We also evaluated TNF-α levels because TNF-α is known to play a key role in granuloma formation and induction of

macrophage activation [29]. The adenoviral vector expressing the CRT-ESAT-6 fusion protein demonstrated an enhanced ability to induce both of these cytokines in comparison with ESAT-6, which generated levels of cytokines similar to those induced by control vector, Lac. These data support calreticulin being able to enhance immunity against M. tuberculosis antigens. The fact that ESAT-6 alone did not show a better cytokine Selleckchem Ku-0059436 response than the control may be because the C57BL/6 mice do not recognize AdESAT6 epitopes or that the immune response generated in these mice is relatively small and cannot be

observed above background levels. It is important to determine whether the increased response is caused by CD8 and/or CD4 T cells, and whether it is a short- or long-term response. Even though it has been demonstrated previously that intranasal vaccination with adenovirus gives rise to a better immune response in the lung versus parenteral vaccination [10, 12], it would be interesting to demonstrate how this will work in our system. Our results support those of others that also showed that calreticulin increased the production of cytokines important in the control of TB [28]. Other studies have demonstrated this website that using a fusion of different M. tuberculosis antigens provides better control of infection in a mouse model of TB [30]. Thus, we also investigated

whether multivalent or mixture-based adenoviral TB vaccines expressing an ESAT-6–CFP10 fusion protein could perform better than ESAT-6 alone when both were linked to CRT. Our result demonstrated that there was no difference between the ESAT-6 and ESAT-6–CFP10 constructs when the cells were stimulated with the ESAT-6 protein. Thus, the fusion did not increase the T cell response to ESAT-6 nor did the ESAT-6 protein stimulate Isotretinoin the T cell response to CFP10. Accordingly, with this result, none of these adenoviruses gave protection against a challenge infection, even those constructs that induce increased IFN-γ and TFN-α antigen-specific cytokine levels. Others have reported similar data: Bennekov et al. [31], using a recombinant adenovirus expressing Ag85B–ESAT, found no protection after vaccination with adenoviral vaccine and also demonstrated that the adenovirus vaccine induced a non-protective, CD8 T cell-targeted response. Recent evidence also demonstrated differences in the types of protective immune response between the C57BL/6 and BALB/c mouse strains. In BALB/c (H-2d) mice, a dominant CD8 T cell response has been reported [32], whereas in C57BL/6 (H-2b) mice, more balanced CD4/CD8 T cell responses, with a more pronounced CD4 response in the lungs, has been reported [33].

Paradoxically, IFN-γ-producing cells were more prevalent than IL-17-producing cells in CNS mononuclear fractions from CXCR3−/− and CXCL10−/−, as well as WT, mice with MOG-induced EAE (Fig. 1D and H). Enrichment of IFN-γ producers within the CNS could be secondary to preferential trafficking, survival,

and/or expansion of Th1 over Th17 cells. If so, the data in Figure 1 would insinuate that MOG-specific Th1 cells cross the blood–brain barrier and are retained in the brain and SC by a CXCR3/CXCL10-independent mechanism. Alternatively, the majority of CNS-infiltrating IFN-γ-producing T cells could represent transformed Th17 cells that FK866 nmr acquire Th1-like characteristics within the CNS microenvironment (the so-called “ex-Th17” cells) [28]. Th17 cells have been shown to access the CNS via a CCR6-CCL20-dependent pathway, which could explain the dispensability of CXCR3-CXC chemokine interactions for the development of IFN-γ-rich neuroinflammatory infiltrates in MOG-immunized mice [26]. In support of the latter hypothesis, mRNA for IL-17A, RORγt, and

CCL20 was upregulated in the CNS of CXCR3−/−, CXCL10−/−, and WT mice with EAE (Fig. 1I and J). Next, we sought to directly compare the relative dependence of MOG-specific Th1 and Th17 cells on CXCR3/ELR− CXC chemokine interactions for their encephalitogenicity. MOG-primed CXCR3−/− T cells exhibited similar cytokine profiles to their WT counterparts following culture under either Th1- or Th17-polarizing EPZ 6438 conditions (Fig. 2A). As expected, MOG-primed, IL-23-polarized CXCR3−/− Th17 cells were

