Serum FAM19A5 in neuromyelitis optica spectrum disorders: Can it be a new biomarker representing clinical status?

Abstract

Background:

Neuromyelitis optica spectrum disorder (NMOSD) targets astrocytes and elevates the levels of astrocyte-injury markers during attacks. FAM19A5, involved in reactive gliosis, is secreted by reactive astrocytes following central nervous system (CNS) damage.

Objective:

To investigate the significance of serum FAM19A5 in patients with NMOSD.

Methods:

We collected clinical data and sera of 199 patients from 11 hospitals over 21 months. FAM19A5 levels were compared among three groups: NMOSD with positive anti-aquaporin-4 antibody (NMOSD-AQP4), other CNS demyelinating disease, and healthy controls.

Results:

The median serum FAM19A5 level was higher in the NMOSD-AQP4 (4.90 ng/mL (3.95, 5.79)) than in the other CNS demyelinating (2.35 ng/mL (1.83, 4.07), p < 0.001) or healthy control (1.02 ng/mL (0.92, 1.14), p < 0.001) groups. There were significant differences in the median serum FAM19A5 levels between the attack and remission periods (5.89 ng/mL (5.18, 6.98); 4.40 ng/mL (2.72, 5.13), p < 0.001) in the NMOSD-AQP4 group. Sampling during an attack (p < 0.001) and number of past attacks (p = 0.010) were independently associated with increased serum FAM19A5.

Conclusion:

Serum FAM19A5 was higher in patients with NMOSD-AQP4 and correlated with clinical characteristics. Thus, serum FAM19A5 may be a novel clinical biomarker for NMOSD-AQP4.

Keywords

Neuromyelitis optica spectrum disorder FAM19A5 astrocyte reactive gliosis CNS demyelinating disease MOG associated disease

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is an immune-mediated inflammatory disease of the central nervous system (CNS) with clinical hallmarks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM).^1,2 Approximately 80% of patients with NMOSD test positive for aquaporin-4 (AQP4) immunoglobulin G (IgG) antibodies, which cause astrocyte damage, inflammatory cell infiltration, and myelin loss.^3,4 AQP4-IgG associated NMOSD appears to target astrocytes, not myelin, leading to elevated markers of astrocyte injury during attacks.^3,5 In particular, astrocyte disintegration and reactive gliosis may be found in both acute and chronic lesions in AQP4-IgG associated NMOSD.^6–10 Thus, NMOSD is now regarded as a primary astrocytopathy with secondary demyelination.¹¹

Family with sequence similarity 19-member A5 (FAM19A5), also known as TAFA5, is a protein predominantly expressed in the brain.^12–14 The FAM19A5 protein is postulated to regulate nervous and immune cells of the brain as a brain-specific chemokine, but its precise functional role is not well understood. A recent study suggested that FAM19A5 is secreted by reactive astrocytes following CNS damage and triggers glial cell hyperproliferation and glial scar formation, a phenomenon called reactive gliosis.⁹ Together, these studies suggest that FAM19A5 is a candidate biomarker for CNS damage related to reactive gliosis.^6,8,15,16 To our knowledge, no study on the role of FAM19A5 in NMOSD, an astrocytopathy characterized by reactive gliosis, has been carried out.

In this study, to evaluate possible roles of FAM19A5 in NMOSD, we determined serum levels of FAM19A5 in patients with NMOSD and compared these levels with those in patients with other CNS demyelinating diseases and with those of healthy controls. In addition, we explored the relationship between FAM19A5 levels and clinical parameters in patients with NMOSD-AQP4 and whether changes in FAM19A5 levels could be used as a biomarker of disease activity in NMOSD.

