Such differences may be one of the causes of cell tropism for PrP

Such differences may be one of the causes of cell tropism for PrPSc accumulation, and furthermore, might result in the prion strain-specific PrPSc accumulation pattern in the brain. Species specificity in cell-free conversion has been reported

(14, 23), and the products preserve strain-specific properties (24). These data suggest that the cell-free conversion reaction mimics some aspects of in vivo conversion of PrPC into PrPSc. In this study, we demonstrated that the effect of reducing conditions and removal of Cys residues on binding and conversion differed among prion strains; indeed, these may mirror prion strain properties in vivo. In fact, classification of the five prion strains Opaganib supplier by their binding and the conversion efficiencies correlated well with classification according to their biological and biochemical properties. Therefore, the

in vivo properties of each strain likely correlate with their conversion capacity. Binding and conversion assays may thus aid in the classification of prion strains. Reduction of the Akt inhibitor intramolecular disulfide bond did not interfere with binding of PrPSc to MoPrP and conversion of MoPrP into PrPres. However, substitution of Cys with Ser in MoPrP inhibited binding and conversion of the ME7 and Obihiro strains and conversion of the Chandler and 79A strains. Therefore, Cys residues may play a key role in the conversion and binding of Chandler and 79A, ME7, and Obihiro PrPSc. However, we cannot rule out the possibility that such a substitution alters the tertiary structure

of the prion protein. Addition of DTT significantly increased the ADP ribosylation factor conversion efficiencies of MoPrP and the Cys-less mutant driven by mBSE PrPSc. This suggests that the effect of DTT may be mediated by a mechanism other than cleaving of the disulfide bond in MoPrP. DTT diminishes the carbohydrate binding activity of a Cys-less mutant of pigpen as well as inhibiting the intact molecule (25). Therefore, in an mBSE-seeded cell-free conversion, DTT may improve the efficiency of mBSE-seeded conversion independently of the reduction of disulfide bonds. In summary, reducing conditions did not inhibit conversion in vitro and markedly increased mBSE-seeded conversion. This suggests that cell-free conversion under reducing conditions mimics the conversion of PrPC into PrPSc within endosomes and lysosomes. In addition, classification of prion strains by their efficiency at binding and conversion of both MoPrP and its Cys-less mutant in the absence and presence of DTT correlates well with classification based on biological and biochemical properties. Therefore, the cell-free conversion assay may be useful in discriminating between prion strains. We are grateful to Dr.

p53−/− mice are more susceptible than WT mice to low dose strepto

p53−/− mice are more susceptible than WT mice to low dose streptozotocin-induced diabetes, a condition that

requires lymphocytes for induction of the disease 9 and destruction of islets. T-cell dependent collagen- and methylated BSA-induced arthritis, but not passive Ab-induced selleck compound arthritis, was more severe in p53−/− mice than in WT counterparts 10, 11. Increased expression of p53 in brain parenchymal T cells of rats with EAE has been reported and this expression was highest at the peak of the disease and declined thereafter, suggesting a role for p53 in pathogenesis of EAE 12. In accordance, p53−/− mice developed more severe EAE than WT mice following immunization with myelin oligodendrocyte glycoprotein peptide 35–55 13. These studies indicate a possible role of p53 in suppressing T-cell responses in vivo. However, a detailed mechanistic study regarding the role of p53 in regulating T cells responses is poorly defined. By analogy to the well-known tumor suppressor functions, p53 may mediate cell cycle and/or apoptosis signals that limit T-cell responses. In vitro studies have AZD2014 solubility dmso shown that activation-induced cell death (AICD) is comparable

in preactivated WT and p53−/− T cells 14, 15. Therefore, it is surprising that 70–90% of p53−/− mice preferentially develop lymphomas, most of which are thymic lymphomas 16, 17, suggesting a pivotal role for p53 in regulating T-cell apoptosis in vivo under normal physiological conditions. Although gamma radiation-induced apoptosis of thymocytes is dependent on p53 18, 19, it is very difficult to believe that under normal housing conditions, p53−/− mice are being exposed to a dose of ionizing/gamma radiation that would otherwise cause apoptosis of WT T cells. The major role of p53 is to induce cell cycle arrest in response to DNA breaks, allowing DNA repair to take place

