Central tolerance shapes the neutralizing B cell repertoire against a persisting virus in its natural host.

Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus-host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire.

Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection.

Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)-driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called "decimation," of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I-driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell-intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell-mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell-based vaccination against persistent viral diseases.

Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody.

The CD40-CD154 costimulatory pathway is essential for T cell-dependent immune responses, development of humoral memory, and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions. CFZ533 inhibited CD154-induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation. Additionally, CFZ533 was unable to mediate depletion of human CD40 expressing B cells. In vivo, CFZ533 blocked primary and recall T cell-dependent antibody responses in nonhuman primates and abrogated germinal formation without depleting peripheral blood B cells. We also established a relationship between plasma concentrations of CFZ533 and CD40 pathway-relevant pharmacodynamic effects in tissue. Collectively these data support the scientific rationale and posology for clinical utility of this antibody in select autoimmune diseases and solid organ transplantation.

Advancing Differentiation of Hepatic Metastases in Malignant Melanoma through Dual-Energy Computed Tomography Rho/Z Maps.

OBJECTIVES: The aim of this study is to evaluate the diagnostic accuracy of dual-energy computed tomography (DECT)-based Rho/Z maps in differentiating between metastases and benign liver lesions in patients diagnosed with malignant melanoma compared to conventional CT value measurements. METHODS: This retrospective study included 73 patients (mean age, 70 ± 13 years; 43 m/30 w) suffering from malignant melanoma who had undergone third-generation DECT as part of tumor staging between December 2017 and December 2021. For this study, we measured Rho (electron density) and Z (effective atomic number) values as well as Hounsfield units (HUs) in hypodense liver lesions. Values were compared, and diagnostic accuracy for differentiation was computed using receiver operating characteristic (ROC) curve analyses. Additional performed MRI or biopsies served as a standard of reference. RESULTS: A total of 136 lesions (51 metastases, 71 cysts, and 14 hemangiomas) in contrast-enhanced DECT images were evaluated. The most notable discrepancy (p < 0.001) between measured values and the highest diagnostic accuracy for distinguishing melanoma metastases from benign cysts was observed for the Z (0.992; 95% CI, 0.956-1) parameters, followed by Rho (0.908; 95% CI, 0.842-0.953) and finally HU120kV (0.829; 95% CI, 0.751-0.891). Conversely, when discriminating between liver metastases and hemangiomas, the HU120kV parameters showed the most significant difference (p < 0.001) and yielded the highest values for diagnostic accuracy (0.859; 95% CI, 0.740-0.937), followed by the Z parameters (0.790; 95% CI, 0.681-0.876) and finally the Rho values (0.621; 95% CI, 0.501-0.730). CONCLUSIONS: Rho and Z measurements derived from DECT allow for improved differentiation of liver metastases and benign liver cysts in patients with malignant melanoma compared to conventional CT value measurements. In contrast, in differentiation between liver hemangiomas and metastases, Rho/Z maps show inferior diagnostic accuracy. Therefore, differentiation between these two lesions remains a challenge for CT imaging.

Prostatic Artery Embolization: Lessons From 551 Procedures at a Single-Center.

RATIONALE AND OBJECTIVES: This retrospective study evaluates the efficacy and safety of Prostatic Artery Embolization (PAE) for the treatment of benign prostatic hyperplasia (BPH) over five years at a single center, conducted by an experienced interventional radiologist. MATERIALS AND METHODS: We analyzed 551 PAE interventions from January 2019 to July 2023. Key metrics included patient demographics, procedural details (radiation exposure, particle size), complication rates, pre- and post-interventional prostatic volume (PV), Prostate-specific Antigen (PSA) levels, International Prostate Symptom Score (IPSS), Quality of Life (QoL) scores and International Index of Erectile Function (IIEF) scores. We assessed data normality, performed group and paired sample comparisons, and evaluated correlations. RESULTS: For 551 men, the average patient age was 68.81 ± 8.61 years undergoing bilateral embolization. The particle size predominantly used was 100-300 µm (n = 441). PAE lead to significant (p < .001) reduction of both PV (-9.67 ± 14.52 mL) and PSA level (-2,65 ± 1.56 ng/mL) between pre- and three months after PAE. Substantial improvement were observed for IPSS (-9 points) and QoL scores (-2 points), with stable IIEF scores. Only minor complications (n = 16) were reported, and no major complications were observed. Between the first PAE in 2019 and the routinely performed PAE in 2023 significant (p < .0001) reductions in fluoroscopy (-25.2%), and procedural times (-26.1%) were observed. CONCLUSION: In conclusion, PAE is a safe and effective treatment for BPH, offering significant improvements in lower urinary tract symptoms (LUTS) and QoL while maintaining sexual function.

Dual-Energy CT Iodine Uptake of Head and Neck: Definition of Reference Values in a Big Data Cohort.

