Genetic and functional analyses indicate that SPAG16 influences MMP-3 regulation and protects against joint destruction in autoantibody-positive RA. These findings could enhance risk stratification in autoantibody-positive RA.
Flavonoids are potent antioxidants, freely available as high-dose dietary supplements. However, they can induce DNA double-strand breaks (DSB) and rearrangements in the mixed-lineage leukemia (MLL) gene, which are frequently observed in childhood leukemia. We hypothesize that a deficient DSB repair, as a result of an Atm mutation, may reinforce the clastogenic effect of dietary flavonoids and increase the frequency of Mll rearrangements. Therefore, we examined the effects of in vitro and transplacental exposure to high, but biological amounts of flavonoids in mice with different genetic capacities for DSB repair (homozygous/heterozygous knock-in for human Atm mutation [Atm-ΔSRI] vs. wild type [wt]). In vitro exposure to genistein/quercetin induced higher numbers of Mll rearrangements in bone marrow cells of Atm-ΔSRI mutant mice compared with wt mice. Subsequently, heterozygous Atm-ΔSRI mice were placed on either a flavonoid-poor or a genistein-enriched (270 mg/kg) or quercetin-enriched (302 mg/kg) feed throughout pregnancy. Prenatal exposure to flavonoids associated with higher frequencies of Mll rearrangements and a slight increase in the incidence of malignancies in DNA repair-deficient mice. These data suggest that prenatal exposure to both genistein and quercetin supplements could increase the risk on Mll rearrangements especially in the presence of compromised DNA repair.
We have previously identified eight novel autoantibody targets in the cerebrospinal fluid of multiple sclerosis (MS) patients, including sperm-associated Ag 16 (SPAG16). In the current study, we further investigated the autoantibody response against SPAG16—a protein with unknown function in the CNS—and its expression in MS pathology. Using isoelectric focusing, we detected SPAG16-specific oligoclonal bands in the cerebrospinal fluid of 5 of 23 MS patients (22%). Analysis of the anti-SPAG16 Ab reactivity in the plasma of a total of 531 donors using ELISA demonstrated significantly elevated anti-SPAG16 Ab levels (p = 0.002) in 32 of 153 MS patients (21%) compared with all other control groups with 95% specificity for the disease. To investigate the pathologic relevance of anti-SPAG16 Abs in vivo, anti-SPAG16 Abs were injected in mice with experimental autoimmune encephalomyelitis, resulting in a significant disease exacerbation. Finally, we demonstrated a consistent upregulation of SPAG16 in MS brain and experimental autoimmune encephalomyelitis spinal cord lesions, more specifically in reactive astrocytes. We conclude that SPAG16 is a novel autoantibody target in a subgroup of MS patients and in combination with other diagnostic criteria, elevated levels of anti-SPAG16 Abs could be used as a biomarker for diagnosis. Furthermore, the pathologic relevance of anti-SPAG16 Abs was shown in vivo.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination, axonal degeneration and gliosis. The progressive form of MS is an important research topic as not much is known about its underlying mechanisms and no therapy is available. Although progressive MS is traditionally considered to be driven by neurodegeneration, compartmentalized CNS inflammation is currently accepted as one of the driving processes behind neurodegeneration and progression. In this review, the involvement of B cells and antibodies in progressive MS is discussed. The identification of meningeal ectopic B cell follicles in secondary progressive MS (SPMS) patients and the successful use of B cell-depleting therapy in primary progressive MS (PPMS) patients have underlined the importance of B cells in progressive MS. Proof is also available for the role of antibodies in neurodegeneration and progression in MS. Here, oligoclonal immunoglobulin M (IgM) production and autoreactive antibodies are described, with a focus on antibodies directed against sperm-associated antigen 16 (SPAG16). Further research into the role of B cells and autoantibodies in MS progression can lead to novel prognostic and theranostic opportunities.
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