MIP-3β/CCL19 is associated with the intrathecal invasion of mononuclear cells in neuroinflammatory and non-neuroinflammatory CNS diseases in dogs
TL;DR: CCL19 CSF concentrations were markedly elevated in patients affected with the neuroinflammatory diseasesSRMA and MUO and showed a strong correlation with the CSF cell count, suggesting this chemokine may play an important role in the pathogenesis of SRMA andMUO.
Abstract: Background
Chemokines such as MIP-3β/CCL19 are important factors in the mechanism of cell migration and pathogenesis of central nervous system (CNS) inflammatory reactions. The hypothesis of this study is that CCL19, also known as MIP-3β, is involved in the pathogenesis of inflammatory and non-inflammatory CNS diseases of dogs. Experiments were performed on cerebrospinal fluid (CSF) and serum samples of dogs affected with steroid responsive meningitis-arteritis (SRMA) during the acute phase as well as during treatment. Dogs with SRMA were compared to dogs with presumed meningoencephalomyelitis of unknown origin (MUO), and both groups sub-categorized into dogs receiving no therapy and with patients receiving prednisolone therapy. Idiopathic epilepsy (IE), a group with normal CSF cell count, was used as a control. Additionally, dogs with intervertebral disc disease (IVDD) of varying severity were analyzed. Chemokine concentrations were determined by enzyme linked immunosorbent assay. Migration assays were performed on seven selected CSF samples using a disposable 96-well chemotaxis chamber.
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TL;DR: Different groups of established and potential diagnostic markers of MUO are presented assessing current results and future potential.
Abstract: Meningoencephalitides of Unknown Origin (MUO) comprises a group of non-infectious inflammatory brain conditions, which frequently cause severe neurological disease and death in dogs. Although multiple diagnostic markers have been investigated, a conclusive diagnosis, at present, essentially relies on postmortem histopathology. However, different groups of biomarkers, e.g. acute phase proteins, antibodies, cytokines, and neuro-imaging markers may prove useful in the diagnostic investigation of dogs with MUO. It appears from the current literature that acute phase proteins such as C-reactive protein are often normal in MUO, but may be useful to rule out steroid responsive meningitis-arteritis as well as other systemic inflammatory conditions. In antibody research, anti-glial fibrillary acidic protein (GFAP) may play a role, but further research is needed to establish this as a consistent marker of particularly Pug dog encephalitis. The proposed diagnostic markers often lack specificity to distinguish between the subtypes of MUO, but an increased expression of interferon-γ (IFN-γ) in necrotizing meningoencephalitis (NME) and interleukin-17 (IL-17) in granulomatous meningoencephalitis (GME) in tissue biopsies may indicate their potential as specific markers of NME and GME, respectively, suggesting further investigations of these in serum and CSF. While neuro-imaging is already an important part of the diagnostic work-up in MUO, further promising results have been shown with Positron Emission Tomography (PET) as well as proton resonance spectroscopy (1H MRS), which may be able to detect areas of necrosis and granulomas, respectively, with relatively high specificity. This review presents different groups of established and potential diagnostic markers of MUO assessing current results and future potential.
9 citations
TL;DR: The data suggest that CCL19 acts as a chicken PWBC chemotactic factor and facilitate the infiltration of PWBC (especially T cells) into the bursae after IBDV infection.
8 citations
TL;DR: The aim of this review is to provide an overview of the current understanding and knowledge on SRMA, with special emphasis on potential biomarkers and their applicability in the diagnostic work-up.
Abstract: Steroid responsive meningitis-arteritis (SRMA) in dogs causes severe inflammation of meningeal arteries leading to generalized meningitis with possible neurological signs, as well as a systemic inflammatory response. The etiology and exact pathogenesis are unknown, but an immune-mediated origin has been suggested and is supported by a positive response to immunosuppressive treatment with corticosteroids. A collection of clinical and paraclinical characteristics may be highly indicative of SRMA, but a single and conclusive diagnostic test or biomarker is currently not available. The aim of this review is to provide an overview of the current understanding and knowledge on SRMA, with special emphasis on potential biomarkers and their applicability in the diagnostic work-up. Though no specific markers for SRMA currently exist, clinically useful markers include IgA and several acute phase proteins e.g. C-reactive protein. A frequent problem of both acknowledged and proposed biomarkers, is, however, their inability to effectively differentiate SRMA from other systemic inflammatory conditions. Other proposed diagnostic markers include genetic markers, acute phase proteins such as serum amyloid A, cytokines such as interleukin-17 and CC-motif ligand 19, endocannabinoid receptors and heat shock protein 70; these suggestions however either lack specificity or need further investigation.
7 citations
Dissertation•
01 Jan 2004
TL;DR: It appears that microglial response to various diseases can be both stereotypic and specific, and findings for the production of another endogenous gas, NO, seems to be stereotypic.
Abstract: Microglial cells are the main immune effector elements of the brain. They respond to
virtually every kind of disruption of homeostasis in the CNS and rapidly
progress from their resting, ramified state to an activated state where they
can proliferate, migrate, express surface molecules de novo or at increased
levels, and exert functions similar to those of macrophages such as phagocytosis
and generation of ROS and NO.