and thus correct mutations in DNA. Therefore, it is anticipated that DNA breaks may lead to oncogenic mutation and development of lymphomas in p53−/− CYTH4 mice. RAG product-mediated cleavage of specific DNA sequences is required for assembly of TCR genes. The rarity of clonal chromosomal translocations involving TCR loci in lymphomas of p53−/− mice and development of T-cell lymphomas in p53−/−RAG1−/− and p53−/−RAG2−/− mice suggest that RAG-mediated DNA breaks are not required for development of T-cell lymphomas in the absence of p53 20. If RAG-mediated programmed DNA breaks are not required for development of lymphomas in p53−/− mice, what is the stimulus for spontaneous development of lymphomas in p53−/− mice? Alternatively, double stranded DNA breaks that arise in S-phase through DNA replication errors during physiological expansion of immature and mature T cells during their development, maintenance and/or immune responses could contribute toward oncogenic mutations and development of lymphomas in p53−/− mice.

4%) (P = 0 011) and MUI occurred in four (36 4%) (P = 0 011) Con

4%) (P = 0.011) and MUI occurred in four (36.4%) (P = 0.011). Conclusion: Significant risk factors for the development of SUI and MUI after transvaginal simple diverticulectomy include a UD measuring over 3 cm and a UD located in the proximal urethra. “
“In the urine storage

phase, mechanical stretch stimulates bladder afferents. These urinary bladder afferent sensory nerves consist of small diameter Aδ- and C-fibers running in the hypogastic and pelvic nerves. Neuroanatomical studies have revealed a complex neuronal network within the bladder wall. The exact mechanisms that underline mechano-sensory transduction in bladder afferent terminals remain ambiguous; however, a wide range of ion channels (e.g. TTX-resistant Na+ channels, Kv channels and hyperpolarization-activated cyclic nucleotidegated

cation channels, degenerin/epithelial Na+ channel), and receptors (e.g. TRPV1, TRPM8, TRPA1, P2X2/3, etc.) have been identified this website at bladder afferent terminals and have implicated in the generation and modulation of afferent signals, which are elcited by a wide range of bladder stimulations including physiological bladder filling, noxious distension, cold, chemical irritation and inflammation. The mammalian transient receptor potential (TRP) family consists of 28 channels that can be subdivided into six different classes: TRPV (Vanilloid), TRPC (Canonical), TRPM (Melastatin), TRPP (Polycystin), TRPML (Mucolipin), and TRPA (Ankyrin). TRP

channels are activated by a diversity of physical (voltage, heat, cold, mechanical stress) or chemical (pH, osmolality) stimuli and by binding of specific ligands, enabling them to act as multifunctional sensors at the cellular level. TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1 have been described in different parts of the urogenital tract. Although only TRPV1 among TRPs has been extensively studied so far, more evidence is slowly accumulating about the role of other TRP channels, ion channels, and receptors in the pathophysiology of the urogenital tract, and may provide a new strategy for the treatment of bladder dysfunction. “
“To evaluate relation between red cell distribution width (RDW) and benign prostatic hyperplasia (BPH). The overall study population consisted of 942 men with lower urinary tract symptoms (LUTS), ranging else in age from 60 to 85 years old. Patients with disorder or medication that can influence lower urinary tract or erythrocytes were excluded from the study. The relationship between RDW, white blood cell (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and prostate volume, International Prostate Symptom Score (IPSS) were assessed with multivariate linear regression model. Patients were analyzed in four groups stratified according to the quartiles of prostate volume. The one-way analysis of variance (anova) was used to compare RDW, WBC CRP, and ESR between different quartiles of prostate volume.

Over the next 3 years she suffered from recurrent sinusitis, otit

Over the next 3 years she suffered from recurrent sinusitis, otitis media, chest infections (sputum cultures positive

