In the hypoglossal nucleus, BBs and TDP-43 inclusions were found in 31.1% and 41.8% of total neurons, respectively, and 29.2% contained both BBs and TDP-43 inclusions (Table 2). In the facial nucleus, BBs and TDP-43 inclusions were found in 21.5% and 24.4% of total neurons, respectively, and 17.3% contained both BBs and TDP-43 inclusions (Table 2). In the present study, the virtual slide system using sequential staining of the same sections with HE and anti-TDP-43 antibody effectively revealed co-localization of BBs and TDP-43 BVD-523 supplier inclusions in the same neurons. TDP-43-immunoreactive wisp-like and skein-like inclusions were closely associated

with BBs (Fig. 1a–d). BBs were also located in the peripheral portion of TDP-43-immunoreactive RXDX-106 solubility dmso round inclusions (Fig. 1e,f). In the spinal cord, 30.5% of anterior horn cells with TDP-43 inclusions contained BBs and 89.8% of anterior horn cells with BBs contained TDP-43 inclusions. In the hypoglossal nucleus, 61.0% of neurons with TDP-43 inclusions contained BBs and 97.2% of neurons with BBs contained TDP-43 inclusions. In the facial nucleus, 76.1% of neurons with TDP-43 inclusions contained BBs and 76.7% of neurons

with BBs contained TDP-43 inclusions. Murayama et al.[7] reported that ubiquitin-positive, ill-defined structures were closely associated with BBs in lower motor neurons in 15 out of 23 cases of sporadic ALS. van Welsem et al.[11] immunohistochemically examined the lower motor neurons (spinal anterior horn and hypoglossal nucleus) in patients with ALS, using antibodies against cystatin C and ubiquitin, and reported that the incidence

of BBs and skein-like inclusions in the lower motor neurons was 15.3% and 5.3%, respectively. The latter authors have also described that BB-containing neurons were devoid of skein-like inclusions, whereas skein-containing neurons always exhibited BBs.[11] We demonstrated that the incidence of co-localization of BBs and TDP-43 inclusions was 15.2% of total neurons in the anterior horn, 29.2% in the hypoglossal nucleus and 17.3% in the facial nucleus. Thus, the incidence of co-localization of these two inclusions is much higher than was previously thought. The frequency of TDP-43 inclusions Thalidomide was significantly higher in neurons with BBs than in those without BBs in the anterior horn (Fig. 2a), hypoglossal nucleus (Fig. 2b) and facial nucleus (Fig. 2c) in patients with ALS by statistical analysis (Chi-square for independence test and Fisher’s exact probability test). Mantel-Haenszel chi-square analysis showed that the frequency of TDP-43 inclusions in the spinal cord and brainstem motor neurons with BBs was significantly higher (P < 0.01) than in those without. Immunoelectron microscopy demonstrated co-existence of TDP-43-immunoreactive structures and BBs in the cytoplasm of anterior horn cells (Fig. 3a). TDP-43-immunoreactive granulofilametous structures were found within and around moderately electron-dense amorphous BBs, surrounded by vesicular structures (Fig.

In this study, we used computer software and protein network servers to analyze the physical Selleckchem IBET762 and chemical properties, secondary structure and antigenicity of IntC300 in order to search for a novel synthetic peptide vaccine candidate against EHEC O157:H7. We performed a comprehensive analysis of all kinds of parameters

to predict B-cell epitopes, designed a peptide, coupled it with KLH, immunized animals and measured antibody titers. We infected the mice with viable EHEC O157:H7 to explore the immune protection conferred by a synthetic peptide epitope against EHEC O157:H7. We hope to find a novel synthetic peptide vaccine candidate against EHEC O157:H7. The amino acid sequence of intimin (GenBank Accession no: CAA77642, 934 aa) from EHEC O157:H7 strain EDL933 was obtained from GenBank and the 300 amino acids (635–934) Pirfenidone mouse at the C-terminus of intimin were chosen as the target for analysis. Its hydrophilic index (Hopp-Woods method) (14), β-turn (Chou-Fasman method) (15), flexibility