Materials and methods

Subjects

Between July 2014 and March 2016, we collected sera and clinical information of patients from 11 referral hospitals that participated in the Korean Nationwide Registry for NMOSD. The inclusion criteria for the NMOSD registry were (1) recurrent or bilateral ON; (2) single LETM or recurrent myelitis; (3) ON, myelitis, or brain symptoms with NMO-typical brain lesions; (4) ON or myelitis with systemic autoimmune disease; and (5) simultaneous ON and myelitis. Patients with multiple sclerosis, CNS infectious disease, non-inflammatory CNS diseases such as malignancy, or a systemic condition influencing analysis of clinical and serological data, such as general infection, malignancy, and hematologic diseases, were excluded. The enrolled patients were further divided into two subgroups based on the recently revised 2015 international consensus diagnostic criteria for NMOSD:¹⁷ NMOSD with AQP4-IgG (NMOSD-AQP4) and other CNS demyelinating disease. The other CNS demyelinating disease group included patients who met the inclusion criteria of the registry but did not meet the diagnostic criteria for NMOSD with positive AQP4-IgG. Therefore, the other CNS demyelinating group included patients with NMOSD without AQP4-IgG and those with serum myelin oligodendrocyte glycoprotein IgG antibodies (MOG-IgG). Healthy volunteers without any neurological or medical problems were enrolled as normal controls. The enrolled individuals voluntarily agreed to participate in the study, and written informed consents were obtained from all patients (IRB No. 2016AN0113).

Clinical evaluation of subjects

Clinical data were obtained from participating hospitals using the Internet-based Clinical Research and Trial management system (iCReaT), a data management system established by the Centers for Disease Control and Prevention, Ministry of Health and Welfare, Republic of Korea (iCReaT No. C140020). We collected clinical information regarding the patients’ sex, age at enrollment, disease duration from the initial attack, sampling time (attack, within 3 months of acute phase; and remission, at least 3 months after acute attack), latest Expanded Disability Status Scale (EDSS) scores, number of attacks, and lesions of past attacks. The lesions of past attacks were divided into three groups (i.e. intracranial lesions, spinal cord lesions, and both intracranial and spinal cord lesions). The group with intracranial lesions comprised patients with only optic nerve lesions, only brain lesions, and with both optic nerve and brain lesions. The group with both intracranial and spinal cord lesions comprised patients with both optic nerve and spinal cord lesions, both spinal cord and brain lesions, and optic nerve with spinal cord and brain lesions.

Serum analysis for AQP4 and MOG antibodies

All patients were tested for serum AQP4-IgG antibodies using the cell-based assay (CBA) commercially available kit (Euroimmun Medical Laboratory Diagnostics Stock Company, Germany).¹⁸ The intensity of AQP4 antibodies was scored from weak positive to three positive (W+ to 3+). The presence of AQP4-IgG antibodies was confirmed if the intensity was 1+ or stronger. In addition, we tested for serum MOG-IgG antibodies in patients with NMOSD without AQP4-IgG using an in house CBA. CBA was performed using HEK293T cells transfected with MOG using Lipofectamine 3000 (Thermo-fisher, USA). Briefly, a 1:20 diluted peripheral blood serum was incubated with the transfected cells for 1 hour at room temperature, after which goat anti-human IgG1 Alexa 488 antibody at 1:750 dilution was added. After washing and cell mounting were done, the samples were visualized under a fluorescent microscope (Nikon, Japan) and two individuals scored the fluorescence intensity as 0: negative, 1: weak positive, and 2–4: positive with increasing binding affinity. Thus, a 2+ binding affinity or higher was considered positive.

Serum analysis for FAM19A5 levels

Serum samples were collected from participants and stored at −80°C until analysis. A 20-μL aliquot of serum diluted 5-fold with phosphate-buffered saline (PBS) was added to each well that was pre-coated with humanized monoclonal anti-FAM19A5 antibody. For accurate quantitative assessments, the signal intensities of unknown samples were compared to the FAM19A5 standard curve with intra- and inter-assay coefficients of variation (CV) of 14.2 ± 3.7 and 4.0 ± 1.7, respectively. To generate the curve, N-HIS-FAM19A5 was diluted with PBS containing 1% BSA (0, 10 pM, 100 pM, 1 nM, 10 nM, 100 nM, 1 μM, 10 μM). Recombinant N-HIS-FAM19A5 was expressed using the vector pCAG1.1 in HEK293T cells and purified using affinity chromatography with Ni-NTA (Qiagen, Hilden, Germany). After incubation at 37°C for 1.5 hours, the reaction mixture was removed from the wells and wells were washed with PBS-Triton X-100. Subsequently, 100 μL of diluted rabbit polyclonal anti-FAM19A5 antibody was added to each well and incubated for 1 hour at room temperature. Horseradish peroxidase-conjugated antibody solution (100 μL) was pipetted into each well, mixed, and incubated at 37°C for 1 hour. The reaction solution was removed from the wells and the wells were washed with PBS-T. A 100-μL aliquot of o-phenylenediamine dihydrochloride substrate solution (Thermo Fisher Scientific USA) was pipetted into each well and the plates were kept at room temperature for 10–30 minutes, followed by addition of 1 N H₂SO₄ to stop the reaction. The absorbance at 492 nm was then determined. The serum FAM19A5 level was measured two times for each sample and the average of those two values with a CV of 11.3 ± 10.6 was then used for the analysis in this study.

