Lymphocytes In Central Nervous System Research Articles

Recurrence of Lymphoblastic Leukemia Manifesting as Bilateral Optic Disk Neovascularization During Complete Clinical Remission--Case Report

<i>Background</i>: The intraocular manifestations of leukemia are diverse. The retina is the most common ophthalmic involvement site. The most common retinal manifestations of acute lymphoblastic leukemia (ALL) include dilated and tortuous vessels, serous retinal detachment (SRD), intraretinal hemorrhages as well as roth spots. Optic nerve infiltration and retinal neovascularization are unusual, especially in complete clinical remission of ALL. However, neovascularization in optic disk has not been observed in ALL during complete clinical remission. <i>Objective</i>: To report clinical characteristics of a bilateral optic disk neovascularization associated with relapse of ALL. <i>Method</i>: A 31-year-old male with ALL after having reached complete remission from chemotherapy complained about a vision loss in both eyes. First examination showed that best corrected visual acuity (BCVA) was 20/200 for his right eye and 20/160 for his left eye, respectively. Fundus examination revealed bilateral profound optic disk edema with multiple yellow-white exudates and retinal hemorrhages. Optical coherence tomography (OCT) showed bilateral optic disk edema and SRD in both maculas. Fundus fluorescein angiography (FFA) showed bilateral optic disk neovascularization. All these changes were present in remission. The patient received intravitreal Conbercept injection 0.5 mg (10 mg/ml) in both eyes for once on June 29, 2019. Optic disk neovascularization resolved three weeks after treatment. BCVA improved to 20/200 in his right eye, but still light perception in his right eye. No optic disk neovascularization recurrence was observed in 3-month follow-up. BCVA of the right eye maintained 20/200 at the latest follow-up. After intravitreal injection for 4 months the patient suffered from cerebral hemorrhage. He received bone marrow biopsy and cerebrospinal fluid sampling. The results showed relapse in hemogram and lymphocytes in central nervous system (CNS). Therefore, the chemotherapy treatment did not cause a new remission of the disease and the patient failed to recover. <i>Conclusion</i>: Optic disk neovascularization may appear as a sign of extramedullary relapse of ALL months in advance of the hematologic relapse. Intravitreal injection of conbercept could be beneficial and safe in treating this neovascularization.

Clinical and Haematological Disorders in Cats with Natural and Progressive Infection by Feline Leukemia Virus (FeLV)

Background: Feline leukemia virus (FeLV) is an important infectious agent in cats, responsible for great health damages and a large death amount. Among the most common clinical disorders caused by FeLV, severe hematological changes are related at the progressive infection, ordinarily presented as cytopenias. Regarding its oncogenic potential, lymphoma and leukemia are the most observed illness originated by the agent. Therefore, this study has the goal of describing and comparing clinical and hematological disorders in FeLV positive cats from a selected population.Materials, Methods &amp; Results: Data of clinical evaluations of felines from a previously performed cross-sectional epidemiological study were compiled. This study obtained the prevalence of FeLV infected cats in Santa Catarina Plateau. Three groups were established from the original sample of 274 cats; Group 1 (control), FeLV negative and none clinical alterations (n = 80); Group 2, FeLV positive and none clinical changes (n = 9); Group 3, FeLV positive cats with clinical disorders (n = 29). Physical and hematological examination data were obtained from the medical records. The clinical changes at Group 3 were mucosal pallor (65.51% [19/29]), neurological disorders (20.69% [6/29]), lymphoma (20.69% [6/29]), coinfections (10.34% [3/29]) and leukemia (6.9% [2/29]). The most observed hematological disorders of Group 3 were anemia (65.51% [19/29]) and thrombocytopenia (62.7% [18/20]). At the complete blood count, the medium erythrocyte and eosinophil count, hemoglobin concentration and hematocrit were lower for Group 3 than the other two groups. The mean number of platelets count were higher for Group 1 than Group 2 and 3. The mean of the other variables remained between reference numbers. However, a descriptive analysis within the groups demonstrated that lymphopenia was observed in 34.48% (10/29) and neutropenia in 17.24% (5/29) at the Group 3. Discussion: The greater FeLV positive cats with clinical alterations number is a result of a sample obtained from a hospital population. In this scenario, cats are submitted to medical appointment in order to solve their clinical signs, not for purpose of infection screening. The frequency of non-neoplasic disease in FeLV positive cats was higher than neoplastic diseases. The mucosal pallor is the most important clinical change and it is an anemia consequence. A large number of clinical signs related in this study was non-specific. All the clinical changes are associated to FeLV infection, regardless the clinical syndrome observed. Neurological disorders frequency at this study was higher than other articles, being related to neoplastic lymphocytes in central nervous system at the resolved cases. Lymphoma and leukemia were the only neoplasms found in this FeLV study. Non-regenerative anemia was the main FeLV associated hematologic change. This disorder is originated by several mechanisms, such as the virus influence on bone marrow precursors and leukemic infiltration. Thrombocytopenia showed lower frequency than anemia and leukopenia, however, it was the second most common alteration in this study, which was observed in Group 2 and 3. The severe cytopenias related in Group 3 are probably due to the destruction or decrease of the production of these cells by the virus replication process. The clinical and hematological disorders found in this study, reveal the serious presentation and usually irreversible situation of this viral infection, originating important health harm to the affected cats.