for Moraxella catarrhalis and Haemophilus species) and viral warts. She has a sister with features of DBA – low haemoglobin at 10·4 g/dl, raised mean corpuscular volume (MCV), lymphopenia, elevated fetal haemoglobin (HbF) (3%), high erythrocyte adenosine deaminase (eADA) levels, mildly reduced T cell numbers and slight reduction in proliferative responses to standard mitogens. The sister’s immunoglobulin levels, including functional antibody levels, are normal and she has not required any specific therapy for her anaemia. Investigations in infancy showed a normocytic selleck chemicals anaemia, normal serum immunoglobulins [IgG 7·3 g/l (normal range 3·0–10·5), IgA 0·28 g/l (0·1–1·2), IgM 1·07 g/l (0·3–1·5)] and good vaccine responses to conjugated Haemophilus influenzae type b and unconjugated pneumococcal polysaccharide vaccines. By the age of 9, serum IgG levels had dropped to 4·94 g/l (normal range 6·0–13·0). Lymphocyte proliferation responses to phytohaemagglutinin, pokeweed mitogen, OKT3, tetanus, varicella ZD1839 datasheet and herpes antigens were reduced. Intravenous immunoglobulin (IVIG) replacement therapy was commenced, and stopped after 8 years for reassessment of immune function. Four years later, she had persistent anaemia (Hb 10·0 g/dl, MCV 95·6fl) and low IgG (3·37 g/l), IgA (0·96 g/l) and IgM (0·79 g/l). Bone marrow cytogenetic


were normal, excluding microdeletions in 19q13 and 5q- syndrome. Specific antibody tests showed absent antibodies against measles and reduced tetanus and pneumococcal antibody levels. She was diagnosed to have common variable immunodeficiency as no other causes of low IgG and low levels of specific antibodies were identified. High resolution CT scan chest showed evidence of right middle lobe bronchiectasis and bilateral lower lobe bronchiectasis worse on the left. Intravenous immunoglobulin therapy was recommenced at this stage. Lymphocyte subset analysis showed lymphopenia at 833 × 106/µl (normal range 1500–3500), CD3+ T cells 536 (800–2700), helper CD4+ T cells 291 (400–1700), cytotoxic CD8+ T cells 191 (300–1200), CD19+ B cells 158 (100–600) and CD16+CD56+ from natural killer cells 32 (90–600). B cell studies showed a reduced class-switched memory B cell subset at 2·5%. Lymphocyte proliferation responses to OKT3, phytohaemagglutinin and pokeweed mitogen remained reduced (see Table 1). Peripheral blood eADA level performed recently was high at 594 (normal range 40–100 u/l), consistent with the diagnosis of DBA. She has remained well on home therapy with weekly subcutaneous immunoglobulin infusions over the last 3 years. Polymerase chain reaction (PCR)-based methods for mutation detection.  Genomic DNA was extracted from the patient’s leucocytes with a commercial DNA purification kit, as per the manufacturer’s instructions.

doi org/10 1002/eji 201041377http://dx doi org/10 1002/eji 201141 “
“Antigen-loaded dendritic cells (DCs) used as anticancer vaccine holds promise for therapy, but needs to be optimized. The most frequently described DC vaccine is being matured with a cocktail containing prostaglandin

E2 (PGE2DC). However, even though PGE2DCs express both costimulatory and migratory receptors, their IL-12p70-prodcution is low, leading to an insufficient Th1 immune response. As an alternative, α-type-1 polarized DCs (αDC1s) have shown a superior production of IL-12p70 and subsequent activation of effector cells. From chronic lymphocytic leukaemia RG-7388 solubility dmso (CLL) patients, αDC1s can be generated to induce a functional Th1-immune response. Yet, another Pifithrin-�� mw costimulatory receptor, CD70, appears to be essential for optimal DC function by promotion of T cell survival and function. So

far, PGE2 is suggested as one of the most important factors for the induction of CD70 expression on DCs. Therefore, we wanted to investigate whether αDC1s have the ability to express functional CD70. We found that CD70 expression on αDC1s could be upregulated in the same manner as PGE2DCs. In an allogeneic mixed leucocyte reaction, we found that antibody-blocking of CD70 on αDC1s from controls reduced effector cell proliferation although this could

not be found when using CLL αDC1s. Nevertheless, CD70-blocking of αDC1s from both controls and patients with CLL had a negative influence on the production of both IL-12p70 Clomifene and the Th1 cytokine IFN-γ, while the production of the Th2 cytokine IL-5 was enhanced. Together, this study further suggests that αDC1s should be considered as a suitable candidate for clinical antitumour vaccine strategies in patients with CLL. “
“Cytomegalovirus (CMV) infection has been implicated in accelerated T cell ageing. End-stage renal disease (ESRD) patients have a severely immunologically aged T cell compartment but also a high prevalence of CMV infection. We investigated whether CMV infection contributes to T cell ageing in ESRD patients. We determined the thymic output by the T cell receptor excision circle (TREC) content and percentage of CD31+ naïve T cells. The proliferative history of the T cell compartment by determination of the relative telomere length (RTL) and the T cell differentiation status was determined by immunophenotyping. It appeared that CMV infection did not affect thymic output but reduced RTL of CD8+ T cells in ESRD patients. Moreover, increased T cell differentiation was observed with higher percentages of CD57+ and CD28null CD4+ and CD8+ memory T cells. These CD28null T cells had significantly shorter telomeres compared to CD28+ T cells.