Statistical analysis

The Kruskal–Wallis test was used to compare mean FAM19A5 levels and demographics between NMOSD-AQP4 patients, patients with other CNS demyelinating diseases, and healthy controls. We also used the Mann–Whitney test to compare the mean FAM19A5 levels in the attack and remission periods in the NMOSD-AQP4 and other CNS demyelinating disease groups. Clinical characteristics between the two groups were compared using the Chi-square test for categorical variables and using the independent t test for continuous variables. The Kruskal–Wallis test was used to compare the FAM19A5 levels in the NMOSD-AQP4, other CNS demyelinating disease, and MOG-IgG associated disease groups. We used the receiver operating characteristic (ROC) curve to find cutoff values for acute status in the NMOSD-AQP4 and other CNS demyelinating disease groups.

In the NMOSD-AQP4 group, the Kruskal–Wallis test was used to compare the mean FAM19A5 levels among the three subgroups based on the lesion location of past attacks. Spearman correlation analysis was used to evaluate the correlation between FAM19A5 levels and AQP4 antibody titers. Univariate and multiple linear regression analyses with forward selection were performed to assess the association of FAM19A5 levels with the clinical characteristics of patients with NMOSD. We used variables with a p value less than 0.05 in the univariate regression analysis for multiple regression analysis.

SPSS version 22.0 (SPSS Inc., USA) was used and we presented data as mean ± SD values. A p < 0.05 was indicative of statistical significance.

Results

Demographics of subjects

The demographic and clinical data of all 88 patients in the NMOSD-AQP4 group, 111 in the other CNS demyelinating disease group, and 8 subjects in the healthy control group are presented in Table 1. The other CNS demyelinating disease group included patients with recurrent or bilateral ON (n = 20) and those with recurrent or longitudinal extensive TM (n = 55). Patients with NMOSD without AQP4-IgG (n = 5) and those with MOG antibody-associated disease (n = 4) were also included in the other CNS demyelinating group. The NMOSD-AQP4 group had a greater proportion of female participants (p < 0.001), longer disease duration (p = 0.001), more frequent relapses (p < 0.001), and higher leukocyte counts in the cerebrospinal fluid (CSF, p = 0.019) than did the other CNS demyelinating disease group. The age at enrollment, oligoclonal band positivity, CSF protein, and latest EDSS score were not significantly different between these two groups.

Table 1.

Clinical characteristics of the NMOSD-AQP4 and other demyelinating groups.

	NMOSD-AQP4 (n = 88)	Other CNS demyelinating disease (n = 111)	Healthy control (n = 8)	p value
Female, n (%)	77 (87.5)	50 (45.0)	3 (42.9)	<0.001
Age at enrollment, years (SD)	47.4 (14.9)	45.1(13.2)	30.6 (3.0)	0.005
Disease duration, years (SD)	6.4 (7.1)	2.9 (7.4)		0.001
Sampling at attack period, n (%)	19 (21.8)	56 (52.3)		<0.001
Annualized relapse rate (SD)	0.63 (0.50)	0.79 (0.65)		0.195
Lesion	n = 77	n = 93
Intracranial lesions (%)	19.5	30.1		0.156
ON, n (%)	16.8	21.5		0.571
Brain lesion n (%)	2.5	7.5		0.303
ON with brain lesion, n (%)	0	1.0		1.000
Spinal cord lesions, n (%)	36.4	59.1		0.014
LETM, n (%)	82.1	89.1		0.293
Both intracranial and spinal cord lesions (%)	44.2	10.8		<0.001
ON with TM, n (%)	35.1	8.6		<0.001
TM with brain lesion, n (%)	2.5	1.0		0.585
ON with TM and brain lesion, n (%)	6.5	1.0		0.090
Number of patients suffered
1 attack, n (%)	27 (31.8)	62 (64.6)		<0.001
2 attacks, n (%)	19 (22.4)	16 (16.7)
3 attacks, n (%)	8 (9.4)	7 (7.3)
⩾4 attacks, n (%)	31 (36.5)	11 (11.5)
Oligoclonal band positivity, n (%)	3 (3.5)	4 (4.0)		0.817
Increased CSF protein, n (%)	20 (23.3)	16 (16.2)		0.462
Increased CSF leukocyte, n (%)	30 (34.1)	20 (18.0)		0.019
Increased IgG index, n (%)	21 (23.9)	20 (18.0)		0.451
EDSS scores, mean (SD)	2.9 (2.2)	2.9 (1.8)		0.839

