Memory B cells can be generated independently of germinal center (GC) formation and affinity maturation in Bcl-6-deficient mice, but the contribution of the GC-independent pathway for memory B-cell generation in normal mice remains unknown. To examine this, we administrated anti-inducible co-stimulator (ICOS) mAbs into mice at the onset of GC formation in the primary response. This manipulation affected the generation of GC B cells in the spleen, but neither IgG1 memory B cell nor production of IgG1 long-term antibody was affected. In ICOS-manipulated mice, GC B cells accumulated somatic mutations in the IgV(H) genes and underwent affinity maturation; however, memory B cells scarcely accumulated mutations and reconstituted the secondary response by low affinity, supporting the notion that low-affinity memory B cells are generated in a GC-independent manner. Thus, it appears that memory B cells are established by two different pathways, associated with or without GC reaction and affinity maturation. The generation and long-term persistence of low-affinity IgG1 memory B cells and antibodies in ICOS-manipulated mice support the idea that low-affinity memory B cells may give rise to long-term antibody-forming cells.
Amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD). Because AD pathologies begin two decades before the onset of dementia, prevention of Aβ amyloidosis has been proposed as a mean to block the pathological cascade. Here, we generate a transgenic plant-based vaccine, a soybean storage protein containing Aβ4–10, named Aβ+, for oral Aβ immunization. One mg of Aβ+ or control protein (Aβ–) was administered to TgCRND8 mice once a week from 9 weeks up to 58 weeks. Aβ+ immunization raised both anti-Aβ antibodies and cellular immune responses. Spatial learning decline was prevented in the Aβ+ immunized group in an extended reference memory version of Morris water maze test from 21 to 57 weeks. In Tris-buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aβ species from Aβ monomer, low to high molecular weight Aβ oligomers, and Aβ smears had different solubility in TgCRND8 brains. Aβ oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aβ oligomers in SDS extracts and Aβ smears in FA fraction of the Aβ+ treated group. There was significant inhibition of histological Aβ burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid-β protein precursor was not different between Aβ+ and Aβ– groups. No evidence of amyloid-related inflammatory angiopathy was observed. Thus, Aβ+ oral immunization could be a promising, cheap, and long-term safe disease-modifying therapy to prevent the pathological process in AD.
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