(Karplus-Schulz method) (16), accessibility (Emini method) (17) and antigenicity (Jameson-Wolf method) (18) were analyzed. The B-cell epitopes of IntC300 were predicted using the method of Kolaskar-Tongaonakar from the protein network server at Harvard University (http://bio.dfci.harvard.edu/Tools/antigenic.pl) (19). After a comparative analysis, a short peptide with consistent parameters in all predictions was chosen as the candidate for B-cell epitope of IntC300. Among the five

predicted antigen peptides, KT-12 (KASITEIKADKT) Nitroxoline met the best antigen parameters and was therefore chosen to be synthesized by Shenzhen Hybio Engineering Shenzhen, China. The parameters for this synthetic peptide were as follows: purity >94.1%, molecular weight 1304.5 and weight 10.8 mg. Ten milligrams of KLH (Sigma, St Louis, MO, USA) was taken and fully dissolved in 1 mL of pH 10 borate buffer, after which 1 μmol of synthetic peptide KT-12 was added. Next 1 mL freshly prepared 0.3% glutaraldehyde solution was added while the solution was shaking at room temperature and the resulting mixture left to react for 2 hr (solution turned yellow). Upon completion of the reaction, the tube was inverted several times, then 0.25 mL 1 M glycerol was added and the mixture incubated for 30 min to block unreacted glutaraldehyde. The sample was dialyzed against 2 L pH 8.5 borate buffer overnight (4°C), the buffer changed and dialysis continued for 4 hr, and the final product packaged and stored at −20°C for future use. The same method was used to prepare the conjugate of BSA (Sigma) with KT-12 for ELISA.

S3). This suggests that modulation of DCs by B10 cells observed in other tissue compartments [17] does not occur in the liver. Having demonstrated that hepatic B cells comprise fewer regulatory subsets than splenic B cells, a question not addressed in this study is why Bregs appear not to contribute to the overall tolerogenic liver environment. One possibility may be to prevent overinhibition of immune responses in the liver. As shown in this report and by others [15-17], the TLR-4 ligand LPS, a normal constituent of portal venous blood, is a potent stimulator of B10 cells. The absence of B10 cells and the presence of B cells with proinflammatory potential in an overall tolerogenic liver environment

could help to balance the hepatic capacities of immune tolerance and immune stimulation. Our data presented here show that the absence of hepatic B cells compromises further the capacity of mDCs to respond to LPS (Fig. 3). To obtain sufficient numbers of liver Wnt inhibitor mDCs for

analysis, Flt3L-treated mice were used in Fig. 3 and Supplementary Figs S2 and S3. We are aware of the caveat that Flt3L might modify the composition of mDC subsets as well as other cells. Extended experiments using animal models are find more needed to confirm the positive regulation of liver mDCs and liver immune responses by hepatic B cells. Future research to understand more clearly the mechanisms underlying hepatic B cell activation and function is merited, and may lead to improved understanding and therapy of different liver-related pathological conditions. The authors thank Dr David Rothstein for the gift of IL-10 reporter mice and Thomson laboratory members for helpful discussion. The work was supported by NIH grant P01AI81678 (A.W.T.), SPTLC1 grant (874279717) from the Roche Organ Transplantation Research Foundation (A.W.T.) and by an American Society of Transplantation Basic Science Fellowship awarded to Hong Zhang. Hong Zhang did most of the experiments and wrote the manuscript, Donna

Beer Stoltz performed immunofluorescence, Geetha Chalasani provided direction for B cell subset analysis and Angus W. Thomson provided intellectual input and guided the preparation of the manuscript. The authors declare no financial or commercial conflicts of interest. Fig. S1. Expression of cell surface activation markers on murine B cells following in-vivo poly I:C administration. C57BL/6 (B6) mice were injected intraperitoneally (i.p.) with lipopolysaccharide (LPS). On days 0 and 1 post-injection, the mice were examined for the expression of the indicated surface molecules on spleen versus hepatic B cells; n = 4 mice per group. On day 1, both liver and splenic B cells up-regulated expression of CD39, CD40, CD80 and CD86; *P < 0·05. No significant difference was observed between the liver and spleen. Data are representative of two independent experiments. Fig. S2. Close proximity of B cells (CD19+) and dendritic cells (DCs) (CD11c+) in liver parenchyma.

