Memory Plasma Cells Research Articles

CAR-engineered T cell therapy as an emerging strategy for treating autoimmune diseases.

CAR-T therapy has demonstrated great success in treating hematological malignancies, which has led to further research into its potential in treating other diseases. Autoimmune diseases have great potential to be treated with this therapy due to the possibility of specific targeting of pathological immune cells and cells that produce autoantibodies, which could lead to permanent healing and restoration of immunological tolerance. Several approaches are currently under investigation, including targeting and depleting B cells via CD19 in the early stages of the disease, simultaneously targeting B cells and memory plasma cells in later stages and refractory states, as well as targeting specific autoantigens through the chimeric autoantibody receptor (CAAR). Additionally, CAR-engineered T regulatory cells can be modified to specifically target the autoimmune niche and modulate the pathological immune response. The encouraging results from preclinical studies have led to the first successful use of CAR-T therapy in humans to treat autoimmunity. This paved the way for further clinical studies, aiming to evaluate the long-term safety and efficacy of these therapies, potentially revolutionizing clinical use.

PSIX-7 Attenuation of Immune Allergic Response Pathways in Canines with Dermatological Problems Fed a Polyphenol-Rich Food

Abstract Pathogenesis of canine dermatological problems is mediated by multiple effector cells including lymphocytes, eosinophils, and mast cells. We have previously reported a significant increase in the gene expression of interleukin-5 receptor alpha (IL-5RA) in dogs with dermatological problemscompared with controls, as well as a modest increase in C-C chemokine receptor 3 (CCR3), IL-4 and IL-5. We now investigated whether 2 tests foods (one rich in polyphenols) would provide beneficial effects in canines with dermatological problems (n = 8) compared with controls (n = 8). Dogs were pre-fed control food for 28 days and then divided into two groups based on their age, gender and phenotype (Healthy, Derm) followed by a cross-over design. At each phase, dogs were fed for 42 days with test food 1 (TF1) and the second group was fed with a greater polyphenol content Test food 2 (TF2) for 42 days followed by a crossover. Blood samples were collected at the end of pre-feed, end of phase 1, and end of phase 2. The study was approved by IACUC and AWC, Hill’s PNC. RNA was extracted from blood collected in PAXgene tubes and gene expression was investigated using the NanoString nCounter platform. To assess the food effect, a mixed model analysis was performed using treatment (food) as a fixed effect and animal as random effect using JMPPro. TF2 fed dogs decreased pruritus scores, increased the response rate (improvement %) to 30.77% compared with dogs fed TF1. There was a significant decrease in the interleukin-5 receptor alpha (IL-5RA) in dogs fed TF2 when compared with baseline (P < 0.05). IL-5RA is a receptor expressed on eosinophils as well as committed eosinophil precursors in the bone marrow. There was also a decrease in FCRL2 in dogs fed TF2 (P < 0.05). This gene is preferentially expressed in memory B-cells and plasma cells and also involved in B-cell receptor signaling. The generation of plasma cells requires naïve B cell activation to differentiate into antibody secreting cells or memory B cells. Given the lower levels of FCRL2 with TF2, it is possible that the production of subsequent IgE is attenuated. Another signaling molecule that was significantly decreased with TF2 was the innate immune response molecule C3AR1, a receptor for Complement C3a that induces chemotaxis, granule release, as well as superoxide production. TF1 and TF2 significantly decreased CCR3, a receptor on eosinophils and basophils. CCR3 antagonists are effective in reducing allergic inflammation. Our results indicate the important role of eosinophilic allergic response in dermatological disorders in dogs. TF2 appears to have a beneficial effect in attenuating allergy-inducing signaling pathways of innate and adaptive immune responses. Targeting these molecules may be important as part of newer therapeutic approaches, including nutritional strategies, to manage dermatological problems in dogs.