NMOSD-AQP4: neuromyelitis optica spectrum disorders with aquaporin-4 antibodies; CNS: central nervous system; SD: standard deviation; ON: optic neuritis; TM: transverse myelitis; LETM: longitudinal extensive TM; EDSS: expanded disability status scale; IgG: immunoglobulin G. Bold indicates statistically significant p values (p<0.05).

FAM19A5 levels

The median serum FAM19A5 level was highest in the NMOSD-AQP4 group (4.90 ng/mL (3.95, 5.79), p < 0.001). Serum FAM19A5 levels were higher in the other CNS demyelinating disease group (2.35 ng/mL (1.83, 4.07)) than in the healthy control group (1.02 ng/mL (0.92, 1.14), p < 0.001; Figure 1). In the NMOSD-AQP4 and other CNS demyelinating groups, the serum FAM19A5 levels were much higher during the attack period (NMOSD-AQP4 group, 5.89 ng/mL (5.18, 6.98); other CNS demyelinating disease group, 3.18 ng/mL (2.24, 4.20)) than during the remission period (NMOSD-AQP4 group, 4.40 ng/mL (2.72, 5.13); other CNS demyelinating disease group, 1.89 ng/mL (1.53, 2.40); p = 0.001 and p < 0.001, respectively; Figure 1). In addition, the serum FAM19A5 levels positively correlated with the AQP4 antibody titer in the NMOSD-AQP4 group (ρ = 0.656, p < 0.001, Figure 2).

The serum FAM19A5 levels (2.59 ng/mL (2.17, 3.05), p = 0.034) in patients with MOG-IgG were lower than those in patients with NMOSD-AQP4 but higher than those in the healthy control subjects (p = 0.007). However, serum FAM19A5 levels were not significantly different between patients with MOG-IgG and those with other CNS demyelinating diseases (p = 0.710).

In the NMOSD-AQP4 group, the serum FAM19A5 levels showed significant differences among three subgroups classified based on the lesion location of past attacks (p = 0.024). Post hoc analysis revealed that serum FAM19A5 levels were significantly higher in patients with both intracranial and spinal cord lesions (5.18 ng/mL (4.17, 6.98)) than in those with spinal cord lesions only (4.44 ng/mL (2.36, 5.13), p = 0.009). There were no significant differences between patients with both intracranial and spinal cord lesions and those with intracranial lesions only (4.90 (4.15, 5.40), p = 0.250). The patients with intracranial lesions tended to have higher serum FAM19A5 levels than those with spinal cord lesions; however, this difference was not statistically significant.

Cutoff values of serum FAM19A5 levels for acute disease status

The area under the curve (AUC) for serum FAM19A5 (i.e. 0.819 in the NMOSD-AQP4 group and 0.823 in the other demyelinating disease group) to distinguish between remission and WW relapse was high. The cutoff values were as follows: cutoff value 5.57 ng/mL, 63.2% sensitivity, 85.3% specificity in the NMOSD-AQP4 group; cutoff value 3.00 ng/mL, 53.6% sensitivity, 86.3% specificity in the other CNS demyelinating disease group.