as efficient as WT Th17 cells in trafficking to the CNS and inducing clinical EAE following adoptive transfer into naïve syngeneic WT hosts (Supporting Information Fig. 1 and Fig. 2B). Surprisingly, IL-12-polarized CXCR3−/− Th1 cells showed no defect in EAE induction (Fig. 2C). In fact, recipients of CXCR3−/− Th1 cells underwent a prolonged disease course with attenuated remission compared to recipients of WT Th1 cells. CXCR3−/− Th1 cells accumulated in the CNS in comparable numbers to WT Th1 donor cells, and the majority of mafosfamide CXCR3−/− donor T cells in the SC were IFN-γ+ (Fig. 2D). CXCL10 is a dominant CXCR3 ligand in the CNS of the EAE models employed in our studies; C57BL/6 mice do not produce functional CXCL11 protein and CXCL10 is significantly upregulated in the inflamed CNS of MOG-immunized mice (Fig. 2E). In parallel experiments, CXCL10−/− and WT hosts exhibited a comparable degree of susceptibility to EAE mediated by WT Th1-polarized, MOG-specific effector T cells (Fig. 2F). Similar to WT recipients of CXCR3−/− Th1 cells, CXCL10−/− recipients of WT Th1 cells experienced a relatively severe disease course. Mice that are genetically deficient in an immunological molecule can develop compensatory pathways as they mature.

To address which downstream metabolic pathway is the major target for the synergistic induction of Foxp3 by simvastatin, we added a farnesyltransferase inhibitor ABT-263 solubility dmso or a geranylgeranyltransferase inhibitor instead of simvastatin. No effects

of the farnesyltransferase inhibitor were seen in cultures with low doses of TGF-β, whereas the geranylgeranyltransferase inhibitor was as effective as simvastatin in functioning synergistically with TGF-β to induce Foxp3. To rule out the contribution of cholesterol biosynthesis in the synergistic effects of simvastatin, we added squalene, which is a downstream metabolite of cholesterol biosynthesis in cells treated with simvastatin, but squalene failed to reverse the synergistic induction of Foxp3 by simvastatin (data not shown).

The major effects of simvastatin on Foxp3 induction involve the geranylgeranylation pathway. Similar conclusions were recently reported by Kagami et al.20 One possible mechanism of action of simvastatin on the induction of Foxp3 might be mediated by epigenetic modulation of the Foxp3 gene. Two CpG islands have been identified in the Foxp3 gene, one in the proximal promoter and the second in the first intronic enhancer region.6,15 The site in the intronic enhancer region is also called the Treg-specific demethylated region and plays a major role in maintaining the stability of Foxp3 expression.15,21 In contrast, methylation of the proximal promoter region is controlled by TGF-β-mediated CHIR-99021 ic50 signals.6 When we analysed the differential effects of simvastatin treatment on these two sites, the CpGs of the Idoxuridine intronic enhancer region were highly methylated in conventional activated T cells, TGF-β-treated T cells, or simvastatin plus TGF-β co-treated cells, and no differences were detected among these groups (data not shown). However, the demethylation status of promoter region correlated with the level of expression of Foxp3 as determined by FACS analysis. Hence, the effects of simvastatin treatment are mediated only by way of

TGF-β-susceptible DNA methylation sites rather than other methylation target sites. A correlation therefore exists between the effects of simvastatin on Foxp3 expression and control of the methylation status of the Foxp3 promoter. Kagami et al.20 have shown that inhibition of protein geranylgeranylation induces SOCS3 expression and attenuates Th17 cell differentiation through the inhibition of STAT3 (signal transducer and activator of transcription 3) signalling. Although inhibition of Th17 differentiation was accompanied by the reciprocal enhancement of Foxp3 differentiation in their studies, we do not believe that induction of SOCS3 expression is the primary mechanism by which simvastatin enhances TGF-β-mediated Foxp3 expression. One of the most striking findings in our studies was that simvastatin could mediate its enhancing effects when added as long as 24 hr after culture initiation.

