Generation of tumor-infiltrating lymphocytes begins when tumor antigens reach the lymph node (LN) to stimulate T cells, yet we know little of how tumor material is disseminated among the large ...variety of antigen-presenting dendritic cell (DC) subsets in the LN. Here, we demonstrate that tumor proteins are carried to the LN within discrete vesicles inside DCs and are then transferred among DC subsets. A synapse is formed between interacting DCs and vesicle transfer takes place in the absence of free exosomes. DCs -containing vesicles can uniquely activate T cells, whereas DCs lacking them do not. Understanding this restricted sharing of tumor identity provides substantial room for engineering better anti-tumor immunity.
Display omitted
•Myeloid cells retain tumor-derived antigens in intracellular vesicles•Dynamic synapses facilitate membrane and vesicular exchange between myeloid cells•Migratory DC pass vesicular tumor antigen to resident DC at points of contact•Migratory versus resident cDC1 exhibit differential T cell priming characteristics
Ruhland et al. capture a novel vesicle-encapsulated and contact-dependent transfer of tumor-derived material and antigens between dendritic cells, leading to effective and varied T cell priming in the lymph node.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Adenosine deaminase 2 (ADA2) have been reported to cause vasculitic diseases and immunodeficiency recently. Patients present with stroke episodes and rashes mimicking polyarteritis nodosa ...(PAN). We report a patient who has been followed up with severe neutropenia and found an unexpectedly revealed novel mutation in CECR1 affecting ADA2.
Methods
We reviewed medical records and clinical history of the patient. No mutations in other known neutropenia genes such as ELA, G6PC3, HAX1, AP3B1, LAMTOR2, VPS13B, VPS45, GFI1, JAGN1, or WAS could be detected. Sanger sequencing was used to confirm the genetic variants in the patient and relatives.
Results
Genetic analysis by exome sequencing revealed a novel mutation in the gene CECR1 (c.G962A; p.G321E) which segregated perfectly in the relatives.
Conclusion
This is the first DADA2 patient presenting with severe neutropenia. We suggest that in patients with unexplained cytopenias combined with immunodeficiency, fevers of unknown origin and high inflammation markers, DADA2 should be considered.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency categorized as common variable immunodeficiency associated with autoimmune manifestations and ...inflammatory bowel diseases; however, the clinical spectrum has been extended. Here, we present our cohort of Turkish LRBA-deficient patients from a single center, demonstrating a diversity of clinical manifestations.
Method
Seven affected individuals from five families were assessed retrospectively in this study.
Results
Of the seven patients with
LRBA
deficiency, four had homozygous, and two had compound heterozygous mutations. One patient remained disease free until the last follow-up (age 17 years). The most common clinical manifestations of the six symptomatic patients were organomegaly (6/6), autoimmunity (6/6), and chronic diarrhea (5/6). Recurrent infectious episodes were observed in three patients. None of the patients had hypogammaglobulinemia at presentation. B cell subpopulation analysis revealed low numbers of switched-memory B cell numbers in two of the four tested patients. During the disease course, three of the patients died, two of them underwent successful hematopoietic stem cell transplantation (HSCT) from matched sibling donors, and one is under abatacept therapy.
Conclusion
LRBA defects should always be kept in mind as a differential diagnosis for patients with autoimmune disease affecting multiple organs, chronic diarrhea, and organomegalies. In our experience, early HSCT is a life-saving therapeutic strategy.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Specific granule deficiency (SGD) is a rare disorder characterized by abnormal neutrophils evidenced by reduced granules, absence of granule proteins, and atypical bilobed nuclei. Mutations in
(
) ...are one molecular etiology of the disease. Although C/EBPε has been studied extensively, the impact of
mutations on neutrophil biology remains elusive. Here, we identified two SGD patients bearing a previously described heterozygous mutation (p.Val218Ala) in
. We took this rare opportunity to characterize SGD neutrophils in terms of granule distribution and protein content. Granules of patient neutrophils were clustered and polarized, suggesting that not only absence of specific granules but also defects affecting other granules contribute to the phenotype. Our analysis showed that remaining granules displayed mixed protein content and lacked several glycoepitopes. To further elucidate the impact of mutant
, we performed detailed proteomic analysis of SGD neutrophils. Beside an absence of several granule proteins in patient cells, we observed increased expression of members of the linker of nucleoskeleton and cytoskeleton complex (nesprin-2, vimentin, and lamin-B2), which control nuclear shape. This suggests that absence of these proteins in healthy individuals might be responsible for segmented shapes of neutrophilic nuclei. We further show that the heterozygous mutation p.Val218Ala in
causes SGD through prevention of nuclear localization of the protein product. In conclusion, we uncover that absence of nuclear C/EBPε impacts on spatiotemporal expression and subsequent distribution of several granule proteins and further on expression of proteins controlling nuclear shape.
