Resection of NAFLD/NASH-related Hepatocellular Carcinoma (HCC): Clinical Features and Outcomes Compared with HCC Due to Other Etiologies.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the leading causes of hepatocellular carcinoma (HCC) worldwide. Limited data exist on surgical outcomes for NAFLD/NASH-related HCC compared with other HCC etiologies. We evaluated differences in clinicopathological characteristics and outcomes of patients undergoing surgical resection for NAFLD/NASH-associated HCC compared with other HCC etiologies. METHODS: Demographic, clinicopathological features, and survival outcomes of patients with surgically resected HCC were collected. NAFLD activity score (NAS) and fibrosis score were assessed by focused pathologic review in a subset of patients. RESULTS: Among 492 patients screened, 260 met eligibility (NAFLD/NASH [n = 110], and other etiologies [n = 150]). Median age at diagnosis was higher in the NAFLD/NASH HCC cohort compared with the other etiologies cohort (66.7 vs. 63.4 years, respectively, P = .005), with an increased percentage of female patients (36% vs. 18%, P = .001). NAFLD/NASH-related tumors were more commonly >5 cm (66.0% vs. 45%, P = .001). There were no significant differences in rates of lymphovascular or perineural invasion, histologic grade, or serum AFP levels. The NAFLD/NASH cohort had lower rates of background liver fibrosis, lower AST and ALT levels, and higher platelet counts (P < .01 for all). Median overall survival (OS) was numerically shorter in NAFLD/NASH vs other etiology groups, however, not statistically significant. CONCLUSIONS: Patients with NAFLD/NASH-related HCC more commonly lacked liver fibrosis and presented with larger HCCs compared with patients with HCC from other etiologies. No differences were seen in rates of other high-risk features or survival. With the caveat of sample size and retrospective analysis, this supports a similar decision-making approach regarding surgical resection for NAFLD/NASH and other etiology-related HCCs.

Developing a Virtual Equity Hub: Adapting the Tumor Board Model for Equity in Cancer Care.

We define cancer equity as all people having as the same opportunity for cancer prevention, treatment, and survivorship care. However, marginalized populations continue to experience avoidable and unjust disparities in cancer care, access to clinical trials, and cancer survival. Racial and ethnic minorities, and individuals with low socioeconomic status, Medicaid insurance, limited health literacy, disabilities, and mental health disorders are more likely to experience delays to cancer diagnosis and less likely to receive guideline-concordant cancer care. These disparities are impacted by the social determinants of health including structural discrimination, racism, poverty, and inequities in access to healthcare and clinical trials. There is an urgent need to develop and adapt evidence-based interventions in collaboration with community partners that have potential to address the social determinants of health and build capacity for cancer care for underserved populations. We established the Virtual Equity Hub by developing a collaborative network connecting a comprehensive cancer center, academic safety net hospital, and community health centers and affiliates. The Virtual Equity Hub utilizes a virtual tumor board, an evidence-based approach that increases access to multi-specialty cancer care and oncology subspecialty expertise. We adapted the tumor board model by engaging person-centered teams of multi-disciplinary specialists across health systems, addressing the social determinants of health, and applying community-based research principles with a focus on populations with poor cancer survival. The virtual tumor board included monthly videoconferences, case discussion, sharing of expertise, and a focus on addressing barriers to care and trial participation. Specifically, we piloted virtual tumor boards for breast oncology, neuro-oncology, and individuals with cancer and serious mental illness. The Virtual Equity Hub demonstrated promise at building capacity for clinicians to care for patients with complex needs and addressing barriers to care. Research is needed to measure the impact, reach, and sustainability of virtual equity models for patients with cancer.

Making computed tomography safer for patients with Crohn's disease.