Correlation between serum FAM19A5 levels and clinical data in the NMOSD-AQP4 group

In univariate linear regression analysis, the sampling in the attack period, the number of past attacks, and the attack-related lesion sites, such as the spinal cord alone or both the intracranial and spinal cord, correlated with an increase in the serum FAM19A5 levels (Table 2). In the multiple linear regression analysis, however, only sampling during the attack period and the number of past attacks were independently associated with serum FAM19A5 levels after adjusting for the other confounding factors (regression coefficients: 1.686 and 0.379; p value: <0.001 and 0.010, respectively).

Table 2.

Association of FAM19A5 levels with clinical characteristics of patients in the NMOSD-AQP4 group.

	B ± SE	p value
Univariate analysis
Sex	0.507 ± 0.573	0.379
Age at enrollment (years)	−0.004 ± 0.013	0.743
Disease duration (years)	0.045 ± 0.027	0.105
Sampling at attack period	1.688 ± 0.411	<0.001
Latest EDSS	0.112 ± 0.100	0.266
Lesion of attacks
Intracranial lesion	0.023 ± 0.516	0.964
Spinal cord lesion	−1.096 ± 0.406	0.009
Both intracranial and spinal cord lesion	1.014 ± 0.395	0.012
Number of past attacks	0.341 ± 0.150	0.026
Multivariate analysis
Sampling at attack period	1.686 ± 0.408	<0.001
Number of past attacks	0.379 ± 0.143	0.010
Spinal cord lesion	–	–
Both intracranial and spinal cord lesion	–	–

NMOSD-AQP4: neuromyelitis optica spectrum disorders with aquaporin-4 antibodies; SE: standard error; EDSS: expanded disability status scale. Bold indicates statistically significant p values (p<0.05).

Discussion

In this study, we found that the serum FAM19A5 level was higher in the NMOSD-AQP4 group (4.90 ng/mL) than in the other CNS demyelinating disease group (2.35 ng/mL), including the MOG-IgG associated disease group, and the healthy control group (1.02 ng/mL). NMOSD is an autoimmune inflammatory disease with a causal auto-antibody against AQP4 and is characterized by astrocyte damage and reactive gliosis.^19–22 This immunopathologic feature of NMOSD that leads to heightened reactive gliosis may be associated with higher FAM19A5 levels in patients with NMOSD-AQP4 relative to those with other CNS demyelinating diseases other than multiple sclerosis.

Serum FAM19A5 may act as a nonspecific marker of brain damage in severe inflammatory CNS conditions.^16,23 However, we found that the serum FAM19A5 level strongly correlated with the AQP4 IgG titer, which is a key factor for the pathogenesis of NMOSD. The AQP4 IgG titers seem not to strongly correlate with clinical outcome or phenotype although several studies have shown that the titers correlated with disease activity. The increased titers observed after clinical relapse decreased after immunosuppressive therapy and then remained low during remission.²⁴ In addition, some studies have shown that the AQP4 IgG titers at the nadir of clinical attacks correlated with the length of longitudinally extensive spinal cord lesions.^24,25 In addition to the strong correlation of FAM19A5 level with AQP4 IgG titer, we found that serum FAM19A5 levels were significantly higher in patients in the NMOSD-AQP4 group than in those in the other CNS demyelinating disease group, including those in the MOG-IgG associated disease (oligodendrocytopathy) group. Together, these results suggest that serum FAM19A5 is a specific marker for astrocytopathy, indicating the disease activity and astrocyte damage severity.²⁶

The reliability of serum FAM19A5 in assessing clinical outcome predictions is one important facet for clinical application. In our study, serum FAM19A5 levels did not show any correlation with the latest EDSS. In addition, the latest EDSS did not show differences between the NMOSD-AQP4 group and the other CNS demyelinating disease group. Although serum FAM19A5 levels did not correlate with the latest EDSS in our study, EDSS is not the only factor that represents the clinical outcome of NMOSD. Other factors that are considered possible contributors to clinical outcome are annualized relapse rate, number of clinical relapses, and magnetic resonance imaging lesion burden. In this study, the number of past clinical relapses and attack-related lesion sites (both intracranial and spinal cord lesions) correlated with an increase in the serum FAM19A5 levels. In this regard, high serum FAM19A5 levels may be a predictor of worse clinical outcome.