In this section, we will discuss the pathological role of the STAT3 pathway and STAT6 pathway in M2-like TAM polarization, and the pharmacological effects of the agents that inhibit these pathways. Several other pathways and M2 targeting agents will be outlined at the end of this section. STAT3 is consistently active in many tumours and acts as a negative regulator for macrophage activation and the host’s inflammatory responses.[120] When the activation of STAT3 was blocked, either with a dominant negative variant or an antisense oligonucleotide, macrophages could increase

the release of IL-12 and RANTES and reverse the systemic immune tolerance.[121] Now, some STAT3 inhibitors are under investigation. For instance, a small molecular inhibitor of STAT3 (WP1066) was found to reverse immune tolerance in patients with malignant glioma, correlating with selectively Selleckchem Silmitasertib induced expressions of co-stimulatory molecules (CD80 and CD86) on peripheral macrophages and tumour-infiltrating microglias, and immune-stimulatory cytokines (e.g. IL-12).[122] Two clinical tyrosine kinase inhibitors (sunitinib and sorafenib) have shown their inhibitory

effects on STAT3 in macrophages in vitro.[123, 124] Sorafenib can restore IL-12 production but suppress IL-10 expression in prostaglandin E2 conditioned macrophages, indicating its effects on reversing the immunosuppressive cytokine profile of TAMs.[124] Moreover, two newly identified inhibitors of M2 differentiation are corosolic acid and oleanolic MLN8237 datasheet acid. They can also suppress the activation Calpain of STAT3.[125, 126] Actually, other novel STAT3 inhibitors, such as STA-21, IS3 295 and S3I-M2001, have been found to be efficient against tumours,[127] although their association with TAM re-polarization needs to

be shown. Another STAT family member important for TAM biology is STAT6. In one study, STAT6–/– mice produced predominantly M1-like tumoricidal TAMs with arginaselow and NOhigh, and > 60% of STAT6–/– mice rejected tumour metastasis.[128] Currently, at least three STAT6 inhibitors (AS1517499, leflunomide and TMC-264) have been identified. But their actions as modulators of TAMs remain to be clarified. Instead, several up-/down-stream mediators of STAT6 are more impressive because they could act as modulators of TAM function. These modulators include phosphatidylinositol 3-kinase (PI3K), Src homology 2-containing inositol-5′-phosphatase (SHIP), Krüppel-like factor 4 (KLF4) and c-Myc. PI3K positively regulates STAT6 activation in macrophages, whereas SHIP negatively regulates PI3K. Either PI3K inhibition or SHIP over-expression has been found to decrease the activity of the STAT6 pathway and to reduce M2 skewing of macrophages.[129] Therefore, the agents that are able to inhibit PI3K or stabilize SHIP activity may be therapeutic adjuvants for cancer. KLF4 is another interesting modulator protein of STAT6. Liao et al.[130] reported that the expression of KLF4 was induced in M2 macrophages and reduced in M1 macrophages.

