CD4+ T cells promote delayed B cell responses in the ischemic brain after experimental stroke

Weitbrecht, Luis; Berchtold, Daniel; Zhang, Tian; Jagdmann, Sandra; Dames, Claudia; Winek, Katarzyna; Meisel, Christian; Meisel, Andreas

doi:10.1016/j.bbi.2020.09.029

Cited by 38 publications

(29 citation statements)

References 55 publications

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“…These data indicate that a sizable fraction of the B-lymphocyte response to stroke is T-lymphocyte independent. However, they do not exclude that a T-lymphocyte dependent B-lymphocyte response occurs simultaneously in wildtype mice, which is in fact supported by Weitbrecht et al’s finding in this special issue that CD4 T cells also promote B cell responses after stroke ( Weitbrecht et al, 2020 ). Notably, although we see an increase in B-lymphocytes in MHCII −/− and CD4 −/− mice compared to WT mice, we do not see a corresponding increase in PCs in these mice, indicating that a smaller percentage of the B-lymphocytes present are maturing into PCs.…”

Section: Discussionmentioning

confidence: 93%

IgA natural antibodies are produced following T-cell independent B-cell activation following stroke

Zbesko

Frye

Becktel

et al. 2021

Brain, Behavior, and Immunity

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Up to 30% of stroke patients experience cognitive decline within one year of their stroke. There are currently no FDA-approved drugs that can prevent post-stroke cognitive decline, in part due to a poor understanding of the mechanisms involved. We have previously demonstrated that a B-lymphocyte response to stroke, marked by IgA + cells, can cause delayed cognitive dysfunction in mice and that a similar adaptive immune response occurs in the brains of some human stroke patients that suffer from vascular dementia. The stimuli which trigger B-lymphocyte activation following stroke, and their target antigens, are still unknown. Therefore, to learn more about the mechanisms by which B-lymphocytes become activated following stroke we first characterized the temporal kinetics of the B-lymphocyte, T-lymphocyte, and plasma cell (PC) response to stroke in the brain by immunohistochemistry (IHC). We discovered that B-lymphocyte, T-lymphocyte, and plasma cell infiltration within the infarct progressively increases between 2 and 7 weeks after stroke. We then compared the B-lymphocyte response to stroke in WT, MHCII −/− , CD4 −/− , and MyD88 −/− mice to determine if B-lymphocytes mature into IgA + PCs through a T-lymphocyte and MyD88 dependent mechanism. Our data from a combination of IHC and flow cytometry indicate that following stroke, a population of IgA + PCs develops independently of CD4 + helper T-lymphocytes and MyD88 signaling. Subsequent sequencing of immunoglobulin genes of individual IgA + PCs present within the infarct identified a novel population of natural antibodies with few somatic mutations in complementarity-determining regions. These findings indicate that a population of IgA + PCs develops in the infarct following stroke by B-lymphocytes interacting with one or more thymus independent type 2 (TI-2) antigens, and that they produce IgA natural antibodies.

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Section: Discussionmentioning

confidence: 93%

IgA natural antibodies are produced following T-cell independent B-cell activation following stroke

Zbesko

Frye

Becktel

et al. 2021

Brain, Behavior, and Immunity

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“…127,133 These delayed responses are dependent on CD4-expressing T cells. 134 There is no (yet) conclusive evidence that autoimmune responses to brain antigens play a major role in chronic sequelae (see below), but they do adversely affect initial stroke outcomes. Brain antigens are released by dying brain cells into the bloodstream.…”

