Explore the vast range of titles available.

A patient with variable immunodeficiency and progressive multifocal leukoencephalopathy was treated with five pembrolizumab infusions. The CSF JC viral load went from 119,000 copies per milliliter to undetectable levels. Neurologic signs stabilized, and the size of some white-matter lesions was reduced on MRI.

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients. Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency. Here the authors perform single-cell omics analyses in CVID-discordant monozygotic twins and show epigenetic and transcriptional alterations associated with activation in memory B cells.

The B cell response to different pathogens uses tailored effector mechanisms and results in functionally specialized memory B (B m ) cell subsets, including CD21 + resting, CD21 – CD27 + activated and CD21 – CD27 – B m cells. The interrelatedness between these B m cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific B m cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21 – B m cells were the predominant subsets during acute infection and early after severe acute respiratory syndrome coronavirus 2-specific immunization. At months 6 and 12 post-infection, CD21 + resting B m cells were the major B m cell subset in the circulation and were also detected in peripheral lymphoid organs, where they carried tissue residency markers. Tracking of individual B cell clones by B cell receptor sequencing revealed that previously fated B m cell clones could redifferentiate upon antigen rechallenge into other B m cell subsets, including CD21 – CD27 – B m cells, demonstrating that single B m cell clones can adopt functionally different trajectories. Boyman and colleagues perform phenotypic and B cell receptor sequencing analysis of memory B cell subsets in severe acute respiratory syndrome coronavirus 2-infected and subsequently vaccinated individuals up to 1 year post-infection to show that single memory B cell clones can adopt different trajectories.

Common variable immunodeficiency (CVID) is associated with an altered immune homeostasis affecting many T-cell subpopulations, including an increased proportion of CD57 CD8 T lymphocytes. This expansion has been associated with the clinical manifestation of granuloma/lymphadenopathy and a positive CMV status. The aim of the study is to describe the prevalence of an expansion of CD57 CD8 T cells in CVID patients and determine its diagnostic value. This is a monocentric retrospective study including 131 patients with a median follow-up of 9 years. The inclusion criteria are a diagnosis of CVID according to European Society for Immunodeficiencies (ESID) criteria and at least two independent assessments of CD57 CD8 T cells. Patients on immunosuppressive therapy were excluded. The expansion of CD57 CD8 T cells was part of the previously described immune alteration, including altered CD4/CD8 ratio and a decrease in naïve CD4 T cells. The loss of significant association with increasing age might corroborate the suggestion of premature immunosenescence in CVID. Significantly higher values of CD57 CD8 T cells were seen in patients with a complicated clinical phenotype, and especially associated with the presence of splenomegaly, status post-splenectomy, and hepatic disease. Additionally, patients with a history of CMV infection presented with elevated CD57 CD8 T cell values. When comparing the potential diagnostic value of expanded CD57 CD8 T cells compared to alterations in other T-cell subsets in relation to specific complications, we could not identify a single complication in CVID patients for which absolute or relative CD57 CD8 T cell counts were superior to more commonly used T-cell populations, except for CMV infection. This is the largest study on the prevalence and diagnostic relevance of the expansion of CD57 CD8 T cells in CVID. Most CD57 CD8 T cells are part of the CD45RA terminal effector subset. While we could not detect an added value of the diagnostic evaluation of CD57 CD8 T cells at this time, further investigation in circulation and tissue might enhance our understanding of the pathogenesis of hepatic disease and thereby gain novel diagnostic value in the future.

Progressive multifocal leukoencephalopathy is a rare opportunistic infection of the brain by John Cunningham polyomavirus in immune-compromised patients. In cases where no overt option for immune reconstitution is available [e.g., in patients with primary immunodeficiency (PID)], the disease is lethal in the majority of patients. Immune checkpoint inhibition has been applied in recent years with mixed outcomes. We present four novel patients and the follow-up of a previously published patient suffering from progressive multifocal leukoencephalopathy (PML) due to PID and/or hematologic malignancy who were treated with the immune checkpoint inhibitor pembrolizumab. In two patients with PID, symptoms improved and stabilized. One patient died because of worsening PML another of intracranial hemorrhage which was unrelated to PML or its treatment with pembrolizumab. The fifth patient suffered from PID and died of a pre-existing immune dysregulation, possibly exacerbated by pembrolizumab. The long-term follow-up of the first patient provides support for therapeutic decisions during this therapy and is the longest published clinical course of a patient with checkpoint inhibition for PML. We conclude that pembrolizumab can control PML symptoms long term in a subgroup of patients with PID, in our cases for 21 and 36 months. However, therapy must be started early because symptoms are only partially reversible. In light of severe adverse events, application of pembrolizumab is only justified if the prognosis for the individual patient is very poor.

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease. Individuals with SYK gain-of-function variants develop immunodeficiency and systemic inflammation, which are recapitulated in a knock-in mouse model. Treatment of these mice with bone marrow transplantation or with a SYK inhibitor ameliorates disease symptoms, highlighting potential therapeutic strategies for patients with SYK mutations.

Primary immunodeficiencies (PIDs) are a widely heterogeneous group of inherited defects of the immune system consisting of many clinical phenotypes with at least 300 underlying genetic deficits currently known. Patients with PIDs can present with, or develop during the course of their life, a susceptibility to recurrent and chronic infection along with autoimmune, allergic, inflammatory, and/or proliferative disorders, all potentially leading to end-organ damage. In recent years, a combination of basic and clinical research has greatly improved understanding of the underlying immunological and genetic defects in PIDs, leading to improved diagnosis, classification, and treatment approaches. In this review, we consider some of the key understandings that should direct diagnostic and treatment approaches in PID and offer insights into current and emerging management approaches and the lifelong care of patients from childhood through to adulthood.

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator ( AIRE ). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination. Age-associated B cells (ABC) have been shown to be associated with autoimmunity and ageing. Here the authors examine whether ABC are transcriptionally or functionally altered in participants with reduced immune cell function and show that, being transcriptionally similar, high pre-vaccine levels are associated with poor vaccine response.

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in (APDS1) or (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3 + regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation. IL-21 is central to follicular helper T cell function and germinal centre responses. Here the authors show that IL-21 signalling directly inhibits T follicular regulatory cells by limiting Bcl-6-dependent IL-2 receptor expression.