to the funeral director then marae. The way in which the tūpāpaku is transported is also significant to many Māori, for example wrapped in allocated linen, feet first and following a pre-determined route away from public thoroughfares. Blessing the room the tūpāpaku died in with a karakia prior to cleaning may also be appropriate. Lck Again seeking advice from local kaumātua and specifically asking whānau is likely to be the best way to

avoid causing inadvertent offense by breaching protocol.[9] Individual patients and whānau may wish to use rongoā (traditional Maori methods of healing) to achieve their goals of care. Considering the Whare Tapa Whā model, rongoā may be valued for their contribution to aspects of well-being other than physical health. Local kaumātua (elders) can advise on local practice. The handling of food, taonga (valuables), the head and human waste are areas to be aware of. Generally, food and medicines for human consumption should be kept separate from items for general use, for example microwaves or refrigerators should be used for either food preparation/storage or non-food uses (e.g. heating wheat bags), not both, tea towels should only be used for drying dishes and tables should not be sat on.

2C) did not differ between groups (p > 0.05). Gefitinib concentration IL-10 was significantly elevated at mRNA and protein levels in chronic periodontitis group when compared to periodontally healthy group (P < 0.05) (Fig. 3A and B, respectively). Conversely, the mRNA levels (Fig. 4A) as well as the protein amount of IL-4 (Fig. 4B) were significantly lower (P < 0.05) in chronic periodontitis group than

healthy ones. Cytokines influence B cell development and homeostasis by regulating their proliferation, survival and function, including the production of Ig. It has been demonstrated that Ig secretion is affected by Th-secreted cytokines such as IL-21, IL-10 and IL-4 and by CD40 [9, 10]. However, the role of these specific mediators of Ig isotype switching in the B cell response on periodontal diseases remains unclear. Therefore, this study evaluated for the first time the gingival levels of some mediators related to Ig isotype switching (IL-21, IL-21R, IL-4, IL-10 and CD40L) and the salivary levels of IgA in chronic periodontitis subjects. Overall, the results demonstrated that the

salivary levels of IgA were upregulated in periodontitis subjects at the same time that the gingival levels of IL-21 and IL-10 were increased and the levels of IL-4 were decreased in periodontitis tissues. Together, these results suggested that some Th-secreted cytokines are probably involved click here in the generation of IgA by B cells in periodontitis tissues that, in turn, may be one of the most important sources of IgA in the saliva of chronic periodontitis subjects. Although there is some controversy next regarding the sources of Ig in saliva, it is important to note that the included chronic periodontitis

subjects were systemically healthy and did not report the presence of other infections besides periodontitis. IL-21 has been well recognized to contribute to the development of Th17 cells [17, 18], which have been shown to play important role in the pathogenesis of periodontitis [19]. However, it seems that IL-21 not only influences T cell responses but also affects the differentiation, activity and maintenance of B cells. Development- and activation-dependent regulation of IL-21R expression on the surface of B cells suggests that IL-21 has important functions in B cell, including the secretion of vast quantities of IgM, IgG and IgA [20, 21]. Similarly, IL-10 is also well recognized as potent inducer of Ig secretion by human B cells [22]. Naïve B cells secreted 30 to 50-fold more IgG and IgA following stimulation with CD40L/IL-21 than with CD40L/IL-10. On the other hand, IL-4 reduces the secretion of IgM, IgG and IgA by CD40L/IL-21-stimulated transitional and naïve cells by ∼3- to 5-fold, although activated memory B cells are not sensitive to this effect of IL-4 [21]. B lymphocyte cultured with CD40L or CD40L/IL-4 induced minimal secretion of IgA, while IL-21 resulted in the production of high levels of IgA.

Thus, in our experimental setting, the simultaneous presence of different immune populations in total PBMCs assured the presence of all the required signals for B-cell differentiation and offered a faithful

representation of what is actually happening in vivo in the peripheral blood of MS patients. Our results demonstrate a fundamental difference in the outcome of either TLR7 or TLR9 stimulation of B cells AZD1152-HQPA price in the context of PBMCs isolated from HDs or MS patients. Indeed, while the treatment with a TLR9 ligand induced a comparable production of both IgG and IgM in control or MS-affected individuals, we highlighted for the first time a clear deficiency in TLR7-mediated B-cell differentiation into Ig-secreting cells in MS patients. In vivo administered IFN-β is able to replenish in MS patients the low TLR7-induced Ig production to the level observed in HDs. In line with this evidence and consistent with previous findings [33], TLR7 expression was also upregulated by IFN-β both in whole PBMCs, purified B cells, and monocytes. Furthermore, three studies reported with different experimental approaches how IFN-α, another subtype of the type I IFN family

to which IFN-β belongs, exogenously provided or in situ produced by plasmacytoid DC, enhances B-cell differentiation into IgM- NU7441 and IgG-producing cells only in response to TLR7, but not TLR9, triggering [34-36]. We believe that in our settings

in vivo IFN-β therapy might have similar activity to what is described in vitro for IFN-α. IFN-β treatment enhances TLR7-induced B-cell responses in MS patients acting at different steps: not only on the regulation of TLR7 gene L-gulonolactone oxidase expression but also on the secretion of soluble factors of key importance for B-cell differentiation, namely IL-6 and BAFF. IL-6 promotes terminal differentiation of B cells to plasma cells [23, 37] and exerts also a pronounced effect on the survival and/or Ig secretion [38]. BAFF regulates, in tandem with APRIL (a proliferation-inducing ligand), B-cell survival, differentiation and class switching, determines the size of the peripheral B-cell pool and is essential for maintenance of the peripheral B-cell repertoire and initiation of T-cell independent B-cell responses [39]. BAFF has been implicated in the development of autoimmunity in experimental settings and in several human B-cell-related autoimmune diseases, including MS [39]. Interestingly, Serafini and Aloisi in collaboration with our team also found that BAFF is expressed in EBV-infected B cells in acute MS lesions and ectopic B-cell follicles [40], highlighting the key role of this factor in B-cell activation also in the MS brain.