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Background Despite efforts for improvement, cerebrospinal fluid (CSF) shunt failure rates remain high. Recent studies have shown promising reductions in failure rates and infection rates with the routine use of perioperative checklists. This study was conducted to pilot test the feasibility and efficacy of integrating specific CSF shunt surgery quality checks into the World Health Organization (WHO) Surgical Safety Checklist. Methods We designed CSF shunt checklist quality items according to a previously established methodology, including solicitation of best practices by a national multidisciplinary expert panel. We examined adherence to key processes before and after implementation as a measure of the efficacy of the integrated checklist. We then surveyed users regarding perceived checklist utility. Results Overall adherence to shunt-specific key processes increased from 8.6 (95% confidence interval [CI], 7.9–9.2) to 9.9 (95% CI, 9.3–10.4; P = 0.0070) per 12 items, driven by the infection control items (4.7 [95% CI, 4.1–5.3] to 6.0 [95% CI, 5.4–6.4] per 8 items; P = 0.0056). All of the survey respondents indicated that the checklist was easy to use. The majority stated that it helped them feel better prepared to perform the procedure consistently according to evidence-based practice, and that if they were to adhere to the checklist consistently, their rate of shunt failure would be expected to decrease. Conclusions The integration of specialty-specific checks into the WHO Safe Surgery Checklist improved adherence to quality processes and generally was well accepted in our pilot study. A larger clinical trial is needed to assess whether this approach could improve shunt outcomes.

Object As part of a project to devise evidence-based safety interventions for specialty surgery, the authors sought to review current evidence in CSF shunt surgery concerning the frequency of adverse events in practice, their patterns, and the state of knowledge regarding methods for their reduction. This review may also inform future and ongoing efforts for the advancement of neurosurgical quality. Methods The authors performed a PubMed search using search terms “cerebral shunt,” “cerebrospinal fluid shunt,” “CSF shunt,” “ventriculoperitoneal shunt,” “cerebral shunt AND complications,” “cerebrospinal fluid shunt AND complications,” “CSF shunt AND complications,” and “ventriculoperitoneal shunt AND complications.” Only papers that specifically discussed the relevant complication rates were included. Papers were chosen to be included to maximize the range of rates of occurrence for the adverse events reported. Results In this review of the neurosurgery literature, the reported rate of mechanical malfunction ranged from 8% to 64%. The use of programmable valves has increased but remains of unproven benefit even in randomized trials. Infection was the second most common complication, with the rate ranging from 3% to 12% of shunt operations. A meta-analysis that included 17 randomized controlled trials of perioperative antibiotic prophylaxis demonstrated a decrease in shunt infection by half (OR 0.51, 95% CI 0.36–0.73). Similarly, use of detailed protocols including perioperative antibiotics, skin preparation, and limitation of OR personnel and operative time, among other steps, were shown in uncontrolled studies to decrease shunt infection by more than half. Other adverse events included intraabdominal complications, with a reported incidence of 1% to 24%, intracerebral hemorrhage, reported to occur in 4% of cases, and perioperative epilepsy, with a reported association with shunt procedures ranging from 20% to 32%. Potential management strategies are reported but are largely without formal evaluation. Conclusions Surgery for CSF shunt placement or revision is associated with a high complication risk due primarily to mechanical issues and infection. Concerted efforts aimed at large-scale monitoring of neurosurgical complications and consistent quality improvement within these highlighted realms may significantly improve patient outcomes.

Intervertebral disc (IVD) degeneration is a disease of the discs connecting adjoining vertebrae in which structural damage leads to degeneration of the disc and surrounding area. Degeneration of the disc is considered to be a normal process of aging, but can accelerate faster than expected or be precipitated by other factors. The scientific community has come a long way in understanding the biological basis and interpreting the lifestyle implications of IVD degeneration. Of all the diseases of the intervertebral disc, degeneration is the most common and has earned much attention due to its diversity in presentation and potential multiorgan involvement. We will provide a brief overview of the anatomic, cellular, and molecular structure of the IVD, and delve into the cellular and molecular pathophysiology surrounding IVD degeneration. We will then highlight some of the newest developments in stem cell, protein, and genetic therapy for IVD degeneration.