In activated T cells, NF-κB transcription

factors, by co-operating with a number of transcriptional learn more regulators, enhance the expression of several genes, including those for the mitogenic cytokine interleukin (IL)-2 and its high-affinity receptor IL-2RA.17,18 Upon interacting with its receptor, IL-2 elicits the co-ordinated activation of several intracellular signalling pathways that promote entry of T cells into the cell cycle, and clonal expansion. For this reason, CD28 costimulation was proposed to trigger T-cell proliferation through accumulation of IL-2, and subsequent activation of its signalling pathway.19 However, a number of observations in CD28-,20 IL-2-21 and cytotoxic T-lymphocyte antigen 4 (CTLA4)-deficient22 mice, as well as in human primary T cells,3 suggest that in CD28-costimulated T cells additional IL-2-independent cell cycle regulatory mechanisms are required for cell proliferation. Recent studies have shown that the duration

of the TCR/CD28 engagement appears to be a critical factor determining the IL-2 requirement for T-cell proliferation: while a short (20–24 hr) engagement of the TCR and CD28 programmes T cells to proliferate in response to autocrine IL-2, a prolonged (72–96 hr) TCR/CD28 engagement circumvents the need for autocrine IL-2 and supports IL-2-independent lymphocyte proliferation.3,23,24 In this study we aimed to determine if, in human naïve CD4+ T cells, PLX4032 stimulated through a short engagement of the TCR and the CD28 co-receptor, signals from IKK promote T-cell proliferation through IL-2-independent cell-cycle regulatory mechanisms. The effects of a neutralizing anti-human IL-2 antibody on the expression of cell-cycle regulatory proteins involved in the G0/G1 transition

and S phase entry of CD28-costimulated human naïve CD4+ T cells were compared with the effects of two selective, structurally unrelated, cell-permeable IKK inhibitors, BMS-34554125 and PS-1145.26 Our results demonstrate that, in addition to having a pivotal role in the up-regulation of Hydroxychloroquine IL-2 and IL-2RA gene expression, proliferative signals from IKK control the expression of the cell-cycle regulatory proteins cyclin D3, cyclin E and CDK2, and the stability of the F-box protein SKP2 and its co-factor CKS1B, through mechanisms independent of IL-2. BMS-345541[4(2′-aminoethyl)amino-1,8-dimethylimidazol [1,2-a]quinoxaline] (B9935) and PS-1145[N-(6-chloro-9H-pyrido[3,4-b]indol-8-yl)-3-pyridinecarboxamide] (P6624), protease inhibitor cocktail (P8340), antibiotic-antimycotic solution (A5955), Laemmli 2× sample buffer (S3401), phosphate-buffered saline (PBS) (P5493), and β-actin monoclonal antibody (A-5441) were from Sigma-Aldrich (Milan, Italy).

Peripheral blood mononuclear cells (PBMCs) were isolated from buffy coat by Ficoll-Hypaque gradient (GE Healthcare learn more Bio-Sciences) from healthy consenting donors. CD14+ monocytes were purified using CD14+

mAb-conjugated magnetic beads (MACS MicroBeads; Miltenyi Biotec), according to the manufacturer’s protocol. Immature MoDCs were generated by culturing CD14+ monocytes in RPMI 1640 medium containing 10% fetal bovine serum (Invitrogen), 800 U/mL GM-CSF, and 500 U/mL IL-4 (BD Biosciences) for 5 days, obtaining more than 90% CD11c+ cells. Medium was replaced with on day 3. For maturation, MoDCs were stimulated with LPS (100 ng/mL), R848 (10 μM), or poly I:C (0.1 μg/mL). Total lysates with intracellular proteins were obtained by treatment of cells with lysis buffer (62.5 mM Tris-HCl, 2% w/v SDS, 10% glycerol, 50 mM DTT, 0.01% w/v bromophenol

blue). Proteins were separated on 10% SDS-PAGE gels and transferred onto a Hybond-C Extramembrane (GE Healthcare). Phospho-IRF3 (Ser396), phospho-STAT1 (Tyr701), and STAT1 were detected by primary rabbit polyclonal antibodies (Cell Signaling). Detection was achieved by Quizartinib research buy HRP labeled secondary antibodies (Cell Signaling) and a chemoluminescence detection kit (GE Healthcare) according to the manufacturer’s instructions. The allostimulatory capacity of the MoDCs was tested in a MLR. Allogeneic PBMCs were cocultured with differently matured DCs in a 96-well Etomidate tissue culture microplate and the proliferative response was assessed at various MoDC:PBMC cell ratios after 5 days by measuring thymidine incorporation (1 μCi/mL (methyl-3H)thymidine; specific activity,

