| 1. |
- Anderberg, C., et al.
(författare)
-
Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination
- 2013
-
Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 210:3, s. 563-579
-
Tidskriftsartikel (refereegranskat)abstract
- Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.
|
|
| 2. |
- Aoun, M., et al.
(författare)
-
Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice
- 2023
-
Ingår i: Journal of Experimental Medicine. - Stockholm : Karolinska Institutet, Dept of Medical Biochemistry and Biophysics. - 0022-1007 .- 1540-9538. ; 220:11
-
Tidskriftsartikel (refereegranskat)abstract
- B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naive B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.
|
|
| 3. |
- Bastard, Paul, et al.
(författare)
-
Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.
- 2021
-
Ingår i: The Journal of experimental medicine. - 1540-9538. ; 218:7
-
Tidskriftsartikel (refereegranskat)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
|
|
| 4. |
- Bodda, C., et al.
(författare)
-
HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
- 2020
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:7
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS-STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. HSV1 ΔDUB also induced elevated IFN expression in murine and human microglia and exhibited reduced viral replication in the brain. This was associated with increased ubiquitination of STING and elevated phosphorylation of STING, TBK1, and IRF3. VP1-2 associated directly with STING, leading to its deubiquitination. Recruitment of VP1-2 to STING was dependent on K150 of STING, which was ubiquitinated by TRIM32. Thus, the DUB activity of HSV1 VP1-2 is a major viral immune-evasion mechanism in the brain. © 2020 Bodda et al.
|
|
| 5. |
- Brownlie, Rebecca J, et al.
(författare)
-
Distinct cell-specific control of autoimmunity and infection by FcgammaRIIb.
- 2008
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205:4, s. 883-95
-
Tidskriftsartikel (refereegranskat)abstract
- FcgammaRIIb is an inhibitory Fc receptor expressed on B cells and myeloid cells. It is important in controlling responses to infection, and reduced expression or function predisposes to autoimmunity. To determine if increased expression of FcgammaRIIb can modulate these processes, we created transgenic mice overexpressing FcgammaRIIb on B cells or macrophages. Overexpression of FcgammaRIIb on B cells reduced the immunoglobulin G component of T-dependent immune responses, led to early resolution of collagen-induced arthritis (CIA), and reduced spontaneous systemic lupus erythematosus (SLE). In contrast, overexpression on macrophages had no effect on immune responses, CIA, or SLE but increased mortality after Streptococcus pneumoniae infection. These results help define the role of FcgammaRIIb in immune responses, demonstrate the contrasting roles played by FcgammaRIIb on B cells and macrophages in the control of infection and autoimmunity, and emphasize the therapeutic potential for modulation of FcgammaRIIb expression on B cells in inflammatory and autoimmune disease.
|
|
| 6. |
- Camponeschi, Alessandro, et al.
(författare)
-
Human CD38 regulates B cell antigen receptor dynamic organization in normal and malignant B cells.
- 2022
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:9
-
Tidskriftsartikel (refereegranskat)abstract
- CD38 is a multifunctional protein expressed on the surface of B cells in healthy individuals but also in B cell malignancies. Previous studies have suggested a connection between CD38 and components of the IgM class B cell antigen receptor (IgM-BCR) and its coreceptor complex. Here, we provide evidence that CD38 is closely associated with CD19 in resting B cells and with the IgM-BCR upon engagement. We show that targeting CD38 with an antibody, or removing this molecule with CRISPR/Cas9, inhibits the association of CD19 with the IgM-BCR, impairing BCR signaling in normal and malignant B cells. Together, our data suggest that CD38 is a new member of the BCR coreceptor complex, where it exerts a modulatory effect on B cell activation upon antigen recognition by regulating CD19. Our study also reveals a new mechanism where α-CD38 antibodies could be a valuable option in therapeutic approaches to B cell malignancies driven by aberrant BCR signaling.
|
|
| 7. |
- Chan, Yi-Hao, et al.
(författare)
-
SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
- 2024
-
Ingår i: The Journal of experimental medicine. - 1540-9538. ; 221:9
-
Tidskriftsartikel (refereegranskat)abstract
- Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
|
|
| 8. |
- Du, X., et al.
(författare)
-
Mevalonate metabolism-dependent protein geranylgeranylation regulates thymocyte egress
- 2020
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 217:2
-
Tidskriftsartikel (refereegranskat)abstract
- Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein–coupled receptors in thymocyte emigration, the downstream signaling mechanism remains poorly defined. Here, we report the discrete roles for the two branches of mevalonate metabolism–fueled protein prenylation pathway in thymocyte egress and immune homeostasis. The protein geranylgeranyltransferase Pggt1b is up-regulated in single-positive thymocytes, and loss of Pggt1b leads to marked defects in thymocyte egress and T cell lymphopenia in peripheral lymphoid organs in vivo. Mechanistically, Pggt1b bridges sphingosine-1-phosphate and chemokine-induced migratory signals with the activation of Cdc42 and Pak signaling and mevalonate-dependent thymocyte trafficking. In contrast, the farnesyltransferase Fntb, which mediates a biochemically similar process of protein farnesylation, is dispensable for thymocyte egress but contributes to peripheral T cell homeostasis. Collectively, our studies establish context-dependent effects of protein prenylation and unique roles of geranylgeranylation in thymic egress and highlight that the interplay between cellular metabolism and posttranslational modification underlies immune homeostasis.
|
|
| 9. |
- Fogelstrand, Per, 1971, et al.
(författare)
-
Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2).
- 2009
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 206:11, s. 2397-406
-
Tidskriftsartikel (refereegranskat)abstract
- Activation of vascular smooth muscle cells (VSMCs) to migrate and proliferate is essential for the formation of intimal hyperplasia. Hence, selectively targeting activated VSMCs is a potential strategy against vaso-occlusive disorders such as in-stent restenosis, vein-graft stenosis, and transplant vasculopathy. We show that CD98 heavy chain (CD98hc) is markedly up-regulated in neointimal and cultured VSMCs, and that activated but not quiescent VSMCs require CD98hc for survival. CD98hc mediates integrin signaling and localizes amino acid transporters to the plasma membrane. SMC-specific deletion of CD98hc did not affect normal vessel morphology, indicating that CD98hc was not required for the maintenance of resident quiescent VSMCs; however, CD98hc deletion reduced intimal hyperplasia after arterial injury. Ex vivo and in vitro, loss of CD98hc suppressed proliferation and induced apoptosis in VSMCs. Furthermore, reconstitution with CD98hc mutants showed that CD98hc interaction with integrins was necessary for the survival of VSMCs. These studies establish the importance of CD98hc in VSMC proliferation and survival. Furthermore, loss of CD98hc was selectively deleterious to activated VSMCs while sparing resident quiescent VSMCs, suggesting that activated VSMCs are physiologically dependent on CD98hc, and hence, CD98hc is a potential therapeutic target in vaso-occlusive disorders.
|
|
| 10. |
- Gustafsson, Jenny K, 1981, et al.
(författare)
-
Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype.
- 2012
-
Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 209:7, s. 1263-72
-
Tidskriftsartikel (refereegranskat)abstract
- Cystic fibrosis (CF) is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator [CFTR]), but the link to the phenomenon of stagnant mucus is not well understood. Mice lacking functional CFTR (CftrΔ508) have no lung phenotype but show similar ileal problems to humans. We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM). In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties. This knowledge may provide novel therapeutic options for CF.
|
|