Section: Adaptive Inflammation After Strokementioning

confidence: 99%

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Endres

Moro

Nolte

et al. 2022

Circulation Research

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146

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Inflammation and immune mechanisms are crucially involved in the pathophysiology of the development, acute damage cascades, and chronic course after ischemic stroke. Atherosclerosis is an inflammatory disease, and, in addition to classical risk factors, maladaptive immune mechanisms lead to an increased risk of stroke. Accordingly, individuals with signs of inflammation or corresponding biomarkers have an increased risk of stroke. Anti-inflammatory drugs, such as IL (interleukin)-1β blockers, methotrexate, or colchicine, represent attractive treatment strategies to prevent vascular events and stroke. Lately, the COVID-19 pandemic shows a clear association between SARS-CoV2 infections and increased risk of cerebrovascular events. Furthermore, mechanisms of both innate and adaptive immune systems influence cerebral damage cascades after ischemic stroke. Neutrophils, monocytes, and microglia, as well as T and B lymphocytes each play complex interdependent roles that synergize to remove dead tissue but also can cause bystander injury to intact brain cells and generate maladaptive chronic inflammation. Chronic systemic inflammation and comorbid infections may unfavorably influence both outcome after stroke and recurrence risk for further stroke. In addition, stroke triggers specific immune depression, which in turn can promote infections. Recent research is now increasingly addressing the question of the extent to which immune mechanisms may influence long-term outcome after stroke and, in particular, cause specific complications such as poststroke dementia or even poststroke depression.

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“…Scrutiny of TLS induction in non-tumor bearing animal models has provided with crucial information for the understanding of the complex, tightly regulated, non-redundant mechanisms that lead to initiation, formation and maintenance of these lymphoid ectopic structures (55). Notably, several recent reports have shed new light in the ontogeny of TLS in mouse models of lung disorders (33,(60)(61)(62)(63)(64)(65)(66). In a model of viral infection with respiratory syncytial virus (RSV), Gassen et al reported a RSVdependent down-modulation of both IL-21 and IL-21R expression by lung Tfh cells, accompanied by an up-regulation of PD-L1 expression on resident B cells and DC, resulting in a defective GC formation and anti-RSV antibody response.…”

Section: Learning From Tls Study In Non-tumor Inflammatory Diseases To Better Understand Tls Role In Cancermentioning

confidence: 99%

Tumor-Associated Tertiary Lymphoid Structures: From Basic and Clinical Knowledge to Therapeutic Manipulation

et al. 2021

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The tumor microenvironment is a complex ecosystem almost unique to each patient. Most of available therapies target tumor cells according to their molecular characteristics, angiogenesis or immune cells involved in tumor immune-surveillance. Unfortunately, only a limited number of patients benefit in the long-term of these treatments that are often associated with relapses, in spite of the remarkable progress obtained with the advent of immune checkpoint inhibitors (ICP). The presence of “hot” tumors is a determining parameter for selecting therapies targeting the patient immunity, even though some of them still do not respond to treatment. In human studies, an in-depth analysis of the organization and interactions of tumor-infiltrating immune cells has revealed the presence of an ectopic lymphoid organization termed tertiary lymphoid structures (TLS) in a large number of tumors. Their marked similarity to secondary lymphoid organs has suggested that TLS are an “anti-tumor school” and an “antibody factory” to fight malignant cells. They are effectively associated with long-term survival in most solid tumors, and their presence has been recently shown to predict response to ICP inhibitors. This review discusses the relationship between TLS and the molecular characteristics of tumors and the presence of oncogenic viruses, as well as their role when targeted therapies are used. Also, we present some aspects of TLS biology in non-tumor inflammatory diseases and discuss the putative common characteristics that they share with tumor-associated TLS. A detailed overview of the different pre-clinical models available to investigate TLS function and neogenesis is also presented. Finally, new approaches aimed at a better understanding of the role and function of TLS such as the use of spheroids and organoids and of artificial intelligence algorithms, are also discussed. In conclusion, increasing our knowledge on TLS will undoubtedly improve prognostic prediction and treatment selection in cancer patients with key consequences for the next generation immunotherapy.

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CD4+ T cells promote delayed B cell responses in the ischemic brain after experimental stroke

Cited by 38 publications

References 55 publications

IgA natural antibodies are produced following T-cell independent B-cell activation following stroke

IgA natural antibodies are produced following T-cell independent B-cell activation following stroke

Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke

Tumor-Associated Tertiary Lymphoid Structures: From Basic and Clinical Knowledge to Therapeutic Manipulation

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