Genetic Reduction of IRF5 Expression after Disease Initiation Reduces Disease in a Mouse Lupus Model by Impacting Systemic and End-Organ Pathogenic Pathways DOI
Alex Pellerin, Ying Tan,

Simon Lu

и другие.

The Journal of Immunology, Год журнала: 2023, Номер 211(9), С. 1308 - 1319

Опубликована: Сен. 18, 2023

Gain-of-function polymorphisms in the transcription factor IFN regulatory 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. Global homozygous or heterozygous deficiency IRF5 from birth confers protection many mouse models. However, less is known about effects targeting after autoimmunity has already developed. This important point to clarify when considering as a potential therapeutic target lupus. In this study, we demonstrate that genetic reduction expression disease initiation reduces severity FcγRIIB-/- Y-linked autoimmune accelerating model. Reduction resulted decrease splenomegaly and lymphadenopathy splenic B cell activation plasmablast numbers. Splenic T differentiation were also impacted demonstrated by increase number naive CD4+ CD8+ cells memory/effector cells. Although serum antinuclear autoantibody levels not altered, led decreased immune complex deposition complement activation, diminished glomerular interstitial disease, infiltrate kidney. Mechanistically, myeloid kidney produced inflammatory cytokines TLR7 TLR9 activation. Overall, during active process sufficient reduce severity. Our data support consideration suggest approaches erythematosus may need impact activity both systemically organs.

Язык: Английский

Lipid Antigens: Revealing the Hidden Players in Adaptive Immune Responses DOI Creative Commons
Tamana Eskandari, Yasamin Eivazzadeh, Fatemeh Khaleghinia

и другие.

Biomolecules, Год журнала: 2025, Номер 15(1), С. 84 - 84

Опубликована: Янв. 8, 2025

Traditionally, research on the adaptive immune system has focused protein antigens, but emerging evidence underscored essential role of lipid antigens in modulation. Lipid are presented by CD1 molecules and activate invariant natural killer T (iNKT) cells group 1 CD1-restricted cells, whereby they impact responses to pathogens tumors. Recent advances mass spectrometry, imaging techniques, lipidomics have revolutionized identification characterization enhanced our understanding their structural diversity functional significance. These advancements paved way for lipid-based vaccines immunotherapies through application nanoparticles synthetic designed boost against cancers infectious diseases. trafficking, molecule interactions, system's response yet be completely understood, particularly context autoimmunity microbial infections. In years come, continued efforts needed uncover its underlying biological mechanisms exploit full potential therapies directed antigens.

Язык: Английский

Процитировано

0
Interferon activation in bone marrow long-lived plasma cells in systemic lupus erythematosus DOI Creative Commons
Diana F. Alzamareh, Nida Meednu,

Neha Nandedkar-Kulkarni

и другие.

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 10, 2025

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 self-proteins or self-nuclear antigens as occurs in autoimmune diseases such systemic lupus erythematosus (SLE). Thus, the elimination of autoreactive improve treatment antibody-driven diseases. However, remain a challenging therapeutic target. Here, we compare matched bone marrow (BM) and peripheral blood (PBL) (PC) compartments SLE healthy donors (HD). We show similar distribution CD138- CD138+ PC, including putative (CD19- CD38+), between HD BM. For both HD, PC at higher frequency BM than PBL. Expression Ki-67 associates with PBL compartment where it is found on all subsets regardless CD19 CD138 expression. Transcriptomic analysis identifies an interferon (IFN) gene signature transitional B cells BM, but surprisingly also derived SLE. phosphorylate STAT1 response to type I IFN stimulation vitro, decreased fold change compared those bind receptor-blocking anifrolumab, lesser degree circulating cells. Anti-nuclear autoantibodies (ANA) supernatant serum patients. Both BM-derived have increased survival their counterparts when treated verdinexor. In summary, these findings evidence activation

Язык: Английский

Процитировано

0
KLF2 expression in IgG plasma cells at their induction site regulates the migration program DOI
Wataru Ise, Takuya Koike,

N. Shimada

и другие.