Previously, an experimental live

attenuated chimeric PCV2 vaccine based on subtype PCV2a and administered IM was tested in a triple challenge model utilizing PCV2b, PRRSV and PPV and compared to other commercially available inactivated or subunit vaccines (41). All of the PCV2 vaccines used in that study MI-503 clinical trial were effective at reducing PCV2 viremia during the growing period and after triple challenge with PCV2-PRRSV-PPV (41). However, in contrast to that study, which used conventional pigs that were seropositive and PCV2 viremic, in the current study we used PCV2 and PRRSV naïve pigs. In the current study, PRRSV viremia occurred in 100% of the animals in all groups infected with PRRSV and was detectable by 7 dpc. Concurrent PRRSV infection did not reduce vaccine efficacy as evidenced by the similar amounts of PCV2 DNA in all vaccinated groups regardless of challenge

status (PCV2 versus PRRSV-PCV2). However, because it is not possible to differentiate between infectious and non-infectious virus particles by a PCR assay, we RXDX-106 research buy were not able to ascertain whether there were differences between groups in the amount of infectious PCV2. Porcine circovirus type 1-2 DNA was identified in individual pigs (5/55) 7 to 21 days post vaccination and was not identified in any of the vaccinated pigs in the later stages of the experiment (0, 7, 14 and 21 dpc). Among the five PCR positive pigs, PCV1-2 DNA was only present at one point in time, indicating a short duration of viremia. This finding confirms the previous findings of Fenaux et al. (39), who did not identify PCV1-2 viremia in any vaccinated pigs. In addition, because co-infecting pathogens such as PRRSV are known to enhance PCV2 replication (23, 24, 50, 51), the absence of PCV1-2 viremia after challenge in PRRSV-infected pigs (IM-PRRSV-I, IM-PCV2-PRRSV-CoI, PO-PRRSV-I, PO-PCV2-PRRSV-CoI), as well as those the absence of PCV2 specific staining in tissues of vaccinated non-challenged

pigs (IM-non-challenged, IM-PRRSV-I, PO-non-challenged, PO-PRRSV-I) further emphasizes the attenuation and safety of this experimental PCV1-2 live vaccine. However, it needs to be emphasized that in the current study PRRSV was given 4 weeks after vaccination. Because PRRSV can be circulating continuously or at any time in relation to vaccination under field conditions, the results in the field could be different because of varying intervals between PRRSV infection and vaccination. A novel aspect of the current study was evaluation of the PO route of administration of the experimental live-attenuated chimeric PCV2 vaccine. Previously, intra-lymphoid and IM routes of vaccination have been utilized for attenuated live PCV1-2 vaccines (37–39).

Furthermore, repeated sequences from the same individual can vary in copy number in different organs and tissues [16]. The general mechanisms

that lead to changes in copy number include homologous recombination and non-homologous repair mechanisms [17]. Changes in copy number might alter the expression levels of genes included in the CNVR. For example, the salivary amylase gene, AMY1, shows CNV in human populations, and the amount of salivary amylase is directly proportional to the copy number of AMY1[18]. More importantly, CNVs shape tissue transcriptomes on a global scale [19]. Additional copies of genes also provide redundancy that allows some copies to evolve new or modified functions while other copies maintain the original function. CNVs can represent benign polymorphic variations or convey clinical phenotypes by mechanisms such as altered gene dosage and gene disruption. CNV see more can be responsible for sporadic birth defects [20], other sporadic traits, Mendelian diseases and complex traits including autism, schizophrenia, epilepsy, Parkinson

disease, Alzheimer disease, human immunodeficiency virus (HIV) infection and mental retardation [21–23]. Interestingly, the set of genes that vary in copy number seems to be enriched for genes involved in olfaction, immunity and secreted proteins [24]. The following diseases are associated with CNVs of the immune genes: (i) CNVs of FCGR3B and FCGR2C (encoding different Fcγ receptors) have been associated with a range of autoimmune diseases, including selleck chemicals llc systemic lupus erythematosus (SLE), polyangiitis, Wegener’s granulomatosis and idiopathic thrombocytopenic purpura [25–27]. (ii) CNVs of the complement genes CFHR1 and CFHR3, which belong to the complement factor H protein family, have been associated with age-related macular degeneration and atypical haemolytic-uraemic syndrome [28–30]. Complement C4 gene copy number has been related directly

with systemic lupus erythematosus (SLE) [31]. (iii) On chromosome 8, a unit of seven β-defensin genes, which encode anti-microbial peptides with other diverse functions such as chemokine activity [32], has variability in its copy number [33]: low copy number has been associated with Crohn’s disease [34,35], and high copy number with predisposition to psoriasis [36]. (iv) In Oxymatrine this review, we will examine one of the most striking examples of CNV in the human genome, the chemokine genes CCL3L and CCL4L. Chemokines are a large superfamily of small structurally related cytokines that regulate cell trafficking of various types of leucocytes to areas of injury, and play key roles in both inflammatory and homeostatic processes. Chemokines are classified into four families based on the arrangement of the first two cysteines of the typically conserved four cysteines: CXC, CC, C and CX3C (where X is any amino acid) [37].

