Vertebral Artery to Middle Cerebral Artery Bypass for Flow Augmentation.

BACKGROUND AND IMPORTANCE: Extracranial-intracranial bypass remains an enduring procedure for a select group of patients suffering from steno-occlusive cerebrovascular disease. Although the superficial temporal artery (STA) to middle cerebral artery (MCA) bypass is most familiar among neurosurgeons, particular circumstances preclude the use of an STA donor. In such cases, alternative revascularization strategies must be pursued. CLINICAL PRESENTATION: A 63-year-old female presented with symptoms of hemodynamic insufficiency and was found to have left common carotid artery occlusion at the origin. She experienced progressive watershed ischemia and pressure-dependent fluctuations in her neurological examination despite maximum medical therapy. The ipsilateral STA was unsuitable for use as a donor vessel. We performed an extracranial vertebral artery (VA) to MCA bypass with a radial artery interposition graft. CONCLUSION: This technical case description and accompanying surgical video review the relevant anatomy and surgical technique for a VA-MCA bypass. The patient was ultimately discharged home at her preoperative neurological baseline with patency of the bypass. The VA can serve as a useful donor vessel for cerebral revascularization procedures in pathologies ranging from malignancies of the head and neck to cerebral aneurysms and cerebrovascular steno-occlusive disease.

Transradial flow diversion with an aberrant right subclavian artery.

Transradial access for diagnostic and therapeutic neurointerventional procedures has gained popularity due to a decreased incidence of access site complications and improved patient comfort compared with transfemoral access.1-4 An aberrant right subclavian artery is an aortic arch variant characterized by a right subclavian artery that arises directly from the arch as the most distal great vessel. Transradial access with an aberrant right subclavian artery is anatomically challenging due to the predilection of the catheter system to collapse into the descending aorta. In this (video 1), we describe a step-by-step technique for transradial access in a patient with an aberrant right subclavian artery undergoing endovascular flow diversion for a left superior hypophyseal artery aneurysm. Particular emphasis is placed on the technique for accessing the proximal arch and aortic valve as well as distal catheter navigation while avoiding prolapse into the descending aorta. neurintsurg;15/11/1164/V1F1V1Video 1 .

Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors.

Background: Brain tumors are the leading cause of cancer death for pediatric patients. Pelareorep, an immunomodulatory oncolytic reovirus, has intravenous efficacy in preclinical glioma models when preconditioned with GM-CSF (sargramostim). We report a phase I trial with the primary goal of evaluating the safety of sargramostim/pelareorep in pediatric patients with recurrent or refractory high-grade brain tumors and a secondary goal of characterizing immunologic responses. Methods: The trial was open to pediatric patients with recurrent or refractory high-grade brain tumors (3 + 3 cohort design). Each cycle included 3 days of subcutaneous sargramostim followed by 2 days of intravenous pelareorep. Laboratory studies and imaging were acquired upon recruitment and periodically thereafter. Results: Six patients participated, including three glioblastoma, two diffuse intrinsic pontine glioma, and one medulloblastoma. Two pelareorep dose levels of 3 × 108 and 5 × 108 tissue culture infectious dose 50 (TCID50) were assessed. One patient experienced a dose limiting toxicity of persistent hyponatremia. Common low-grade (1 or 2) adverse events included transient fatigue, hypocalcemia, fever, flu-like symptoms, thrombocytopenia, and leukopenia. High-grade (3 or 4) adverse events included neutropenia, lymphopenia, leukopenia, hypophosphatemia, depressed level of consciousness, and confusion. All patients progressed on therapy after a median of 32.5 days and died a median of 108 days after recruitment. Imaging at progression did not show evidence of pseudoprogression or inflammation. Correlative assays revealed transient but consistent changes in immune cells across patients. Conclusions: Sargramostim/pelareorep was administered to pediatric patients with recurrent or refractory high-grade brain tumors. Hyponatremia was the only dose limiting toxicity (DLT), though maximum tolerated dose (MTD) was not determined.

Early expression of mature αß TCR in CD4-CD8- T cell progenitors enables MHC to drive development of T-ALL bearing NOTCH mutations.

During normal T cell development in mouse and human, a low-frequency population of immature CD4-CD8- double-negative (DN) thymocytes expresses early, mature αß T cell antigen receptor (TCR). We report that these early αß TCR+ DN (EADN) cells are DN3b-DN4 stage and require CD3δ but not major histocompatibility complex (MHC) for their generation/detection. When MHC - is present, however, EADN cells can respond to it, displaying a degree of coreceptor-independent MHC reactivity not typical of mature, conventional αß T cells. We found these data to be connected with observations that EADN cells were susceptible to T cell acute lymphoblastic leukemia (T-ALL) transformation in both humans and mice. Using the OT-1 TCR transgenic system to model EADN-stage αß TCR expression, we found that EADN leukemogenesis required MHC to induce development of T-ALL bearing NOTCH1 mutations. This leukemia-driving MHC requirement could be lost, however, upon passaging the tumors in vivo, even when matching MHC was continuously present in recipient animals and on the tumor cells themselves. These data demonstrate that MHC:TCR signaling can be required to initiate a cancer phenotype from an understudied developmental state that appears to be represented in the mouse and human disease spectrum.

TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells.

Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNF receptor superfamily member 13B (TNFRSF13B) variants, which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells' functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of those with antibody-mediated rejection (AMR) but fewer than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses, we investigated alloimmunity and rejection in mice. Cardiac allografts in Tnfrsf13b-mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b-deficient mice were not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased "natural" IgM and compromised complement regulation, leading to complement deposition in allografted hearts and autogenous kidneys. Thus, WT TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhance morbidity associated with immune responses.

TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.

TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.

Intervention for symptomatic vertebrobasilar disease.

Disease of the vertebral (VA) and basilar arteries (BA) can lead to stroke of the posterior circulation and may warrant management strategies which differ from the anterior circulation. The mechanism and location of the disease determine its natural history and therefore affect the relative risks and benefits of the possible treatment options. Vertebrobasilar (VB) atherosclerotic disease is a source of both hemodynamic and embolic posterior circulation stroke. Advances in medical therapy have decreased the rate of stroke after initial symptomatic presentation. Antiplatelet therapy, blood pressure control, and optimization of secondary risk factors can reduce recurrent stroke risk in both intracranial and extracranial VB disease. However, symptomatic intracranial disease is still associated with a high risk of subsequent stroke, particularly those with hemodynamic compromise who represent a higher risk population. Patients with hemodynamic impairment may benefit from judicious application of endovascular and microsurgical interventions to augment blood flow. Stenting, angioplasty alone, bypass surgery, and endarterectomy, represent endovascular and surgical tools available to address medically refractory VB disease. Apart from atherosclerotic disease, dissection is another etiology of VB stroke, most frequently affecting the extracranial VA. Treatment is predominantly antithrombotic therapy although surgical or endovascular intervention can be required in rare cases of persistent embolism or hemodynamic compromise. In contrast, extrinsic compromise of the VA represents a separate extracranial pathology and is best treated with mechanistically targeted surgeries or extracranial bypass.

Cyclophilins A and B oppositely regulate renal tubular epithelial cell phenotype.

Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial-mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor ß (TGFß)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGFß-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair.

Chemotherapy-induced cellular senescence suppresses progression of Notch-driven T-ALL.

T cell acute lymphoblastic leukemia (T-ALL) is a serious hematologic malignancy that occurs in children and young adults. Current therapies include intensive chemotherapy and ionizing radiation that preferentially kill malignant cells. Unfortunately, they are frequently accompanied by unintended negative impacts, including the induction of cellular senescence and long-term toxicities in normal host tissues. Whether these senescent cells resulting from therapy increase the susceptibility to relapse or secondary cancers is unknown. Using transgenic and pharmacological approaches to eliminate doxorubicin-induced senescent cells in a Notch-driven T-ALL relapse mouse model, we find that these cells inhibit tumor recurrence, suggesting that senescence in response to treatment suppresses tumorigenesis. This finding, together with extensive evidence from others demonstrating that age-associated health problems develop dramatically earlier among childhood cancer survivors compared to age-matched counterparts, suggests a relationship between therapy-induced senescence and tumorigenesis. Although cancer risk is increased through accelerated premature-aging in the long run, therapy-induced senescence appears to protect survivors from recurrence, at least in the short run.

Immunotherapy in pediatric B-cell acute lymphoblastic leukemia.

Advances in multi-agent chemotherapy and supportive care have dramatically improved survival of children with B-cell acute lymphoblastic leukemia (B-ALL); however, patients with relapsed and refractory disease continue to represent a therapeutic challenge. Hematopoietic stem cell transplant was the first immunotherapeutic approach to be used in the treatment of patients with relapsed or refractory disease. However, novel therapies such as bispecific antibodies that engage T-cells and chimeric antigen receptor T-cells (CAR-T) therapy have emerged as novel FDA-approved options that have the potential to become the new standard of care for these difficult-to-treat leukemias. With multiple immunotherapeutic agents in the drug development pipeline, it is important for cancer researchers and oncologists to be familiar with these agents, including their mechanism of action, side effects and efficacy. In this paper, we review the role of the human immune system in the development and treatment of childhood ALL and provide an overview of current and upcoming immunotherapeutic treatment approaches.

Atypical Presentation of a Pediatric Cerebellar Ganglioglioma.