Background and aims: Computed tomography (CT), often more accessible than magnetic resonance imaging (MRI), remains widely used though radiation exposure is an obvious disadvantage. We previously showed that modern CT technology can achieve over 70% reduction in radiation-dose without loss of accuracy. Here, we compare low- versus conventional-dose CT in patients with known Crohn's disease to assess clinical confidence and accuracy of the low-dose procedure in the semi-acute setting.Methods: A comparative study of low-dose CT with full iterative reconstruction (IR) versus conventional-dose CT was conducted in 50 consecutive outpatients with Crohn's disease. Clinicians were provided with the low-dose images and reports, whereas conventional-dose images were reviewed after 4 weeks.Results: The clinical question was adequately addressed with low-dose IR imaging in all cases. Complications of Crohn's were detected in 37/50 (74%) with no disagreement between low- and conventional-dose imaging. The effective radiation dose reduction was 76.5% (low-dose mean 2.15 mSv versus conventional-dose CT 6.99 mSv).Conclusion: Low-dose IR CT is safe and accurate for evaluating distribution and complications of known Crohn's disease in the outpatient setting. We propose that low-dose radiation imaging should be adopted as standard-of-care for the evaluation of Crohn's disease and an acceptable alternative to MR particularly in the acute setting. ClinicalTrials.gov: NCT03140306.

Diagnostic accuracy of ultrasonography-guided core needle biopsy of parotid gland neoplasms: A large, single-institution experience in United Kingdom.

Salivary gland tumours present a pleomorphic and complex morphology and, apart from the most common neoplasms with well-established histopathological criteria, may create diagnostic difficulty for histopathologists. The majority of salivary gland tumours occur in the parotid gland and the use of ultrasound guided parotid biopsy (US-PB) has increased. US-PB in contrast with fine needle aspiration (FNA), which is an easy and relatively painless technique, is performed under local anaesthesia, usually by radiologists. US-PB offers some advantages over the FNA such as tumour grading and the possibility of performing immunohistochemistry. We report our experience of the diagnostic value of US-PB in a large, referral centre in the United Kingdom.

Cervical malignant mixed mesonephric tumour: A case report with local recurrence after six-years and next-generation sequencing analysis with particular reference to the ataxia telangiectasia mutated gene.

Malignant mixed mesonephric tumours (MMMsT) of the female genital tract are extremely rare, and the majority are located in the wall of the cervix uteri. At present, there are no reports of the molecular characterisation of MMMsT of the female genital tract. Herein, we report the morphological, immunohistochemical and molecular features of this rare malignancy using next-generation sequencing (NGS) analysis. A 58-year-old woman presented with vaginal bleeding. In 2013, she had been diagnosed with a cervical carcinosarcoma of probable mesonephric origin and International Federation of Gynaecology and Obstetrics (FIGO) stage IB that had been treated by total hysterosalpingo-oopherectomy without adjuvant chemo-radiotherapy. Ultrasonography showed a vaginal mass measuring 25 mm in the maximum dimension. Biopsy was performed and showed a biphasic neoplasm composed of adenocarcinoma and sarcoma. Immunohistochemistry showed positive staining for epithelial membrane antigen (EMA), pancytokeratin (MNF116), paired box 8 (PAX-8), ß-catenin, cytokeratin 7, cyclin D1, GATA3 and CD10. Androgen receptor positivity was detected in very limited areas. Cytokeratin 20, carcinoembryonic antigen (CEA), oestrogen receptor (ER), progesterone receptor (PR), transcription termination factor 1 (TTF1), Wilm's tumour antigen-1 (WT-1), calretinin and p16 were negative. The immunohistochemical profile was consistent with mesonephric origin. NGS analysis identified a variant of the ataxia-telangiectasia mutated (ATM) gene (p.Phe858Leu; c.2572 T>C; COSM21826). The number of detected allele frequency reads of ATM mutation following clinical relapse was higher, compared to its baseline: 65 vs. 96%. The differential diagnosis of MMMsT includes mesonephric hyperplasia, malignant mixed Mullerian tumour (carcinosarcoma), endometrioid adenocarcinoma and endometrial stromal sarcoma. The clinical significance of the observed ATM variant in the case reported herein is unknown. The present findings need further verification, as the mutation in ATM may result in chemotherapy resistance or conversely, may be exploited for targeted therapies.