Purpose: We sought to determine if dosimetric differences exist between Ray-Trace (RT) and Monte-Carlo (MC) calculation algorithms for radiosurgery for tumors of the clivus, given their proximity to air-tissue inhomogeneity. Methods: We retrospectively identified 10 patients with a tumor of the clivus where the target was located near an air-tissue interface. CyberKnife treatment was delivered in 1 to 5 fractions. Plans originally calculated with the RT algorithm were re-calculated with the same monitor units (MU) with the MC algorithm. Similarly, plans originally calculated with MC were recalculated with RT. MC calculations were performed using High Resolution with 2% uncertainty on the MultiPlan 4.6 planning system. If the RT plans were originally calculated using water-air density model, they were re-calculated with Body standard density model, and then compared with MC plans computed with Body standard density model. The maximum dose (Dmax) to the planning target volumes (PTV) and critical structures, minimum dose (Dmin) and coverage percentage for the PTV were calculated. Results: For 8 cases, MC PTV Dmin was a median 5% (range 0–10%) and Dmax a median 6% (range 3–9%) higher than for RT. For 2 cases, MC PTV Dmin was 6 and 2% and Dmax was 1 and 3%more » lower than for RT. MC PTV Dmin and Dmax maybe higher or lower than for RT even though the target coverage for MC was less than for RT (median 4%, range 0–13%) with the same MU used. The degree of differences depends on the location of the target relative to the air-tissue inhomogeneity. Examples are shown that the targets are underdosed near the air-tissue inhomogenity. Conclusion: Monte Carlo dose calculations are recommended for targets near tissue homogeneity such as the clivus. Assuming that Monte Carlo more closely approximates the true dosimetry, the use of Ray Trace could overestimate target coverage.« less

Though currently available clinical treatments and therapies have clearly extended the survival of patients with brain tumors, many of these advances are short lived, particularly with respect to high grade gliomas such as glioblastoma multiforme. The missing link to an efficacious treatment of high grade gliomas is a more complete understanding of the basic molecular and cellular origin of brain tumors. However, new discoveries of stem cell and developmental neurobiology have now borne the cancer stem cell hypothesis, drawing off of intriguing similarities between benign and malignant cells within the central nervous system. Investigation of cancer stem cell hypothesis and brain tumor propagation is the current frontier of stem cell and cancer biology. Neurosurgery is also watching closely this promising new area of focus. "Molecular neurosurgery", glioma treatments involving biologics using neural stem cells to target the cancer at the level of individual migratory cell, is a rapidly evolving field. This coming progression of applied cancer stem cell research, coupled with current modalities, promises more comprehensive brain cancer interventions.

The successful treatment and potential treatment of the central nervous system (CNS) pathology remains the most challenging frontier in medical science. The clinical modalities presently available are mostly of limited efficacy and with the aging population, neurodegerative diseases and CNS neoplasms are increasingly prevalent. Neural stem cells (NSCs) have provided optimism for the horizon of therapeutic progress in treating neurological diseases. These mutipotent (able to differentiate into neurons, astrocytes and oligodendrocytes) cells can be obtained directly from the CNS or derived from of embryonic stem cells (ESCs). NSCs can be genetically manipulated in vitro to express desired transgenes for improved expandability, as well as for delivery of toxic payloads. NSCs also demonstrate the ability to engraft within the CNS, migrate to CNS pathology and in certain scenarios to reconstitute the injured or diseased nervous system.

The successful treatment and potential treatment of the central nervous system (CNS) pathology remains the most challenging frontier in medical science. The clinical modalities presently available are mostly of limited efficacy and with the aging population, neurodegerative diseases and CNS neoplasms are increasingly prevalent. Neural stem cells (NSCs) have provided optimism for the horizon of therapeutic progress in treating neurological diseases. These mutipotent (able to differentiate into neurons, astrocytes and oligodendrocytes) cells can be obtained directly from the CNS or derived from of embryonic stem cells (ESCs). NSCs can be genetically manipulated in vitro to express desired transgenes for improved expandability, as well as for delivery of toxic payloads. NSCs also demonstrate the ability to engraft within the CNS, migrate to CNS pathology and in certain scenarios to reconstitute the injured or diseased nervous system.

