Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Self-peptide-dependent autoproliferation (AP) of B and T cells is a key mechanism in MS. Here, we show that pro-inflammatory B-T cell-enriched cell clusters (BTECs) form during AP and mirror features of a germinal center reaction. T-bet+CXCR3+ B cells are the main cell subset amplifying and sustaining their counterpart Th1 cells via interferon (IFN)-γ and are present in highly inflamed meningeal tissue. The underlying B cell activation signature is reflected by epigenetic modifications and receptor-ligand interactions with self-reactive T cells. AP+ CXCR3+ B cells show marked clonal evolution from memory to somatically hypermutated plasmablasts and upregulation of IFN-γ-related genes. Our data underscore a key role of T-bet+CXCR3+ B cells in the pathogenesis of MS in both the peripheral immune system and the CNS compartment, and thus they appear to be involved in both early relapsing-remitting disease and the chronic stage.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.
© 2024. The Author(s).

KMT2A-rearranged acute lymphoblastic infant leukemia (KMT2A-r iALL) is associated with outsize risk of relapse and relapse mortality. We previously reported strong upregulation of the immediate early gene EGR3 in KMT2A::AFF1 iALL at relapse; now we provide analyses of the EGR3 regulome, which we assessed through binding and expression target analysis of an EGR3-overexpressing t(4;11) cell culture model. Our data identify EGR3 as a regulator of early B-lineage commitment. Principal component analysis of 50 KMT2A-r iALL patients at diagnosis and 18 at relapse provided strictly dichotomous separation of patients based on the expression of four B-lineage genes. Absence of B-lineage gene expression translates to more than two-fold poorer long-term event-free survival. In conclusion, our study presents four B-lineage genes with prognostic significance, suitable for gene expression-based risk stratification of KMT2A-r iALL patients.
© 2023. The Author(s).

Bone marrow plasma cells (BMPC) emerge as a consequence of immune reactions and are considered the source of antibodies that protect against recurrent infectious diseases throughout life. Despite their importance, it remains unclear if these cells reflect different activation environments or the differentiation/maturation stages of their precursors. Here we track the recruitment of plasma cells, generated in primary and secondary immune reactions to SARS-CoV-2 spike protein vaccines, to the human bone marrow. Trajectories based on single cell transcriptomes and antigen-receptor clonotypes of antibody-secreting cells exiting the immune reaction and of those residing in the bone marrow, allow to follow the evolution of the immune response to these vaccines, leading to sequential colonization of these cells to different compartments (clans) of BMPC, and their establishment as long-lived (memory) plasma cells. In primary immune reactions, both CD19 low (clans 1 and 4) and CD19 high (clan 0) BMPC are generated. In secondary immune reactions, mostly CD19 high BMPC of the largest compartment (clan 0) are generated, resulting from the reactivation of memory B lymphocytes. The latter is also observed in vaccinated convalescent individuals and upon recall vaccination against diphtheria/tetanus/pertussis (DTP). Thus, humoral immunological memory, i.e. serum antibodies secreted by long-lived memory BMPC, is generated already in the primary immune response, more so in the secondary, and it represents the evolution of the immune response.