Park JC, Noh J, Jang S, Kim KH, Choi H, Lee D, Kim J, Chung J, Lee DY, Lee Y, Lee H, Yoo DK, Lee AC, Byun MS, Yi D, Han SH, Kwon S, Mook-Jung I. Association of B cell profile and receptor repertoire with the progression of Alzheimer's disease. Cell Rep. 2022 Sep 20;40(12):111391. PubMed.
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Uppsala Universitet
An increasing body of evidence links the immune system to the development of Alzheimer’s disease. In this study, the authors have studied the association between B cells and their receptor repertoire in AD. Evidence is presented for both quantitative and qualitative changes in B cells during the progression of AD.
A key finding is that patients whose PiB-PET SUV ratio increased over two years had a significantly higher B-cell count compared to those who remained stable or showed a decreased PiB-PET SUV ratio. An increase in B-cell numbers could of course be a consequence of Aβ pathology, and the concept of Aβ aggregates giving rise to formation of auto-antibodies that react with Aβ plaques is a phenomenon that has been studied previously. It has also been exploited in the "reverse translational medicine" approach that was used for selection of the Aβ antibody aducanumab (Sevigny et al., 2016) from PBMCs of healthy centenarians.
The authors further report that the repertoire of AD B-cell receptors (BCRs) is different from that of control B-cells, and that there is a common BCR profile in AD-derived B-cells. It would be interesting to further investigate whether this common profile links BCRs to a specific antigen, e.g. Aβ.
An additional possible mechanistic link between B-cells and Aβ pathology suggests that with more B-cells, AD patients produce more IgG antibodies, which can lead to the loss of function of microglia and thereby dysregulation of Aβ clearance. As a proof of principle, iSPC-derived microglia were treated with Aβ in the absence or presence of high concentrations of IgG. The combination of chronic Aβ treatment and excessive IgG exposure led to a marked decrease in the phagocytic activity of microglia, resulting in impaired degradation of Aβ.
These results find support in a study by Kim et al., who showed a therapeutic effect of B cell depletion through restoration of TGF-β in microglia (Kim et al., 2021). However, while AD patients demonstrate a relatively modest increase in B-cell numbers, the cell experiments in the current study were conducted with high concentration of IgG (to mimic AD) in comparison with no IgG (to mimic controls). Thus, while this is an interesting theory, further studies will be needed to establish that microglial dysfunction is indeed caused by increased concentrations of IgG, and explore whether B-cells could be a target for development of novel therapies.
References:
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6. PubMed.
Kim K, Wang X, Ragonnaud E, Bodogai M, Illouz T, DeLuca M, McDevitt RA, Gusev F, Okun E, Rogaev E, Biragyn A. Therapeutic B-cell depletion reverses progression of Alzheimer's disease. Nat Commun. 2021 Apr 12;12(1):2185. PubMed.
University of Eastern Finland
Park et al. have set the focus on elucidating the interplay between the peripheral immune system and Alzheimer’s disease (AD)-related pathology. Consequently, it was found that the population of B lymphocytes and the counts of immunoglobulins (Ig) were increased upon two-year follow-up time in relation to the increased cerebral β-amyloid deposition in the human brain tissue detected by using PiB-PET imaging.
Moreover, the deep profiling of the B lymphocytes obtained from AD patients and elderly normal controls by using next-generation-sequencing (NGS)-based B-cell receptor (BCR) repertoire analyses revealed a high somatic hypermutation rate and sequence divergence, as well as a class-switch change from IgM isotype to IgG and IgA isotypes in the AD samples as compared to control samples. Importantly, pairwise sharing analysis showed commonalities in BCR repertoires among the AD patients, suggesting an immunological response in B lymphocytes against common antigens, such as Aβ or tau in AD patients.
Finally, the authors showed that combined chronic treatment of iPSC-derived microglia with Aβ and IgG reduced the microglia’s homeostatic ability (decreased expression of TGF-β) as well as their phagocytic activity.
Collectively, this is an extremely interesting and timely study, which suggests that the immunological responses in peripheral B lymphocytes associate with increased Aβ pathology in the brain tissues of AD patients. Importantly, the study also highlights B lymphocytes as potential biomarker as well as therapeutic targets in AD.
However, it should be noted that no change or even decrease in the number of B lymphocytes has been reported in AD patients. Also, it is still under discussion whether the B lymphocyte population alleviates or exacerbates the deposition of Aβ. This reinforces the need for further studies among much larger AD cohorts using similar longitudinal procedures as in the Park et al. study.
Finally, recent genetic findings in AD have systematically pointed toward the association of risk-modifying variants in genes involved in immunity and microglia. It is therefore crucial to elucidate the potential effects of these variants on the functional aspects of B lymphocytes in relation to AD pathologies, as many of these AD-associated risk or protective genes are also playing central role in B lymphocytes.
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