Just a few short years ago, we still used to think that we were born with a finite number of irreplaceable neurons. However, in recent years, there has been increasingly persuasive evidence that suggests that neural stem cell (NSC) maintenance and differentiation continue to take place throughout the mammal’s lifetime. Studies suggest that neural stem cells not only persist to mammalian adulthood, but also play a continuous role in brain tissue repair throughout the organism’s lifespan. These preliminary results further imply that NSC transplantation strategies might have therapeutic promise in treating neurodegenerative diseases often characterized by isolated or global neuronal and glial loss. The destruction of neural circuitry in neuropathologies such as stroke, Parkinson’s disease, MS, SCI prevents signals from being sent throughout the body effectively and is devastating and necessitates a cure.NSC transplantation is among one of the foremost researched fields because it offers promising therapeutic value for regenerative therapy central nervous system (CNS) diseases. Both chemotropic and exogenous cell graft mechanisms of CNS repair are under review for their therapeutic value and it is hoped that one day, these findings will be applied to human neurodegenerative disorders. The potential applications for NSC transplantations to treat both isolated and global neurodysfunction in humans are innumerable; these prospects include inherited pediatric neurodegenerative and metabolic disorders such as lysosomal storage diseases including leukodystrophies, Sandhoff disease, hypoxic-ischemic encephalopathy and adult CNS disorders characterized by neuronal or glial cell loss such as Parkinson’s disease, multiple sclerosis, stroke and spinal cord injury.

Though currently available clinical treatments and therapies have clearly extended the survival of patients with brain tumors, many of these advances are short lived, particularly with respect to high grade gliomas such as glioblastoma multiforme. The missing link to an efficacious treatment of high grade gliomas is a more complete understanding of the basic molecular and cellular origin of brain tumors. However, new discoveries of stem cell and developmental neurobiology have now borne the cancer stem cell hypothesis, drawing off of intriguing similarities between benign and malignant cells within the central nervous system. Investigation of cancer stem cell hypothesis and brain tumor propagation is the current frontier of stem cell and cancer biology. Neurosurgery is also watching closely this promising new area of focus. “Molecular neurosurgery”, glioma treatments involving biologics using neural stem cells to target the cancer at the level of individual migratory cell, is a rapidly evolving field. This coming progression of applied cancer stem cell research, coupled with current modalities, promises more comprehensive brain cancer interventions.

Though currently available clinical treatments and therapies have clearly extended the prognostic outlook for many patients with brain tumors, many of these advances are short lived, particularly with respect to high-grade gliomas such as glioblastoma multiforme. The missing link to a efficacious treatment of these cancers is a more complete understanding of the basic molecular and cellular origin of brain tumors. However, new discoveries of stem cell and developmental neurobiology have now borne the cancer stem cell hypothesis, drawing off of intriguing similarities between neoplastic and malignant cells within the central nervous system. Investigation of this mechanism of brain tumor propagation is the current frontier of stem cell and cancer biology. Neurosurgery is also watching closely of this promising new area of focus. “Molecular neurosurgery,” glioma treatments involving biologics, such as homing neural stem cells, that target the cancer at the level of individual migratory cell, is a quickly developing field. This coming progression of applied cancer stem cell research, coupled with current modalities, promises more comprehensive brain cancer interventions.

