While durable antibody responses from long-lived plasma cell (LLPC) populations are important for protection against pathogens, LLPC may be harmful if they produce antibodies against self-proteins or self-nuclear antigens as occurs in autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, the elimination of autoreactive LLPC may improve the treatment of antibody-driven autoimmune diseases. However, LLPC remain a challenging therapeutic target. Here, we compare the matched bone marrow (BM) and peripheral blood (PBL) plasma cell (PC) compartments of SLE and healthy donors (HD). We show a similar distribution of CD138- and CD138+ PC, including putative LLPC (CD19- CD138+ CD38+), between SLE and HD BM. For both SLE and HD, CD138+ PC are at a higher frequency in BM than PBL. Expression of Ki-67 associates with the PBL compartment where it is found on all PC subsets regardless of CD19 or CD138 expression. Transcriptomic analysis identifies an interferon (IFN) gene signature in transitional B cells in the SLE BM, but surprisingly also in the BM PC derived from SLE. BM PC and B cells phosphorylate STAT1 in response to type I IFN stimulation in vitro, but with decreased fold change compared to those from the PBL. While BM PC bind type I IFN receptor-blocking antibody anifrolumab, it is to a lesser degree than circulating B cells. Anti-nuclear autoantibodies (ANA) are found in the BM supernatant and PBL serum of SLE patients. Both SLE and HD BM-derived PC have increased survival compared to their PBL counterparts when treated with verdinexor. In summary, these findings show evidence of IFN activation in BM PC from SLE.
Copyright © 2025 Alzamareh, Meednu, Nandedkar-Kulkarni, Krenitsky, Barnard, Yasaka, Durrett, Thakar, Rangel-Moreno, Anolik and Barnas.

Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine. Our findings revealed that patients with SLE exhibited reduced avidity of anti-receptor-binding domain antibodies, leading to decreased neutralization potency and breadth. We also observed a sustained anti-spike response in IgD-CD27- 'double-negative (DN)' DN2/DN3 B cell populations persisting during memory responses and with greater representation in the SLE cohort. Additionally, patients with SLE displayed compromised anti-spike T cell immunity. Notably, low vaccine efficacy strongly correlated with higher values of a newly developed extrafollicular B and T cell score, supporting the importance of distinct B cell endotypes. Finally, we found that anti-BAFF blockade through belimumab treatment was associated with poor vaccine immunogenicity due to inhibition of naive B cell priming and an unexpected impact on circulating T follicular helper cells.
© 2024. The Author(s).

Antibody-dependent complement activation plays a key role in the natural human immune response to infections. Currently, the understanding of which antibody-antigen combinations drive a potent complement response on bacteria is limited. Here, we develop an antigen-agnostic approach to stain and single-cell sort human IgG memory B cells recognizing intact bacterial cells, keeping surface antigens in their natural context. With this method we successfully identified 29 antibodies against K. pneumoniae, a dominant cause of hospital-acquired infections with increasing antibiotic resistance. Combining genetic tools and functional analyses, we reveal that the capacity of antibodies to activate complement on K. pneumoniae critically depends on their antigenic target. Furthermore, we find that antibody combinations can synergistically activate complement on K. pneumoniae by strengthening each other's binding in an Fc-independent manner. Understanding the molecular basis of effective complement activation by antibody combinations to mimic a polyclonal response could accelerate the development of antibody-based therapies against problematic infections.
© 2024. The Author(s).

Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68low monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68hi monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-β and IFNs is done respectively by PC/PE and bile acids in CD68low and CD68hi monocytes. The inhibition of viral sensing by PC/PE-induced TGF-β is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.
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).