Extracellular adenosine signaling induces CX3CL1 expression in the brain to promote experimental autoimmune encephalomyelitis

BackgroundMultiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are debilitating neuroinflammatory diseases mediated by lymphocyte entry into the central nervous system (CNS). While it is not known what triggers lymphocyte entry into the CNS during neuroinflammation, blockade of lymphocyte migration has been shown to be effective in controlling neuroinflammatory diseases. Since we have previously shown that extracellular adenosine is a key mediator of lymphocyte migration into the CNS during EAE progression, we wanted to determine which factors are regulated by adenosine to modulate EAE development.MethodsWe performed a genetic analysis of wild type and CD73−/− (that are unable to produce extracellular adenosine and are protected from EAE development) to identify factors that are both important for EAE development and controlled by extracellular adenosine signaling.ResultsWe show that extracellular adenosine triggered lymphocyte migration into the CNS by inducing the expression of the specialized chemokine/adhesion molecule CX3CL1 at the choroid plexus. In wild type mice, CX3CL1 is upregulated in the brain on Day 10 post EAE induction, which corresponds with initial CNS lymphocyte infiltration and the acute stage of EAE. Conversely, mice that cannot synthesize extracellular adenosine (CD73−/− mice) do not upregulate CX3CL1 in the brain following EAE induction and are protected from EAE development and its associated lymphocyte infiltration. Additionally, blockade of the A2A adenosine receptor following EAE induction prevents disease development and the induction of brain CX3CL1 expression. The CX3CL1 induced during EAE is found on the choroid plexus, which is the barrier between the blood and cerebral spinal fluid in the brain and is a prime entry point into the CNS for immune cells. Furthermore, CX3CL1 expression can be induced in the brains of mice and in choroid plexus cell line following A2A adenosine receptor agonist administration. Most importantly, we show that CX3CL1 blockade protects against EAE development and inhibits lymphocyte entry into the CNS.ConclusionsWe conclude that extracellular adenosine is an endogenous modulator of neuroinflammation during EAE that induces CX3CL1 at the choroid plexus to trigger lymphocyte entry into the brain.

Adoptive transfer of Th1-conditioned lymphocytes promotes axonal remodeling and functional recovery after spinal cord injury

The role of T lymphocytes in central nervous system (CNS) injuries is controversial, with inconsistent results reported concerning the effects of T-lymphocyte transfer on spinal cord injury (SCI). Here, we demonstrate that a specific T-lymphocyte subset enhances functional recovery after contusion SCI in mice. Intraperitoneal adoptive transfer of type 1 helper T (Th1)-conditioned cells 4 days after SCI promoted recovery of locomotor activity and tactile sensation and concomitantly induced regrowth of corticospinal tract and serotonergic fibers. However, neither type 2 helper T (Th2)- nor IL-17-producing helper T (Th17)-conditioned cells had such effects. Activation of microglia and macrophages were observed in the spinal cords of Th1-transfered mice after SCI. Specifically, M2 subtype of microglia/macrophages was upregulated after Th1 cell transfer. Neutralization of interleukin 10 secreted by Th1-conditioned cells significantly attenuated the beneficial effects by Th1-conditioned lymphocytes after SCI. We also found that Th1-conditioned lymphocytes secreted significantly higher levels of neurotrophic factor, neurotrophin 3 (NT-3), than Th2- or Th17-conditioned cells. Thus, adoptive transfer of pro-inflammatory Th1-conditioned cells has neuroprotective effects after SCI, with prospective implications in immunomodulatory treatment of CNS injury.

