Pathogenetic factors for excessive IgA production: Th2-dominated immune response in canine steroid-responsive meningitis-arteritis

Schwartz, Michael F.; Puff, Christina; Stein, Veronika M.; Baumgärtner, Wolfgang; Tipold, Andrea

doi:10.1016/j.tvjl.2009.12.001

Cited by 23 publications

(27 citation statements)

References 31 publications

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“…Th1 synthesize IFN-γ and mediate protection against intracellular pathogens [51]. In former studies, this cytokine was only detected in low levels in SRMA [17], we confirmed this finding in the current study, demonstrating low IFN-γ spot-forming cells in dogs with SRMA. Th2 cells synthesize IL-4, IL-13, and IL-25, moderate the clearance of extracellular pathogens [51], and were found to occur in SRMA [17].…”

Section: Discussionsupporting

confidence: 90%

“…Up to now, no infectious agents eliciting the disease have been consistently detected [4, 6, 7, 10–12]. Several studies [13–17] confirmed an immune-mediated disease. Furthermore, high concentrations of immunoglobulin A (IgA) have been found both intrathecally and systemically in dogs affected with SRMA [13, 18].…”

Section: Introductionmentioning

confidence: 99%

“…A predominance of T helper lymphocytes (CD4+) in the peripheral blood [15] with a prominent Th2-mediated immune response in dogs suffering from SRMA was shown [17]. Furthermore, increased levels of interleukin 6 (IL-6) and transforming growth factor beta 1 (TGF-ß 1 ) have been found in CSF.…”

Section: Introductionmentioning

confidence: 99%

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Th17-skewed immune response and cluster of differentiation 40 ligand expression in canine steroid-responsive meningitis-arteritis, a large animal model for neutrophilic meningitis

Freundt-Revilla

Maiolini

Carlson

et al. 2017

J Neuroinflammation

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BackgroundSteroid-responsive meningitis-arteritis (SRMA) is an immune-mediated disorder characterized by neutrophilic pleocytosis and an arteritis particularly in the cervical leptomeninges. Previous studies of the disease have shown increased levels of IL-6 and TGF-ß1 in cerebrospinal fluid (CSF). In the presence of these cytokines, naive CD4+ cells differentiate into Th17 lymphocytes which synthesize interleukin 17 (IL-17). It has been shown that IL-17 plays an active role in autoimmune diseases, it induces and mediates inflammatory responses and has an important role in recruitment of neutrophils. The hypothesis of a Th17-skewed immune response in SRMA should be supported by evaluating IL-17 and CD40L, inducing the vasculitis.MethodsAn enzyme-linked immunosorbent assay (ELISA) was performed to measure IL-17 and CD40L in serum and CSF from a total of 79 dogs. Measurements of patients suffering from SRMA in the acute state (SRMA A) were compared with levels of patients under treatment with steroids (SRMA T), recurrence of the disease (SRMA R), other neurological disorders, and healthy dogs, using the two-part test. Additionally, secretion of IL-17 and interferon gamma (IFN-γ) from the peripheral blood mononuclear cells (PBMCs) was confirmed by an enzyme-linked immunospot (ELISpot) assay.ResultsSignificant higher levels of IL-17 were found in CSF of dogs with SRMA A compared with SRMA T, other neurological disorders and healthy dogs (p < 0.0001). In addition, levels of CD40L in CSF in dogs with SRMA A and SRMA R were significantly higher than in those with SRMA T (p = 0.0004) and healthy controls (p = 0.014). Furthermore, CSF concentrations of IL-17 and CD40L showed a strong positive correlation among each other (rSpear = 0.6601; p < 0.0001) and with the degree of pleocytosis (rSpear = 0.8842; p < 0.0001 and rSpear = 0.6649; p < 0.0001, respectively). IL-17 synthesis from PBMCs in SRMA patients was confirmed; however, IL-17 is mainly intrathecally produced.ConclusionsThese results imply that Th17 cells are inducing the autoimmune response in SRMA and are involved in the severe neutrophilic pleocytosis and disruption of the blood-brain barrier (BBB). CD-40L intrathecal synthesis might be involved in the striking vasculitis. The investigation of the role of IL-17 in SRMA might elucidate important pathomechanism and open new therapeutic strategies.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Th17-skewed immune response and cluster of differentiation 40 ligand expression in canine steroid-responsive meningitis-arteritis, a large animal model for neutrophilic meningitis

Freundt-Revilla

Maiolini

Carlson

et al. 2017

J Neuroinflammation

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“…In that, activated T cells produce large amounts of interleukin-4 (IL-4), which stimulates B cells to produce large amounts of immunoglobulin a. That infiltrates into the meningeal vessels (mainly in the cervical area) causing vasculitis and meningitis (Schwartz et al, 2011). Increased concentration of immunoglobulin a in blood and cerebrospinal fluid (Tipold and Jaggy, 1994;Tipold et al, 1995), remission of clinical signs after the administration of immunosuppressive doses of steroids (Meric et al, 1985) and absence of identifiable infectious organisms (Harcourt, 1978;Poncelet and Balligand, 1993;Tipold and Jaggy, 1994) lend support to this hypothesis.…”