50 Ci/mmol; New England Nuclear). Supernatants from MoDC:PBMC cells coculture (ratio 1:10) were harvested at 24 h and analyzed for IFN-γ release by ELISA (eBioscience). Cytokine levels in the culture supernatants were evaluated using ELISA kits for IL-12p70 (BD Biosciences) and IFN-γ (eBioscience) according to the manufacturer’s protocol. IFN-β levels were measured in B16 supernatants (PBL Interferon Source) according to the manufacturer’s protocol. Anti-CD86 and anti-CD40 mAbs conjugated with their respective fluorochromes were from BD Biosciences. Cytometry was performed in a FacsCanto II flow cytometer (BD Biosciences) and data were analyzed using FlowJo software (Tree Star Inc.). B16 cell apoptosis was evaluated by a double-staining procedure with the PE Annexin V binding assay and 7-amino-actinomycin D (7-AAD) staining (BD Biosciences) by flow cytometry. For the gated cells, the percentages of annexin V-negative or annexin V-positive cells and 7-AAD-negative or 7-AAD-positive cells, as well as double-positive cells, were evaluated based on quadrants determined from single-stained and unstained control samples.

Finally, by using primary microglia from IL-12 receptor β1-deficient (IL-12Rβ1−/−)

and IL-12Rβ2−/− mice, we demonstrate that IL-12 induces the expression of IL-7 in microglia and macrophages via both IL-12Rβ2 and IL-12Rβ1. These studies delineate a novel biological function of IL-12 that is absent in IL-23 and other p40 family members. “
“Similarly to Helicobacter selleckchem pylori but unlike Vibrio cholerae O1/O139, Campylobacter jejuni is non-motile at 20°C but highly motile at ≥37°C. The bacterium C. jejuni has one of the highest swimming speeds reported (>100 μm/s), especially at 42°C. Straight and spiral bacterial shapes share the same motility. C. jejuni has a unique structure in the flagellate polar region, which is characterized by a cup-like structure (beneath the inner membrane), a funnel shape (opening onto the polar surface) and less dense space (cytoplasm). Other Campylobacter species (coli, fetus, and lari) have similar motility and flagellate polar structures, albeit with slight differences. This is especially true for Campylobacter fetus, which has a flagellum only at one pole and a cup-like structure composed of two membranes. With the recently increasing consumption of poultry Akt inhibitor and poultry products [1-3], Campylobacter, mainly C. jejuni, are the leading cause of bacterial food poisoning in Japan and in many other countries. In Japan, eating of raw animal products such

as chicken meat (“sasami”), chicken liver and cow liver is associated with Campylobacter infections. This organism is also one of the important causes of travelers’ diarrhea [4]. C. jejuni infection commonly causes enteritis, which can manifest as watery diarrhea or bloody see more diarrhea with fever and abdominal cramps [5, 6]. It is also associated with systemic infections such as bacteremia and GBS [6, 7]. Death is rare [5]. In contrast to humans, C. jejuni are part of the normal flora of the intestines of chickens (which have a higher

body temperature, 42°C, than do humans) and are secreted into their stools. This organism almost never causes intestinal diseases in chickens [8]. C. coli is also associated with human infection, accounting for 1–25% of them [3]. Campylobacter jejuni is spiral in shape, has a single flagellum at each pole and exhibits high motility, this last feature being required for its colonization of animal and human test subjects [9]; motility is also important for C. jejuni adherence and invasion in vitro [10]. Over 40 genes are involved in biogenesis and assembly of C. jejuni flagella [11]; however, the bacterial polar structures responsible for their extremely high motility are not known. In this study, we examined the structures in the flagellate polar region of C. jejuni (and other Campylobacter species) by scanning and transmission electron microscopy to gain a better understanding of C. jejuni motility.

