CNS immune responses following experimental stroke - PubMed (original) (raw)

CNS immune responses following experimental stroke

Dannielle Zierath et al. Neurocrit Care. 2010 Apr.

Abstract

Background and purpose: Animals subjected to an inflammatory insult with lipopolysaccharide (LPS) at the time of stroke are predisposed to develop a detrimental autoimmune response to myelin basic protein (MBP). In this study, we sought to determine whether other inflammatory stimuli could similarly invoke central nervous system (CNS) autoimmunity and whether these detrimental autoimmune responses occurred to antigens other than MBP.

Methods: Male Lewis rats underwent 3 h middle cerebral artery occlusion (MCAO) and received intraperitoneal injections of LPS, staphylococcal enterotoxin B (SEB), lipoteichoic acid (LTA) or saline at the time of reperfusion. Behavioral tests were performed at set time intervals after MCAO and animals were sacrificed at 1 month to analyze the immune response to MBP, neuron specific enolase (NSE) and proteolipid protein (PLP).

Results: Lymphocytes from SEB treated animals were highly reactive to all tested CNS antigens, but treatment with LPS was most likely to lead to a TH: 1(+) response. A TH: 1(+) response to MBP, NSE or PLP in spleen was associated with worse outcome, although the response to NSE was most predictive of poor outcome. Animals with a cell mediated autoimmune response to either MBP or NSE in spleen had a concomitant humoral response to these antigens.

Conclusions: These data show that LPS, but not other inflammatory stimuli, increase the likelihood of developing a detrimental autoimmune response to an array of brain antigens.

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Figures

Fig. 1

Fig. 1

Effect of LPS, SEB and LTA administration on outcome. Animals treated with LPS had higher temperatures 6 h after MCAO (a), but temperatures were otherwise similar between treatment groups. Treatment with LPS was associated with higher (worse) neurological scores at multiple time points after MCAO, but treatment with LTA was associated with the worst scores 1 month after MCAO (b). There were significant differences in the degree of weight loss following MCAO, but the degree of weight loss was not significantly different from that of saline treated animals (c). Performance on the foot fault test (d) and the rotarod (e) did not differ between treatment groups. * P < 0.05, ** P < 0.01 compared to saline treatment using ANOVA with post-hoc Dunnet's

Fig. 2

Fig. 2

Antigen-specific IFN-γ and TGF_β_-1 immune responses in brain and spleen. Treatment with SEB resulted in marked activation of the immune response, with an increase in the number of antigen-specific cells producing both cytokines (IFN-γ and TGF_β_-1) in brain (a) and spleen (b). * P < 0.05, ** P < 0.01 compared to saline treatment using ANOVA with post-hoc Dunnet's

Fig. 3

Fig. 3

T

h

1 responses to MBP, NSE and PLP; individual animal data. Individual animal data are presented and depict the ratio of the relative increase in the number of cells responding to MBP, NSE and PLP with the secretion of IFN-γ to that responding with the secretion of TGF_β_-1 among mononuclear cells isolated from brain (a–c) and spleen (d–f). A value ≥1.48 (gray line) is considered indicative of a T

h

1 response. * P < 0.05 compared to saline treatment using ANOVA with post-hoc Dunnet's

Fig. 4

Fig. 4

Neurological scores as a function of the immune response following MCAO. For animals with a T

h

1(+) response to MBP, NSE or PLP in spleen, the neurological scores were higher (worse) following MCAO (a–c). * P < 0.05, ** P < 0.01 using the _t_-test

Fig. 5

Fig. 5

Change in weight as a function of the immune response following MCAO. A T

h

1(+) response to MBP in spleen was not associated with a differential in weight gain after MCAO (a). A T

h

1(+) immune response to NSE or PLP in spleen was associated with less weight gain after stroke (b, c), especially for those animals with a T

h

1 response to PLP. * P < 0.05 using the _t_-test

Fig. 6

Fig. 6

Immunological outcome and foot fault performance. A T

h

1(+) response to MBP in spleen did not affect performance on the foot fault test after MCAO (a). Animals evidencing a T

h

1(+) response to NSE (b) or PLP (c) in spleen made more errors on the foot fault test 1 month after MCAO. * P < 0.05, ** P < 0.01 using the _t_-test

Fig. 7

Fig. 7

Immunological outcome and rotarod performance. Animals exhibiting a T

h

1(+) response to MBP (a), NSE (b) or PLP (c) in spleen performed less well on the rotarod (with shorter latency to fall) after stroke. * P < 0.05, ** P < 0.01 using the _t_-test

Fig. 8

Fig. 8

Overlap in the immune response to antigen in brain and spleen among individual animals. In both spleen (a) and brain (b), there were 5 animals that evidenced a T

h

1(+) response to all 3 antigens studied. There was little overlap in the T

h

1(+) response to MBP (c) or PLP (e) in spleen and brain, while the overlap for NSE was more substantial (d)

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