Antigen-specific immune reactions to ischemic stroke

Brain proteins are detected in the cerebrospinal fluid (CSF) and blood of stroke patients and their concentration is related to the extent of brain damage. Antibodies against brain antigens develop after stroke, suggesting a humoral immune response to the brain injury. Furthermore, induced immune tolerance is beneficial in animal models of cerebral ischemia. The presence of circulating T cells sensitized against brain antigens, and antigen presenting cells (APCs) carrying brain antigens in draining lymphoid tissue of stroke patients support the notion that stroke might induce antigen-specific immune responses. After stroke, brain proteins that are normally hidden from the periphery, inflammatory mediators, and danger signals can exit the brain through several efflux routes. They can reach the blood after leaking out of the damaged blood-brain barrier (BBB) or following the drainage of interstitial fluid to the dural venous sinus, or reach the cervical lymph nodes through the nasal lymphatics following CSF drainage along the arachnoid sheaths of nerves across the nasal submucosa. The route and mode of access of brain antigens to lymphoid tissue could influence the type of response. Central and peripheral tolerance prevents autoimmunity, but the actual mechanisms of tolerance to brain antigens released into the periphery in the presence of inflammation, danger signals, and APCs, are not fully characterized. Stroke does not systematically trigger autoimmunity, but under certain circumstances, such as pronounced systemic inflammation or infection, autoreactive T cells could escape the tolerance controls. Further investigation is needed to elucidate whether antigen-specific immune events could underlie neurological complications impairing recovery from stroke

Differences in Antiphospholipid Antibody Profile between Patients with Obstetric and Thrombotic Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune condition characterised by the presence of antiphospholipid antibodies (aPL) associated with vascular thrombosis and/or pregnancy complications. In a cohort of 74 yet diagnosed APS individuals fulfilling Sydney laboratory criteria (twice positive for lupus anticoagulant, anticardiolipin, aCL, and/or anti-β2glycoprotein I, aβ2GPI), 33 out of 74 were obstetric APS (OAPS) and 41 thrombotic APS (TAPS) patients. 39% of TAPS patients were women. Although aPL detection was persistent, we observed an oscillatory aPL positivity in 56.7% and a transient seroconversion in 32.4% of APS patients at enrolment. Thus, we tested their sera in a line immunoassay that simultaneously detected IgG or IgM for criteria (aCL and aβ2GPI) and non-criteria (anti-phosphatidylserine, aPS; anti-phosphatidic acid, aPA; anti-phosphatidylinositol, aPI; anti-annexin 5, aA5; anti-prothrombin, aPT; anti-phosphatidylethanolamine; anti-phosphatidylglycerol, and anti-phosphatidylcholine) aPL. OAPS and TAPS patients displayed different but overlapping clusters based on their aPL reactivities. Specifically, while OAPS patients showed higher aPA, aPS, aA5, aβ2GPI and aPT IgM levels than TAPS patients, the latter displayed higher reactivity in aCL, aPI and aA5 IgG. Eventually, with a cut-off of the 99 th percentile established from a population of 79 healthy donors, TAPS patients significantly tested more positive for aCL and aA5 IgG than OAPS patients, who tested more positive for aPA, aPS and aβ2GPI IgM. Transiently seronegative APS patients showed non-criteria aPL positivity twice in sera obtained 3 months apart. Overall, our data show that APS patients presented clusters of aPL that define different profiles between OAPS and TAPS, and persistent non-criteria aPL positivity was observed in those who are transiently seronegativ

IL-10 deficiency exacerbates the brain inflammatory response to permanent ischemia without preventing resolution of the lesion

El pdf del artículo es la versión post-print.Stroke induces inflammation that can aggravate brain damage. This work examines whether interleukin-10 (IL-10) deficiency exacerbates inflammation and worsens the outcome of permanent middle cerebral artery occlusion (pMCAO). Expression of IL-10 and IL-10 receptor (IL-10R) increased after ischemia. From day 4, reactive astrocytes showed strong IL-10R immunoreactivity. Interleukin-10 knockout (IL-10 KO) mice kept in conventional housing showed more mortality after pMCAO than the wild type (WT). This effect was associated with the presence of signs of colitis in the IL-10 KO mice, suggesting that ongoing systemic inflammation was a confounding factor. In a pathogen-free environment, IL-10 deficiency slightly increased infarct volume and neurologic deficits. Induction of proinflammatory molecules in the IL-10 KO brain was similar to that in the WT 6 hours after ischemia, but was higher at day 4, while differences decreased at day 7. Deficiency of IL-10 promoted the presence of more mature phagocytic cells in the ischemic tissue, and enhanced the expression of M2 markers and the T-cell inhibitory molecule CTLA-4. These findings agree with a role of IL-10 in attenuating local inflammatory reactions, but do not support an essential function of IL-10 in lesion resolution. Upregulation of alternative immunosuppressive molecules after brain ischemia can compensate, at least in part, the absence of IL-10. © 2013 ISCBFM.Work supported by the Spanish Ministry of Economy (SAF2011-30492), and the European Community (FP7, grant agreements: n°201024 ARISE and n°278850 InMiND), and the ERANET-NEURON project (PRI-PIMNEU-2011-1342). IPP and EBT had PhD fellowships from the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) of the Generalitat de Catalunya and the FPU program of the Spanish Ministry of Economy, respectively.Peer Reviewe