Baseline Screening MRI Uptake and Findings in Women with ≥ 20% Lifetime Risk of Breast Cancer.

BACKGROUND: The American Cancer Society recommends screening magnetic resonance imaging (MRI) for patients with a ≥ 20% lifetime breast cancer risk. This study assesses the outcomes of baseline MRI screens in women from a high-risk breast clinic (HRBC). METHODS: We retrospectively reviewed patients from our institution's HRBC, excluding those with prior breast cancer and predisposing genetic mutations. Screening MRI was recommended for a lifetime risk of ≥ 20% using the Tyrer-Cuzick model. We determined baseline MRI results, biopsy rates, and frequency of MRI-detected high-risk lesions (HRLs) and breast cancers. RESULTS: Overall, 319 women attended our HRBC; median age was 48 years and 4.7% had prior atypia/lobular carcinoma in situ. Screening MRI was recommended for 282 patients, of whom 196 (69.5%) completed a baseline screen. A Breast Imaging-Reporting and Data System (BIRADS) 3 or 4 finding occurred in 19.6% of patients; 23 (12.3%) required 6-month follow-up MRI, 16 (8.6%) underwent core biopsy, and 4 (2.1%) underwent excisional biopsy after initial core. An additional 7 (3.7%) patients had a non-breast incidental finding. An HRL was identified in 2 (1.1%) patients (atypical ductal and lobular hyperplasia, respectively), and 2 (1.1%) were diagnosed with T1N0 breast cancers. CONCLUSIONS: In the setting of an HRBC, 70% of women with a ≥ 20% lifetime risk of breast cancer pursued screening MRI when recommended. On baseline screen, the rate of MRI-detected breast cancer was low (1%); however, malignancies were mammographically occult and identified at an early stage. Despite a low cancer rate, nearly one in four women required additional diagnostic investigation. Prescreening counselling should include a discussion of this possibility, and longer-term follow-up of screening MRI is needed in this high-risk population.

The Last Day Narratives: An Exploration of the End of Life for Patients with Cancer from a Caregivers' Perspective.

Background: Surviving family caregivers describe the end-of-life experience as "very distressing" and half of those surveyed indicate inadequate emotional support; however, little is known about the causes of distress on the last day of life. Objective: The purpose of this study was to explore the experience of the last day of life from the perspective of the surviving caregiver. Design: The study used a narrative inquiry approach. Setting/Subject: Surviving caregivers of deceased adult cancer patients at a single institution were invited to participate. Measurements: After reviewing, coding, and categorizing the narratives individually, they were collectively considered and thematically analyzed across all cases to provide a summative analysis. Results: Six themes captured the overall experiences: (1) relationships and communication with health care providers impact overall experience, (2) being able to prepare for death was a source of comfort, (3) being a caregiver impacts quality of life and identity, (4) spiritual visitations as a welcome experience, (5) navigating the dying days and early grief period wrought with guilt and closure, and (6) loss of community contributes to distress and distracts from healing. Conclusions: In this study, distress was most often linked to communication failures. Caregivers also experienced distress and guilt related to the loss of their caregiver role. Findings also support a need for increased preparation for caregivers. Finally, the study showed the frequency of visitations/spiritual experiences during grieving.

Sinusitis, an under-reported adverse effect in children treated with radioactive iodine therapy and review of the current literature.

Background Radioactive iodine (RAI) therapy is prevalent in the treatment of Graves' disease. Adverse effects in pediatrics are not well-described. Case presentation A 13-year-old female underwent RAI therapy for Graves' disease. Eight days later, she developed facial pain and forehead burning. She was diagnosed with sinusitis and started on pseudoephedrine with resolution in 24 h. Conclusions She endured prolonged discomfort due to an under-recognized adverse effect of RAI. Studies identify the nose as a site of RAI accumulation and smaller nasal passages may predispose children to sinusitis. We report the first pediatric case of sinusitis following RAI. With the increasing use of RAI to treat Graves' disease, clinicians must recognize this adverse effect.