It has
long been believed that microglial cells follow an uniform unspecific
reaction pattern upon activation. Evidence has grown that this view seriously
underrates microglial competence in the immune surveillance of the CNS.
The
purpose of this study was to elucidate whether the canine microglial reaction
pattern differs in response to different alterations in the CNS and whether
the findings of our preliminary study on demyelination due to CDV infection
were specific to a demyelinating disease or also apply to other disease
entities. This would indicate that the canine microglial reaction is
stereotypic. To our best knowledge, this study is the first comparative
characterization of microglial cells ex vivo in different diseases.
Canine
microglial cells from dogs suffering from different intracranial and extracranial
diseases were characterized immunophenotypically and functionally ex vivo by
flow cytometry. The dogs were divided into eight examination groups according
to histopathological diagnosis. The results of each group were evaluated and
compared to those of a preliminary study of the microglial ex vivo
examination in dogs of a vaccine challenge experiment with canine distemper
virus infection and demyelination in CNS.
In the
vaccine challenge experiment, microglia of dogs with histopathologically confirmed
demyelination due to CDV infection showed marked upregulation of the surface
molecules CD18, CD11b, CD11c, CD1c, MHC class I, MHC class II, and a tendency
for increased expression intensity of ICAM-1 (CD54), B7-1 (CD80), and B7-2
(CD86). Functionally, microglial cells in demyelination due to CDV were shown
to have significantly enhanced phagocytosis and generation of ROS.
A
tendency for an upregulated expression was found for various surface
molecules on microglia in different CNS alterations. Statistical significance
was found only in certain surface molecules: there was an upregulated
expression of CD11b in dogs with intracranial tumors and inflammation; MHC II
was also upregulated in dogs with intracranial inflammation, whereas upregulation
of B7-1 and B7-2 was found only in dogs with demyelination. Functionally,
phagocytosis was significantly enhanced in dogs with demyelination and in
those with intracranial inflammation, but ROS generation was significantly
enhanced only in dogs with demyelination.
In
conclusion, it appears that microglial response to various diseases can be
both stereotypic and specific. Our results point to a certain degree of
conformity in the immunophenotypical response of microglia, whereas the
functional response of canine microglia seems to differentiate between
different underlying pathologies. Phagocytosis was found to be enhanced for
inflammation and demyelination in the CNS, which therefore indicates a more
specific microglial response. Significant enhancement of ROS generation was
found only in dogs with demyelination and not in those with other diseases.
This strongly suggests a specific response of microglia to demyelination and
underscores the pivotal role of microglia in the pathogenesis of demyelination.
In contrast
to findings regarding ROS generation, findings for the production of another
endogenous gas, NO, seems to be stereotypic. In our study there were no
enhanced levels of NO neither in microglial culture supernatant nor in CSF
corresponding to a specific disease entity.
4 citations
Dissertation•
01 Jan 2016
TL;DR: In this paper, the potential of these markers to quantify the degree of spinal cord damage was evaluated and whether they could consequently serve as prognostic indicators, and a calculation of the combination of multiple CSF biomarkers was performed in order to assess whether this could enhance the predictive value.
Abstract: Intervertebral disc herniation is a
common cause of spinal cord injuries (SCI) in dogs. The prognosis in these
dogs is determined by the severity of SCI and the degree of neurological
deficits. The prediction of a reliable prognosis can be challenging in
paraplegic dogs, particularly when they lost nociception.
Tau protein, macrophage inflammatory
protein-3s (MIP-3s) and glial fibrillary acidic protein (GFAP) are potential
markers of SCI. The aim of this study was to assess the value of these
substances as cerebrospinal fluid (CSF) biomarkers for dogs with SCI. Therefore,
the potential of these markers to quantify the degree of spinal cord damage
was evaluated and whether they could consequently serve as prognostic
indicators. Additionally, a calculation of the combination of multiple CSF
biomarkers was performed in order to assess whether this could enhance the
predictive value. The concentrations of tau protein, MIP-3s
and GFAP were measured in cisternal and lumbar CSF samples of 49 paraplegic
dogs using enzyme-linked immunosorbent assays (ELISA). The dogs with acute/subacute
( 28 days; n = 13) SCI were classified
according to the presence (grade 4) or absence (grade 5) of deep pain
perception (Sharp & Wheeler, 2005). Outcome of
dogs with acute/subacute SCI was monitored by neurological follow-up exams
and was defined to be successful when an improvement of at least one grade
was noted within four weeks after surgery. The CSF of seven healthy beagle
dogs served as control.
