High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura

The major therapeutic goal for immune thrombocytopenic purpura (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. Eighty percent of patients with ITP possess anti–integrin αIIbβ3 IgG autoantibodies that cause platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in approximately 50% of patients to recover a normal platelet count after anti-CD20 rituximab-mediated B cell depletion and splenectomy suggests that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SCs) reside in other anatomical compartments. We analyzed more than 3,300 single IgG-SCs from spleen, bone marrow, and/or blood of 27 patients with ITP, revealing high interindividual variability in affinity for αIIbβ3, with variations over 3 logs. IgG-SC dissemination and range of affinities were, however, similar for each patient. Longitudinal analysis of autoreactive IgG-SCs upon treatment with the anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti–αIIbβ3 IgG-SCs in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.     

SARS-CoV-2 Accessory Protein ORF8 Decreases Antibody-Dependent Cellular Cytotoxicity

Viruses use many different strategies to evade host immune responses. In the case of SARS-CoV-2, its Spike mutates rapidly to escape from neutralizing antibodies. In addition to this strategy, ORF8, a small accessory protein encoded by SARS-CoV-2, helps immune evasion by reducing the susceptibility of SARS-CoV-2-infected cells to the cytotoxic CD8+ T cell response. Interestingly, among all accessory proteins, ORF8 is rapidly evolving and a deletion in this protein has been linked to milder disease. Here, we studied the effect of ORF8 on peripheral blood mononuclear cells (PBMC). Specifically, we found that ORF8 can bind monocytes as well as NK cells. Strikingly, ORF8 binds CD16a (FcγRIIIA) with nanomolar affinity and decreases the overall level of CD16 at the surface of monocytes and, to a lesser extent, NK cells. This decrease significantly reduces the capacity of PBMCs and particularly monocytes to mediate antibody-dependent cellular cytotoxicity (ADCC). Overall, our data identifies a new immune-evasion activity used by SARS-CoV-2 to escape humoral responses.     

Giant cell arteritis or polymyalgia rheumatica after influenza vaccination: A study of 12 patients and a literature review

IntroductionGiant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases common in people over the age of 50 years. Seasonal influenza vaccination (IV) is strongly recommended in this population, among whom it is considered to be effective and well tolerated. IV-induced GCA or PMR are thought to be exceptional.Patients and methodsWe retrieved all post-IV cases from an inception cohort of patients with newly diagnosed GCA. We also included two patients with post-IV PMR and reviewed all published reports of post-IV GCA or PMR, with selection of cases demonstrating disease onset within 1 month following IV. We compared the results of HLA-DRB1 typing, performed in seven patients with post-IV GCA or PMR, with those of 11 GCA patients with familial aggregation and 16 randomly selected GCA patients without a reported trigger.ResultsOf 358 GCA recruited since 2002, 10 (2.8%) qualified for post-IV GCA, of whom two also showed familial aggregation. Thirty-two patients (19 with GCA and 13 with PMR) including our patients were reviewed; their mean age was 71.8 ± 7.4 years and the M/F ratio was 0.8. Six patients (19%) had a history of PMR. Patients with post-IV GCA/PMR had the DRB1*13:01 haplotype more frequently compared to those with familial GCA (5/7 vs. 2/11, p = 0.048) or with GCA without a known trigger (3/16, p = 0.026). Post-IV PMR generally appeared self-limited, whereas post-IV GCA often displayed a more protracted course (chronic relapsing disease in one-third of the patients).ConclusionPost-IV onset of GCA/PMR is not an exceptional occurrence and may be part of the spectrum of the autoimmune syndrome induced by adjuvants (ASIA). IV can trigger GCA or PMR, especially in persons at higher spontaneous risk, such as those with a personal or familial history of GCA/PMR. Whether the presence of the DRB1*13:01 allele further increases the risk of post-IV GCA/PMR through a stronger vaccine-induced immune reaction deserves further investigation. Unlike PMR, GCA can be a serious complication of IV.     

Fortuitous discovery of non-fluorocholine-fixing papillary carcinoma of vesicular variant of the thyroid

European Archives of Oto-Rhino-Laryngology - Characterization of thyroid nodules is crucial to propose surgical intervention for histological verification. Cervical ultrasound potentially combined...     

Paradoxical brain embolism shadowing massive pulmonary embolism

Patent foramen ovale is frequently observed in the general population. In case of massive pulmonary embolism, the sudden increase in the right heart cavity's pressure may cause a right-to-left shunting across this foramen, which could be associated with conflicting outcomes. Herein, we report a case of reversible cardiac arrest preceded by seizures, and followed by hemodynamic stability without any vasopressor. A brain CT-scan showed a limited ischemic stroke. Initial echocardiographic assessment revealed an acute cor pulmonale and a right-to-left intracardiac shunt across a large patent foramen ovale, suggesting the diagnosis of massive pulmonary embolism that was lately confirmed by a multidetector CT-angiography. Anticoagulation therapy was rapidly complicated by a hemorrhagic transformation of the ischemic stroke leading to a fatal outcome. This case illustrates the double-edged circulatory effect of shunting across a patent foramen ovale in case of massive pulmonary embolism: it may have limited circulatory failure but caused in the meanwhile a fatal paradoxical brain embolism.     

The genetics of platelet count and volume in humans

The last decade has witnessed an explosion in the depth, variety, and amount of human genetic data that can be generated. This revolution in technical and analytical capacities has enabled the genetic investigation of human traits and disease in thousands to now millions of participants. Investigators have taken advantage of these advancements to gain insight into platelet biology and the platelet’s role in human disease. To do so, large human genetics studies have examined the association of genetic variation with two quantitative traits measured in many population and patient based cohorts: platelet count (PLT) and mean platelet volume (MPV). This article will review the many human genetic strategies—ranging from genome-wide association study (GWAS), Exomechip, whole exome sequencing (WES), to whole genome sequencing (WGS)—employed to identify genes and variants that contribute to platelet traits. Additionally, we will discuss how these investigations have examined and interpreted the functional implications of these newly identified genetic factors and whether they also impart risk to human disease. The depth and size of genetic, phenotypic, and other -omic data are primed to continue their growth in the coming years and provide unprecedented opportunities to gain critical insights into platelet biology and how platelets contribute to disease.