Reverse epitope mapping of the E2 glycoprotein in antibody associated hepatitis C virus.

The humoral immune system responds to chronic hepatitis C virus (HCV) infection by producing neutralising antibodies (nAb). In this study we generated three HCV pseudoparticles in which E1E2 glycoprotein sequence was targeted by the host humoral immune system. We used patient derived virus free Fabs (VF-Fabs) obtained from HCV genotype 1a (n = 3), genotype 1b (n = 7) and genotype 3a (n = 1) for neutralisation of HCVpp produced in this study both individually and in combination. Based on the available anti-HCV monoclonal nAb mapping information we selected amino acid region 384-619 for conformational epitope mapping. Amongst our notable findings, we observed significant reduction in HCVpp infectivity (p<0.05) when challenged with a combination of inter genotype and subtype VF-Fabs. We also identified five binding motifs targeted by patient derived VF-Fab upon peptide mapping, of which two shared the residues with previously reported epitopes. One epitope lies within an immunodominant HVR1 and two were novel. In summary, we used a reverse epitope mapping strategy to identify preferred epitopes by the host humoral immune system. Additionally, we have combined different VF-Fabs to further reduce the HCVpp infectivity. Our data indicates that combining the antigen specificity of antibodies may be a useful strategy to reduce (in-vitro) infectivity.

Humoral immune system targets clonotypic antibody-associated hepatitis C virus.

Hypervariable region 1 (HVR1) is one of the potential neutralization domains in the E2 glycoprotein of hepatitis C virus (HCV). Point mutations of the HVR1 can lead to humoral immune escape in HCV-infected patients. In this study, we segregated the chronically infected viraemic sera from HCV-infected patients into populations of antibody-free virus and antibody-associated virus (AAV) and mapped potential epitopes within the E1E2 gene junction of AAV sequences (residues 364-430). Furthermore, we generated HCV pseudoparticles (HCVpp) derived from AAV sequences to assess their infectivity. We studied the neutralization potential of virus-free Fab obtained from antibody-virus complexes, in the HCVpp system. We observed selective targeting of clonotypic HCV variants from the quasispecies pool. Moreover, we identified potential neutralizing epitopes within the HVR1 and an additional epitope that overlapped with a broadly neutralizing AP33 epitope (amino acid 412-423 in E2). We observed a marked difference in the infectivity of HCVpp generated using E1E2 sequences isolated from AAV. We document reduction in the infectivity of HCVpp-H77 and HCVpp derived from AAV sequences when challenged with virus-free Fab. Our results provide novel insights into the complexities of engagement between HCV and the humoral immune system.

Are there biological differences between screen-detected and interval colorectal cancers in the English Bowel Cancer Screening Programme?

BACKGROUND: We measured biomarkers of tumour growth and vascularity in interval and screen-detected colorectal cancers (CRCs) in the English Bowel Cancer Screening Programme in order to determine whether rapid tumour growth might contribute to interval CRC (a CRC diagnosed between a negative guaiac stool test and the next scheduled screening episode). METHODS: Formalin-fixed, paraffin-embedded sections from 71 CRCs (screen-detected 43, interval 28) underwent immunohistochemistry for CD31 and Ki-67, in order to measure the microvessel density (MVD) and proliferation index (PI), respectively, as well as microsatellite instability (MSI) testing. RESULTS: Interval CRCs were larger (P=0.02) and were more likely to exhibit venous invasion (P=0.005) than screen-detected tumours. There was no significant difference in MVD or PI between interval and screen-detected CRCs. More interval CRCs displayed MSI-high (14%) compared with screen-detected tumours (5%). A significantly (P=0.005) higher proportion (51%) of screen-detected CRC resection specimens contained at least one polyp compared with interval CRC (18%) resections. CONCLUSIONS: We found no evidence of biological differences between interval and screen-detected CRCs, consistent with the low sensitivity of guaiac stool testing as the main driver of interval CRC. The contribution of synchronous adenomas to occult blood loss for screening requires further investigation.