In addition, sex hormones were reported to influence the activity of NK cells, which appeared to be critical in the early response to Neospora infection in calves [38, 39] and thus could have an additional impact on the reduction in immunity against N. caninum during pregnancy. However, the data on cytokine transcript expression shown here have been obtained at the end of the experiment and did not provide a clear picture on the timing of events during this website vaccination and challenge Infection. Thus, further studies are required to analyse the cytokine patterns at different time points

during vaccination and infection. In terms of controlling the infection by N. caninum in mice, there is no consensus on the roles of Th1 and Th2 cytokines. Vaccination of mice with native NcSRS2 induced a protective Th2-biased immune response against congenital infection [40].

In accordance with our results, others have suggested that a strong Th1 response may cause foetal death [41, 42] or enhance dissemination selleck chemicals of the parasite by the lack of antibodies [43], which could explain the post-natal death of offspring. In other vaccination studies, high expression of the IFN-γ in vaccinated mice was associated with lack of protection against Neospora challenge [44, 45]. On the other hand, a strongly Th2-type biased immune response was also shown to be associated with exacerbation of the disease [46, 47]. A balanced Th1/Th2 response might confer the necessary protection, especially during pregnancy, to avoid allo-rejection of what is essentially a foreign graft [48]. A number of studies in cattle highlighted Carbohydrate the role of IFN-γ in mediating the pathological consequences of N. caninum infection, leading to foetal death [42, 49, 50]. However, the apparent dual function of IFN-γ

in Neospora infection to promote either pathology relating to foetal loss or inducing protective effects in terms of cerebral infection remains enigmatic. Multiple cytokines act synergistically, and each cytokine may change the action of one or several others [51]. Flynn and Marshall [52] suggested the major factor that could affect and drive the overall actions of IFN-γ during infection may be the proinflammatory mediator, IL-17A. The proinflammatory IL-17A cytokine and corresponding Th17 T cells developed from peripheral multipotent naïve CD4+ T-cell precursors (Th0) have been implicated in the pathogenesis of many infectious diseases, including those caused by the closely related T. gondii. The importance of CD4+ T cells populations for healthy pregnancy and the improper changes linked with adverse pregnancy has been demonstrated [53]. Regulatory T cells (Treg) described as CD4+CD25+Foxp3+ cells are also a subset of CD4+ T cells.

Cryptococcosis was uncommon in children. A total of 57 (59.4%) and 23 (24.0%) patients were Malay and Chinese respectively. Human immunodeficiency virus infection was the major underlying disease reported in 36 (37.5%) patients. C. neoformans var. grubii (serotype A and molecular type VNI) was the predominant Cryptococcus species isolated from 88.5% of cryptococcal cases in this country. Cryptococcal cases due to C. neoformans var. grubii were reported from all the

five regions in Malaysia, with the most number of cases reported from the central and northern regions. Cryptococcus gattii (all were serotype B and molecular types VGI/II) was isolated from all regions except selleckchem the southern region. Compared with a study conducted prior to the AIDS era, our findings show substantial changes in the demographical characteristics of patients. “
“Micafungin is an echinocandin with broad spectrum

activity against Candida spp. and Aspergillus spp. This agent is extensively used to treat these opportunistic fungal pathogens in immunocompromised hosts. This review summarises the clinical pharmacology of micafungin, including pharmacokinetics, pharmacodynamics and use in special PF-562271 in vivo populations. “
“Recurrent vulvovaginal candidosis is a frequent disease with a serious impact on women’s quality of life. Mostly, recurrences are caused by identical Candida strains suggesting C. albicans persistence in the female anogenital area. Objectives of the presented Dichloromethane dehalogenase work were to identify the site of C. albicans persistence, to determine clinical symptoms and signs related to C. albicans positive vulvar cultures and to introduce a new therapeutic approach in women with RVVC. Women with an acute, culture-confirmed episode of RVVC at time of visit were included in this prospective case series. Swabs were obtained from both vagina and inter-labial sulcus. Women received a combined 20-day regimen of 100 mg oral fluconazole