Objective:  In 50 normotensive pregnancies, we examined the relationship between fetal growth, arterial wave reflection, and microvascular function at 22, 34 weeks gestation, and six weeks postpartum. Methods: 

Arterial wave reflection was determined PLX3397 by measuring augmentation index (AIx). Changes in skin microcirculation to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed using laser Doppler imaging. Results:  At 22 weeks, birth weight centile correlated with AIx adjusted for maternal age, MAP, heart rate and timing of reflected wave (r = −0.363, p = 0.012), and with ACh responses (r = 0.317, p = 0.022). ACh responses correlated with adjusted AIx (r = −0.420, p = 0.003). At 34 weeks, birth weight centile correlated with the adjusted AIx (r = −0.301, p = 0.048). ACh responses were borderline

correlated with adjusted AIx (r = −0.323, p = 0.074). At six weeks postpartum, no significant correlations were found between birth weight centile, AIx, and ACh responses. SNP responses did not correlate with AIx or birth weight centile at any time point. Conclusion:  During normal pregnancy, changes in vascular function might reflect important adaptations that are required to facilitate normal fetal growth. This was highlighted in the present study by the findings of a positive correlation between birth weight and endothelial function and a negative correlation between birth weight and arterial wave reflection. “
“To explore the dynamic changes of capillary permeability and the expression of VEGF in cerebral cortex after RIBI. Male SD rats were randomly divided into the RIBI http://www.selleck.co.jp/products/CHIR-99021.html group and control group, and the RIBI group CHIR-99021 order was randomly subdivided into five groups for analysis on day 1, 3, 7, 14, and 28, respectively. We established

an RIBI model, and then evaluated BBB permeability by EB. We also measured the expression of VEGF with IHC stain and western blot. EB extravasation in injured cortex of RIBI group was increased at five time points compared with the control group. The western blot results and IHC revealed that the levels of VEGF expression in the RIBI groups was significantly increased at day 1 compared with the control group, then rose to a maximum at day 7, and subsequently the levels of expression recovered from day 14 to 28. The increases in both BBB permeability and VEGF expression in the brain cortex of RIBI groups at same time period confirmed the possibility of brain injury following irradiation of 6 Gy. “
“This chapter contains sections titled: Introduction Microcirculatory Alterations Visualized with OPS/SDF Imaging Response of Microcirculatory Variables to Therapeutic Interventions Perspective References “
“The knowledge of the basic principles of lymphatic function, still remains, to a large degree, rudimentary and will require significant research efforts. Recent studies of the physiology of the MLVs suggested the presence of an EDRF other than NO.

Once the cytoplasmic tails of α and β subunits undergo FK506 significant separation and the extracellular parts stand up, the high-affinity conformation is generated.6,10 In recent years, growing evidence suggests that both external and

internal mechanical forces play important roles in integrin activation and bidirectional signalling. Fluid shear stress is one major external force that exerts on integrins in circulating leucocytes or those in transendothelial migration process. In contrast, when the cytoplasmic tails of integrins interact with different signalling molecules inside leucocytes, such as talin, kindlins, vinculins and actin, tension or internal force is generated.11 It has been reported that integrin α5β1 is activated by tension force generated between the extracelluar fibronectin-coated surface and the intercellular cytoskeleton.12 Other reports also shed light on our understanding of the connection between chemical signalling and the force mechanics of the integrin network.13 The catch bond formation in the activation of the integrin headpiece is another example of an external force to activate integrins.14 Except for the role of external and internal mechanical BYL719 concentration forces and integrin

conformational changes in affinity modulation, integrin has also been shown to form clusters or accumulate at one PDK4 part of the cell to increase its avidity. In resting T lymphocytes, integrin is distributed evenly on the cell surface. After antigen activation, integrin, especially LFA-1, accumulates at the interface between a T cell and an antigen-presenting cell (APC), resulting in high avidity to enhance ligand binding.15 Not only is LFA-1 accumulated at the interface of a T–APC conjugate,