Soft Bodies, Hard Jaws: An Introduction to the Symposium, with Rotifers as Models of Jaw Diversity.

Jaws have evolved numerous times in the animal kingdom and they display a wide variety of structural, compositional, and functional characteristics that reflect their polyphyletic origins. Among soft-bodied invertebrates, jaws are known from annelids, chaetognaths, flatworms, gnathostomulids, micrognathozoans, mollusks, rotifers, and several ecdysozoans. Depending on the taxon, jaws may function in the capture of prey (e.g., chaetognaths and flatworms), processing of prey (e.g., gnathostomulids and onychophorans), or both (e.g., rotifers). Although structural diversity among invertebrates' jaws is becoming better characterized with the use of electron microscopy, many details remain poorly described, including neuromuscular control, elemental composition, and physical characteristics, such as hardness and resistance to wear. Unfortunately, absence of relevant data has impeded understanding of their functional diversity and evolutionary origins. With this symposium, we bring together researchers of disparately jawed taxa to draw structural and mechanistic comparisons among species to determine their commonalities. Additionally, we show that rotifers' jaws, which are perhaps the best-characterized jaws among invertebrates, are still enigmatic with regard to their origins and mechanics. Nevertheless, technologies such as energy dispersive X-ray spectroscopy (EDX) and 3D modeling are being used to characterize their chemical composition and to develop physical models that allow exploration of their mechanical properties, respectively. We predict that these methods can also be used to develop biomimetic and bioinspired constructs based on the full range of the complexity of jaws, and that such constructs also can be developed from other invertebrate taxa. These approaches may also shed light on common developmental and physiological processes that facilitate the evolution of invertebrates' jaws.

Network Analysis of the Chronic Hepatitis C Virome Defines Hypervariable Region 1 Evolutionary Phenotypes in the Context of Humoral Immune Responses.

UNLABELLED: Hypervariable region 1 (HVR1) of hepatitis C virus (HCV) comprises the first 27 N-terminal amino acid residues of E2. It is classically seen as the most heterogeneous region of the HCV genome. In this study, we assessed HVR1 evolution by using ultradeep pyrosequencing for a cohort of treatment-naive, chronically infected patients over a short, 16-week period. Organization of the sequence set into connected components that represented single nucleotide substitution events revealed a network dominated by highly connected, centrally positioned master sequences. HVR1 phenotypes were observed to be under strong purifying (stationary) and strong positive (antigenic drift) selection pressures, which were coincident with advancing patient age and cirrhosis of the liver. It followed that stationary viromes were dominated by a single HVR1 variant surrounded by minor variants comprised from conservative single amino acid substitution events. We present evidence to suggest that neutralization antibody efficacy was diminished for stationary-virome HVR1 variants. Our results identify the HVR1 network structure during chronic infection as the preferential dominance of a single variant within a narrow sequence space. IMPORTANCE: HCV infection is often asymptomatic, and chronic infection is generally well established in advance of initial diagnosis and subsequent treatment. HVR1 can undergo rapid sequence evolution during acute infection, and the variant pool is typically seen to diverge away from ancestral sequences as infection progresses from the acute to the chronic phase. In this report, we describe HVR1 viromes in chronically infected patients that are defined by a dominant epitope located centrally within a narrow variant pool. Our findings suggest that weakened humoral immune activity, as a consequence of persistent chronic infection, allows for the acquisition and maintenance of host-specific adaptive mutations at HVR1 that reflect virus fitness.

The development of a mental health screening tool and referral pathway for police custody.