Glioma stem cells (GSCs) have higher self-renewal capacity than neural stem cells (NSCs). However it is still not clear how GSCs enhance their self-renewal and whether or not enhanced self-renewal alone without affecting cell proliferation can promote gliomagenesis. Here we report the generation of a novel conditional KO allele of QKI, a tumor suppressor in GBM with RNA binding motif. When QKI was deleted in NSCs isolated from subventricular zone of Nestin-CreERT2 QKIL/L mice, multiple NSC markers were dramatically increased, including Notch1, Sox2, beta-catenin, ID1 and BLBP. When QKI was deleted in adult Nestin-CreERT2 QKIL/L mice, the NSC population, which is characterized by long-term BrdU retention and GFAP+/Nestin+ double positive staining, was greatly increased, indicating that deletion of QKI enhances NSC self-renewal. Surprisingly, we found that deletion of QKI also decreases cell proliferation rate of NSCs/GSCs, suggesting that QKI deletion makes NSCs/GSCs more quiescent. When QKI-/- NSCs were cultured in differentiation medium, they were not able to differentiate like QKI+/+ NSCs, indicating that QKI is required for NSC lineage determination. To determine whether QKI KO promotes gliomagenesis, we generated a Nestin-CreERT2 QKIL/L PtenL/L P53L/L cohort, in which 92% of the mice developed glioblastoma starting at 2 months. However, the Nestin-CreERT2 PtenL/L P53L/L cohort did not develop any glioma up to a year; therefore QKI deletion greatly promotes gliomagenesis. Transcriptomic and proteomic profiling coupled with PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) analyses revealed that genes involved in receptor trafficking were greatly enriched by QKI deletion. Specifically, 34% of the genes up-regulated by QKI deletion are involved in receptor delivery, and 39% of the genes down-regulated by QKI deletion are subunits of receptor degradation machineries such as endosomes and lysosomes. High level of receptor delivery and low level of receptor degradation concomitantly enrich receptors on the membrane and enhance the activity of the receptors that are involved in maintaining stemness, including RTK, Notch1 and Frizzled. Inhibition of the activity of receptors such as EGFR can diminish the enhanced self-renewal and decreased differentiation caused by QKI deletion. Taken together, our data suggest that QKI deletion increases receptor delivery and decreases endocytosis-mediated degradation, consequently enhancing the receptor activity and self-renewal capacity. Therapeutically, because QKI deletion greatly reduces lysosome level and protein degradation capacity, QKI-low cells are under much higher ER-stress compared with QKI-high cells; hence high level of ER-stress may provide an Achilles’ heel for QKI-low glioblastoma, and pharmacologically inducing more ER-stress could render cytotoxicity to QKI-low glioma cells while keep normal cells intact. Citation Format: Takashi Shingu, Allen Ho, Liang Yuan, Jian Hu. QKI deletion enhances self-renewal of glioma stem cells and promotes gliomagenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 978. doi:10.1158/1538-7445.AM2015-978

Object As part of a project to devise evidence-based safety interventions for specialty surgery, we sought to review current evidence concerning the frequency of adverse events in open cerebrovascular neurosurgery and the state of knowledge regarding methods for their reduction. This review represents part of a series of papers written to consolidate information about these events and preventive measures as part of an ongoing effort to ascertain the utility of devising system-wide policies and safety tools to improve neurosurgical practice. Methods The authors performed a PubMed search using search terms “cerebral aneurysm”, “cerebral arteriovenous malformation”, “intracerebral hemorrhage”, “intracranial hemorrhage”, “subarachnoid hemorrhage”, and “complications” or “adverse events.” Only papers that specifically discussed the relevant complication rates were included. Papers were chosen to be included to maximize the range of rates of occurrence for the reported adverse events. Results The review revealed hemorrhage-related hyperglycemia (incidence rates ranging from 27% to 71%) and cerebral salt-wasting syndromes (34%–57%) to be the most common perioperative adverse events related to subarachnoid hemorrhage (SAH). Next in terms of frequency was new cerebral infarction associated with SAH, with a rate estimated at 40%. Many techniques are advocated for use during surgery to minimize risk of this development, including intraoperative neurophysiological monitoring, but are not universally used due to surgeon preference and variable availability of appropriate staffing and equipment. The comparative effectiveness of using or omitting monitoring technologies has not been evaluated. The incidence of perioperative seizure related to vascular neurosurgery is unknown, but reported seizure rates from observational studies range from 4% to 42%. There are no standard guidelines for the use of seizure prophylaxis in these patients, and there remains a need for prospective studies to support such guidelines. Intraoperative rupture occurs at a rate of 7% to 35% and depends on aneurysm location and morphology, history of rupture, surgical technique, and surgeon experience. Preventive strategies include temporary vascular clipping. Technical adverse events directly involving application of the aneurysm clip include incomplete aneurysm obliteration and parent vessel occlusion. The rates of these events range from 5% to 18% for incomplete obliteration and 3% to 12% for major vessel occlusion. Intraoperative angiography is widely used to confirm clip placement; adjuncts include indocyanine green video angiography and microvascular Doppler ultrasonography. Use of these technologies varies by institution. Discussion A significant proportion of these complications may be avoidable through development and testing of standardized protocols to incorporate monitoring technologies and specific technical practices, teamwork and communication, and concentrated volume and specialization. Collaborative monitoring and evaluation of such protocols are likely necessary for the advancement of open cerebrovascular neurosurgical quality.