Extracellular adenosine as a master regulator of immune cell migration into the central nervous system via induction of CX3CL1 (60.9)

Abstract Having the ability to modulate lymphocyte entry into the central nervous system (CNS) would benefit patients with neuroinflammatory diseases. We have previously shown that extracellular adenosine regulates CNS entry of lymphocytes during experimental autoimmune encephalomyelitis (EAE), the animal model for the CNS inflammatory disease multiple sclerosis. For instance, while extracellular adenosine levels are vastly increased following inflammatory cellular damage (from the hydrolysis of released cytoplasimic ATP by CD39 and CD73), mice lacking CD73 or given adenosine receptor (AR) antagonists have significantly reduced CNS lymphocyte entry during EAE. We now show through detailed genetic studies that AR signaling regulates lymphocyte migration into the CNS though induction of CX3CL1, a specialized chemokine that acts as both an adhesion molecule and chemoattractant for lymphocytes, monocytes, and NK cells. We show that AR signaling is necessary and sufficient to induce CNS expression of CX3CL1 (as compared to over 40 other chemokines and adhesion molecules). AR regulation of CX3CL1 is critical for EAE progression, as daily anti-CX3CL1 treatments prevent CNS lymphocyte infiltration during EAE. Importantly, AR signaling induces CX3CL1 expression on the choroid plexus, a known CNS entry point for lymphocytes. As AR signaling can promote lymphocyte transmigration across a choroid plexus transwell barrier, we conclude that adenosine is a master regulator of CNS lymphocyte entry.

Extracellular adenosine triggers lymphocyte entry into the central nervous system during experimental autoimmune encephalomyelitis by regulating chemokine and adhesion molecule expression in the brain (44.12)

Abstract Lymphocyte entry into the central nervous system (CNS) is a highly regulated process which serves to promote tissue repair while protecting against potentially fatal inflammation. As the formation of extracellular adenosine (catalyzed from ATP by CD39 and CD73) during inflammation serves as a negative-feedback signal to prevent excessive cell damage, our results suggest that adenosine receptor (AR) signaling also regulates CNS lymphocyte infiltration. We have shown that extracellular adenosine is required for the progression experimental autoimmune encephalomyelitis (EAE), the animal model of autoimmune inflammatory disease Multiple Sclerosis. We now show that AR signaling induces the CNS expression of the chemokine CX3CL1 (fractalkine), which acts as a chemoattractant for monocytes, lymphocytes, and NK cells. In addition, CX3CL1 expression is up-regulated in the CNS immediately prior to EAE onset only in wild type, but not CD73-/- mice, which cannot produce extracellular adenosine, are protected from EAE, and have minimal CNS lymphocyte infiltration following EAE induction. Moreover, CD39, CD73, and ARs are found clustered in the brain only at the choroid plexus, a structure which is known to regulate lymphocyte migration into the CNS. As AR signaling can induce CX3CL1 and ICAM-1 expression and lymphocyte transmigration across an in vitro choroid plexus transwell barrier, we conclude that AR signaling regulates lymphocyte entry into the CNS.

The key to the blood brain door: Differential signaling of the adenosine receptor subtypes regulates lymphocyte entry into the central nervous system at the choroid plexus (95.12)