BACKGROUND: Time spent in police custody should present an opportunity for the early identification of mental ill health. However, this stage of the criminal justice system (CJS) is currently the least developed in terms of its links with health and social services. In England, police custody sergeants administer a standardized risk assessment tool to determine a detainee's need for health-care and/or risk reduction measures while detained. Specialized mental health services are often reliant on this process to generate referrals; however, previous research has shown this to be ineffective. The aim of this study was to develop an improved mental health screening tool and referral pathway to better identify individuals with mental ill health in police custody. METHODS: Mental health professionals, police officers and service users across six sites throughout England took part in qualitative interviews, controlled feedback consultations and an action learning group. RESULTS: By combining a previously validated CJS mental health screening tool with elements of the custody risk assessment, the Police Mental Health Screening Questionnaire (PolQuest) was created. It is accompanied by a referral pathway that outlines services' responsibilities, expected actions and response times. CONCLUSION: The study resulted in a screening tool, referral pathway and training package. PolQuest is expected to facilitate the mental health screening of all adult detainees; improve the early identification of mental ill health; aid timely access to services; provide clear indicators for referral; and reduce ambiguity in the roles and responsibilities of staff across a range of criminal justice and health-care services.

The use of complementary and alternative medicine in an Irish cohort of people with an iatrogenic hepatitis C infection: results from a health and lifestyle survey.

INTRODUCTION: A cohort of people with iatrogenic HCV infection, current or resolved, in Ireland have access to primary and secondary health care services, including specified complementary and alternative medicine (CAM) services, free of charge. OBJECTIVES: Information about their pattern of CAM usage and its association with various demographic and lifestyle factors, and current HCV status, was sought as part of a health and lifestyle survey, in order to provide information for health service planning. DESIGN AND METHODS: The survey was carried out by self-administered postal questionnaire. The level of CAM usage was compared to an age- and sex-matched sample of the general population. RESULTS: The response was 48% (720/1485). Compared to the general population, the HCV population was significantly more likely to have attended a CAM practitioner (50.1% vs 23.9%, OR 3.2; 95% CI 2.7-3.9). Within the HCV population, multivariate analysis showed that females (OR 3.1; 95% CI 1.9-4.9), those who reported fibromyalgia (OR 2.7; 95% CI 1.8-3.9) and those who reported anxiety (OR 1.4; 95% CI 1.0-2.0) were significantly more likely to have used CAM, and smokers significantly less likely (OR 0.6; 95% CI 0.4-0.8). CAM attendance did not vary by current HCV status. Reflexology, acupuncture and massage were the most commonly used forms of CAM. CONCLUSIONS: This study demonstrates that CAM services are used by a high proportion of people with iatrogenic chronic HCV. A more holistic approach to health care, using a biopsychosocial model framework, may better meet the physical and psychological health needs of this group.

The mediating role of depressive symptoms in the relationship between adverse childhood experiences and smoking.

PURPOSE OF THE STUDY: Adverse childhood experiences (ACEs), including various types of abuse and other forms of household dysfunction (i.e. witnessing domestic violence, parental substance abuse, etc.), have been consistently linked to increased rates of health risk behaviors and negative health outcomes in adulthood. Using data from the 2010 Centers for Disease Control and Prevention's (CDC) annual, nationwide Behavioral Risk Factor Surveillance System (BRFSS) telephone survey, this study tested whether self-reported symptoms of depression mediate the significant relationship between the number of ACEs an individual reports (expressed as an "ACE score") and whether they are a current or past smoker. METHODS: A path model was produced using multiple regression, and indirect effects were tested using bootstrapping of 2000 samples. RESULTS: Results of analyses indicated that, among White, Asian, and Hispanic participants, self-reported depressive symptoms are indeed a significant, but only partial, mediator between participants' ACE score and their smoking status. CONCLUSIONS: These results suggest that for smokers of White, Hispanic, and Asian ethnicity, screening for a history of ACEs and treatment for depressive symptoms may be indicated. However, while depressive symptoms may explain some of the associations between ACEs and smoking, these results suggest that other, unexamined factors also contribute to this pathway.