but it is also highly rearranged, together with other important T-cell surface receptors such as T-cell receptor (TCR)/CD3, to form the immunological synapse that is also termed supramolecular activation cluster (SMAC). Engaged TCRs translocate to the centre of the contact area to form the central SMAC and a ring of LFA-1 forms the peripheral SMAC with the cytoskeleton protein talin. Although the role of the immunological synapse formation in T-cell activation is still unclear, it is generally accepted that the immunological synapse facilitates the translocation of cytolytic granules during the killing of targets by cytolytic T lymphocytes or natural killer cells.16,17 Similarly, LFA-1 also contributes to the formation of virological synapses that enhance the transmission of viruses, such as human T-cell lymphotropic virus 1 or HIV-1 between infected and non-infected cells.18 To bind to integrin ligands, integrin needs to be converted to an active state. Activation of integrin is a highly regulated process.

1,44 To examine whether IFN-α exerts a comparable effect on rhesus B-cell responses under conditions Selleckchem MG132 of TLR7/8 stimulation, rhesus and human B cells were

sorted based on their expression of CD20 and CD19, respectively, and stimulated with TLR7/8-L or CpG C in the presence or absence of exogenous IFN-α. The optimal dose of IFN-α for enhancing B-cell proliferation was first determined on human B cells (Fig. 4a) and used for subsequent experiments (1000 U/ml). This is in the same range as the concentration of IFN-α found in TLR-stimulated PBMC cultures. We found that although there was a considerably lower level of proliferation of rhesus B cells than human B cells, there was a clear augmentative effect of IFN-α in both cases (Fig. 4b). As found for human B cells, IFN-α enhanced rhesus B-cell proliferation the strongest in response to TLR7/8-L although there was also a significant effect in response www.selleckchem.com/products/Everolimus(RAD001).html to CpG C. Our data therefore suggest that the presence of IFN-α significantly enhances rhesus B-cell proliferation in response to TLR7/8-L similarly as previously reported for human B cells. We next investigated whether the IFN-α-mediated increased B-cell proliferation led to an increased differentiation into antibody-secreting cells. We and others have previously found that human B-cell differentiation into antibody-producing cells can be defined

by up-regulation of CD27 to a distinct CD27high population and that the number of CD27high B cells in the culture strongly correlates with the level of antibody production.2,3 Although it was recently shown that CD27 expression identifies B cells of the memory phenotype in rhesus macaques,30 the presence of CD27high B cells

and their potential link to antibody-producing cells were Sunitinib supplier not previously investigated in the rhesus system. To compare the phenotypic differentiation of human versus rhesus B cells, we stimulated B cells with TLR7/8-L and CpG C in the presence or absence of IFN-α and analysed the cells for a series of markers. As expected in the human cultures, a distinct population of CD27high B cells was observed in response to CpG C treatment but not in response to TLR7/8-L alone (Fig. 5a). However, when the B cells were treated with IFN-α together with TLR7/8-L a significant fraction of the B cells differentiated into CD27high cells. In contrast, no CD27high B-cell population was observed in the rhesus cultures in response to any of the stimulation conditions (Fig. 5b). Another indicator of human B-cell differentiation is the loss of CD20 expression together with the up-regulation of CD38.45 In the human cultures, we found that there was a slight up-regulation of CD20 when analysing the total CD20 expression in the culture, which depended on the potency of the stimuli. In contrast, in the human CD27high B-cell population the expression of CD20 was generally lower than in the rest of the B cells.

Adoptive transfer of TCR transgenic T cells specific for LCMV, followed by infection with the chronic strain of the virus, led to clonal deletion of the transferred

cells. However, prior to deletion, the transferred cells were found to lose cytotoxic activity. The chronic viral infection ‘exhausted’ the T-cell adaptive immune response by both clonal deletion and anergy of effector function [4]. The advent of tetramer technology made possible the further refinement of the definition of this process. Detection of Ag-specific cells by tetramers demonstrated that LBH589 price not all clones are deleted in response to chronic LCMV. Thus, the term exhaustion was refined to describe the remaining Ag-specific population with diminished effector function, as measured by CTL activity and the secretion Seliciclib datasheet of IFN-γ [5, 6]. The significance of this exhausted population in human chronic viral infections was subsequently confirmed by the finding that the inhibitory receptor PD-1 marked exhausted cells with diminished proliferative capacity in HIV infection [7]. In order to investigate the transcriptional control of the exhausted phenotype, investigators carried out differential gene expression analysis by microarray of exhausted