BACKGROUND: Despite a considerable amount of literature on dual-energy CT (DECT) iodine uptake of the head and neck, the physiologic iodine uptake of this region has not been defined yet. This study aims to establish reference values for the iodine uptake of healthy organs to facilitate clinical application. METHODS: Consecutive venous DECT scans of the head and neck were reviewed, and unremarkable exams were included (n = 617). A total of 35 region of interest measurements were performed in 16 anatomical regions. Iodine uptake was compared among different organs/tissues and subgroup analysis was performed (male (n = 403) vs. female (n = 214); young (n = 207) vs. middle-aged (n = 206) vs. old (n = 204); and normal weight (n = 314) vs. overweight (n = 196) vs. obese (n = 107)). RESULTS: Overall mean iodine uptake values ranged between 0.5 and 9.4 mg/mL. Women showed higher iodine concentrations in the cervical vessels and higher uptake for the parotid gland, masseter muscle, submandibular glands, sublingual glands, palatine tonsils, tongue body, thyroid gland, and the sternocleidomastoid muscle than men (p ≤ 0.04). With increasing age, intravascular iodine concentrations increased as well as iodine uptake for cerebellum and thyroid gland, while values for the tongue and palatine tonsils were lower compared to younger subjects (p ≤ 0.03). Iodine concentrations for parotid glands and sternocleidomastoid muscles decreased with a higher BMI (p ≤ 0.004), while normal-weighted patients showed higher iodine values inside the jugular veins, other cervical glands, and tonsils versus patients with a higher BMI (p ≤ 0.04). CONCLUSION: physiologic iodine uptake values of cervical organs and tissues show gender-, age-, and BMI-related differences, which should be considered in the clinical routine of head and neck DECT.

Diagnosis of an Acute Anterior Wall Infarction in Dual-Energy CT.

Due to its high morbidity and mortality, myocardial infarction is the leading cause of death worldwide. Against this background, rapid diagnosis is of immense importance. Especially in case of an atypical course, the correct diagnosis may be delayed and thus lead to increased mortality rates. In this report, we present a complex case of acute coronary syndrome. A triple-rule-out CT examination was performed in dual-energy CT (DECT) mode. While pulmonary artery embolism and aortic dissection could be ruled out with conventional CT series, the presence of anterior wall infarction was only detectable on DECT reconstructions. Subsequently, adequate and rapid therapy was then initiated leading to survival of the patient.

Impact of Intravenously Injected Contrast Agent on Bone Mineral Density Measurement in Dual-Source Dual-Energy CT.

PURPOSE: To assess the influence of intravenously injected contrast agent on bone mineral density (BMD) assessment in dual-source dual-energy CT. METHODS: This retrospective study included 1,031 patients (mean age, 53 ± 7 years; 519 women) who had undergone third-generation dual-source dual-energy CT in context of tumor staging between January 2019 and December 2019. Dedicated postprocessing software based on material decomposition was used for phantomless volumetric BMD assessment of trabecular bone of the lumbar spine. Volumetric trabecular BMD values derived from unenhanced and contrast-enhanced portal venous phase were compared by calculating correlation and agreement analyses using Pearson product-moment correlation, linear regression, and Bland-Altman plots. RESULTS: Mean BMD values were 115.53 ± 37.23 and 116.10 ± 37.78 mg/cm3 in unenhanced and contrast-enhanced dual-energy CT series, respectively. Values from contrast-enhanced portal venous phase differed not significantly from those of the unenhanced phase (p = 0.44) and showed high correlation (r = 0.971 [95% CI, 0.969-0.973]) with excellent agreement in Bland-Altman plots. Mean difference of the two phases was 0.61 mg/cm3 (95% limits of agreement, -17.14 and 18.36 mg/cm3). CONCLUSION: Portal venous phase dual-source dual-energy CT allows for accurate opportunistic BMD assessment of trabecular bone of the lumbar spine compared to unenhanced imaging. Therefore, dual-source CT may provide greater flexibility regarding BMD assessment in clinical routine and reduce radiation exposure by avoiding additional osteodensitometry examinations, as contrast-enhanced CT scans in context of tumor staging are increasingly performed in dual-energy mode.

Vectored antibody gene delivery restores host B and T cell control of persistent viral infection.

Passive antibody therapy and vectored antibody gene delivery (VAGD) in particular offer an innovative approach to combat persistent viral diseases. Here, we exploit a small animal model to investigate synergies of VAGD with the host's endogenous immune defense for treating chronic viral infection. An adeno-associated virus (AAV) vector delivering the lymphocytic choriomeningitis virus (LCMV)-neutralizing antibody KL25 (AAV-KL25) establishes protective antibody titers for >200 days. When therapeutically administered to chronically infected immunocompetent wild-type mice, AAV-KL25 affords sustained viral load control. In contrast, viral mutational escape thwarts therapeutic AAV-KL25 effects when mice are unable to mount LCMV-specific antibody responses or lack CD8+ T cells. VAGD augments antiviral germinal center B cell and antibody-secreting cell responses and reduces inhibitory receptor expression on antiviral CD8+ T cells. These results indicate that VAGD fortifies host immune defense and synergizes with B cell and CD8 T cell responses to restore immune control of chronic viral infection.