The relationship between BAFF serum levels, anti-NMDAR autoantibodies and fatigue in patients with systemic lupus erythematosus and multiple sclerosis

Basta, Fabio; Möckel, Tamara; Petersohn, Jan; Meineck, Myriam; Triantafyllias, Konstantinos; Engel, Sinah; Weinmann, Arndt; Luessi, Felix; Weinmann‐Menke, Julia; Schwarting, Andreas

doi:10.1016/j.autrev.2021.102802

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…Given the recently identified association between serum BAFF levels and autoantibodies against the NR2 subunit of N-methyl-D-aspartate receptor (NMDAR) and motor fatigue in systemic lupus erythematosus (SLE) patients ( 86 ), it would be highly interest to test whether anti-NMDAR autoantibodies could contribute to fatigue levels in primary SS patients as well.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants of the BAFF Gene and Risk of Fatigue Among Patients With Primary Sjögren’s Syndrome

et al. 2022

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Background/PurposePrimary Sjögren’s Syndrome (SS) is characterized by B lymphocyte hyperactivity with B cell activating factor (BAFF) acting as an important regulator. Single Nucleotide Polymorphisms (SNPs) of the BAFF gene have been implicated in the pathogenesis of several autoimmune diseases characterized by heightened fatigue levels, including primary SS. We aimed to explore potential associations between BAFF SNPs and fatigue status of primary SS patients.MethodsFatigue status was assessed in 199 consecutive primary SS patients (Greek cohort) using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale. Clinical, histological, laboratory, psychometric and personality data were also collected. DNA extracted from peripheral blood of all patients underwent evaluation for the presence of five BAFF SNPs (rs9514827, rs1041569, rs9514828, rs1224141, rs12583006) by PCR. To confirm our findings, an independent replicative cohort of 62 primary SS patients (Dutch cohort) was implemented. Finally, 52 multiple sclerosis (MS) patients were served as disease controls (MS cohort). Analysis of BAFF SNPs in association with fatigue levels was performed by the online platforms SNPStats and SHEsis and the SPSS 26 and Graph Pad Prism 8.00 software.ResultsTT genotype of the rs9514828 BAFF polymorphism was significantly less frequent in the fatigued primary SS patients of the Greek cohort compared to the non-fatigued (14.1% vs 33.3%). The corresponding ORs [95%CI] in the dominant and overdominant models were 0.33 [0.15-0.72], p=0.003 and 0.42 [0.23-0.78], p=0.005 respectively. The association remained significant after adjustment for the variables contributing to fatigue in the univariate analysis (OR [95% CI]: 0.3 [0.1-0.9], p=0.026). Accordingly, in the Dutch cohort, there was a trend of lower mental fatigue among patients carrying the TT rs9514828 BAFF genotype compared to their CC counterparts (4.1 ± 2.4 vs 6.0 ± 2.2 respectively, p=0.06). The rs9514828 BAFF SNP was not significantly associated with fatigue in the MS cohort.ConclusionsWe report a novel association between genetic makeup and primary SS-associated fatigue with the rs9514828 TT genotype decreasing the likelihood of fatigue development among these patients. These findings need validation in multi-center studies.

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Section: Discussionmentioning

confidence: 99%

Genetic Variants of the BAFF Gene and Risk of Fatigue Among Patients With Primary Sjögren’s Syndrome

et al. 2022

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“…BAFF and BAFF is not only biologically activated as a membrane bound protein, but also found in soluble form [27][28][29]. The soluble BAFF (sBAFF) is formed from the hydrolysis of membrane-type BAFF and can improve the activity of B cells, CD4+T cells, and NK cells to increase the body's immune responses [30].…”

Section: Introductionmentioning

confidence: 99%

Distinct binding mode of BAFF antagonist antibodies belimumab and tabalumab, analyzed by computer simulation

Sun¹,

Wei²

2022

J Mol Model

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B-cell activating factor (BAFF) can binding to specific receptors and activate signaling pathways associated with B cell activation. Belimumab and tabalumab are anti-BAFF monoclonal antibodies, while belimumab was proved by FDA in 2011 as a targeted therapy for systemic lupus erythematosus (SLE) and showed better clinical effect than tabalumab. The combination modes of BAFF-belimumab complex and BAFF-tabalumab complex were simulated to better understand the reason for the difference of the inhibition effect between belimumab and tabalumab. The structures of belimumab and tabalumab were constructed by homology modeling.The combination mode of BAFF-belimumab complex was analyzed by molecular dynamics simulation, and the combination mode of BAFF-tabalumab complex was analyzed by protein-protein docking after molecular dynamics simulation. Both belimumab and tabalumab contacted with BAFF at the same hydrophobic center which the natural receptors of BAFF bind to. I51, F54, K58 D100, D101, L102, L103, P105 of belimumab heavy chain and R27, Y30, K49, S65 of belimumab light chain contribute to the BAFF-belimumab interaction mainly by hydrogen bond, salt bridge and hydrophobic effect. More important, Belimumab could contact with L83 of BAFF and produced a steric hindrance with the adjacent BAFF trimers, while tabalumab could not. Belimumab had better clinical effect than tabalumab mainly because it could bind to L83 of BAFF and affect the formation of BAFF 60-mer, in addition to inhibition of the interaction of BAFF with its receptors.

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Section: Introductionmentioning

confidence: 99%

Distinct Binding Mode of BAFF antagonist antibodies Belimumab and Tabalumab, analyzed by computer simulation

Sun

Wei

2021

Preprint

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B-cell activating factor (BAFF) can binding to specific receptors and activate signaling pathways associated with B cell activation. Belimumab and tabalumab are anti-BAFF monoclonal antibodies, while belimumab was proved by FDA in 2011 as a targeted therapy for systemic lupus erythematosus (SLE) and showed better clinical effect than tabalumab. The combination modes of BAFF-belimumab complex and BAFF-tabalumab complex were simulated to better understand the reason for the difference of the inhibition effect between belimumab and tabalumab. The structures of belimumab and tabalumab were constructed by homology modeling. The combination mode of BAFF-belimumab complex was analyzed by molecular dynamics simulation, and the combination mode of BAFF-tabalumab complex was analyzed by protein-protein docking after molecular dynamics simulation. Both belimumab and tabalumab contacted with BAFF at the same hydrophobic center which the natural receptors of BAFF bind to. I51, F54, K58 D100, D101, L102, L103, P105 of belimumab heavy chain and R27, Y30, K49, S65 of belimumab light chain contribute to the BAFF-belimumab interaction mainly by hydrogen bond, salt bridge and hydrophobic effect. More important, Belimumab could contact with L83 of BAFF and produced a steric hindrance with the adjacent BAFF trimers, while tabalumab could not. Belimumab had better clinical effect than tabalumab mainly because it could bind to L83 of BAFF and affect the formation of BAFF 60-mer, in addition to inhibition of the interaction of BAFF with its receptors.

show abstract

The relationship between BAFF serum levels, anti-NMDAR autoantibodies and fatigue in patients with systemic lupus erythematosus and multiple sclerosis

Cited by 5 publications

References 21 publications

Genetic Variants of the BAFF Gene and Risk of Fatigue Among Patients With Primary Sjögren’s Syndrome

Genetic Variants of the BAFF Gene and Risk of Fatigue Among Patients With Primary Sjögren’s Syndrome

Distinct binding mode of BAFF antagonist antibodies belimumab and tabalumab, analyzed by computer simulation

Distinct Binding Mode of BAFF antagonist antibodies Belimumab and Tabalumab, analyzed by computer simulation

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