(Cary, NC, USA) Differences between the two infection subgroups

(Cary, NC, USA). Differences between the two infection subgroups (suspected

and documented sepsis) and the control group for each parameter at the first and second study CH5424802 periods were evaluated using the one-way anova test followed by the Fisher’s PLSD test, which was also used to estimate differences within the groups at the three study periods. Differences were considered significant at P < 0.05. Diagnostic accuracy of the inflammatory mediators was evaluated by estimating the sensitivity, specificity and the positive and negative predictive value at the first day of suspicion of infection, calculated using the optimal cut-off value. To quantify the overall ability of any study index to discriminate between neonates with infection and those without, infection

receiver operation curves (ROC) were constructed and the area under the ROC was calculated. This allowed comparison of the infection indices independently this website of the selected cut-off point for each of them. In the 25 neonates with a positive blood culture, the following organisms were isolated: Escherichia coli, (7 cases), Klebsiella (3), Staphylococcus aureus (2), Streptococcus group B (2), Corynobacter (1), Listeria (1), Streptococcus viridans (1), Staphylococcus coagulase negative (8). In 13 cases, the sepsis was classified as early (less than third day of life) and in other 12 cases as late (greater than third day). Comparisons between the three groups were made only for the first two study periods as the age of the neonates at the third study period was different (mean age 14, 7, 28 days for the sepsis, suspected infection and control groups, respectively). Table 1 shows the measurements of the parameters examined in the three study groups. At the first study period, CRP, IL1-b, IL6 and TNF-α were higher in the sepsis group than in the other two groups. At the second study period, IL1-b, IL-6 and

TNF-α had decreased in the sepsis group, but remained higher in the other two groups. IgM was DNA Damage inhibitor higher in the sepsis group at the second study period, and IgG was lower in the sepsis and the suspected infection groups at both first and second study periods than in the control group. NK cells and B cells were higher in the sepsis group and in the suspected infection group at the first and second study periods while the CD3+/CD4+, CD3+/CD8+ and CD4+/CD8+ ratios did not differ between the groups at any study period (Table 2). The WBC count, differential count and platelet count in the three groups were similar at all three study periods. In the control group of healthy full-term neonates with no signs of infection, the cytokine levels were low and remained unchanged during the first month of life while the levels of IgA and IgM increased and IgG decreased (Table 1).

Activated DCs present antigens normally not presented via MHC mol

Activated DCs present antigens normally not presented via MHC molecules under non-inflammatory conditions, e.g. in the absence of infection. This might notably be the case for self-antigens released in the inflammatory milieu physiologically or upon immune-mediated tissue damage. A possible candidate in this regard is HSP60, which can enhance the function of CD4+CD25+ Tregs directly 22, but whose immunodominant peptide p277 bears tolerogenic properties in T1D, such that it is now evaluated in clinical studies to treat this disease 47, 48. As discussed above, endogenous molecules like HSP60 may thus be released during viral infection and confer CD4+CD25+ Treg enhancement directly

via TLR2, but also indirectly via antigenic presentation by DCs. In addition, presentation of other self-antigens Selleckchem CT99021 by DCs under inflammatory conditions might promote the recruitment of FK506 research buy diabetogenic CD8+ T cells in the vicinity of DCs and their subsequent impairment by these cells. Such a phenomenon could occur for example through the PD-L1/programmed death-1 pathway, as suggested by our previous study 12. In this regard, our present results and data not shown indicate that lymphoid cells stimulated through TLR2 in vitro or in vivo acquire high PD-L1 expression. In sum, it is possible that the contribution

of DCs in TLR2-mediated prevention of T1D is to promote Treg function while curbing autoreactive responses. A promising alternative to the therapeutic induction or enhancement of Tregs in vivo to treat