Background: Waldenstrom’s Macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma with limited options of therapy. The PI3k/Akt pathway is a critical regulator of cell survival. Our previous studies using proteomic analysis have demonstrated upregulation of members of the PI3k/Akt pathway in WM. We examined whether the new Akt inhibitor perifosine (NSC 639966; Keryx, NY) induces cytotoxicity in WM. Methods: WM cell lines (BCWM1 and WSU-WM) and IgM secreting low-grade lymphoma cell lines (MEC1, RL) were used. Primary CD19+ malignant cells were obtained from patients after informed consent. Inhibition of proliferation was measured using the MTT assay; DNA synthesis was measured using the thymidine uptake assay and apoptosis using Apo2.7 flow cytometry. Bone marrow stromal cells (BMSC) confer growth and resistance to conventional treatments. We therefore, tested the effect of perifosine on WM cells co-cultured with BMSC. Immunoblotting for signaling pathways was performed at different time (30 minutes to 16 hrs) and doses of therapy. In vivo activity of perifosine was assessed using a SCID-irradiated model with subcutaneous tumors in which perifosine was administered by oral gavage daily (35 mg/kg/day). A two-sided t-test was used to determine statistical differences. Results: Perifosine inhibited phosphorylation of Akt in a dose- and time- dependent fashion, as well as downstream GSK3a/b and ribosomal phospho-S6. Perifosine inhibited Akt activity as confirmed by Akt kinase assay. Perifosine induced significant cytotoxicity and inhibition of DNA synthesis with an IC50 of 5-20uM in all cell lines tested. Similar effects were observed in primary CD19+ patient WM cells. Perifosine induced apoptosis in WM cells as demonstrated by flow cytometry. The mechanism of apoptosis induced by perifosine was through activation of SAPK/JNK pathway, followed by caspase-8, -9 and PARP cleavage. The JNK inhibitor SP600125 abrogated perifosine-induced apoptosis. The growth inhibitory effects of perifosine were significant even in the presence of BMSC, IL-6 and IGF-1, which induce resistance to conventional therapies. Importantly, perifosine did not induce cytotoxicity in healthy donor peripheral blood mononuclear cells or in hematopietic stem cells in a methylcellulose colony forming cell assay, indicating lack of toxicity on normal cells. Interestingly, MAPK members such as MEK/ERK were activated by perifosine. The MEK inhibitor U0126 significantly enhanced perifosine-induced cytotoxicity in WM cells, indicating that this combination may be synergistic in vivo. Finally, perifosine induced significant reduction in WM tumor growth in vivo, as compared to control cohort treated with vehicle only at week 6 (p=0.05). Conclusion: Perifosine has significant antitumor activity in WM both in vitro and in vivo. These results provide the framework for clinical evaluation of perifosine in WM. Supported in part by the Leukemia and Lymphoma Society, the Lymphoma Research Foundation and an American Society of Hematology Scholar Award. * XL and XJ are co-first authors.

The objective of this study was to determine the molecular alterations that occur at the protein level in patients with WM in order to identify novel targets of therapy, determine new markers of prognosis, and begin to delineate the pathogenesis of WM. Five bone marrow samples were obtained after informed consent from patients with symptomatic WM. Two bone marrow samples were obtained from age-matched controls and were pooled. All samples were purified with anti-CD19+ beads with over 90% purity. Protein quantification was performed and 1ug of protein was obtained for each sample and control. The nanoscale protein micorarray technique (BD Clontech, CA) was used to measure changes in the patterns of protein expression between WM samples and control lymphocytes. This is a new technique that detects differences in protein abundance between the tumor and control samples by hybridizing fluorescently labeled (Cy3 and Cy5) protein mixtures onto slides spotted with 512 monoclonal antibodies against human polypeptides. It requires minimal amount of protein. Two microarray slides were used for each experiment and a control experiment of control versus control was performed for normalization of the data. The slides were scanned using the Axon GenePix 4000B scanner. Two ratios were generated from the spot images for each protein target. The mean of the ratios of Cy5/Cy3 of both slides were analyzed using Clontech software and used to calculate an Internally Normalized Ratio (INR = ÷Ratio1/Ratio2, ratios 1 and 2 correspond to slides 1 and 2) for each spot on the array. The INR values were input into GeneSpring 6.0 software (Silicon Genetics, Redwood City CA). The data was normalized to the mean INR of the control samples. Proteins whose expression fold change relative to control was greater than 1.3 fold were determined. All samples were of symptomatic WM. There were 3 females and 2 males. The median age was 61 years (range, 47–83). Four patients were newly diagnosed and one had received prior rituximab, CHOP ad thalidomide therapy. Clustering analysis did not demonstrate a difference between newly diagnosed and treated samples. There were 72 proteins up or downregulated by 1.3 fold in all WM samples as compared to control. These included proteins in the PI3K pathway such as VHR, PTP1B, PI3K (p110alpha) and Rb2. Protein kinases such as PKCi, PKCbeta, PKC gamma, PKC delta, PLCgamma were all upregulated in WM samples. Other proteins included the B-cell specific activator protein PAX-5, the ubiquitin protein UBCH6, the STAT kinase STAT4, the GTPase Rho A-binding kinase ROK alpha, and the apoptosis protein SMAC/DIABLO. We demonstrate that several isoforms of the PKC family of proteins are upregulated in WM. PKC proteins regulate apoptosis, proliferation and migration in many cancer cells. These proteins may be useful targets of therapy in future clinical trials in WM. Other inhibitors that may be useful in WM include ubiqutin/proteosome inhibitors such as bortezomib and PI3K pathway inhibitors such AKT or mTOR inhibitors. Our results also confirm the presence of PAX-5 in WM consistent with previous cytogenetic studies. Supported in part by an ASH scholar award and Research Fund for Waldenstrom.