Transcatheter aortic valve implantation in patients with ascending aortic dilatation: safety of the procedure and mid-term follow-up†.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI) does not enable concomitant or simultaneous ascending aortic intervention. This investigation evaluates the safety of TAVI in patients with ascending aortic dilatation and demonstrates mid-term follow-up. METHODS: From November 2007 to December 2012, among 1143 patients with severe aortic stenosis screened for TAVI, a cohort of 457 patients met the inclusion criteria. Of these, a total of 98 patients [71% males, median age 85.0 (9.0) years] were diagnosed with concomitant ascending aortic dilatation (4.0-5.0 cm). An additional 2 patients had an ascending aortic diameter of >5.0 cm. The mid-term follow-up (652.2 patient-years) was 100% complete. RESULTS: There was no iatrogenic dissection in patients with dilatated ascending aorta. Intraoperative aortic rupture occurred in 1 patient with mildly dilatated ascending aorta. One-year survival rates in patients with dilatated and non-dilatated ascending aorta were 65 of 75 (87%) and 201 of 242 (83%, P = 0.573). The mean ascending aortic diameter remained stable at 4.1 (0.2) and 4.7 (0.2) cm in patients with mild and moderate dilatation, respectively, with a median follow-up of 14 months after TAVI. Two patients with an aortic diameter of over 5.0 cm survived the procedure and expired 7 and 20 months after TAVI due to tumour and heart failure, respectively. CONCLUSIONS: Ascending aortic dilatation is diagnosed in almost one-fourth of patients treated with TAVI. Their intraprocedural risk of adverse aortic events is low. The ascending aortic dilatation does not affect mid-term survival in the TAVI population.

Aberrant antibody affinity selection in SHIP-deficient B cells.

The strength of the Ag receptor signal influences development and negative selection of B cells, and it might also affect B-cell survival and selection in the GC. Here, we have used mice with B-cell-specific deletion of the 5'-inositol phosphatase SHIP as a model to study affinity selection in cells that are hyperresponsive to Ag and cytokine receptor stimulation. In the absence of SHIP, B cells have lower thresholds for Ag- and interferon (IFN)-induced activation, resulting in augmented negative selection in the BM and enhanced B-cell maturation in the periphery. Despite a tendency to spontaneously downregulate surface IgM expression, SHIP deficiency does not alter anergy induction in response to soluble hen-egg lysozyme Ag in the MDA4 transgenic model. SHIP-deficient B cells spontaneously produce isotype-switched antibodies; however, they are poor responders in immunization and infection models. While SHIP-deficient B cells form GCs and undergo mutation, they are not properly selected for high-affinity antibodies. These results illustrate the importance of negative regulation of B-cell responses, as lower thresholds for B-cell activation promote survival of low affinity and deleterious receptors to the detriment of optimal Ab affinity maturation.

Dual signaling by innate and adaptive immune receptors is required for TLR7-induced B-cell-mediated autoimmunity.

Toll-like receptor 7 (Tlr7) has been linked to systemic lupus disease incidence in humans and mice, but how TLR7 potentiates autoimmunity is unclear. We used a Tlr7 transgenic (tg) mouse model to investigate the cellular and molecular events required to induce spontaneous autoimmunity through increased TLR7 activity. We determined that Tlr7 exerts B-cell-intrinsic effects in promoting spontaneous germinal center (GC) and plasmablast B-cell development, and that these B-cell subsets are dependent on T-cell-derived signals through CD40L and SLAM-associated protein (SAP), but not IL-17. Antigen specificity also factored into TLR7-induced disease, as both a restricted T cell receptor (TCR) specificity and MHC haplotype H2(k/k) protected Tlr7tg mice from spontaneous lymphocyte activation and autoantibody production. Inflammatory myeloid cell expansion and autoimmunity did not develop in Tlr7tgIgH(-/-) mice, suggesting either that spontaneous TLR7 activation does not occur in dendritic cells, or, if it does occur, cannot drive these events in the absence of B-cell aid. These data indicate that autoimmune disease in Tlr7tg mice is contingent upon B cells receiving stimulation both through innate pathways and T-cell-derived signals and suggest a codependent relationship between B cells and T cells in the development of autoimmunity.