Interferon-driven deletion of antiviral B cells at the onset of chronic infection

Fallet, Bénédict; Narr, Kerstin; Ertuna, Yusuf I.; Remy, Melissa M; Sommerstein, Rami; Cornille, Karen; Kreutzfeldt, Mario; Pagé, Nicolas; Zimmer, Gert; Geier, Florian; Straub, Tobias; Pircher, Hanspeter; Larimore, Kevin; Greenberg, Philip D.; Merkler, Doron; Pinschewer, Daniel D.

doi:10.1126/sciimmunol.aah6817

Cited by 85 publications

(36 citation statements)

References 67 publications

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“…Of note, virus-induced IFN-I was also reported to confer disintegration of B cell follicles 29 and to drive B cell reduction by differentiating B cells into short-lived antibody-secreting cells. 30 This mechanism called ‘B cell decimation’ was independent of B cell-intrinsic IFN-I sensing. 30 …”

Section: Discussionmentioning

confidence: 99%

B cell depletion impairs vaccination-induced CD8⁺T cell responses in a type I interferon-dependent manner

et al. 2021

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ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

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Section: Discussionmentioning

confidence: 99%

B cell depletion impairs vaccination-induced CD8⁺T cell responses in a type I interferon-dependent manner

et al. 2021

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“…Effects on B cell development after long-term exposure to IFNα have been reported. 22 , 23 We did not observe alterations of platelet function, size, or numbers or neutropenia in these mice ( Figures 5 E and 5F; Figure S9 C).…”

Section: Resultsmentioning

confidence: 72%

Targeting transgenic proteins to alpha granules for platelet-directed gene therapy

Woods

Latorre‐Rey

Schenk

et al. 2022

Molecular Therapy - Nucleic Acids

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Platelets are anucleate blood cells that are shed from megakaryocytes (MKs) into the bloodstream to maintain hemostasis and promote wound healing after vascular injury. To carry out their functions, platelets become activated and release bioactive substances from their secretory granules. As alpha granules (αGs) in resting platelets store proteins and release them only after activation, the packaging of proteins into αGs is an attractive strategy to deliver therapeutic proteins. Here, we propose an adjustable model for targeting transgenic proteins to platelet αGs using third-generation self-inactivating lentiviral vectors. The vectors express from the murine platelet factor 4 promoter (mPf4P), restricting transgene expression to the MK lineage. For the delivery and retention of expressed proteins in αGs, proteins are fused to short peptide sorting signals derived from the human cytokine RANTES or from the transmembrane protein P-selectin. We demonstrate effective targeting of GFP to αGs of murine and human in vitro -differentiated MKs and murine platelets in vivo . Furthermore, interferon-α (IFNα), as a potentially therapeutic cytokine, was successfully delivered to and stored in murine platelets in vivo , was released after activation, and inhibited virus replication in vitro . Our vectors create possibilities for numerous applications in cell therapy utilizing platelets as carriers of therapeutic proteins.

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“…48 Thus, it is important to distinguish the chilblains-like pattern from the livedo-like pattern, 49 because the latter indicates severe disease with a coagulopathy, often leading to death. 50 Negative serologies in patients with mild disease can be explained through type-I interferon (IFN) pathway activation, thereby suppressing the humoral antibody response and explaining the reported rapid loss of antibodies, 55 especially in pauci-symptomatic persons 56 In our initial report, 1 based on clinical and histopathological similarities to secondary chilblain LE and monogenic interferonopathies, we suspected viralinduced type-I IFN activation, an assertion that has since been supported by others. 35,44,[57][58][59] Type-I IFN levels fall with age and heightened production in young, healthy people leads to successful control of COVID-19 but also results in chilblains, not as a direct viral response but as a paraviral immune response.…”

Section: Discussionmentioning

confidence: 89%

A clinicopathological description of COVID‐19‐induced chilblains (COVID‐toes) correlated with a published literature review

et al. 2021

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Background: The abundance of publications of COVID-19-induced chilblains has resulted in a confusing situation. Methods: This is a prospective single-institution study from 15 March to 13 May 2020. Thirty-two patients received PCR nasopharyngeal swabs. Of these, 28 patients had a thoracic CT-scan, 31 patients had blood and urine examinations, 24 patients had skin biopsies including immunohistochemical and direct immunofluorescence studies, and four patients had electron microscopy. Results: COVID-19-induced chilblains are clinically and histopathologically identical to chilblains from other causes. Although intravascular thrombi are sometimes observed, no patient had a systemic coagulopathy or severe clinical course. The exhaustive clinical, radiological, and laboratory work-up in this study ruled-out other primary and secondary causes. Electron microscopy revealed rare, probable viral particles whose core and spikes measured from 120 to 133 nm within endothelium and eccrine glands in two cases. Conclusion: This study provides further clinicopathologic evidence of COVID-19-related chilblains. Negative PCR and antibody tests do not rule-out infection. Chilblains represent a good prognosis, occurring later in the disease course. No systemic coagulopathy was identified in any patient. Patients presenting with acral lesions should be isolated, and chilblains should be distinguished from thrombotic lesions (livedo racemosa, retiform purpura, or ischemic acral necrosis).

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Interferon-driven deletion of antiviral B cells at the onset of chronic infection

Abstract: Interferon-driven inflammation in chronic viral infection blocks generation of sustained B cell responses. See related Research Articles by Moseman et al. and Sammicheli et al. and a Focus by Laidlaw et al.

Cited by 85 publications

References 67 publications

B cell depletion impairs vaccination-induced CD8⁺T cell responses in a type I interferon-dependent manner

B cell depletion impairs vaccination-induced CD8⁺T cell responses in a type I interferon-dependent manner

Targeting transgenic proteins to alpha granules for platelet-directed gene therapy

A clinicopathological description of COVID‐19‐induced chilblains (COVID‐toes) correlated with a published literature review

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Interferon-driven deletion of antiviral B cells at the onset of chronic infection

Abstract: Interferon-driven inflammation in chronic viral infection blocks generation of sustained B cell responses. See related Research Articles by Moseman et al. and Sammicheli et al. and a Focus by Laidlaw et al.

Cited by 85 publications

References 67 publications

B cell depletion impairs vaccination-induced CD8+T cell responses in a type I interferon-dependent manner

B cell depletion impairs vaccination-induced CD8+T cell responses in a type I interferon-dependent manner

Targeting transgenic proteins to alpha granules for platelet-directed gene therapy

A clinicopathological description of COVID‐19‐induced chilblains (COVID‐toes) correlated with a published literature review

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B cell depletion impairs vaccination-induced CD8⁺T cell responses in a type I interferon-dependent manner

B cell depletion impairs vaccination-induced CD8⁺T cell responses in a type I interferon-dependent manner