ABSTRACT
Objectives:
In the present study, we studied a cohort of patients with very early onset inflammatory bowel disease (IBD) to determine the frequency of mutations in the interleukin 10 (IL10) ...receptor genes as a cause of early‐onset IBD.
Methods:
Sanger sequencing was performed to determine the presence of IL10 and/or IL10 receptor mutations in 17 patients with a diagnosis of very early onset IBD (disease onset <2 years of age in 15 patients, between 3 and 4 years in the other 2). Mutation screening was performed including all of the coding regions of the IL10, IL10RA, and IL10RB genes. We then compared the follow‐up findings of the patients with IL10 receptor mutations in terms of demographic, clinical, laboratory, and treatment response properties with those of patients diagnosed as having very early onset IBD with no mutation.
Results:
We identified 3 patients bearing mutations in the IL10 or IL10 receptor genes, including 1 mutation in IL10RB that has been described recently (c.G477A, p.Trp159*) and 2 novel mutations affecting the IL10RA gene (c.T192G, p.Tyr64* and c.T133G, p.Trp45Gly). Collectively, these mutations thus provided genetic etiology for 17.6% of the cohort under investigation. The presence of a family history of IBD and the clinical course of Crohn disease differed between patients with mutations in the IL‐10 pathway and those without such mutations. Although perianal fistulas were found in all of the patients with IL10 receptor mutations, they were found in only 14.3% of those without such mutations. The lower values of weight‐for‐age and height‐for‐age z scores, necessity for more intensive therapy, achievement of longer periods until remission, and frequent relapses in the patients bearing mutations in the IL10 receptor genes all underlined the severity of the disease and its relatively poor response to treatment.
Conclusions:
In spite of the small number of patients with mutations affecting the IL‐10 signaling pathway in our study, in all of the patients with IL10 receptor mutations, the disease onset occurs at an early age, the prognosis is poor, and the response to treatment is insufficient.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with a spectrum of disease severity. The mechanistic explaining variations related to airway ...epithelium are relatively understudied. Here, we biobanked airway organoids (AO) by preserving stem cell function. We optimized viral infection with H1N1/PR8 and comprehensively characterized epithelial responses to SARS-CoV-2 infection in phenotypically stable AO from 20 different subjects. We discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection. TSPAN8 facilitates SARS-CoV-2 infection rates independently of ACE2-Spike interaction. In head-to-head comparisons with Ancestral SARS-CoV-2, Delta and Omicron VOC displayed lower overall infection rates of AO but triggered changes in epithelial response. All variants shared highest tropism for ciliated and goblet cells. TSPAN8-blocking antibodies diminish SARS-CoV-2 infection and may spur novel avenues for COVID-19 therapy.