Abstract Lymphocyte entry into the central nervous system (CNS) is a highly regulated process which serves to promote tissue repair (when required) while protecting against potentially fatal inflammation. As the formation of extracellular adenosine (catalyzed from ATP by CD39 and CD73) during inflammation serves as a negative-feedback signal to prevent excessive cell damage, our results suggest that adenosine receptor (AR) signaling also regulates CNS lymphocyte infiltration. We have recently shown that CD73 and AR signaling are required for CNS lymphocyte entry during experimental autoimmune encephalomyelitis (EAE), the animal model of autoimmune inflammatory disease Multiple Sclerosis. We now show that CD39, CD73, and the A1- and A2A-AR subtypes are found clustered in the CNS only at the choroid plexus, a structure which regulates lymphocyte migration from the blood to the cerebrospinal fluid. Moreover, while A1- and A2A-AR activation have functionally opposing cellular effects (cAMP studies), mice given A2AAR antagonists are protected against EAE and CNS lymphocyte infiltration while A1AR-/- mice develop severe EAE. Additionally, AR signaling can induce lymphocyte transmigration across an in vitro choroid plexus transwell barrier while A2AAR activation promotes the upregulation of ICAM-1. Therefore, we conclude that AR signaling at the choroid plexus mediates CNS lymphocyte entry. AI 57854 and NS 063011

CSF lymphocyte subsets in aseptic meningitis: dual-labelling analysis with flow cytometry

In order to characterize the CSF (cerebrospinal fluid) lymphocytes in CNS (central nervous system) inflammation, we examined paired samples of CSF and PB (peripheral blood) of 19 patients with acute aseptic meningitis, performing the dual labelling method on flow cytometry. Significantly higher percentages of CD3+ (T cell), CD4+ (helper-inducer), Leu3a+ Leu15- (cytotoxic-T) and HLA-DR+ CD3+ (activated-T) cells were identified in the CSF than in the PB of these patients. We observed significantly lower percentages of CD19+ (B cell), Leu2a+ Leu18+ (suppressor-inducer) and HLA-DR+ CD3- cells in the CSF than in the PB of these patients. Relative increases in helper-inducer, cytotoxic-T and activated-T cells in the CSF of aseptic meningitis are supposed to represent an active inflammatory process. However, whether these changes are specific or pathognomonic to any disease(s) remains to be solved.

Increased Presence of T Lymphocytes in Central Nervous System of EPM Affected Horses

Equine protozoal myeloencephalitis (EPM), caused by Sarcocystis neurona infection in the central nervous system (CNS), affects up to 1% of all horses during their lifetimes. Neither the protective immune response nor the immunopathology associated with the disease is well understood. To begin to clarify the pathogenesis of the disease, immunohistochemical staining for B and T lymphocytes was performed on spinal cord sections obtained from 17 horses, all of which were all positive for S. neurona based on immunohistochemical staining. Fifteen of the 17 horses included in the study were killed due to neurologic dysfunction; 2 of the 17 horses were killed because of fractures. All 17 horses had histologic changes consistent with S. neurona infection. A significantly greater number of T cells were seen in sections from S. neurona-infected versus control horses. Because this was a small descriptive study, we were not able to determine the mechanisms of enhanced T-cell recruitment in the sections from the S. neurona-infected horses.

Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon γ–producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

Theiler's virus-infected l-selectin-deficient mice have decreased infiltration of CD8 + T lymphocytes in central nervous system but clear the virus

Mice with targeted deletion of l-selectin gene ( l-sel −/−) were used to investigate the role of adhesion molecule in immunologic responses following virus infection in the central nervous system (CNS). l-Sel −/− mice from a resistant H-2 b genetic background and parental wild-type H-2 b (C57BL/6) mice were infected with Theiler's murine encephalomyelitis virus (TMEV) intracerebrally and the kinetics of virus replication and infiltration of immune cells in the CNS determined. The levels of infectious TMEV, as measured by plaque assay at 3, 7, 14, and 28 days after infection were between 4 and 6 log 10 PFU of virus per gram of CNS tissues at days 3 and 7 post-infection, and then decreased to undetectable levels by day 14 after infection in both strains of mice. The l-sel −/− mice had decreased numbers of CD8 + T lymphocytes (17.72%±2.4) infiltrating into the CNS at 7 days post-infection when compared to wild-type mice (31.02%±7.5). In addition, the l-sel −/− mice had significantly lower levels of TMEV-specific serum IgG resulting in lower virus neutralizing activity of the serum when compared to wild-type mice. However, the l-sel −/− mice had 2.5-fold increase in B lymphocytes in the CNS (8.29%±1.1) when compared to wild-type mice (3.2%±0.4). Taken together, these data indicate that l-selectin plays a role in recruitment of B and CD8 + T lymphocytes into the CNS following virus infection, which, however, did not affect the ability of the mice to clear TMEV infection.