Tau protein and MIP-3s concentrations
were significantly higher in paraplegic dogs with acute/subacute SCI compared
to healthy dogs and to dogs with chronic SCI. GFAP concentration in cisternal
CSF of dogs with acute/subacute SCI and grade 5 were significantly higher
compared to healthy dogs. However, no difference in GFAP concentrations
between paraplegic and healthy dogs was detected in lumbar CSF nor between
dogs with acute/subacute and chronic SCI. Paraplegic dogs with chronic SCI
had significantly elevated tau protein and MIP-3s concentrations in lumbar
CSF compared to control dogs. Dogs with neurological improvement had
significantly lower cisternal tau protein values, especially those without
deep pain perception. This predictive value of CSF tau protein concentrations
could not be enhanced by a combination of multiple CSF biomarkers. In conclusion, tau protein, MIP-3s and
GFAP are potential biomarkers in dogs with SCI. The cisternal tau protein
concentration may serve as a prognostic indicator in dogs with SCI. A
combination of all three CSF biomarkers together could not enhance the
prognostic accuracy.
3 citations
Cites background from "MIP-3β/CCL19 is associated with the..."
...Somit lassen diese Ergebnisse auf eine Beteiligung des MIP-3ß bei Prozessen der Sekundärschädigung von Rückenmarksverletzungen schließen (Bartels et al., 2014)....
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References
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TL;DR: Current understanding of the roles played by chemokines in the functional biology of secondary lymphoid organs will be reviewed and a central role for the chemokine family of molecules has been uncovered.
Abstract: As few as one in 100,000 B and T lymphocytes are specific for a single protein antigen, such as tetanus toxin, yet these cells must come together if an antibody response is to occur. Bringing antigen-presenting cells and rare antigen-specific B and T lymphocytes into physical contact is a principal function of secondary lymphoid organs. In the last few years, details have begun to emerge on the cues that guide cell movements inside lymphoid organs, and a central role for the chemokine family of molecules has been uncovered. Here, current understanding of the roles played by chemokines in the functional biology of secondary lymphoid organs will be reviewed.
1,064 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...CCL19 is constitutively expressed in the CNS for fast immunosurveillance [11] and is produced by different cells such as dendritic cells (DC), macrophages and some non-hematopoietic cells [11,12]....
[...]
TL;DR: The immune system is composed of single cells, and its function is entirely dependent on the capacity of these cells to traffic, localize within tissues, and interact with each other in a precisely coordinated fashion.
Abstract: The immune system is composed of single cells, and its function is entirely dependent on the capacity of these cells to traffic, localize within tissues, and interact with each other in a precisely coordinated fashion. There is growing evidence that the large families of chemokines and chemokine receptors provide a flexible code for regulating cell traffic and positioning in both homeostatic and inflammatory conditions. The regulation of chemokine receptor expression during development and following cell activation explains the complex migratory pathways taken by dendritic cells, T and B lymphocytes, providing new insights into the mechanisms that control priming, effector function, and memory responses.
1,042 citations
TL;DR: A novel chemokine-dependent reciprocal cross-talk between neutrophils and Th17 cells is revealed, which may represent a useful target for the treatment of chronic inflammatory diseases.
695 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...Activated neutrophils induced chemotaxis of Th17 cells and in turn could attract more neutrophils [35]....
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...’s study revealed that a novel chemokine-dependent reciprocal cross-talk between neutrophils and Th17 cells exists [35]....
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TL;DR: Insight is provided into the mechanisms that control T-cell priming as well as memory and effector immune responses, following antigenic stimulation.
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538 citations
"MIP-3β/CCL19 is associated with the..." refers background in this paper
...It binds to the CCR7 receptor which is expressed on myeloid cells [13], mature DC, T cells, as well as activated B cells [14-16]....
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TL;DR: Results indicate that following SCI, all classes of neural cells initially contribute to the organization of inflammation, whereas recruited immune cells mostly contribute to its maintenance at later time points.
Abstract: We have studied the spatial and temporal distribution of six proinflammatory cytokines and identified their cellular source in a clinically relevant model of spinal cord injury (SCI). Our findings show that interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF) are rapidly (<5 and 15 minutes, respectively) and transiently expressed in mice following contusion. At 30-45 minutes post SCI, IL-1beta and TNF-positive cells could already be seen over the entire spinal cord segment analyzed. Multilabeling analyses revealed that microglia and astrocytes were the two major sources of IL-1beta and TNF at these times, suggesting a role for these cytokines in gliosis. Results obtained from SCI mice previously transplanted with green fluorescent protein (GFP)-expressing hematopoietic stem cells confirmed that neural cells were responsible for the production of IL-1beta and TNF for time points preceding 3 hours. From 3 hours up to 24 hours, IL-1beta, TNF, IL-6, and leukemia inhibitory factor (LIF) were strongly upregulated within and immediately around the contused area. Colocalization studies revealed that all populations of central nervous system resident cells, including neurons, synthesized cytokines between 3 and 24 hours post SCI. However, work done with SCI-GFP chimeric mice revealed that at least some infiltrating leukocytes were responsible for cytokine production from 12 hours on. By 2 days post-SCI, mRNA signal for all the above cytokines had nearly disappeared. Notably, we also observed another wave of expression for IL-1beta and TNF at 14 days. Overall, these results indicate that following SCI, all classes of neural cells initially contribute to the organization of inflammation, whereas recruited immune cells mostly contribute to its maintenance at later time points.
537 citations
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