title: BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset.
abstract: B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS.
  
  
  
  Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh).
  
  
  
  Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes (p < 0.01), lower values of BAFF Index (11.9 ± 6.1 vs 17.5 ± 5.2, p < 0.01), and higher CSF CXCL13 levels (27.7 ± 33.5 vs 0.9 ± 1.5, p < 0.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis (r > 0.5 and p < 0.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB- (p < 0.05) and HC (p < 0.01), and correlated to CSF CXCL13 concentrations (r 0.77, p < 0.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41 ± 0.1 vs 2.49 ± 0.1 mm, p < 0.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB-.
  
  
  
  The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by higher leukocyte counts in the CSF and early evidence of cortical thinning, further suggesting a role for this chemokine as a possible marker of disease severity.
authors.affiliation: Multiple Sclerosis Centre, Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy. marco.puthenparampil@studenti.unipd.it.
authors.forename: M
authors.initials: M
authors.lastname: Puthenparampil
authors.affiliation: Multiple Sclerosis Centre, Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Federle
authors.affiliation: Multiple Sclerosis Centre, Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Miante
authors.affiliation: Multiple Sclerosis Centre, Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zito
authors.affiliation: Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Toffanin
authors.affiliation: Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ruggero
authors.affiliation: Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ermani
authors.affiliation: Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pravato
authors.affiliation: Multiple Sclerosis Centre, Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Poggiali
authors.affiliation: Multiple Sclerosis Centre, Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Perini
authors.affiliation: Multiple Sclerosis Centre, Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Rinaldi
authors.affiliation: Multiple Sclerosis Centre, Department of Neurosciences DNS, University Hospital-Medical School, via Giustiniani 5, 3518, Padova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Gallo
mesh_terms: D000328:Adult; D001284:Atrophy; D053264:B-Cell Activating Factor / Q000097:blood / Q000134:cerebrospinal fluid* / Q000276:immunology; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology*; D054382:Chemokine CXCL13 / Q000097:blood / Q000134:cerebrospinal fluid* / Q000276:immunology*; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid* / Q000150:complications* / Q000000981:diagnostic imaging; D043025:Oligoclonal Bands / Q000097:blood / Q000134:cerebrospinal fluid*; D012720:Severity of Illness Index; D013223:Statistics as Topic
chemical_list: D053264:B-Cell Activating Factor; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D016207:Cytokines; D043025:Oligoclonal Bands; C505719:TNFSF13B protein, human
keywords: BAFF; CXCL13; Cerebrospinal fluid; FLS; IL21; IgGOB; Intrathecal IgG synthesis; Multiple sclerosis