SARS-CoV-2 specific plasma cells acquire long-lived phenotypes in human bone marrow

SARS-CoV-2 specific antibody-secreting plasma cells (PC) mediating specific humoral immunity have been identified in the human bone marrow (BM) after COVID-19 or vaccination against SARS-CoV-2. However, it remained unclear whether or not they acquire phenotypes of human memory plasma cells. SARS-CoV-2-specific human bone marrow plasma cells (BMPC) were characterised by tetramer-based, antigen-specific flow cytometry and FluoroSpot assay. SARS-CoV-2 spike-S1-specific PC were detectable in all tested BM samples of previously vaccinated individuals, representing 0.22% of total BMPC. The majority of SARS-CoV-2-specific BMPC expressed IgG and their specificity for the spike S1 protein indicated emergence from a systemic vaccination response. Of note, one-fifth of SARS-CoV-2-specific BMPC showed the phenotype of memory plasma cells, i.e., downregulated CD19 and present or absent CD45 expression. Our data indicate the establishment of phenotypically diverse SARS-CoV-2-specific PC in the human BM after basic mRNA immunization, including the formation of memory phenotypes. These results suggest the induction of durable humoral immunity after basic mRNA vaccination against SARS-CoV-2. The study was supported by funding by the DFG grants TRR130 TP24, ME 3644/8-1, and the Berlin Senate. SR received funding from DFGSFB-1444 C01 Central Service Project.

Impaired expansion and selection of geminal center B cells in lupus drives autoantibody-producing cells

Abstract Lupus is a systemic autoimmune disease characterized by the presence of autoantibodies that form immune complexes in tissues leading to the recruitment of immune cells and subsequent inflammation and organ damage. The origin of autoantibody-secreting B cells is not clear, but the germinal center (GC) is of particular interest as the B cells here undergo somatic hypermutation, which may result in the generation of autoreactive memory or long-lived plasma cells. Within the GC, B cells cycle between two major zones: the dark zone (DZ) where mutation and proliferation occur, and the light zone (LZ) where affinity-based selection occurs. We found in lupus-prone mice that as autoantibodies increased, there was a reduction in proliferation measured by EdU incorporation in conjunction with dysregulation of the GC zones as B cells here became skewed towards a LZ phenotype (CXCR4 loCD86 +). As MYC expression in LZ B cells correlates with the strength of selection, we examined MYC levels by flow cytometry and Amnis and found it and its nuclearization decreased as disease progressed. Single cell BCR sequencing of GC B cells throughout the course of disease revealed a loss in BCR repertoire diversity and mutations. Furthermore, we found that despite the accumulation of LZ B cells, there was an increase in the generation of plasma cells and memory-like CD11c +Tbet +B cells, suggesting aberrant selection and differentiation into these potentially autoantibody-secreting cells. Thus, our findings suggest that as lupus disease progresses, the ability of GC B cells in the LZ to undergo proper selection is impaired, resulting the permissive selection of autoreactive B cells and differentiation into autoantibody-secreting cells. Supported by grants from the NIH/NIAMS (R01 AR073912, R01 AR073912 - 03W1)

Cytokine-mediated STAT-dependent pathways underpinning human B-cell differentiation and function.

B cells are fundamental to host defence against infectious diseases; indeed, the ability of humans to elicit robust antibody responses following exposure to foreign antigens underpins long-lived humoral immunity and serological memory, as well as the success of most currently administered vaccines. However, B cells also have a dark side - they can cause myriad diseases, including autoimmunity, atopy, allergyand malignancy. Thus, it is critical to understand the molecular requirements for generating effective, high-affinity, specific immune responses following natural infection or vaccination, as well as for constraining B-cell function to mitigate B-cell-mediated immune dyscrasias. In this review, we discuss recent developments that have been derived from the identification and detailed analysis of individuals with inborn errors of immunity that disrupt cytokine signalling, resulting in immune dysregulatory conditions. These studies have defined fundamental cytokine/cytokine receptor/signal transducer and activator of transcription (STAT) signalling pathways that are critical for the generation and maintenance of human memory B-cell and plasma cell subsets during host defence, as well as revealed mechanisms of disease pathogenesis causing immune deficiency, autoimmunityand atopy. More importantly, these studies have identified molecules that could be targeted to either enhance humoral immunity in the settings of infection or vaccination, or attenuate humoral immunity that contributes to antibody-mediated autoimmunity or allergy.