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(5)

Опубликована: Фев. 20, 2025

Newly generated plasma cells in secondary lymphoid organs migrate to niches the bone marrow, wherein they survive as long-lived (LLPCs). Although LLPCs have been extensively characterized, it is still unclear what key determinant(s) are for cell longevity. One model postulates that heterogeneity established at induction site, thereby instructing their Here, we found that, among newly IgG cells, integrin β7hi marks predisposed home whereas β7lo remain organs. Mechanistically, this egress-prone fraction had a higher expression of KLF2 transcription factor, loss which resulted defective egress by downregulating S1PR1 and CD11b. Disruption results antibody durability, making mice more susceptible influenza reinfection. Thus, migration program site plays critical role determining durability.

Язык: Английский

Процитировано

0
Microbiome-mediated modulation of immune memory to P. yoelii affects the resistance to secondary cerebral malaria challenge DOI Creative Commons
Elizabeth M. Fusco,

Layne Bower,

Rafael B. Polidoro

и другие.

ImmunoHorizons, Год журнала: 2025, Номер 9(5)

Опубликована: Март 26, 2025

Abstract Malaria is caused by protozoan parasites in the genus Plasmodium. Over time individuals slowly develop clinical immunity to malaria, but this process occurs at variable rates, and mechanism of protection not fully understood. We have recently demonstrated that genetically identical C57BL/6N mice, gut microbiota composition dramatically impacts quality humoral immune response Plasmodium yoelii subsequent against a lethal secondary challenge with berghei ANKA mice. Here, we utilize identical, microbiome–dependent model investigate how modulate immunological memory, hypothesizing microbiome formation functionality memory. In support hypothesis, P. hyperparasitemia–resistant mice exhibit increased ANKA–induced experimental cerebral malaria (ECM) compared hyperparasitemia–susceptible Despite differences ECM, yoelii–resistant –susceptible accumulate similar numbers memory B cells (MBCs) T cells. Following ANKA, generated more rapid germinal center reactions; however, had titers yoelii– berghei–specific antibodies. contrast, an number regulatory which may dampen immune-mediated breakdown blood–brain barrier susceptibility berghei–induced ECM. These findings demonstrate ability shape potential enhance resistance severe outcomes.

Язык: Английский

Процитировано

0
Quantifying the waning of humoral immunity DOI Creative Commons
Ananya Saha,

Hasan Ahmed,

Cora Hirst

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Май 14, 2025

Abstract Immunological memory is a defining feature of immunity, yet surprisingly there no consensus on how to quantitatively describe antibody titers wane over time. A major problem that the slow waning requires collection data for decades post-infection or vaccination. Our analysis largest existing dataset shows power-law model describes better than other frequently used models. suggests: (i) Protective levels antibodies many vaccine/virus antigens may be maintained longer previously estimated. (ii) The rate protein toxoid vaccines such as tetanus similar those elicited by live virus infections. (iii) long-term can estimated from much shorter time-frame about 1-3 years following immunization, suggesting using could allow rapid estimation immunity new vaccines.

Язык: Английский

Процитировано

0
Minimally invasive longitudinal intravital imaging of cellular dynamics in intact long bone DOI
Nayan D. Bhattacharyya, Wunna Kyaw, Michelle M. McDonald

и другие.

Nature Protocols, Год журнала: 2023, Номер 18(12), С. 3856 - 3880

Опубликована: Окт. 19, 2023

Язык: Английский

Процитировано

8
Beyond the skin: B cells in pemphigus vulgaris, tolerance and treatment DOI Creative Commons
Anne-Lise Strandmoe, Jeroen Bremer, Gilles F.H. Diercks

и другие.