In this study, the most useful value of serum FAM19A5 would be in predicting the likelihood of relapse. Since progressive disease is extremely rare and subclinical disease activity appears to be unusual in NMOSD, it is difficult to use serum FMA19A5 level as an indicator of neurodegeneration or subclinical disease activity. Instead, we found that there were significant differences in the mean serum FAM19A5 levels between the attack and remission periods. Among the clinical variables, clinical relapse was most strongly associated with higher serum FAM19A5 levels. In addition, ROC curve analysis showed that the serum FAM19A5 level had a high discriminatory ability (AUC = 0.819 in NMOSD-AQP4; AUC = 0.823 in other CNS demyelinating disease) to distinguish between remission and relapse. In the acute attack period, many types of inflammatory cells proliferate and migrate to repair and replace CNS tissue injured by inflammation.²⁷ The serum FAM19A5 level may be increased in response to the heightened reactive gliosis following inflammation in acute attacks. Therefore, serum FAM19A5 can be used as a good indicator of relapse in NMOSD. In particular, a change in serum FAM19A5 levels may be used to differentiate relapse from vague or nonspecific symptom fluctuations in patients with NMOSD.

Patients with both intracranial and spinal cord lesions had higher serum FAM19A5 levels than did those with only spinal cord lesions. This finding might be related to the greater extent of astrocyte damage when both the intracranial and spinal cord are affected. However, there were no significant differences in serum FAM19A5 levels between patients with both intracranial and spinal cord lesions and those with intracranial lesions only. The extent of the involved lesion is insufficient to explain these findings. Although not statistically significant, patients with intracranial lesions tended to have higher serum FAM19A5 levels than those with spinal cord lesions. This finding is consistent with that of a previous study, which found that high levels of FAM19A5 were observed in intracranial regions but not in other tissues.¹² This region-specific expression of FAM19A5 may explain some of the above findings that cannot be explained by the extent of the affected lesion. Further studies are needed to determine whether changes in the serum FAM19A5 levels are associated with a specific lesion location.

Some limitations of our study must be considered. First, our study lacked a multiple sclerosis control as well as other neurological disease controls related to reactive gliosis (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Gliosis is a prominent feature in the pathogenesis of multiple sclerosis which can involve much wider areas in the CNS when compared with NMOSD. However, this study was based on the Korean nationwide registry for NMOSD and, therefore, could not include patients with multiple sclerosis. Further large-scale studies involving multiple sclerosis and other neurological diseases related to reactive gliosis are needed in the future. Another limitation of this study is the small number of healthy control subjects. We tried to exclude any confounding factors related to CNS pathology and we selected subjects without any medical history that could affect the CNS. This resulted in the elimination of healthy elderly subjects. In future studies, it will be important to investigate the relationship between aging and FAM19A5 levels. In addition, our clinical data were incomplete; information about treatment was missing because records for this multicenter study were individually entered by researchers. In particular, the type of treatment may have a very significant effect on serum FAM19A5 levels. Therefore, when future studies are planned, an analysis of deeply phenotyped cases with more qualified clinical data including treatment data must be included. Finally, our study did not include an analysis of FAM19A5 levels in the CSF, which could be more directly related to the pathogenesis.

In conclusion, the elevation of serum FAM19A5 levels in patients with NMOSD-AQP4 is related to the immunopathological features affecting astrocytes and correlates with acute relapse and lesion location. These results suggest that FAM19A5 is a novel clinical biomarker representing the clinical status of NMOSD-AQP4.

Footnotes

Author Contributions

B.-J.K. contributed in the conception of the study and assessment of the manuscript; H.W.R., E.B.C., B.J.K., J.-H.M., J.M.S., H.Y.S., S.-Y.K., O.-H.K., S.-S.L., J.Y.O., E.-H.S., S.-Y.H., and J.-Y.C. contributed in the acquisition, analysis, and review of the data; H.L.L., H.Y.S., B.C.K., J.Y.S., and B.-J.K. prepared the manuscript. All authors approved the manuscript.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.B.C. and J.Y.S. are shareholders, and B.C.K. is a shareholder and CEO of Neuracle Science Co. Ltd. Other authors declare no conflict of interest.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Korean Centers for Disease Control and Prevention (No. 2017E6300202) and by a grant from the National Research Foundation of Korea (NRF2017R1A2B4006975).

ORCID iD

Byung-Jo Kim

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. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 2014; 81(2): 229–248.