Rethinking ‘immunological memory’: Local and systemic immunity provided by bone marrow‐resident memory cells

AbstractIt has been 25 years since we first described long‐lived memory plasma cells of the bone marrow, 13 years since we identified bone marrow resident memory T cells and 2 years since we showed that the bone marrow is also a preferred location of resident memory B cells. The bone marrow is increasingly recognized as a fundamental component of long‐lasting immunological memory, not only providing protective immunity but also fuelling chronic inflammation. We now understand that the bone marrow functions as the ‘backbone’ of immunological memory, hosting the memory plasma cells which provide not only humoral immunity but also memory B and T cells, which constitute ‘reactive memory’. This knowledge now allows us to define true cellular ‘correlates of protection’ for systemic immunity, its quality and duration, as induced by infection and vaccination, something that has never been more important given the recent SARS‐CoV‐2 pandemic. While memory plasma cells of the bone marrow indicate long‐lasting humoral protection, memory T (and B) cells mobilized into the blood in secondary immune reactions indicate the strength of reactive memory. In this review, we have contextualized many of our own findings from the last two decades that have contributed to our understanding of how bone marrow‐resident memory cells provide local and systemic immunity.

Phenotypic and functional changes of T cell subsets after CoronaVac vaccination

BackgroundThe pandemic coronavirus disease 2019 (COVID-19) is a major global public health concern and several protective vaccines, or preventive/therapeutic approaches have been developed. Sinovac-CoronaVac, an inactivated whole virus vaccine, can protect against severe COVID-19 disease and hospitalization, but less is known whether it elicits long-term T cell responses and provides prolonged protection. MethodsThis is a longitudinal surveillance study of SARS-CoV-2 receptor binding domain (RBD)-specific IgG levels, neutralizing antibody levels (NAb), T cell subsets and activation, and memory B cells of 335 participants who received two doses of CoronaVac. SARS-CoV-2 RBD-specific IgG levels were measured by enzyme-linked immunosorbent assay (ELISA), while NAb were measured against two strains of SARS-CoV-2, the Wuhan and Delta variants. Activated T cells and subsets were identified by flow cytometry. Memory B and T cells were evaluated by enzyme-linked immune absorbent spot (ELISpot). FindingsTwo doses of CoronaVac elicited serum anti-RBD antibody response, elevated B cells with NAb capacity and CD4+ T cell-, but not CD8+ T cell-responses. Among the CD4+ T cells, CoronaVac activated mainly Th2 (CD4+ T) cells. Serum antibody levels significantly declined three months after the second dose. InterpretationCoronaVac mainly activated B cells but T cells, especially Th1 cells, were poorly activated. Activated T cells were mainly Th2 biased, demonstrating development of effector B cells but not long-lasting memory plasma cells. Taken together, these results suggest that protection with CoronaVac is short-lived and that a third booster dose of vaccine may improve protection.

A ubiquitous bone marrow reservoir of preexisting SARS-CoV-2-reactive memory CD4+ T lymphocytes in unexposed individuals.

Circulating, blood-borne SARS-CoV-2-reactive memory T cells in persons so far unexposed to SARS-CoV-2 or the vaccines have been described in 20-100% of the adult population. They are credited with determining the efficacy of the immune response in COVID-19. Here, we demonstrate the presence of preexisting memory CD4+ T cells reacting to peptides of the spike, membrane, or nucleocapsid proteins of SARS-CoV-2 in the bone marrow of all 17 persons investigated that had previously not been exposed to SARS-CoV-2 or one of the vaccines targeting it, with only 15 of these persons also having such cells detectable circulating in the blood. The preexisting SARS-CoV-2-reactive memory CD4+ T cells of the bone marrow are abundant and polyfunctional, with the phenotype of central memory T cells. They are tissue-resident, at least in those persons who do not have such cells in the blood, and about 30% of them express CD69. Bone marrow resident SARS-CoV-2-reactive memory CD4+ memory T cells are also abundant in vaccinated persons analyzed 10-168 days after 1°-4° vaccination. Apart from securing the bone marrow, preexisting cross-reactive memory CD4+ T cells may play an important role in shaping the systemic immune response to SARS-CoV-2 and the vaccines, and contribute essentially to the rapid establishment of long-lasting immunity provided by memory plasma cells, already upon primary infection.

The contribution of neuropathology to multiple sclerosis research.

Background and purposeNeuropathology plays a major role in deciphering disease mechanisms in multiple sclerosis (MS). This review article describes recent advances in neuropathological research related to inflammatory demyelinating diseases.MethodsA retrospective review of neuropathological studies published during the last two decades was conducted.ResultsThe importance of neuropathology is generally seen in its contribution to the diagnosis of diseases of the nervous system and, in particular, in neuro‐oncology. However, when it also includes analysis of the global three‐dimensional extension of brain damage and the temporal sequence of lesion evolution and relates this to molecular changes in the lesions, it offers the potential to decipher disease pathogenesis and to contribute to the development of effective and causative treatments. In MS research, neuropathology has been essential in discriminating the disease from other inflammatory autoimmune or demyelinating diseases, such as neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD). It defined the hallmark of chronic progressive disease in MS patients as slowly expanding tissue damage, which occurs not only within and around lesions but also in the normal appearing white and gray matter. It showed that these changes occur in the course of a tissue‐resident immune response within the central nervous system, involving tissue‐resident effector memory cells and plasma cells. Molecular studies in neuropathologically defined micro‐dissected MS lesions identified a cascade of oxidative injury, mitochondrial damage and subsequent virtual hypoxia as a major pathway of tissue injury in MS.ConclusionsThe results of these studies were highly relevant for the identification of potential therapeutic targets in MS patients and the design of pivotal clinical trials.

Abstract 3586: Immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CART cell therapy

Abstract Introduction: Patients with hematologic malignancies are at an increased risk of morbid/mortality from COVID-19. Our prospective clinical study evaluated immune responses to COVID-19 mRNA vaccines in patients with B-cell lymphoma who had received CD19-directed chimeric antigen receptor (CAR) T cell therapy. Methods: We measured SARS-CoV-2 neutralizing activity of plasma from 18 patients and 4 healthy controls (HC) and antibody titers against viral spike proteins (S1, S2, RBD) including their “delta” variants using an enzyme-linked immunoassay (ELISA). We measured B cell subpopulations in the patients’ blood using flow cytometry. Results: We found that the peripheral blood plasma from 3/4 HCs showed substantial SARS-CoV-2 neutralizing activity already at 4 weeks after the first dose of COVID-19 mRNA vaccine while none of the CD19 CART patients evidenced any antibody-mediated neutralizing activity at the same point in time. At 4 weeks after receiving the second dose of the vaccine, all 4 HCs showed complete neutralizing activity. In marked contrast, only 1 of 14 CART patients evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity. Assessing whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CART patients, we found that IgG antibody levels against common microbial and viral antigens like influenza, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and tetanus toxoid, were comparable to those observed in HCs. However, while at 4 weeks post second dose of the vaccine the HCs showed high levels of vaccine-induced IgG antibody titers against all the viral spike proteins (S1, S2, RBD), including the “delta” variants of the S1 and RBD proteins, the vast majority of our CART patients did not evidence any SARS-CoV-2-specific antibodies. Importantly, a third “booster” vaccination did not lead to an improvement in the antiviral immunity in the 4 CART patients analyzed. When we assessed B cell subpopulations in the blood of patients and HCs, we found that prior treatments had completely eradicated all CD19+/CD20+ B cells in the patients while numbers of long-lived memory plasma cells were comparable to those of HCs. Conclusions: In this study, 17 of 18 patients with lymphoma who received CD19 CART therapy had very poor immunoreactivity to 1-3 doses of mRNA-based COVID-19 vaccines. Importantly, antibody responses to common recall antigens were preserved, suggesting impaired immune response primarily against novel antigens like SARS-COV-2. This lack of immunoreactivity against novel antigens was probably based on the eradication of earlier-stage B cell subpopulations after treatment with anti-CD19 and anti-CD20 immunotherapies. Citation Format: Thierry Iraguha, Saurabh Dahiya, Stephanie Avila, Aaron Rapoport, Tim Luetkens, Djordje Atanackovic. Immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CART cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3586.

The epigenetic regulation of the germinal center response

In response to T-cell-dependent antigens, antigen-experienced B cells migrate to the center of the B-cell follicle to seed the germinal center (GC) response after cognate interactions with CD4+ T cells. These GC B cells eventually mature into memory and long-lived antibody-secreting plasma cells, thus generating long-lived humoral immunity. Within GC, B cells undergo somatic hypermutation of their B cell receptors (BCR) and positive selection for the emergence of high-affinity antigen-specific B-cell clones. However, this process may be dangerous, as the accumulation of aberrant mutations could result in malignant transformation of GC B cells or give rise to autoreactive B cell clones that can cause autoimmunity. Because of this, better understanding of GC development provides diagnostic and therapeutic clues to the underlying pathologic process. A productive GC response is orchestrated by multiple mechanisms. An emerging important regulator of GC reaction is epigenetic modulation, which has key transcriptional regulatory properties. In this review, we summarize the current knowledge on the biology of epigenetic mechanisms in the regulation of GC reaction and outline its importance in identification of immunotherapy decision making.

Data-Driven Mathematical Model of Apoptosis Regulation in Memory Plasma Cells.

Memory plasma cells constitutively produce copious amounts of antibodies, imposing a critical risk factor for autoimmune disease. We previously found that plasma cell survival requires secreted factors such as APRIL and direct contact to stromal cells, which act in concert to activate NF-κB- and PI3K-dependent signaling pathways to prevent cell death. However, the regulatory properties of the underlying biochemical network are confounded by the complexity of potential interaction and cross-regulation pathways. Here, based on flow-cytometric quantification of key signaling proteins in the presence or absence of the survival signals APRIL and contact to the stromal cell line ST2, we generated a quantitative model of plasma cell survival. Our model emphasizes the non-redundant nature of the two plasma cell survival signals APRIL and stromal cell contact, and highlights a requirement for differential regulation of individual caspases. The modeling approach allowed us to unify distinct data sets and derive a consistent picture of the intertwined signaling and apoptosis pathways regulating plasma cell survival.

B lymphocytes and plasma cells as drivers of rheumatic diseases

Verschiedene Arbeitsgruppen am Deutschen Rheuma-Forschungszentrum Berlin haben in enger Zusammenarbeit mit der Medizinischen Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie an der Charité wichtige Beiträge zur Bedeutung der B‑Zellen und Plasmazellen bei rheumatischen Erkrankungen geleistet, die nicht nur für die Rheumatologie, sondern für alle klinischen Fachgebiete, in denen antikörpervermittelte Erkrankungen eine Rolle spielen, relevant sind. Insbesondere wird auf die gestörte B‑Zell-Homöostase, die Bedeutung des Immunglobulin M(IgM)-Fc-Rezeptors für die Regulation der Autoimmunität, die Rolle der langlebigen Gedächtnis-Plasmazelle bei der Aufrechterhaltung der Autoimmunität sowie die Sicherung ihres Überlebens in speziellen, von Stromazellen organisierten Nischen im Knochenmark und in entzündeten Geweben eingegangen. Die Forschungsergebnisse haben zu einem besseren Verständnis der immunologischen und molekularen Mechanismen bei rheumatischen Erkrankungen und ihrer Therapie beigetragen. Die Identifizierung der langlebigen Gedächtnis-Plasmazelle hat zu vielversprechenden therapeutischen Ansätzen mit kurativem Potenzial bei Autoimmunerkrankungen geführt.

Altered Germinal-Center Metabolism in B Cells in Autoimmunity.

B lymphocytes play an important role in the pathophysiology of many autoimmune disorders by producing autoantibodies, secreting cytokines, and presenting antigens. B cells undergo extreme physiological changes as they develop and differentiate. Aberrant function in tolerogenic checkpoints and the metabolic state of B cells might be the contributing factors to the dysfunctionality of autoimmune B cells. Understanding B-cell metabolism in autoimmunity is important as it can give rise to new treatments. Recent investigations have revealed that alterations in metabolism occur in the activation of B cells. Several reports have suggested that germinal center (GC) B cells of individuals with systemic lupus erythematosus (SLE) have altered metabolic function. GCs are unique microenvironments in which the delicate and complex process of B-cell affinity maturation occurs through somatic hypermutation (SHM) and class switching recombination (CSR) and where Bcl6 tightly regulates B-cell differentiation into memory B-cells or plasma cells. GC B cells rely heavily on glucose, fatty acids, and oxidative phosphorylation (OXPHOS) for their energy requirements. However, the complicated association between GC B cells and their metabolism is still not clearly understood. Here, we review several studies of B-cell metabolism, highlighting the significant transformations that occur in GC progression, and suggest possible approaches that may be investigated to more precisely target aberrant B-cell metabolism in SLE.

Follicular dendritic cells restrict interleukin-4 availability in germinal centers and foster memory B cell generation

B cells within germinal centers (GCs) enter cycles of antibody affinity maturation or exit the GC as memory cells or plasma cells. Here, we examined the contribution of interleukin (IL)-4 on B cell fate decisions in the GC. Single-cell RNA-sequencing identified a subset of light zone GC B cells expressing high IL-4 receptor-a (IL4Ra) and CD23 and lacking a Myc-associated signature. These cells could differentiate into pre-memory cells. B cell-specific deletion of IL4Ra or STAT6 favored the pre-memory cell trajectory, and provision of exogenous IL-4 in a wild-type context reduced pre-memory cell frequencies. IL-4 acted during antigen-specific interactions but also influenced bystander cells. Deletion of IL4Ra from follicular dendritic cells (FDCs) increased the availability of IL-4 in the GC, impaired the selection of affinity-matured B cells, and reduced memory cell generation. We propose that GC FDCs establish a niche that limits bystander IL-4 activity, focusing IL-4 action on B cells undergoing selection and enhancing memory cell differentiation.

Keeping up with the stress of antibody production: BAFF and APRIL maintain memory plasma cells.

Memory plasma cells, also called long-lived plasma cells, provide 'humoral immunity' by continued secretion of protective antibodies against pathogens, which the immune system has once encountered. They are maintained mainly in the bone marrow, docking on to stromal cells individually. In those niches they can apparently persist for decades (Chang et al., 2018 [1]). Integrin-mediated contact to the stromal cell provides an essential survival signal to the plasma cell, activating the PI3K signalling pathway, downregulating FoxO1/3a and repressing the activation of caspases 3 and 7. In a redundant form, the cytokines BAFF and APRIL, ligands of the plasma cell receptors TACI and BCMA, provide a second essential survival signal, preventing activation of caspase 12, as triggered by endoplasmic reticulum stress.

Coordinated Changes in Glycosylation Regulate the Germinal Centre Through CD22

Germinal centres (GC) are sites of B-cell expansion and selection, which are essential for antibody affinity maturation. Compared to naive B-cells, GC B-cells have notable changes in their cell surface glycans. While these changes are routinely used to identify the GC, functional roles for these changes have yet to be ascribed. Detection of GCs by the antibody GL7 reflects a reduction in the glycan ligands for CD22, which is an inhibitory co-receptor of the B-cell receptor (BCR). To test a functional role for downregulated CD22 ligands in the GC, we generated a mouse model that maintains CD22 ligands on GC B-cells. With this model, we demonstrate that glycan remodeling plays a critical role in the maintenance of B-cells in the GC. Sustained expression of CD22 ligands induces higher levels of apoptosis in GC B-cells, resulting in reduced memory B-cell and plasma cell output as well as delayed affinity maturation of antibodies. The defect we observe in this model is dependent on CD22, highlighting that coordinated downregulation of CD22 ligands on B cells plays a critical function in the GC. Collectively, our study uncovers a crucial role for glycan remodeling and CD22 in B-cell fitness in the GC.

Long-term antibody response and protective effect induced by attenuated scorpion toxins: Involvement of memory plasma cells

In Algeria, Androctonus australis hector scorpion envenomation remains a major problem of public health because of non-efficient therapy. The development of safe vaccine against scorpion venom could be one key strategy for the envenomation prevention. The irradiation of venom by γ-rays develops suitable immunogens which produced effective antivenom and safe vaccine. In this study, we investigated the ability of the irradiated toxic fraction (γ-FtoxG50) to induce long-term memory humoral response in immunized animals (mice and rabbits), by involving the long-lived plasma cells to prevent efficiently the lethality of scorpion envenomation. For this purpose, an appropriate immunization schedule was established in mice and rabbits using three (3) similar doses of γ-FtoxG50 associated with Alum adjuvant.Obtained results indicate that the long-term immunogenicity of γ-FtoxG50 is able to induce the long-term memory humoral response with a high level of specific antibodies. The long-term persistence of antibody levels could depend on bone marrow memory plasma cells. These cells produce continuously antibodies without antigen stimulus. Furthermore, an enhanced memory response was obtained post-repeated envenomation with toxic native venom that leads to improved protection of animals. Together, pre-existing protective antibodies and the activation of memory B-cells could induce a rapid neutralization of scorpion toxins and long-term protection against scorpion envenomation.

The Bone Marrow as Sanctuary for Plasma Cells and Memory T-Cells: Implications for Adaptive Immunity and Vaccinology

The bone marrow (BM) is key to protective immunological memory because it harbors a major fraction of the body’s plasma cells, memory CD4+ and memory CD8+ T-cells. Despite its paramount significance for the human immune system, many aspects of how the BM enables decade-long immunity against pathogens are still poorly understood. In this review, we discuss the relationship between BM survival niches and long-lasting humoral immunity, how intrinsic and extrinsic factors define memory cell longevity and show that the BM is also capable of adopting many responsibilities of a secondary lymphoid organ. Additionally, with more and more data on the differentiation and maintenance of memory T-cells and plasma cells upon vaccination in humans being reported, we discuss what factors determine the establishment of long-lasting immunological memory in the BM and what we can learn for vaccination technologies and antigen design. Finally, using these insights, we touch on how this holistic understanding of the BM is necessary for the development of modern and efficient vaccines against the pandemic SARS-CoV-2.

Maintenance of quiescent immune memory in the bone marrow

The adaptive immune system has the important ability to generate and maintain a memory for antigens once encountered. Recent progress in understanding the organization of immunological memory has challenged the established paradigm of maintenance of memory by restless, circulating, and "homeostatically" proliferating lymphocytes. Among other tissues, the bone marrow has emerged as a preferred resting place for memory lymphocytes providing both local and systemic long-term protection. Why the bone marrow? There, mesenchymal stromal cells provide a privileged environment for quiescent memory B and T lymphocytes, the protagonists of secondary immune reactions, and for memory plasma cells providing persistent humoral immunity. In this review, we discuss the dedicated role of the bone marrow for the maintenance of memory lymphocytes and its implications for immunological memory.