British Journal of Dermatology, Год журнала: 2024, Номер 191(2), С. 164 - 176

Опубликована: Март 19, 2024

Pemphigus vulgaris (PV) is a rare autoimmune bullous disease characterized by blistering of the skin and mucosa owing to presence autoantibodies against desmosome proteins desmoglein 3 occasionally in conjunction with 1. Fundamental research into pathogenesis PV has revolutionized its treatment outcome rituximab, B-cell-depleting therapy. The critical contribution B cells pemphigus well accepted. However, exact pathomechanism, mechanisms onset, course relapse remain unclear. In this narrative review, we provide an overview fundamental progress that unfolded over past few centuries give rise current emerging therapies. Furthermore, summarize multifaceted roles PV, including their development, maturation antibody activity. Finally, explored how these various aspects B-cell function contribute pave way for innovative therapeutic interventions.

Язык: Английский

Процитировано

3
Fine-tuning spatial-temporal dynamics and surface receptor expression support plasma cell-intrinsic longevity DOI Creative Commons
Zhixin Jing, Phillip M. Galbo, Luis Ovando

и другие.

eLife, Год журнала: 2023, Номер 12

Опубликована: Сен. 28, 2023

Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, factors that control LLPC specification remain poorly resolved. Using intravital two-photon imaging, we find in contrast to most (PCs) bone marrow (BM), LLPCs are uniquely sessile organized into clusters APRIL, an important factor. deep, bulk RNA sequencing, surface protein flow-based phenotyping, express a unique transcriptome phenotype compared PCs, fine-tuning expression key cell molecules, CD93, CD81, CXCR4, CD326, CD44, CD48, for adhesion homing. Conditional deletion Cxcr4 PCs immunization leads rapid mobilization from BM, reduced antigen-specific ultimately accelerated decay antibody titer. In naïve mice, endogenous BCR repertoire exhibits diversity, somatic mutations, increased public clones IgM isotypes, particularly young suggesting non-random. As mice age, BM PC compartment becomes enriched LLPCs, which may outcompete limit entry new niche pool.

Язык: Английский

Процитировано

6
The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells DOI Creative Commons
Koushik Roy, Mainak Chakraborty, Ashok Kumar

и другие.

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Дек. 11, 2023

Memory B cells and antibody-secreting are the two prime effector cell populations that drive infection- vaccine-induced long-term antibody-mediated immunity. The immunity mostly relies on formation of specialized structures within secondary lymphoid organs, called germinal centers (GCs), facilitate interactions between cells, T antigen-presenting cells. Antigen-activated may proliferate differentiate into GC-independent plasmablasts memory or GC undergo proliferation coupled to somatic hypermutation their immunoglobulin genes for antibody affinity maturation. Subsequently, mature GC-dependent plasma Here, we review how NFκB signaling system controls generation plasmablasts/plasma We also identify discuss some important unanswered questions in this connection.

Язык: Английский

Процитировано

6
Fine-tuning spatial-temporal dynamics and surface receptor expression support plasma cell-intrinsic longevity DOI Creative Commons
Zhixin Jing, Phillip M. Galbo, Luis Ovando

и другие.

eLife, Год журнала: 2024, Номер 12

Опубликована: Июнь 18, 2024

Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, factors that control LLPC specification remain poorly resolved. Using intravital two-photon imaging, we find in contrast to most (PCs) bone marrow (BM), LLPCs are uniquely sessile organized into clusters APRIL, an important factor. deep, bulk RNA sequencing, surface protein flow-based phenotyping, express a unique transcriptome phenotype compared PCs, fine-tuning expression key cell molecules, CD93, CD81, CXCR4, CD326, CD44, CD48, for adhesion homing. Conditional deletion Cxcr4 PCs immunization leads rapid mobilization from BM, reduced antigen-specific ultimately accelerated decay antibody titer. In naïve mice, endogenous BCR repertoire exhibits diversity, somatic mutations, increased public clones IgM isotypes, particularly young suggesting non-random. As mice age, BM PC compartment becomes enriched LLPCs, which may outcompete limit entry new niche pool.

Язык: Английский

Процитировано

2