BACKGROUND/AIMS: Gangliogliomas (GGs) are rare central nervous system tumors occurring primarily in the supratentorial compartment with infratentorial instances most often involving the brain stem. Infratentorial GGs typically present with signs and symptoms of increased intracranial pressure (ICP), cranial nerve deficits, or focal cerebellar findings; rarely, these tumors have been associated with focal seizures. METHODS: In this report, we describe an atypical presentation of a cerebellar GG in a 20-month-old male who initially presented with syncope and emesis in the absence of electrographic evidence of seizures, radiographic evidence of hydrocephalus, or elevated ICP. The epidemiology, radiographic, and pathological findings as well as the treatment of these tumors are also discussed. RESULTS: After gross total resection, the patient experienced full resolution of all his preoperative symptoms without the development of new neurological deficits. CONCLUSIONS: Unlike their supratentorial counterparts, infratentorial GGs do not commonly present with seizures although rare reports exist in the literature of seizures attributed to cerebellar GG. Moreover, cerebellar GGs may produce nonspecific symptoms in the absence of concrete diagnostic findings. Such a presentation should prompt further neurological evaluation. Most cases of isolated cerebellar GG can be successfully treated with surgical resection and carry a favorable prognosis.

Protein synthesis inhibition enhances paraptotic death induced by inhibition of cyclophilins in glioblastoma cells.

Treatment of cancer is frequently unsuccessful related to the loss of apoptotic signaling in malignant cells. This is a particular problem for high-grade gliomas, such as Glioblastoma Multiforme (GBM), which are almost universally fatal within a year or so of diagnosis. Novel therapies that capitalize on non-apoptotic cell death pathways may yield more effective outcomes, if their underlying mechanisms can be more completely deciphered. In a recent publication (ref 10), the mechanisms by which cellular cyclophilins support GBM cell survival have been identified. Inhibition of cyclophilins activated paraptosis, which relied on a combination of endoplasmic reticulum (ER) stress and transient activation of autophagy. An important aspect of this effect was the relative rates of cap-dependent versus cap-independent protein synthesis, which were differentially modulated by protein synthesis inhibitors or mTOR inhibition. Although cycloheximide has previously been characterized as an inhibitor of paraptosis, in the case of cyclophilin inhibition, it appears to significantly enhance stress-related paraptosis and cell death. This work reveals an important role for cap-independent protein translation and autophagy in the ability of GBM cells to resist non-apoptotic death, and adds to our understanding of the events that underlie paraptosis.

CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion.

Calcium-modulating cyclophilin ligand (CAML) is an endoplasmic reticulum (ER) protein that functions, along with WRB and TRC40, to mediate tail-anchored (TA) protein insertion into the ER membrane. Physiologic roles for CAML include endocytic trafficking, intracellular calcium signaling, and the survival and proliferation of specialized immune cells, recently attributed to its requirement for TA protein insertion. To identify a possible role for CAML in cancer cells, we generated Eµ-Myc transgenic mice that carry a tamoxifen-inducible deletion allele of Caml. In multiple B-cell lymphoma cell lines derived from these mice, homozygous loss of Caml activated apoptosis. Cell death was blocked by Bcl-2/Bcl-xL overexpression; however, rescue from apoptosis was insufficient to restore proliferation. Tumors established from an Eµ-Myc lymphoma cell line completely regressed after tamoxifen administration, suggesting that CAML is also required for these cancer cells to survive and grow in vivo. Cell cycle analyses of Caml-deleted lymphoma cells revealed an arrest in G2/M, accompanied by low expression of the mitotic marker, phospho-histone H3 (Ser10). Surprisingly, lymphoma cell viability did not depend on the domain of CAML required for its interaction with TRC40. Furthermore, a small protein fragment consisting of the C-terminal 111 amino acid residues of CAML, encompassing the WRB-binding domain, was sufficient to rescue growth and survival of Caml-deleted lymphoma cells. Critically, this minimal region of CAML did not restore TA protein insertion in knockout cells. Taken together, these data reveal an essential role for CAML in supporting survival and mitotic progression in Myc-driven lymphomas that is independent of its TA protein insertion function.

Cycloheximide promotes paraptosis induced by inhibition of cyclophilins in glioblastoma multiforme.

Cancer is the second leading cause of death worldwide. Current treatment strategies based on multi-agent chemotherapy and/or radiation regimens have improved overall survival in some cases. However, resistance to apoptosis often develops in cancer cells, and its occurrence is thought to contribute to treatment failure. Non-apoptotic cell death mechanisms have become of great interest, therefore, in hopes that they would bypass tumor cell resistance. Glioblastoma multiforme (GBM), a grade IV astrocytic tumor is the most frequent brain tumor in adults, and has a high rate of mortality. We report that NIM811, a small molecule cyclophilin-binding inhibitor, induces catastrophic vacuolization and cell death in GBM cells. These unique features are distinct from many known cell death pathways, and are associated with an incompletely defined cell death mechanism known as paraptosis. We found that NIM811-induced paraptosis is due to unresolved ER stress. The abnormal upregulation of protein translation was responsible for the build-up of misfolded or unfolded proteins in ER, whereas pro-survival autophagy and UPR signals were shutdown during prolonged treatment with NIM811. Although cycloheximide has been claimed to suppress paraptosis, instead we find that it only temporarily delayed vacuole formation, but actually enhanced paraptotic cell death in the long term. On the other hand, mTOR inhibitors rescued cells from NIM811-induced paraptosis by sustaining autophagy and the UPR, while specifically restraining cap-dependent translation. These findings not only provide new insights into the mechanisms underlying paraptosis, but also shed light on a potential approach to enhance GBM treatment.

ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas.

Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/- mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities. Cancer Res; 77(14); 3766-77. ©2017 AACR.

Combined Anterior-Posterior Decompression and Fusion for Cervical Spondylotic Myelopathy.

We conducted a study to evaluate the operative details, perioperative complications, and short-term outcomes associated with combined anterior-posterior decompression and fusion (CAPDF) for treating cervical spondylotic myelopathy (CSM). We retrospectively reviewed the charts of 21 patients who underwent CAPDF at our institution. Pertinent information, including demographics, surgery indication, perioperative complications, operative time, levels fused (and number of levels fused) anteriorly and posteriorly, estimated blood loss, and length of stay, was gathered. Outpatient follow-up data were available for 20 of the 21 patients, and postoperative neurologic status was evaluated with Nurick grades as well as by subjective means. Mean age was 62.1 years (range, 44-79 years). Of the 21 patients, 9 were female, and 12 were male. Before surgery, all patients had a diagnosis of CSM of varying degree. Mean number of levels fused was 2 (range, 1-3) anteriorly and 3 (range, 1-4) posteriorly. Mean operative time, which included patient repositioning, was 4 hours 55 minutes (range, 3:04-6:22). Mean estimated blood loss was 131 mL (range, 55-278 mL), and mean length of stay was 5 days (range, 2-10 days). The most commonly encountered complication was dysphagia (28.6%, 6/21). Neither neurologic instability nor mortality was observed after surgery. Neurologic status was subjectively improved for 19 patients and unimproved for 1 patient; no patient's neurologic status was worse. Mean Nurick grade was 1.9 before surgery and 1.1 after surgery (mean difference, 0.80; P < .001), at a mean follow-up of 96 days (range, 51-149 days). When indicated, CAPDF is an efficient and effective treatment for CSM. This study found the procedure to be associated with minor complications, no new neurologic deficits, and high levels of neurologic improvement. The positive short-term outcomes and low rate of long-term complications in our study, combined with data from previous comparative studies, suggest that same-day surgery is superior to staged surgery.

Hemostasis in endoscopic endonasal skull base surgery using the Aquamantys bipolar sealer: Technical note.

BACKGROUND: A major challenge during endoscopic transsphenoidal surgery is adequate intraoperative hemostasis. The Aquamantys® is a relatively new bipolar sealing device which uses radiofrequency energy and saline. This promotes hemostasis while decreasing charring and thermal spread. In this paper, we describe our experience with the Aquamantys® Mini EVS 3.4 Epidural Vein Sealer Bipolar Electrocautery System (Medtronic Advanced Energy, Portsmouth, NH, USA) during endoscopic surgery for tumors of the skull base with particular attention to ergonomic benefits and technical nuances. METHODS: We conducted a retrospective review of all patients undergoing endoscopic surgery for skull base tumors from September 2012 to June 2016 at our institution. All procedures used the Aquamantys® system. 45 cases were identified. RESULTS: Successful hemostasis was achieved in all cases with an average estimated blood loss (EBL) of 46mL (Range 10-250). There were no intraoperative complications. The single-shaft design allowed for excellent manipulation compared to pistol-grip bipolar forceps. The thermal energy provided excellent radial coverage without extensive penetration into viable pituitary tissue. CONCLUSION: To our knowledge, this is the largest series documenting the use of the Aquamantys® system in skull base surgery. The device is easily mobile and highly effective within the endonasal corridor and should be a tool in the repertoire of the endoneurosurgeon. Randomized control trials would be useful in comparing EBL between the Aquamantys® and standard bipolar electrocautery.

Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice.

BACKGROUND: The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation. OBJECTIVE: We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice. METHODS: Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI. TACI-driven proliferation, isotype switching, and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge. RESULTS: Levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine were significantly lower in A181E-heterozygous than TACI-sufficient Swedish blood donors never immunized with pneumococcal antigens. Although overexpressed hTACI A181E and mTACI A144E acted as dominant-negative mutations in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, such as TACI+/- mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in a proliferation-inducing ligand-driven B-cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to phosphocholine, and survival after intranasal pneumococcal challenge. CONCLUSION: These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers.