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Severity and patterns of blood-nerve barrier breakdown in patients with chronic inflammatory demyelinating polyradiculoneuropathy: correlations with clinical subtypes.

Shimizu F, Sawai S, Sano Y, Beppu M, Misawa S, Nishihara H, Koga M, Kuwabara S, Kanda T - PLoS ONE (2014)

Bottom Line: Furthermore, the severity of BNB disruption after exposure to the sera was associated with higher Hughes grade, lower MRC score, more pronounced slowing of motor nerve conduction in the median nerve and higher frequency of abnormal temporal dispersion.The extent of BNB disruption in the setting of CIDP is associated with clinical disability and demyelination in the nerve trunk.These observations may explain the phenotypical differences between CIDP subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.

ABSTRACT

Objective: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is currently classified into clinical subtypes, including typical and atypical forms (multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and distal acquired demyelinating symmetric neuropathy (DADS)). The aim of this study was to elucidate the patterns and severity of breakdown of the blood-nerve barrier (BNB) in each CIDP subtype.

Methods: We evaluated the effects of sera obtained from patients with typical CIDP, MADSAM and DADS and control subjects on the expression levels of tight junction proteins and transendothelial electrical resistance (TEER) value in human peripheral nerve microvascular endothelial cells (PnMECs).

Results: The sera obtained from the patients with the three clinical phenotypes of CIDP decreased the amount of claudin-5 protein levels and TEER values in the PnMECs. In addition, the sera obtained from typical CIDP patients more prominently reduced claudin-5 protein levels and TEER values in the PnMECs than did that obtained from the MADSAM and DADS patients. Furthermore, the severity of BNB disruption after exposure to the sera was associated with higher Hughes grade, lower MRC score, more pronounced slowing of motor nerve conduction in the median nerve and higher frequency of abnormal temporal dispersion.

Conclusions: Sera derived from typical CIDP patients destroy the BNB more severely than those from MADSAM or DADS patients. The extent of BNB disruption in the setting of CIDP is associated with clinical disability and demyelination in the nerve trunk. These observations may explain the phenotypical differences between CIDP subtypes.

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The sera obtained from the patients with t-CIDP, MADSAM and DADS disrupted the BNB.(A) – (D) Effects of the sera obtained from patients with three different phenotypes of chronic inflammatory demyelinating polyneuropathy (CIDP) on the protein levels of claudin-5 and occludin in the FH-BNBs, as determined using a Western blot analysis. The cells were exposed to sera from either patients with typical CIDP (t-CIDP) (A), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (B) or distal acquired demyelinating symmetric neuropathy (DADS) (C) or healthy volunteers (D). (E) The sera obtained from the patients with t-CIDP, MADSAM neuropathy and DADS neuropathy decreased the protein ratio of claudin-5 to actin proteins in the FH-BNBs compared to that observed following exposure to the sera from the healthy volunteers. The decrease in the claudin-5 levels in the FH-BNBs was greater after incubation with the sera obtained from the t-CIDP patients than after that with the sera from the patients with MADSAM and DADS. (F) There were no significant differences between the patients with the three different phenotypes of CIDP and the healthy controls regarding the occludin protein levels in the FH-BNBs. (G) The effects of the sera on the transendothelial electrical resistance (TEER) values in the FH-BNBs were also evaluated. Adding sera obtained from the patients with t-CIDP, MADSAM neuropathy or DADS neuropathy resulted in decreased TEER values in the FH-BNBs in comparison with that observed in the cells treated with the sera obtained from the healthy volunteers. Markedly decreased TEER values in FH-BNBs were also observed in the FH-BNBs following incubation with the sera obtained from the t-CIDP patients compared to that noted in the cells incubated with sera from patients with MADSAM or DADS neuropathy. The TEER values were decreased following exposure to the sera obtained from the patients with DADS neuropathy compared to that observed after exposure to the sera obtained from the patients with MADSAM neuropathy. The bars indicate the mean level in each group. Control: non-conditioned DMEM containing 20% FBS. t-CIDP: conditioned medium with 10% sera obtained from patients with t-CIDP diluted with non-conditioned DMEM containing 10% FBS. MADSAM: conditioned medium with 10% sera obtained from patients with MADSAM diluted with non-conditioned DMEM containing 10% FBS. DADS: conditioned medium with 10% sera obtained from patients with DADS diluted with non-conditioned DMEM containing 10% FBS. Normal: conditioned medium with 10% sera obtained from a healthy volunteer diluted with non-conditioned medium of DMEM containing 10% FBS.
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pone-0104205-g001: The sera obtained from the patients with t-CIDP, MADSAM and DADS disrupted the BNB.(A) – (D) Effects of the sera obtained from patients with three different phenotypes of chronic inflammatory demyelinating polyneuropathy (CIDP) on the protein levels of claudin-5 and occludin in the FH-BNBs, as determined using a Western blot analysis. The cells were exposed to sera from either patients with typical CIDP (t-CIDP) (A), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (B) or distal acquired demyelinating symmetric neuropathy (DADS) (C) or healthy volunteers (D). (E) The sera obtained from the patients with t-CIDP, MADSAM neuropathy and DADS neuropathy decreased the protein ratio of claudin-5 to actin proteins in the FH-BNBs compared to that observed following exposure to the sera from the healthy volunteers. The decrease in the claudin-5 levels in the FH-BNBs was greater after incubation with the sera obtained from the t-CIDP patients than after that with the sera from the patients with MADSAM and DADS. (F) There were no significant differences between the patients with the three different phenotypes of CIDP and the healthy controls regarding the occludin protein levels in the FH-BNBs. (G) The effects of the sera on the transendothelial electrical resistance (TEER) values in the FH-BNBs were also evaluated. Adding sera obtained from the patients with t-CIDP, MADSAM neuropathy or DADS neuropathy resulted in decreased TEER values in the FH-BNBs in comparison with that observed in the cells treated with the sera obtained from the healthy volunteers. Markedly decreased TEER values in FH-BNBs were also observed in the FH-BNBs following incubation with the sera obtained from the t-CIDP patients compared to that noted in the cells incubated with sera from patients with MADSAM or DADS neuropathy. The TEER values were decreased following exposure to the sera obtained from the patients with DADS neuropathy compared to that observed after exposure to the sera obtained from the patients with MADSAM neuropathy. The bars indicate the mean level in each group. Control: non-conditioned DMEM containing 20% FBS. t-CIDP: conditioned medium with 10% sera obtained from patients with t-CIDP diluted with non-conditioned DMEM containing 10% FBS. MADSAM: conditioned medium with 10% sera obtained from patients with MADSAM diluted with non-conditioned DMEM containing 10% FBS. DADS: conditioned medium with 10% sera obtained from patients with DADS diluted with non-conditioned DMEM containing 10% FBS. Normal: conditioned medium with 10% sera obtained from a healthy volunteer diluted with non-conditioned medium of DMEM containing 10% FBS.

Mentions: We first examined the effects of the sera obtained from the patients with the three clinical subtypes of CIDP on the expression levels of tight junction proteins and the TEER values in the FH-BNBs. Consequently, the protein ratio of claudin-5 to actin proteins was significantly lower in the FH-BNBs exposed to sera from the patients with t-CIDP, MADSAM and DADS than in those incubated with sera from the healthy controls, as determined in a Western blot analysis (Figs. 1 A–E). In contrast, the ratio of occludin to actin proteins in the FH-BNBs did not change after a challenge with the sera obtained from the CIDP patients or healthy controls (Figs. 1A–D, F). Meanwhile, the TEER values in the FH-BNBs were significantly decreased following exposure to the sera obtained from the t-CIDP, MADSAM and DADS patients in comparison to that observed after exposure to sera of the healthy control (Fig. 1G). Furthermore, the ratio of claudin-5 to actin proteins and the TEER values observed after exposure to the sera obtained from t-CIDP patients were significantly lower than those observed after exposure to the sera obtained from the MADSAM and DADS patients (Figs. 1E, G). Moreover, the TEER values observed after exposure to the sera obtained from the DADS patients were significantly lower than those observed after exposure to the sera obtained from the MADSAM patients, although the ratio of claudin-5 to actin proteins was not significantly different between the two groups (Figs. 1E, G).


Severity and patterns of blood-nerve barrier breakdown in patients with chronic inflammatory demyelinating polyradiculoneuropathy: correlations with clinical subtypes.

Shimizu F, Sawai S, Sano Y, Beppu M, Misawa S, Nishihara H, Koga M, Kuwabara S, Kanda T - PLoS ONE (2014)

The sera obtained from the patients with t-CIDP, MADSAM and DADS disrupted the BNB.(A) – (D) Effects of the sera obtained from patients with three different phenotypes of chronic inflammatory demyelinating polyneuropathy (CIDP) on the protein levels of claudin-5 and occludin in the FH-BNBs, as determined using a Western blot analysis. The cells were exposed to sera from either patients with typical CIDP (t-CIDP) (A), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (B) or distal acquired demyelinating symmetric neuropathy (DADS) (C) or healthy volunteers (D). (E) The sera obtained from the patients with t-CIDP, MADSAM neuropathy and DADS neuropathy decreased the protein ratio of claudin-5 to actin proteins in the FH-BNBs compared to that observed following exposure to the sera from the healthy volunteers. The decrease in the claudin-5 levels in the FH-BNBs was greater after incubation with the sera obtained from the t-CIDP patients than after that with the sera from the patients with MADSAM and DADS. (F) There were no significant differences between the patients with the three different phenotypes of CIDP and the healthy controls regarding the occludin protein levels in the FH-BNBs. (G) The effects of the sera on the transendothelial electrical resistance (TEER) values in the FH-BNBs were also evaluated. Adding sera obtained from the patients with t-CIDP, MADSAM neuropathy or DADS neuropathy resulted in decreased TEER values in the FH-BNBs in comparison with that observed in the cells treated with the sera obtained from the healthy volunteers. Markedly decreased TEER values in FH-BNBs were also observed in the FH-BNBs following incubation with the sera obtained from the t-CIDP patients compared to that noted in the cells incubated with sera from patients with MADSAM or DADS neuropathy. The TEER values were decreased following exposure to the sera obtained from the patients with DADS neuropathy compared to that observed after exposure to the sera obtained from the patients with MADSAM neuropathy. The bars indicate the mean level in each group. Control: non-conditioned DMEM containing 20% FBS. t-CIDP: conditioned medium with 10% sera obtained from patients with t-CIDP diluted with non-conditioned DMEM containing 10% FBS. MADSAM: conditioned medium with 10% sera obtained from patients with MADSAM diluted with non-conditioned DMEM containing 10% FBS. DADS: conditioned medium with 10% sera obtained from patients with DADS diluted with non-conditioned DMEM containing 10% FBS. Normal: conditioned medium with 10% sera obtained from a healthy volunteer diluted with non-conditioned medium of DMEM containing 10% FBS.
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Related In: Results  -  Collection