•Airway organoids from different donors display distinct compositions of cell types•Organoid biobank models the spectrum of the epithelium response to pathogens•TSPAN8 is a conserved mediator of infection for SARS-CoV-2 variants
Roose and colleagues generated a biobank of 20 airway organoids for modeling variations of airway epithelium response to SARS-CoV-2. They discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection independently of ACE2-Spike interaction. Pre-treatment of airway organoids with a blocking TSPAN8 antibody decreased SARS-CoV-2 infection levels in airway organoids, suggesting TSPAN8 as a therapeutic target for COVID-19.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BackgroundTIGIT is an inhibitory receptor expressed on T and NK cell subsets that outcompetes an activating receptor, CD226, for shared ligands. The TIGIT checkpoint blockade field has focused on ...evaluating efficacy and elucidating mechanisms of action related to Fc-enabled antibody formats. Here, we report efficacy and pharmacology associated with clinical and mouse tool Fc-silent anti-TIGIT antibodies relative to Fc-enabled counterparts.MethodsHuman NSCLC tumor (pre-treatment stages I-IV) and mouse MC38 tumor and tumor-draining lymph node (tdLN) cell suspensions were interrogated for expression of TIGIT and associated receptors by flow cytometry. Anti-tumor efficacy and pharmacodynamic changes were assessed using tool Fc-silent or Fc-enabled anti-mouse TIGIT antibodies in the MC38 tumor model. The ability of human TIGIT-specific clinical antibodies that are Fc-silent (domvanalimab) or Fc-enabled (AB308) to promote NK-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated using an in vitro co-culture system and by measuring absolute T cell counts in longitudinal peripheral blood patient samples from Phase 1 dose escalation clinical trials NCT03628677 and NCT04772989. Anecdotal clinical outcomes in two patients from NCT03628677 receiving domvanalimab in combination with an anti-PD-1 antibody, zimberelimab, are also reported.ResultsHuman and mouse tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg), CD4+ non-Treg, and on CD8+ T cells with tumor-reactive or exhausted/dysfunctional phenotypes. In mice, combining Fc-silent or Fc-enabled anti-TIGIT with anti-PD-1 antibodies resulted in enhanced tumor control, but by mechanisms that differentially shape the tumor microenvironment. Fc-silent anti-TIGIT did not deplete Treg yet promoted activation of tumor-specific precursor-exhausted CD8+ populations in the tdLN. In contrast, Fc-enabled anti-TIGIT depleted Treg in mice. Consistent with the murine system, Fc-enabled human TIGIT-specific antibody AB308 induced ADCC against TIGIT-expressing human Treg in vitro, with preferential depletion of a Helios+ Treg subset with an activated/effector phenotype. In humans, significant and stable decreases in Treg were measured in the peripheral blood of cancer patients treated with AB308. In contrast, domvanalimab did not deplete Treg in vitro, and patients treated with domvanalimab in combination with anti-PD-1 antibody zimberelimab experienced partial responses while maintaining stable peripheral Treg frequencies on treatment.ConclusionsWe demonstrate that Fc-silent anti-TIGIT antibodies potentiate activation of tumor-specific T cells and anti-tumor efficacy without depleting Treg (figure 1). These data provide critical insights related to activity of anti-TIGIT antibodies lacking Fc functionality, such as domvanalimab.Ethics ApprovalAnimal studies were performed at Arcus Biosciences in accordance with federal, state, and institutional guidelines and were approved by Arcus Biosciences’ Institutional Animal Care and Use Committee. Dissociated tumor biopsies were obtained from Discovery Life Sciences with informed written consent and according to Institutional Review Board approved guidelines in accordance with the Declaration of Helsinki. Clinical studies were performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Protocols and amendments were approved by institutional review boards for each study site. All patients provided written informed consent.Abstract 475 Figure 1
CD55 prevents convertase enzyme formation in the complement cascade, acting as a brake on complement activation. Inactivating mutations in
CD55
result in hyperactivation of complement, angiopathic ...thrombosis, and protein-losing enteropathy.
Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients ...from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11
CTLA-4
vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.
Generation of tumor-infiltrating lymphocytes (TILs) begins when tumor antigens reach the lymph node (LN) to stimulate T cells, yet we know little of how tumor material is disseminated amongst the ...large variety of antigen-presenting dendritic cell (DC) subsets in the LN. Here, we demonstrate that tumor proteins are carried to the LN within discrete vesicles inside DC and are then transferred amongst DC subsets. A synapse is formed between interacting DC and vesicle transfer takes place in the absence of free exosomes. DC containing vesicles can uniquely activate T cells whereas DC lacking them do not. Understanding this restricted sharing of tumor identity provides substantial room for engineering better anti-tumor immunity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