versus other Ag-specific populations induced by LCMV. From this analysis, it was discovered that the transcriptional repressor, Blimp-1, was significantly upregulated in the exhausted population [8]. The role of Blimp-1 was first defined in the B lymphocyte, where it plays a vital role in terminal differentiation [9]. The finding that Blimp-1 was expressed in CD8+ T cells [10, 11] prompted investigators to search for a similar role for Blimp-1 within CD8+ T cells. Two independent groups demonstrated that, in response to viral challenge, responding Blimp-1-deficient CD8+ T cells had lower percentages of cells that were terminally differentiated [12, 13]. There has been less information regarding the role of Blimp-1 in murine CD4+ T lymphocytes, though similar attenuation of

in vivo proliferative responses has been observed [14]. In order to determine the role that senescence-associated Blimp-1 Cyclin-dependent kinase 3 has in viral-induced T-cell exhaustion, mice with a T-cell deficiency of Blimp-1 were challenged with chronic LCMV. Blimp-1-deficient cells were found to express, at a lower number and at a lower level, a number of the exhaustion-defining inhibitory receptors, including PD-1 [15]. Alongside its ability to control inhibitory receptor expression in chronic viral infections, Blimp-1 has effects on the other defining characteristic of exhausted T lymphocytes including cytokine production, with Blimp-1 expression being shown to prevent T-cell secretion of IL-2 and IFN-γ in CD4+ T cells [14]. The inability of HIV-exhausted T cells to secrete IL-2 and IFN-γ has been documented and is another feature of the difference between those with CHI and LTNPs [16, 17].

To determine whether PCs secreting IgG to dsDNA and nucleolin make up the majority of IgG-secreting cells in nephritic kidneys, we analyzed BMS-777607 in vitro the total numbers of IgG-secreting cells and the numbers of cells secreting IgG antibodies to dsDNA and nucleolin. ELISPOT with single cell suspension from >30-wk-old female NZB/W F1 mice displaying high titers of anti-dsDNA autoantibodies and proteinuria resulted in significantly increased numbers of infiltrating IgG-secreting cells in their inflamed kidneys when compared to young healthy NZB/W F1 and to non-autoimmune C57BL/6 mice (Fig. 2A).

Most importantly, a large fraction of autoreactive cells produced antibodies reacting with dsDNA (31%) and/or

nucleolin (24%) (Figs. 2B, C and 3B). Hence, autoantibodies, especially anti-dsDNA antibodies involved in the pathogenesis of lupus nephritis, are produced within the inflamed organ. Previous experiments revealed enriched anti-dsDNA antibodies after elution of immunoglobulins from glomeruli, we now demonstrate the existence and disease-dependent appearance of these presumably pathogenic ASCs in the renal tissue of lupus mice 16. Similar to our results, Espeli et al. recently identified anti-dsDNA secreting cells in inflamed kidneys of NZB/W F1 mice. However, they neither analyzed additional autoantigens such as nucleolin nor compared frequencies selleck of autoreactive PCs in kidneys with their frequencies in

spleen and BM 13. Our results suggest that, in addition to circulating anti-dsDNA IgG produced elsewhere, IgG antibodies produced by PCs that have infiltrated inflamed kidneys also contribute to lupus nephritis. Possibly, the absence of autoantibody production with high local antibody concentrations within kidneys could account for the variable or mild nephritogenicity of certain transferred anti-dsDNA antibodies in mouse models 17. However, the pathogenic these relevance of in situ production of autoantibodies yet needs to be determined. Next, we compared the total cell numbers and relative frequencies of cells secreting IgG, anti-dsDNA-IgG and anti-nucleolin-IgG in nephritic kidneys with their frequencies in the spleen and femoral BM (Fig. 3A and B). Interestingly, the percentage of autoreactive PCs within the population of all IgG-secreting cells was increased in the nephritic kidneys of lupus mice with advanced disease compared to spleen and BM (Fig. 3B). Furthermore, a comparison of antigen-specific PCs within each individual mouse seems to indicate that a low frequency of splenic auto-ASCs correlated with an increased frequency within the kidneys and vice versa. Although a preferential migration of autoreactive PCs from the spleen into the inflamed kidneys might explain these findings, this model lacks experimental evidence.