CNS-border associated macrophages respond to acute ischemic stroke attracting granulocytes and promoting vascular leakage

The central nervous system (CNS) contains several types of immune cells located in specific anatomic compartments. Macrophages reside at the CNS borders surrounding the brain vessels, in leptomeningeal spaces and the choroid plexus, where they interact with the vasculature and play immunological surveillance and scavenging functions. We investigated the phenotypic changes and role of these macrophages in response to acute ischemic stroke. Given that CD163 expression is a hallmark of perivascular and meningeal macrophages in the rat and human brain, we isolated CD163+ brain macrophages by fluorescence activated cell sorting. We obtained CD163+ cells from control rats and 16 h following transient middle cerebral artery occlusion, after verifying that infiltration of CD163+ peripheral myeloid cells is negligible at this acute time point. Transcriptome analysis of the sorted CD163+ cells identified ischemia-induced upregulation of the hypoxia inducible factor-1 pathway and induction of genes encoding for extracellular matrix components and leukocyte chemoattractants, amongst others. Using a cell depletion strategy, we found that CNS border-associated macrophages participate in granulocyte recruitment, promote the expression of vascular endothelial growth factor (VEGF), increase the permeability of pial and cortical blood vessels, and contribute to neurological dysfunction in the acute phase of ischemia/reperfusion. We detected VEGF expression surrounding blood vessels and in some CD163+ perivascular macrophages in the brain tissue of ischemic stroke patients deceased one day after stroke onset. These findings show ischemia-induced reprogramming of the gene expression profile of CD163+ macrophages that has a rapid impact on leukocyte chemotaxis and blood-brain barrier integrity, and promotes neurological impairment in the acute phase of stroke

Poststroke Lung Infection by Opportunistic Commensal Bacteria Is Not Mediated by Their Expansion in the Gut Microbiota

Respiratory and urinary tract infections are frequent complications in patients with severe stroke. Stroke-associated infection is mainly due to opportunistic commensal bacteria of the microbiota that may translocate from the gut. We investigated the mechanisms underlying gut dysbiosis and poststroke infection.Funded by Fundació la Marató de TV3 (ref. 201723-30-31-32) to Drs Planas, Urra, and Sancho; the Ministerio de Ciencia e Innovación (MICINN)/AEI/10.13039/501100011033 and European Regional Development Fund (ERDF) A way of making Europe by the European Union (PID2020-113202RB-I00 to Dr Planas); CSIC Interdisciplinary Thematic Platform Plataforma Temática Interdisciplinar (PTI)+Neuro-Aging of the Consejo Superior de Investigaciones Científicas (Dr Planas) funded M. Gallizioli. The work of Instituto de Productos Lácteos (IPLA)-Consejo Superior de Investigaciones Científicas (CSIC) group was partly financed by grant AYUD/2021/ 50981 from Principality of Asturias. The work of Institut de Química Avançada de Catalunya (IQAC)-CSIC was financed by Ministerio de Economía y Competitividad (AGL2017-83599-R) and MICINN (PID2020-117009RB-I00). Dr Díaz-Marugan was funded by La Caixa Foundation (ID 100010434; code LCF/BQ/DE16/11570021). Dr Arboleya received a postdoctoral Juan de la Cierva contract (MICINN, Ref. IJCI-2017-32156). Work in Dr Sancho laboratory was funded by Centro de Investigaciones Cardiovasculares (CNIC), European Union’s Horizon 2020 research and innovation program under grant agreement ERC-2016-Consolidator Grant 725091, and MICINN (PID2019-108157RB/AEI/10.13039/501100011033).Peer reviewe