T1D is their expansion in vitro for cell-based therapy. Our results suggest that stimulation via TLR2 might be well-suited for this purpose. Strategies exist to grow human CD4+CD25+ Tregs in large numbers in culture 49, and effort is currently undertaken to develop this approach in clinical trials 50. A number of strategies consist of expanding Tregs polyclonally through stimulation via the TCR, along with co-stimulation (e.g. anti-CD3 and anti-CD28). While such expanded Tregs exhibit good preventive capacity in autoimmune diabetes, they seem to show rather limited efficacy in the reversion (as opposed to prevention) of new-onset disease. This may be due in part to their non-antigen-specific nature, but also notably to the inability of TCR-restricted Aurora Kinase stimulation to augment their suppressive function. Our results indicate that stimulation through TLR2 could be used as a means to not only increase the number of CD4+CD25+ Tregs in vitro, but also ameliorate their in vivo tolerogenic property in T1D. We identify here a mechanism by which innate immunity, namely TLR2 stimulation, promotes immunoregulation and controls autoimmune processes in T1D. Therefore, it appears that similar phenomena account for both development and prevention of autoimmune diabetes. This suggests that the recurring occurrence of infectious events during early life might promote autoimmunity but will also drive the immune system to build increased immunoregulatory force.

Based on the imaging results and her clinical symptoms, she was f

Based on the imaging results and her clinical symptoms, she was finally diagnosed with non-herpetic limbic encephalitis

and treated with methyl-prednisolone pulse therapy (1 g/day for 3 days). Immediately after starting steroid treatment, her fever and headache disappeared, and her short-term memory loss subsequently improved. However, because her mild somnolence persisted, a second cycle of methyl-prednisolone pulse therapy (1 g/day for 3 days) was commenced on day 18 of the illness. After Cabozantinib this treatment, the patient recovered completely without any neurological sequelae. As HSV infections are commonly associated with encephalitis, PCR detection of viral DNA in CSF is a popular method for diagnosing encephalitis. In general, patients who are suspected to have encephalitis, including limbic encephalitis, undergo an examination to determine whether the diagnosis is herpes simplex encephalitis. Non-herpetic acute limbic encephalitis case, which has been determined to be HSV-negative by PCR analysis of the CSF, could be caused by any of the six other human herpesviruses. In order to investigate this possibility we used real-time PCR methods, which have been suggested to be valuable tools for diagnosing encephalitis (11–14), to measure the viral DNA load in CSF samples. The reliability of the previously established real-time PCR methods

is Selleckchem Sirolimus high, and the sensitivities of these methods (10 gene copies/reaction) were considered to be sufficient for detection of small amounts of viral DNA in CSF. None of the CSF samples collected from non-herpetic acute limbic DOK2 encephalitis patients contained DNA from the six herpesviruses, except for one patient who was EBV DNA-positive. Although HHV-6 is thought to be a causative agent for post-transplant acute limbic encephalitis (3–5), none of the CSF samples in this study contained HHV-6 DNA. Although in vitro examinations were not performed to evaluate the patients’ immunity, their medical records indicated that all of them appeared to be immunocompetent.

Therefore, although there were a limited number of samples in this study, these results suggest that HHV-6 is not the main causative agent for non-herpetic acute limbic encephalitis in immunocompetent individuals. However, a limitation of this study is that only one CSF sample from each patient was tested. It is well known that repeat examination of CSF samples is useful to determine whether or not causative agents are present in the CSF. Large number of samples should be analyzed to further elucidate this question in a future study. Only one CSF sample contained EBV DNA, and this was at 1184 copies/ml. As the patient did not show typical clinical features of infectious mononucleosis, serological examination for EBV infection was not performed.

Thanks are also due to the many individuals who also help out wit

Thanks are also due to the many individuals who also help out with the CARI Critical Appraisal Training Day, the members of other various CARI Guideline Groups, those involved in Implementation activities and the CARI Steering Committee members for their continued support of CARI. Thanks are also due to the DNT Committee, KHA and the ANZSN Council for their wise and constructive governance of CARI. “
“Date written: June 2007 Final submission: October 2008 No recommendations possible based on Level I or II evidence (Suggestions are based on Level III and IV evidence) There is no evidence of increased problems with fertility or pregnancy complications in female

donors. No recommendation. A frequent question of potential donors of child-bearing age is whether donation will affect the ability to have a normal pregnancy. Furthermore, there is a theoretical concern that increased renal blood flow and GFR during pregnancy could be deleterious BI 6727 order to a solitary kidney. The purpose of these guidelines is to review the available evidence relating to pregnancy outcomes following live kidney donation. Databases searched: MeSH terms and text words for kidney transplantation and living donor were combined with MeSH terms and text words for pregnancy. The search was carried out in