Section: Steroid-responsive Meningitis-arteritismentioning

confidence: 99%

An update on meningoencephalomyelitis of unknown aetiology in dogs

Charalambous

Δανουρδησ)²,

Hatzis³

et al. 2017

J Hellenic Vet Med Soc

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Inflammatory diseases of the central nervous system are common causes of neurological dysfunction in the dog and can be grouped into two broad categories; those of infectious and those of unknown aetiology. Μeningoencephalomyelitis of unknown aetiology include non-infectious inflammatory central nervous system diseases in which abnormal findings on magnetic resonance imaging and cerebrospinal fluid analysis indicate inflammatory central nervous system disease, but for which histopathological confirmation has not been reached. Meningoencephalomyelitis of unknown aetiology describes a group of non-infectious inflammatory diseases of the central nervous system. These include the granulomatous meningoencephalomyelitis and the necrotising encephalitis, the latter can be further distinguished into two subtypes: necrotising meningoencephalitis and necrotising leucoencephalitis. Steroid-responsive meningitis-arteritis may be also included to this category and, usually, does not present signs of encephalitis or/and myelitis (except in the chronic form) and is easier diagnosed even without histopathological examination. In most cases of meningoencephalomyelitis of unknown aetiology, a presumptive diagnosis can be achieved by the assessment of case presentation, theneurologic signs, cerebrospinal fluid testing, cross-sectional imaging of the central nervous system and appropriate microbiological tests.Definite diagnosis is achieved with histopathological examination. The underlying cause for these diseases is unknown. The clinical signs in meningoencephalomyelitis of unknown aetiology is variable and depends on which area of the central nervous sytem is affected. Meningoencephalomyelitis is acute in onset, progressive in nature and associated with multifocal to diffuse neuroanatomic localization. Extraneural signs are less common and these usually include pyrexia and peripheral neutrophilia. The differential diagnosis for dogs presented for an acute onset of multifocal central nervous system signs includes genetic abnormalities, metabolic disorders, infectious meningoencephalitis, toxin exposure, stroke and neoplasia.The diagnostic approach includes a complete blood count, a comprehensive chemistry panel, urinalysis, survey radiographs of the thorax plus abdominal ultrasound to rule out systematic disease and metastatic neoplasia, computed-tomography or magnetic reso meningitisnance imaging, cerebrospinal fluid analysis and microbiological tests.When neoplasia is suspected, computed-tomography-guided brain biopsy may be required for the differentiation. Meningoencephalomyelitis of unknown aetiology responds more or less to immunosuppressive therapies, but the prognosis should be guarded to poor with the exception of steroid-responsive meningitisarteritis, for which it is good. Treatment protocols are based on prednisolone, but new immunosuppressive agents have now been added in those to control the diseases and they seem to be effective. However, gold standard protocols have yet to be established.

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“…Therefore, three diseases were chosen: steroid-responsive meningitis-arteritis (SRMA), meningoencephalomyelitis of unknown origin (MUO), and intervertebral disc disease (IVDD). In SRMA, a Th2-mediated immune response was shown [21,22] and a Th17 skewed immune response may be accountable for maintaining the inflammatory reaction [23,24]. For comparison, MUO was chosen as a disease group with a predominantly mononuclear pleocytosis within the CSF [1,25,26] despite the heterogeneity of the group.…”

Section: Introductionmentioning

confidence: 99%

MIP-3β/CCL19 is associated with the intrathecal invasion of mononuclear cells in neuroinflammatory and non-neuroinflammatory CNS diseases in dogs

Bartels

Darrow²,

Schatzberg³

et al. 2014

BMC Vet Res

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BackgroundChemokines 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.ResultsCCL19 was detectable in CSF samples of all dogs. Dogs with untreated SRMA and MUO displayed pronounced CCL19 elevations compared to the control group and patients receiving glucocorticosteroid treatment. CSF cell counts of untreated SRMA and MUO patients were significantly positively correlated with the CCL19 CSF concentration. IVDD patients also had elevated CCL19 concentration compared to controls, but values were considerably lower than in inflammatory CNS diseases. Selected CSF samples displayed chemotactic activity for mononuclear cells in the migration assay.ConclusionsCCL19 CSF concentrations were markedly elevated in patients affected with the neuroinflammatory diseases SRMA and MUO and showed a strong correlation with the CSF cell count. This chemokine may play an important role in the pathogenesis of SRMA and MUO. The elevation of CSF CCL19 in IVDD suggests that it may also be involved in the secondary wave of spinal cord injuries.

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Pathogenetic factors for excessive IgA production: Th2-dominated immune response in canine steroid-responsive meningitis-arteritis

Cited by 23 publications

References 31 publications

Th17-skewed immune response and cluster of differentiation 40 ligand expression in canine steroid-responsive meningitis-arteritis, a large animal model for neutrophilic meningitis

Th17-skewed immune response and cluster of differentiation 40 ligand expression in canine steroid-responsive meningitis-arteritis, a large animal model for neutrophilic meningitis

An update on meningoencephalomyelitis of unknown aetiology in dogs

MIP-3β/CCL19 is associated with the intrathecal invasion of mononuclear cells in neuroinflammatory and non-neuroinflammatory CNS diseases in dogs

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