Antigen-specific immune reactions to ischemic stroke

© 2014 Urra, Miró, Chamorro and Planas. Brain proteins are detected in the cerebrospinal fluid (CSF) and blood of stroke patients and their concentration is related to the extent of brain damage. Antibodies against brain antigens develop after stroke, suggesting a humoral immune response to the brain injury. Furthermore, induced immune tolerance is beneficial in animal models of cerebral ischemia. The presence of circulating T cells sensitized against brain antigens, and antigen presenting cells (APCs) carrying brain antigens in draining lymphoid tissue of stroke patients support the notion that stroke might induce antigen-specific immune responses. After stroke, brain proteins that are normally hidden from the periphery, inflammatory mediators, and danger signals can exit the brain through several efflux routes. They can reach the blood after leaking out of the damaged blood-brain barrier (BBB) or following the drainage of interstitial fluid to the dural venous sinus, or reach the cervical lymph nodes through the nasal lymphatics following CSF drainage along the arachnoid sheaths of nerves across the nasal submucosa. The route and mode of access of brain antigens to lymphoid tissue could influence the type of response. Central and peripheral tolerance prevents autoimmunity, but the actual mechanisms of tolerance to brain antigens released into the periphery in the presence of inflammation, danger signals, and APCs, are not fully characterized. Stroke does not systematically trigger autoimmunity, but under certain circumstances, such as pronounced systemic inflammation or infection, autoreactive T cells could escape the tolerance controls. Further investigation is needed to elucidate whether antigen-specific immune events could underlie neurological complications impairing recovery from stroke.Authors receive financial support by the Spanish Ministries of Economy MINECO (SAF2011-30492) and Health (FIS PI12/01437), and the European Community FP7 (ERA-NET program PRI-PIMNEU-2011-1342). Francesc Miró is supported by the “Red Invictus” of the Instituto de Salud Carlos III (RD12/0014/0011)Peer Reviewe

Antigen Presentation After Stroke

Stroke induces a local inflammatory reaction and a plethora of innate immune responses in the brain where antigen-presenting cells become prominent. However, to date, it is still unclear whether antigen presentation is relevant to the neuropathological and functional outcome of stroke. Stroke does not trigger overt autoimmune reactions, but neural antigens have been found in lymphoid tissues of patient with stroke and it is unknown whether they promote tolerance or immune reactions that under certain conditions might contribute to the functional worsening observed in some patients. Autoantibodies to neural molecules have also been reported in patients with stroke, but the subclass of antibodies is important for their function, and the contribution of such findings to stroke outcome is not yet clear. Notably, stroke induces immunodepression highlighted by a transient lymphopenia, lymphoid organ atrophy, and monocyte deactivation. While these effects might reduce the chances of autoreactivity, they increase the risk of infection in patients with stroke and most frequently in those with severe stroke. Therefore any potential brain protective effect of stroke-induced immunodepression by attenuating or preventing lymphocyte-mediated brain damage is confounded by stroke severity and an increased incidence of infections. Systemic inflammation due to a number of comorbidities that are frequent in patients with stroke is also associated to a poor outcome. Herein, we review some relevant findings regarding the identification of neural antigens in stroke and discuss their potential contribution to the functional outcome of stroke.This work was supported by the Spanish Ministries of Economy MINECO (SAF2014-56279-R) and Health (FIS PI12/01437), and the European Community FP7 (FP7-PEOPLE-2013-ITN-n°07962, supporting M.G.). F.M.M. is supported by the “Red Invictus” of the Instituto de Salud Carlos III (RD12/0014/0011).Peer Reviewe

Selective Ccr2 gene deletion in myeloid cells impairs spontaneous functional recovery following stroke in mice

Trabajo presentado en el 10th International Symposium on Neuroprotection and Neurorepair, celebrado en Desden, Alemania, del 9 al 11 de octubre de 2018Peer reviewe

Stroke-induced immunosuppression: implications for the prevention and prediction of post-stroke infections

Abstract Stroke produces a powerful inflammatory cascade in the brain, but also a suppression of the peripheral immune system, which is also called stroke-induced immunosuppression (SIIS). The main processes that lead to SIIS are a shift from a lymphocyte phenotype T-helper (Th) 1 to a Th2 phenotype, a decrease of the lymphocyte counts and NK cells in the blood and spleen, and an impairment of the defense mechanisms of neutrophils and monocytes. The direct clinical consequence of SIIS in stroke patients is an increased susceptibility to stroke-associated infections, which is enhanced by clinical factors like dysphagia. Among these infections, stroke-associated pneumonia (SAP) is the one that accounts for the highest impact on stroke outcome, so research is focused on its early diagnosis and prevention. Biomarkers indicating modifications in SIIS pathways could have an important role in the early prediction of SAP, but currently, there are no individual biomarkers or panels of biomarkers that are accurate enough to be translated to clinical practice. Similarly, there is still no efficient therapy to prevent the onset of SAP, and clinical trials testing prophylactic antibiotic treatment and β-blockers have failed. However, local immunomodulation could open up a new research opportunity to find a preventive therapy for SAP. Recent studies have focused on the pulmonary immune changes that could be caused by stroke similarly to other acquired brain injuries. Some of the traits observed in animal models of stroke include lung edema and inflammation, as well as inflammation of the bronchoalveolar lavage fluid

Surgical stress alters the intestinal immune system in the mouse model of cerebral ischemia/reperfusion

Trabajo presentado en el 10th International Symposium on Neuroprotection and Neurorepair, celebrado en Desden, Alemania, del 9 al 11 de octubre de 2018Peer reviewe