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. 2019 Nov 22:10:1232.
doi: 10.3389/fneur.2019.01232. eCollection 2019.

Intrathecal, Not Systemic Inflammation Is Correlated With Multiple Sclerosis Severity, Especially in Progressive Multiple Sclerosis

Joshua L Milstein  1 , Christopher R Barbour  1 , Kayla Jackson  1 , Peter Kosa  1 , Bibiana Bielekova  1
Affiliations

Intrathecal, Not Systemic Inflammation Is Correlated With Multiple Sclerosis Severity, Especially in Progressive Multiple Sclerosis

Joshua L Milstein et al. Front Neurol. .

Abstract

Objective: To test the hypothesis that Multiple Sclerosis (MS) patients have increased peripheral inflammation compared to healthy donors and that this systemic activation of the immune system, reflected by acute phase reactants (APRs) measured in the blood, contributes to intrathecal inflammation, which in turn contributes to the development of disability in MS. Methods: Eight serum APRs measured in a prospectively-collected cross-sectional cohort with a total of 51 healthy donors and 291 untreated MS patients were standardized and assembled into related biomarker clusters to derive global measures of systemic inflammation. The resulting APR clusters were compared between diagnostic categories and correlated to equivalently-derived cerebrospinal fluid (CSF) biomarkers of innate and adaptive immunity. Finally, correlations were calculated between biomarkers of systemic and intrathecal inflammation and MS severity measures, which predict future rates of disability progression. Results: While two blood APR clusters were elevated in MS patients, only one exhibited a weak correlation with MS severity. All CSF inflammation clusters, except CSF albumin, correlated with at least one measure of MS severity, with biomarkers of humoral adaptive immunity exhibiting the strongest correlations, especially in Progressive MS. Conclusion: Systemic inflammation does not appear to be strongly associated with intrathecal inflammation in MS. Positive correlations between markers of intrathecal inflammation, especially of humoral immunity, with MS severity measures support a pathogenic role of intrathecal (compartmentalized) inflammation in central nervous system tissue destruction, including in Progressive MS.

Keywords: T cells; acute phase reactants; adaptive immunity; cerebrospinal fluid; inflammation; innate immunity; multiple sclerosis; systemic infections.

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Figures

Figure 1
Figure 1
Comparing HD and MS biomarker residual levels after adjusting for race, age, and sex. Mean comparisons between HD and MS biomarker Z score residuals after matching and adjusting for race, age, and sex and p-values after adjusting for multiple comparisons are shown. All comparisons are shown in table format in (A,B) and graphical depictions are also presented for blood APRs (C) and CSF markers (D) individually that demonstrated differences between HD and MS patients. MS patients had higher levels of ferritin in the blood and elevated levels of CHI3L1, sCD27, sBCMA, IgG, and IgG index in the CSF. Serum albumin and transferrin were decreased in MS patients, which is suggestive of an increased inflammatory profile due to these proteins being negative APRs. *p < 0.05, **p < 0.01, ****p < 0.0001. APR, acute phase reactant; CHI3L1, chitinase-3-like 1; CRP, C-reactive protein; CSF, cerebrospinal fluid; ESR, erythrocyte sedimentation rate; HD, healthy donor; IgG, immunoglobulin G; MS, Multiple Sclerosis; sBCMA, soluble B cell maturation antigen; sCD, soluble cluster of differentiation; SD, standard deviation; WBC, white blood cell count.
Figure 2
Figure 2
Blood biomarkers can be clustered to create more globalized, biologically-relevant measures of systemic inflammation. Z scores of negative APRs in the blood (serum albumin, iron, and transferrin) were first multiplied by −1 and subsequently adjusted for race, age, and sex. Afterwards, Pearson correlations between individual blood biomarker Z score residuals were calculated. Biomarkers that correlated were subsequently grouped into clusters. This resulted in three separate clusters: the first containing ceruloplasmin, CRP, ESR, and iron (A); the second comprised of serum albumin and WBC (B); and the third with ferritin and transferrin (C). The axes are selected to have better visual assessment of majority of patients' biomarkers. Thus, a few individual points may be missing in these graphs. APR, acute phase reactant; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MS, Multiple Sclerosis; WBC, white blood cell count.
Figure 3
Figure 3
CSF biomarkers can be clustered into biologically-relevant measures of intrathecal inflammation. Pearson correlations between individual CSF biomarker Z score residuals were calculated. Biomarkers that correlated with others were grouped into clusters. Because nearly all of the measured CSF biomarkers correlated with each other in patients with MS (data not shown), two clusters were made; the first using the biologically-related CSF myeloid lineage markers CHI3L1, sCD14, and sCD163 (A) and the second comprising of sBCMA, CSF IgG, and IgG index (B). All other CSF biomarkers not included in these clusters (CSF albumin and sCD27) were used for future analyses as standalone proteins. The axes are selected to have better visual assessment of majority of patients' biomarkers. Thus, a few individual points may be missing in these graphs. CHI3L1, chitinase-3-like 1; CSF, cerebrospinal fluid; IgG, immunoglobulin G; MS, Multiple Sclerosis; sBCMA, soluble B cell maturation antigen; sCD, soluble cluster of differentiation.
Figure 4
Figure 4
Select systemic and CSF inflammatory clusters are upregulated in MS patients. Differences between mean biomarker cluster scores between HD and MS groups after adjusting for multiple comparisons were assessed using unpaired t-tests (A). We found that MS patients had elevated cluster scores compared to healthy donors for Blood cluster 2, Blood cluster 3, CSF cluster 1, and CSF cluster 2 (B). *p < 0.05, ***p < 0.001, ****p < 0.0001. CSF, cerebrospinal fluid; HD, healthy donor; MS, Multiple Sclerosis; SD, standard deviation.
Figure 5
Figure 5
Inflammatory blood and CSF immune biomarkers correlate with MS severity among all MS patients combined. Spearman correlations between all blood and CSF clusters and MS-DSS, MSSS, and ARMSS using all MS patients are shown after adjusting for multiple comparisons (A). Relationships between cluster scores and severity measures with p < 0.05 are bolded and graphically depicted (B). The axes are selected to have better visual assessment of majority of patients' cluster scores. Thus, a few individual points may be missing in these graphs. ARMSS, Age Related Multiple Sclerosis Severity; CSF, cerebrospinal fluid; MS, Multiple Sclerosis; MS-DSS, Multiple Sclerosis-Disease Severity Scale; MSSS, Multiple Sclerosis Severity Score.
Figure 6
Figure 6
CSF biomarkers of innate and adaptive immunity correlate with MS severity in subjects with PMS, but not RRMS. Spearman correlations between all blood and CSF clusters and MS-DSS, MSSS, and ARMSS in only RRMS (A) or Progressive MS (B) patients are shown after adjusting for multiple comparisons. Relationships between cluster scores and severity measures with p < 0.05 are bolded and graphically depicted (C). The axes are selected to have better visual assessment of majority of patients' cluster scores. Thus, a few individual points may be missing in these graphs. ARMSS, Age Related Multiple Sclerosis Severity; CSF, cerebrospinal fluid; MS, Multiple Sclerosis; MS-DSS, Multiple Sclerosis-Disease Severity Scale; MSSS, Multiple Sclerosis Severity Score.
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