Age-associated B cells in autoimmune diseases

Mouat, Isobel C.; Goldberg, Erin; Horwitz, Marc S.

doi:10.1007/s00018-022-04433-9

Cited by 86 publications

(66 citation statements)

References 99 publications

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“…The number of ABCs increases with age, particularly in females (3,(6)(7)(8)(9)(10). ABC numbers are also increased in people with autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS), and in a subset of people with common variable immunodeficiency that display autoimmune complications (3,6,7,(9)(10)(11)(12)(13). In a mouse model of SLE, knocking out T-bet specifically in B cells impairs the development of germinal centers, decreases autoantibody levels, and dampens kidney damage and mortality (14).…”

Section: Introductionmentioning

confidence: 99%

Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS

et al. 2022

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While age-associated B cells (ABCs) are known to expand and persist following viral infection and during autoimmunity, their interactions are yet to be studied together in these contexts. Here, we directly compared CD11c + T-bet + ABCs using models of Epstein-Barr virus (EBV), gammaherpesvirus 68 (γHV68), multiple sclerosis (MS), and experimental autoimmune encephalomyelitis (EAE), and found that each drives the ABC population to opposing phenotypes. EBV infection has long been implicated in MS, and we have previously shown that latent γHV68 infection exacerbates EAE. Here, we demonstrate that ABCs are required for γHV68-enhanced disease. We then show that the circulating ABC population is expanded and phenotypically altered in people with relapsing MS. In this study, we show that viral infection and autoimmunity differentially affect the phenotype of ABCs in humans and mice, and we identify ABCs as functional mediators of viral-enhanced autoimmunity.

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Section: Introductionmentioning

confidence: 99%

Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS

et al. 2022

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“…Setting aside the question of whether the plasma cell differentiation depends on T cells, this suggests that the B-cell-driven immune response may have been closely involved in the pathogenesis of AIH in this case, wherein autoreactive B cells to hepatocytes could be activated by TLR7 stimulation via mRNA vaccination to produce specific autoantibodies that may participate in the immune-mediated liver injury. This proposed mechanism could be supported by the evidence that ABCs expanded in patients with SS not only produce antibodies specific to various selfantigens but are also responsive to TLR stimulation [15,16].…”

Section: Discussionmentioning

confidence: 89%

“…Interestingly, it has most recently been hypothesized that age-associated B cells (ABCs), which belong to the memory compartment, a unique subset of B cells expressing CD11c and Tbet, are potentially induced by mRNA COVID-19 vaccines and may be implicated in autoimmune phenomena [14]. ABCs are increased during aging, infection, and autoimmunity, such as several autoimmune diseases, including SS [15,16]. Of note, ABCs are shown to be hyper-responsive to TLR7 signaling and are poised to generate autoreactive antibody-secreting plasmablasts in systemic lupus erythematosus [17].…”

Section: Discussionmentioning

confidence: 99%

Autoimmune Hepatitis Following mRNA COVID-19 Vaccination in a Very Old Patient With Preexisting Sjögren’s Syndrome: A Case Report

Yoshida¹,

Iwata²,

Ishii³

et al. 2022

Cureus

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A case of autoimmune hepatitis (AIH) following COVID-19 vaccination in a very old patient is presented. An 85-year-old woman who had preexisting Sjögren's syndrome (SS) but had never shown evidence of liver disease was admitted to our hospital due to jaundice and liver dysfunction. Further laboratory tests, imaging studies, and liver histology proved this to be a case of definite AIH. Eight weeks before the disease onset, she had received the second dose of mRNA COVID-19 vaccination. To our knowledge, this is the first case of AIH following COVID-19 vaccination in a patient with a history of SS.

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“…ABCs are antigen-experienced B cells that are characterized by a T-bet-mediated transcriptional program ( 67 ). ABCs plays a critical role in regulating immune response to infectious agents mediated by IgG2a/c and inflammatory cytokines ( 68 , 69 ).…”

Section: Discussionmentioning

confidence: 99%

Radiation therapy induces immunosenescence mediated by p90RSK

Imanishi

Cheng

Kotla

et al. 2022

Front. Cardiovasc. Med.

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Radiation therapy (RT) to the chest increases the patients’ risk of cardiovascular disease (CVD). A complete understanding of the mechanisms by which RT induces CVD could lead to specific preventive, therapeutic approaches. It is becoming evident that both genotoxic chemotherapy agents and radiation induce mitochondrial dysfunction and cellular senescence. Notably, one of the common phenotypes observed in cancer survivors is accelerated senescence, and immunosenescence is closely related to both cancer risk and CVD development. Therefore, suppression of immunosenescence can be an ideal target to prevent cancer treatment-induced CVD. However, the mechanism(s) by which cancer treatments induce immunosenescence are incompletely characterized. We isolated peripheral blood mononuclear cells (PBMCs) before and 3 months after RT from 16 thoracic cancer patients. We characterized human immune cell lineages and markers of senescence, DNA damage response (DDR), efferocytosis, and determinants of clonal hematopoiesis of indeterminant potential (CHIP), using mass cytometry (CyTOF). We found that the frequency of the B cell subtype was decreased after RT. Unsupervised clustering of the CyTOF data identified 138 functional subsets of PBMCs. Compared with baseline, RT increased TBX21 (T-bet) expression in the largest B cell subset of Ki67–/DNMT3a+naïve B cells, and T-bet expression was correlated with phosphorylation of p90RSK expression. CD38 expression was also increased in naïve B cells (CD27–) and CD8+ effector memory CD45RA T cells (TEMRA). In vitro, we found the critical role of p90RSK activation in upregulating (1) CD38+/T-bet+ memory and naïve B, and myeloid cells, (2) senescence-associated β-gal staining, and (3) mitochondrial reactive oxygen species (ROS) after ionizing radiation (IR). These data suggest the crucial role of p90RSK activation in immunosenescence. The critical role of p90RSK activation in immune cells and T-bet induction in upregulating atherosclerosis formation has been reported. Furthermore, T-bet directly binds to the CD38 promoter region and upregulates CD38 expression. Since both T-bet and CD38 play a significant role in the process of immunosenescence, our data provide a cellular and molecular mechanism that links RT-induced p90RSK activation and the immunosenescence with T-bet and CD38 induction observed in thoracic cancer patients treated by RT and suggests that targeting the p90RSK/T-bet/CD38 pathway could play a role in preventing the radiation-associated CVD and improving cancer prognosis by inhibiting immunosenescence.

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Age-associated B cells in autoimmune diseases

Cited by 86 publications

References 99 publications

Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS

Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS

Autoimmune Hepatitis Following mRNA COVID-19 Vaccination in a Very Old Patient With Preexisting Sjögren’s Syndrome: A Case Report

Radiation therapy induces immunosenescence mediated by p90RSK

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