The tumor necrosis factor family member CD70 (CD27L) is an integral membrane protein transiently expressed on antigen-activated T and B lymphocytes. CD70 regulates lymphocyte survival and differentiation of CD27 positive resting T cells and antigen-primed B cells. Aberrant CD70 expression has been detected on hematologic tumors including diffuse large cell, follicular, and mantle cell lymphomas, chronic lymphocytic leukemia and Reed-Sternberg cells in Hodgkin’s disease. Here we report for the first time the expression of CD70 on multiple myeloma (MM). Nine of thirteen MM cell lines examined expressed detectable surface CD70 with receptor copy numbers ranging from 9,000 to 145,000. Furthermore, seven of twelve primary MM isolates and six of six Waldenstrom’s macroglobulinemia (WM) isolates tested were positive for CD70. The presence of CD70 on MM and WM, combined with the antigen’s limited expression on normal non-hematopoietic tissues makes CD70 an attractive target for antibody-directed therapy of plasma cell disorders. We have engineered chimeric and humanized variants (human IgG1 isotype) of the murine anti-CD70 monoclonal antibody, 1F6. Both chimeric and humanized 1F6 variants retain the binding specificity of the murine parent monoclonal antibody (mAb) and acquired Fc-dependent effector functions including antibody-dependent cellular cytotoxicity (ADCC), complement dependent cytoxicity (CDC) and macrophage-mediated antibody-dependent cellular phagocytic (ADCP) activities against CD70+ tumor cells. Specific lysis (ADCC, CDC) or tumor cell uptake (ADCP) was observed when engineered anti-CD70 mAb were used at ≥10 ng/mL against a panel of CD70-expressing hematologic tumors. The significance of these in vitro observations was further established by the ability of anti-CD70 mAb to significantly improve the survival of mice bearing disseminated CD70-expressing tumors. The in vitro function and in vivo efficacy of anti-CD70 were dependent upon Fc-FcγR interactions, as activity and survival benefit was lost with anti-FcγR blockade or when the targeting antibody was engineered to eliminate FcγR binding. Our data suggest that humanized anti-CD70 mAb possesses potent antitumor activity and has potential utility for therapy of hematologic cancers including MM and WM.

Summary: Tim-1, a phosphatidylserine receptor expressed on B cells, induces interleukin 10 (IL-10) production by sensing apoptotic cells. Here we show that mice with B cell-specific Tim-1 deletion develop tissue inflammation in multiple organs including spontaneous paralysis with inflammation in the central nervous system (CNS). Transcriptomic analysis demonstrates that besides IL-10, Tim-1+ B cells also differentially express a number of co-inhibitory checkpoint receptors including TIGIT. Mice with B cell-specific TIGIT deletion develop spontaneous paralysis with CNS inflammation, but with limited inflammation in other organs. Our findings suggest that Tim-1+ B cells are essential for maintaining self-tolerance and restraining tissue inflammation, and that Tim-1 signaling-dependent TIGIT expression on B cells is essential for maintaining CNS-specific tolerance. A possible critical role of aryl hydrocarbon receptor (AhR) in regulating the B cell function is discussed, as we find that AhR is among the preferentially expressed transcription factors in Tim-1+ B cells and regulates their TIGIT and IL-10 expression.