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pone-0104205-g001: The sera obtained from the patients with t-CIDP, MADSAM and DADS disrupted the BNB.(A) – (D) Effects of the sera obtained from patients with three different phenotypes of chronic inflammatory demyelinating polyneuropathy (CIDP) on the protein levels of claudin-5 and occludin in the FH-BNBs, as determined using a Western blot analysis. The cells were exposed to sera from either patients with typical CIDP (t-CIDP) (A), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (B) or distal acquired demyelinating symmetric neuropathy (DADS) (C) or healthy volunteers (D). (E) The sera obtained from the patients with t-CIDP, MADSAM neuropathy and DADS neuropathy decreased the protein ratio of claudin-5 to actin proteins in the FH-BNBs compared to that observed following exposure to the sera from the healthy volunteers. The decrease in the claudin-5 levels in the FH-BNBs was greater after incubation with the sera obtained from the t-CIDP patients than after that with the sera from the patients with MADSAM and DADS. (F) There were no significant differences between the patients with the three different phenotypes of CIDP and the healthy controls regarding the occludin protein levels in the FH-BNBs. (G) The effects of the sera on the transendothelial electrical resistance (TEER) values in the FH-BNBs were also evaluated. Adding sera obtained from the patients with t-CIDP, MADSAM neuropathy or DADS neuropathy resulted in decreased TEER values in the FH-BNBs in comparison with that observed in the cells treated with the sera obtained from the healthy volunteers. Markedly decreased TEER values in FH-BNBs were also observed in the FH-BNBs following incubation with the sera obtained from the t-CIDP patients compared to that noted in the cells incubated with sera from patients with MADSAM or DADS neuropathy. The TEER values were decreased following exposure to the sera obtained from the patients with DADS neuropathy compared to that observed after exposure to the sera obtained from the patients with MADSAM neuropathy. The bars indicate the mean level in each group. Control: non-conditioned DMEM containing 20% FBS. t-CIDP: conditioned medium with 10% sera obtained from patients with t-CIDP diluted with non-conditioned DMEM containing 10% FBS. MADSAM: conditioned medium with 10% sera obtained from patients with MADSAM diluted with non-conditioned DMEM containing 10% FBS. DADS: conditioned medium with 10% sera obtained from patients with DADS diluted with non-conditioned DMEM containing 10% FBS. Normal: conditioned medium with 10% sera obtained from a healthy volunteer diluted with non-conditioned medium of DMEM containing 10% FBS.
Mentions: We first examined the effects of the sera obtained from the patients with the three clinical subtypes of CIDP on the expression levels of tight junction proteins and the TEER values in the FH-BNBs. Consequently, the protein ratio of claudin-5 to actin proteins was significantly lower in the FH-BNBs exposed to sera from the patients with t-CIDP, MADSAM and DADS than in those incubated with sera from the healthy controls, as determined in a Western blot analysis (Figs. 1 A–E). In contrast, the ratio of occludin to actin proteins in the FH-BNBs did not change after a challenge with the sera obtained from the CIDP patients or healthy controls (Figs. 1A–D, F). Meanwhile, the TEER values in the FH-BNBs were significantly decreased following exposure to the sera obtained from the t-CIDP, MADSAM and DADS patients in comparison to that observed after exposure to sera of the healthy control (Fig. 1G). Furthermore, the ratio of claudin-5 to actin proteins and the TEER values observed after exposure to the sera obtained from t-CIDP patients were significantly lower than those observed after exposure to the sera obtained from the MADSAM and DADS patients (Figs. 1E, G). Moreover, the TEER values observed after exposure to the sera obtained from the DADS patients were significantly lower than those observed after exposure to the sera obtained from the MADSAM patients, although the ratio of claudin-5 to actin proteins was not significantly different between the two groups (Figs. 1E, G).

Bottom Line: Furthermore, the severity of BNB disruption after exposure to the sera was associated with higher Hughes grade, lower MRC score, more pronounced slowing of motor nerve conduction in the median nerve and higher frequency of abnormal temporal dispersion.The extent of BNB disruption in the setting of CIDP is associated with clinical disability and demyelination in the nerve trunk.These observations may explain the phenotypical differences between CIDP subtypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.

ABSTRACT

Objective: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is currently classified into clinical subtypes, including typical and atypical forms (multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) and distal acquired demyelinating symmetric neuropathy (DADS)). The aim of this study was to elucidate the patterns and severity of breakdown of the blood-nerve barrier (BNB) in each CIDP subtype.

Methods: We evaluated the effects of sera obtained from patients with typical CIDP, MADSAM and DADS and control subjects on the expression levels of tight junction proteins and transendothelial electrical resistance (TEER) value in human peripheral nerve microvascular endothelial cells (PnMECs).

Results: The sera obtained from the patients with the three clinical phenotypes of CIDP decreased the amount of claudin-5 protein levels and TEER values in the PnMECs. In addition, the sera obtained from typical CIDP patients more prominently reduced claudin-5 protein levels and TEER values in the PnMECs than did that obtained from the MADSAM and DADS patients. Furthermore, the severity of BNB disruption after exposure to the sera was associated with higher Hughes grade, lower MRC score, more pronounced slowing of motor nerve conduction in the median nerve and higher frequency of abnormal temporal dispersion.

Conclusions: Sera derived from typical CIDP patients destroy the BNB more severely than those from MADSAM or DADS patients. The extent of BNB disruption in the setting of CIDP is associated with clinical disability and demyelination in the nerve trunk. These observations may explain the phenotypical differences between CIDP subtypes.

Show MeSH
Related in: MedlinePlus