Article Figures & Data
Figures
- Figure 1 Overview of the BAFF/APRIL System
BAFF and APRIL are produced by immune cells, including PMNs, M/DCs, and stromal cells (left side, source of BAFF and APRIL). The membrane-bound receptors BCMA and TACI are shed from B cells/plasma cells (right side, source of sBCMA and sTACI). sTACI blocks APRIL and BAFF, whereas sBCMA blocks APRIL (central part, decoy activity of sBCMA and sTACI). The receptor binding of APRIL and BAFF to their receptors BCMA, TACI, and BAFF-R on the cell surface of B cells/plasma cells is shown (lower part, receptor binding of BAFF and APRIL). APRIL binds also to heparan sulfate proteoglycans and astrocytes. ADAM 10 = A disintegrin and metalloproteinase domain-containing protein 10; APRIL = A proliferation-inducing ligand; BAFF = B cell–activating factor; BAFF-R = BAFF receptor; BCMA = B-cell maturation antigen; M/DCs = monocytes and dendritic cells; PMNs = polymorphonuclear cells; TACI = transmembrane activator and CAML interactor.
- Figure 2 Effect of Ocrelizumab Treatment on Components of the BAFF/APRIL System in the Serum of Patients
Serum levels of BAFF (A), sTACI (B), and APRIL (C) were evaluated from patient cohort 1 by ELISA from patients receiving ocrelizumab at baseline (n = 17), TP1 (mean 18 days; n = 17), TP2 (mean 6.7 months; n = 17), TP3 (mean 12.9 months; n = 17), TP4 (mean 19.1 months; n = 14), TP5 (mean 25.2 months; n = 10), and TP6 (mean 31.3 months; n = 7). Raw values are provided in eTable 3 (links.lww.com/NXI/A799). Data are presented as log2 fold change compared with baseline. We performed a 1-sample t test to compare baseline and follow-up samples. p Values are shown if they were <0.05. Data are given as arithmetic mean ± SEM. Negative correlation between BAFF and sTACI levels is shown by the Pearson correlation analyses of log2 fold change of BAFF to log2 fold change of sTACI in the serum of patient cohort 1 (D). APRIL = A proliferation-inducing ligand; BAFF = B cell–activating factor; TACI = transmembrane activator and CAML interactor.
- Figure 3 Effect of Ocrelizumab Treatment on Components of the BAFF/APRIL System in CSF
CSF levels of BAFF (A), sTACI (B), APRIL (C) and sBCMA (D) were evaluated from patient cohort 2 by ELISA from patients receiving ocrelizumab at baseline (n = 19) and follow-up (12-19 months after the first ocrelizumab infusion). Data are presented as log2 fold change compared with baseline. We performed a 1-sample t test to compare baseline and follow-up samples. p Values are shown if they were <0.05. Data are given as arithmetic mean ± SEM. Raw values are provided in eTable 3 (links.lww.com/NXI/A799). APRIL = A proliferation-inducing ligand; BAFF = B-cell activating factor; sBCMA = soluble B-cell maturation antigen; CSF = cerebrospinal fluid; sTACI = soluble transmembrane activator and CAML interactor.
- Figure 4 Establishment of ELISA Detecting sTACI-BAFF Complexes
(A) Measurement of sTACI (pg/mL) spiked with different amounts of BAFF using an ELISA approach. We added a 2-fold dilution series of BAFF (2,500 to 9.8 pg/mL) to 2 stable concentrations of sTACI (500 pg/ml left part) or 132 pg/mL of (right part) and compared with sTACI alone without BAFF. The left-most column represents no BAFF addition. (B) ELISA design used for the detection of sTACI-BAFF complexes. Anti-BAFF capture antibody and anti-sTACI detection antibody were used to detect sTACI-BAFF complexes. (C) Detection of sTACI-BAFF complexes (OD). Serial dilutions of 1,600, 800, and 400 pg/mL of BAFF were incubated with 500, 250, and 125 pg/mL of sTACI, respectively. BAFF = B cell–activating factor; TACI = transmembrane activator and CAML interactor.
- Figure 5 Identification and Quantification of sTACI-BAFF Complexes
(A) sTACI-BAFF complexes were measured by ELISA in patient cohort 1 in serum samples of patients at baseline (n = 17), TP1 (mean 18 days; n = 17), TP2 (mean 6.7 months; n = 17), TP3 (mean 12.9 months; n = 17), TP4 (mean 19.1 months; n = 14), TP5 (mean 25.2 months; n = 10), and TP6 (mean 31.3 months; n = 7). (B) Serum levels of sTACI-BAFF complex were evaluated in 15 patients from cohort 2 at baseline and follow-up (12–19 months after the first ocrelizumab infusion). Data are presented as log2 fold change compared with baseline. We performed a 1-sample t test to compare baseline and follow-up samples. Detailed values are given in eTable 3 (links.lww.com/NXI/A799). Data are given as arithmetic mean ± SEM. (C) The BAFF levels in serum correlated with sTACI-BAFF complexes (Pearson correlation analyses of log2 fold change of BAFF to log2 fold change of sTACI-BAFF complexes, p = 0.0032, r = 0.3252, cohort 1). BAFF = B cell–activating factor; TACI = transmembrane activator and CAML interactor; TP1 = time point 1.
- Figure 6 Illustration Showing Our Findings With the Proposed Consequences
The upper part illustrates our findings: ocrelizumab treatment results in an increase of BAFF and reduced free sTACI in both serum and CSF. In serum, this is associated with increased formation of sTACI-BAFF complexes. sTACI-BAFF complexes were not detected in CSF samples in our study. The lower part links our findings to published work: sTACI is a decoy for APRIL13 (left). In the absence of the decoy sTACI (right), APRIL might induce IL10 production from astrocytes23 and promote the development of regulatory IgA plasma cells,29–31 which can home to the brain and secrete IL-10.32,33 APRIL = A proliferation-inducing ligand; BAFF = B cell–activating factor; TACI = transmembrane activator and CAML interactor.
Tables
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Hastening the Diagnosis of Amyotrophic Lateral Sclerosis
Dr. Brian Callaghan and Dr. Kellen Quigg