Medline (1966 – September Week 2, 2006). The Cochrane Renal Group Trials click here Register was also searched for trials not indexed in Medline. The National Transplantation Pregnancy Registry (NTPR) [[email protected]] in the U.S. was contacted to provide any additional sources of abstracts. Date of search: 26 September 2006. Update search: Databases searched: MeSH terms and text words for kidney transplantation were combined with MeSH terms and text words for living donor and combined with MeSH terms and text words for open and laparoscopic nephrectomy. The search was carried out in Medline (1966

– March Week 1, 2009). The Cochrane Renal Group Trials Register was also searched for trials not indexed in Medline. Date of searches: 9 March 2009. The largest study by Wrenshall et al.1 is a retrospective questionnaire of female donors. Of 144 respondents (65%) the self-reported incidence Calpain of infertility and miscarriage was no different from those previously reported in a normal population. Pre-eclampsia was self-reported in 4.4% of donors (normal population incidence approximately 6–8%). There was no data on renal function and the true incidence of problems may have been underestimated because of the need for self-reporting. A retrospective review of 39 pregnancies (32 live births)2 in 23 women who had previously donated kidneys did not demonstrate any significant incidence of hypertension or proteinuria during the pregnancies. Ibrahim et al.3 reported on the outcome of 216 donors who had at least one pregnancy after donating a kidney. Of the 1537 female donors attending one centre, 939 responded to a survey regarding pregnancy.

5) In views of the unselective binding specificity of CpGPTO-ind

5). In views of the unselective binding specificity of CpGPTO-induced immunoglobulin (Fig. 6b,c), we argued that binding of CpGPTO to the antigen receptor could drive a ‘PTO- or DNA-reactive’ B-cell subset into receptor revision as reported previously.[31] Intriguingly, high expression of RAG-1 and Ku70 marked a subpopulation of CpGPTO-induced B-cell blasts as cells prone for receptor revision that were shown to originate from IgM+ CD27+ B cells (Fig. 6a). Although the concept that IgM memory B cells undergo receptor revision is controversial, the physiological antigen

promiscuity of the IgM receptor underscores that receptor revision in these cells could be beneficial. Moreover, it is well-acknowledged that marginal zone Selleck Crizotinib B cells (discussed as murine counterparts of human peripheral blood IgM+ CD27+ B cells) are strongly responsive to TLR stimulation.[47-50] Nevertheless, it was recently suggested that CpGPTO induces proliferation of transitional B cells,[51] a B-cell subset expressing polyreactive IgM and sensitive to treatment with syk inhibitors.[52] Albeit the frequency of these cells in freshly isolated peripheral blood B cells from the donors

used in this study was very low (0·1–1%), and blast formation was not observed in the CD27– fraction (Fig. 6a), we cannot exclude transitional B cells as the target subpopulation undergoing TLR9-induced receptor revision. Further studies will be needed to answer this question. Taken together, our data provide evidence CAL-101 chemical structure that TLR9 can participate in receptor revision. This was demonstrated for LC rearrangement (Fig. 5) but could also affect VH element replacement.[53, 54] Our study further suggests that CpGPTO can be used to study receptor revision

triggered by chromatin-bearing autoantigens. It can, however, only be speculated how TLR9 affects receptor Ixazomib revision in vivo: TLR9 could contribute to exceeding a certain activation threshold necessary to tackle receptor revision or could act as a sensor for chromatin-bearing autoantigens, subsequently licensing receptor revision. Hence, a strong and long-lasting B-cell stimulus such as CpGPTO in vitro or that occurring in vivo, i.e. in autoimmune diseases (or possibly that upon CpGPTO administration) could trigger receptor revision in the periphery in the attempt to correct or eliminate autoreactivity as physiologically seen in the bone marrow. Nonetheless, in the periphery this process might result in increased autoreactivity of the immunoglobulin in predisposed individuals. In earlier studies receptor revision is, therefore, viewed as a pathological event. Our results, describe a mechanism possibly contributing to severe adverse events after CpGPTO treatment. Nevertheless, we can only speculate that the observations made in vitro could be associated with the manifestation of autoimmunity in vivo, e.g. the triggering of Wegener granulomatosis reported in the CpGPTO-adjuvanted hepatitis B vaccination trial.