Chemotactic activity and IL-8 levels in the cerebrospinal fluid in canine steroid responsive meningitis–arteriitis

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Abstract

Steroid responsive meningitis–arteriitis (SRMA) is a systemic immune disorder, characterized by inflammatory-stenosing lesions of the meningeal arteries and meningitis. The predilection of the disease for the central nervous system (CNS) remains unexplained. In this study, chemotactic activity and chemotactic factors were measured in the cerebrospinal fluid (CSF) of dogs with SRMA. CSF of dogs with SRMA exerted a marked chemotactic activity for leukocytes. Neutrophils were attracted to a similar degree as by CSF from animals with bacterial encephalitis. Chemotactic activity was also noted for mononuclear cells, however, by far weaker than in CSF from animals with viral encephalitis. While the inflammatory process could be suppressed with glucocorticoid treatment, the chemotactic activity of CSF persisted. We could identify IL-8-like activities using a desensitization assay in the CSF of animals with SRMA and also found increased IgA levels. Increased chemotactic activity for polymorphonuclear leukocytes correlated positively with the levels of IL-8-like activity in CSF. Our observations clearly suggest that in SRMA chemotactic factors are generated in the CNS. These include IL-8, but probably also others. The intensity of this production appears to correlate with IgA levels in the CSF suggesting either a causal link or reflecting the severity of the inflammation.

Introduction

Steroid responsive meningitis–arteriitis (SRMA) in dogs also named `beagle pain syndrome' (Hayes et al., 1989) and `juvenile polyarteriitis syndrome' (Scott-Moncrieff et al., 1992) is a highly painful disease with frequent relapses, characterized by inflammatory-stenosing lesions of the arteries (Meric et al., 1985; Meric et al., 1986; Presthus, 1991). SRMA is a naturally occurring animal model for human vasculitides of unknown etiology, e.g., Kawasaki disease (Burns et al., 1991; Felsburg et al., 1992).

The cause and pathogenesis of the disease remain unknown. There appears to be a dysregulation of the immune system, perhaps resulting from an interaction with a hitherto undefined environmental factor. Abnormal immune function in SRMA has been documented in a number of pathological and laboratory observations (Burns et al., 1991; Felsburg et al., 1992; Scott-Moncrieff et al., 1992; Tipold and Jaggy, 1994; Tipold et al., 1995), the most important of which is excessive IgA production. Although SRMA is a systemic disease and arteriitis has been found in various organs notably in the coronary vessels, the most prominent expression of the disease is in the nervous system with involvement of meningeal arteries and the meninges themselves. Two forms were recognized (Tipold and Jaggy, 1994): The acute form shows cervical rigidity and pain, fever and massive pleocytosis with predominantly polymorphonuclear leukocytes (PMN) in the cerebrospinal fluid (CSF). In the protracted form, additional neurological deficits occur with a mixed cell population or even a predominance of mononuclear cells (MN) in the CSF. In both stages, high levels of IgA are produced systemically as well as intrathecally (Tipold and Jaggy, 1994; Tipold et al., 1995).

The predilection for meningeal arteries and meninges in SRMA is puzzling. The understanding of the mechanism by which the process becomes compartmentalized in the central nervous system (CNS) could bring some insight into the pathogenesis of the disease. In the present study, we postulated that the localization of the inflammatory process in the CSF compartment must be governed by the intrathecal release of chemotactic factors. Therefore, we searched for the presence of chemotactic factors for neutrophils and mononuclear cells in the CSF from dogs with SRMA. We also attempted to identify one of these factors focusing on interleukin-8 (IL-8). IL-8 has been shown to be chemotactic for neutrophils, basophils and in part also for T-lymphocytes but not monocytes (Larsen et al., 1989; Bacon and Camp, 1990; Leonard et al., 1990) and has been found in the CSF of humans with a variety of CNS diseases (Van Meir et al., 1992; Mastroianni et al., 1994; López-Cortés et al., 1995; Østergaard et al., 1996; Sprenger et al., 1996; Yokoyama et al., 1996).

Section snippets

Dogs

A total of 47 dogs were subjected to a complete general and neurological examination. Laboratory examinations included in all cases hematology, blood chemistry profile and CSF analysis (Table 1).

Cell count and cytology of CSF samples

Results of cell count and cytology of CSF samples are summarized in Table 1. The cell count in CSF of bacterial encephalitis was significantly higher than the cell count in chronic SRMA (p=0.0003) and canine distemper (p=0.0029). Pleocytosis in bacterial encephalitis was predominantly due to polymorphonuclear cells. CSF cells in viral encephalitis were strictly mononuclear. The cell count in acute and chronic SRMA was not significantly different (p=0.0702). However, CSF samples of dogs with

Discussion

Although SRMA appears to be a systemic immunopathological disease, the inflammatory process has a marked predilection for arteries and tissues of the subarachnoidal space. This selective involvement of the CSF compartment has not been explained to date. Therefore, in the present study we searched for chemotactic activity in CSF of dogs suffering from SRMA. We found that CSF of dogs with SRMA exerted a marked chemotactic activity for leukocytes. Neutrophils were attracted to a similar degree as

Acknowledgements

This work was supported by grants of the Swiss National Science Foundation (grant no. 32-44483.95, 32-46784.96 and 32-050203.97). The generous gift of crIL-8 by Repligen (Needham, MA, USA) and of a polyclonal antibody against crIL-8 by R.K. Straubinger (James A. Baker Institute for Animal Health, Cornell University, Ithaca, NY, USA) is gratefully acknowledged. We thank Prof. Dr. M. Baggiolini (Theodor Kocher Institute, University of Berne) for the useful discussions regarding the development of

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