and ciclopiroxolamin cream topically. Follow-up visits were at 3, 6, 9 and 12 months. Of 139 women, 105 (76%) had at least one C. albicans positive culture from the external vulva. Vulvar positive cultures correlated with pruritus (OR 5.4; P < 0.001), vulvar edema (OR 3.8; P = 0.03) and fissures (OR 2.4; P = 0.03). Recurrence rates were 27%, 33% and 34% (at 6, 9, 12 months, respectively). The external vulva appears to represent a site of C. albicans persistence and source of endogenous re-infection in patients with RVVC. The combined treatment compared favorably with published fluconazole maintenance regimens. "
“To detect the frequency and expression of eight ALS (agglutinin-like sequence) genes and the HWP1 genotype in a group of Candida albicans strains isolated from Mexican women suffering from vaginal candidosis. A group of 264 women (age 15–57 years) with vaginal infections were evaluated. C. albicans was identified by PCR amplification of the rRNA internal transcribed spacer regions ITS1 and ITS2.

CD27–CD70 selleck signals are important in the germinal differentiation of B cells into antibody-secreting plasma cells [14–16]. The importance of CD27–CD70 in autoimmune diseases has been underscored by a number of studies. CD27hi plasma B cells were shown to increase in humans afflicted with lupus and the increase was correlated with disease

severity [17]. That CD27hi B cells play critical roles in disease severity in patients with systemic lupus erythematosus (SLE) was confirmed by immunosuppressive therapy that resulted in a reduction of CD27hi plasma cells and concomitant disease remission [18]. In addition, soluble CD27 was found to be elevated in the sera of patients with SLE [19]. Furthermore, large numbers of human leucocyte antigen D-related (HLA-DR)hiCD27+ plasmablasts were found in patients with SLE, their numbers correlating with the extent of lupus activity and anti-dsDNA levels [20]. Similarly, CD70 was overexpressed in aged CD4+ T cells

in Pictilisib solubility dmso Murphy Roth Large (MRL)/lpr mice [21]. Treatment of Swiss Jackson Laboratory (SJL) mice with anti-CD70 antobodies was found to prevent the development of experimental autoimmune encephalomyelitis (EAE) in a TNF-α-dependent manner, but this effect was independent of impairment of T and B cell effector functions [22]. The mechanisms underlying these various effects are not clear. CD4+ T cells have been observed in synovia in rheumatoid arthritis, and psoriatic arthritis patients have been shown to express high levels of CD70 [23]. Treatment with anti-CD70 antibody led to significant improvement in clinical symptoms, and marked reductions

in autoantibody production, inflammation and bone and cartilage destruction [24] (Table 1, Fig. 1a). In chronic inflammatory disorders, B cells can contribute to tissue damage by producing autoantibodies and presenting antigens to T cells. B cells make important contributions to disease severity in autoimmune diseases such as rheumatoid arthritis (RA) Non-specific serine/threonine protein kinase [25]. Thus, CD27+ memory B cells were found to be very abundant in the synovial fluid of patients with juvenile idiopathic arthritis and are believed to prime T cells as a result of their increased expression of CD86 [26]. CD30 was identified originally in 1982 on tumour cells of Hodgkin’s lymphoma [27]. Also called Ki-1, it is a membrane glycoprotein consisting of two chains with molecular weights of 120 and 105 kDa. It is expressed by a subset of activated T cells (both CD4+ and CD8+), NK cells and B cells, and is expressed constitutively in decidual and exocrine pancreatic cells, with maximum expression on CD45RO+ memory T cells [28]. The CD30 ligand (CD30L; CD153) is a 26–40 kDa protein cloned in 1993 and present on a variety of cells, including activated T cells, macrophages, resting B cells, granulocytes, eosinophils and neutrophils [29].