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Naive B cell

A naive B cell is a mature B lymphocyte that has not yet encountered its specific antigen, representing the initial stage of peripheral B cell development after maturation in the bone marrow.^[1] These cells express surface immunoglobulins IgM and IgD as part of their B cell receptor (BCR) complex, along with co-receptors such as CD19 and CD21, enabling them to recognize and bind antigens upon first exposure.^[2] Positioned in secondary lymphoid organs like the spleen, lymph nodes, and mucosa-associated lymphoid tissue, naive B cells recirculate through blood and lymphatics, awaiting activation to initiate humoral immunity by differentiating into antibody-secreting plasma cells or long-lived memory B cells.^[3] Naive B cells originate from hematopoietic stem cells in the bone marrow through a series of developmental stages, including pro-B, pre-B, and immature B cell phases, where they undergo V(D)J recombination to generate diverse BCRs and are subjected to positive and negative selection to ensure self-tolerance.^[1] Upon exiting the bone marrow as immature IgM+ cells, they migrate to the spleen for further maturation into transitional B cells, eventually becoming fully mature naive B cells that co-express IgM and IgD while lacking memory markers like CD27.^[2] This maturation process is tightly regulated to prevent autoimmunity, with only a small fraction of bone marrow B cell precursors successfully entering the peripheral pool.^[1] Morphologically, naive B cells are small- to medium-sized lymphocytes featuring a round nucleus with dense, clumped chromatin, scant basophilic cytoplasm, and no prominent nucleolus, distinguishing them from activated or memory B cells.^[1] B cells constitute approximately 5% to 15% of circulating lymphocytes, with naive B cells forming the majority of this population (typically 50-70% of B cells),^[3]^[4]^[5] and are primarily found in the primary follicles of lymphoid tissues, where they form dense clusters awaiting antigen presentation. Functionally, naive B cells serve as antigen-specific sensors in the adaptive immune system; their BCRs provide the first signal for activation, often requiring a second signal from helper T cells via CD40-CD40L interaction for full proliferation and differentiation.^[2] Upon activation, naive B cells can enter germinal centers in secondary follicles, where they undergo somatic hypermutation and class-switch recombination to produce high-affinity antibodies of various isotypes, or they may rapidly differentiate into short-lived plasma cells for immediate responses, particularly marginal zone naive B cells responding to blood-borne pathogens.^[1] This transition from naive to effector or memory states is critical for generating immunological memory, enabling faster and more robust responses to subsequent antigen encounters.^[3] Dysregulation in naive B cell function or numbers is implicated in immunodeficiencies and autoimmune diseases, underscoring their foundational role in B cell-mediated immunity.^[2]

Overview

Definition

Naive B cells are mature B lymphocytes that have successfully completed their maturation process in the bone marrow but have not yet encountered their specific cognate antigen, positioning them as the initial responders in humoral immunity.^[6]^[7] These cells represent a quiescent stage in B cell development, where they remain antigen-inexperienced and capable of initiating primary immune responses upon activation.^[1]^[8] They originate through B lymphopoiesis from hematopoietic stem cells (HSCs) within the bone marrow, the primary site of B cell genesis in mammals.^[6]^[1] During this process, progenitor cells differentiate into pro-B cells, pre-B cells, and immature B cells that express a functional B cell receptor (BCR) (IgM). These immature B cells exit the bone marrow and undergo further maturation in the periphery to become mature naive B cells co-expressing IgM and IgD, both sharing the same antigen-specific variable region derived from germline V(D)J recombination.^[6]^[1] In their naive state, these B cells circulate through the bloodstream and lymphatic system in a resting, non-proliferative condition, primarily localizing to primary follicles in secondary lymphoid organs such as lymph nodes and spleen.^[1]^[7] This quiescent circulation allows them to survey for antigens efficiently, remaining poised for activation by antigen binding to the BCR, which triggers downstream signaling for differentiation into antibody-secreting cells or memory B cells.^[8]^[6]

Role in Adaptive Immunity

Naive B cells represent the foundational precursors in the humoral arm of adaptive immunity, circulating as mature, antigen-inexperienced lymphocytes that express surface immunoglobulin receptors with specificity established through V(D)J recombination during their development in the bone marrow.^[9] Upon encountering cognate antigens in secondary lymphoid organs, these cells become activated, marking the initiation of antigen-specific antibody production that underpins targeted pathogen neutralization and clearance.^[7] This activation process drives naive B cells to differentiate into short-lived plasmablasts and plasma cells, which rapidly secrete antibodies to mount the primary immune response, providing immediate humoral defense against infection.^[7] Concurrently, a subset of activated naive B cells enters germinal centers, where they proliferate and further differentiate into long-lived memory B cells, ensuring sustained protection against reinfection.^[7] The immunological diversity generated by V(D)J recombination in naive B cells enables recognition of a vast array of antigens, forming the basis for adaptive specificity and versatility.^[9] Through germinal center reactions triggered by naive B cell activation, processes such as somatic hypermutation facilitate affinity maturation, refining antibody binding strength, while class-switch recombination alters the antibody isotype to optimize effector functions, thereby contributing to durable, high-quality long-term immunity.^[10]

Development and Maturation

Origin in Bone Marrow

Naive B cells originate in the bone marrow, where hematopoietic stem cells (HSCs) residing in specialized niches differentiate into lymphoid progenitors. HSCs, which possess self-renewal capacity and multilineage potential, first give rise to multipotent progenitors that progress through stages including common lymphoid progenitors (CLPs). CLPs represent the earliest committed lymphoid cells capable of generating B cells, T cells, natural killer cells, and dendritic cells, marking the point of divergence from myeloid lineages.^[11] Commitment to the B cell lineage occurs within the bone marrow microenvironment, driven by key transcription factors that enforce lineage-specific gene expression. Early B cell specification is initiated by E2A and early B cell factor 1 (EBF1), which activate B cell-associated genes and promote accessibility of immunoglobulin loci for recombination. EBF1, in particular, interacts with chromatin remodeling complexes to enable initial B lineage priming in CLPs. Subsequently, paired box 5 (Pax5), a master regulator induced by EBF1 and interleukin-7 (IL-7) signaling, solidifies B cell commitment by activating essential genes such as CD19 and completing the repression of non-B lineage programs, including those for T cell or myeloid fates. Pax5-deficient progenitors retain multipotency, underscoring its pivotal role in irreversible B lineage restriction.^[12]^[11] The pro-B cell stage follows lineage commitment and is defined by the initiation of immunoglobulin heavy chain (IgH) gene rearrangement, a process essential for B cell receptor assembly. In early pro-B cells, D-to-JH joining occurs first on both IgH alleles, facilitated by recombination-activating gene (RAG) proteins and influenced by germline transcription. This progresses to V-to-DJH joining in late pro-B cells, with successful rearrangement yielding a functional μ heavy chain. These stages occur in subcompartments supported by stromal interactions, and failure in rearrangement triggers apoptosis to maintain repertoire diversity.^[11]^[13] Transition to the pre-B cell stage requires productive IgH rearrangement, leading to the expression of a pre-B cell receptor (pre-BCR) complex. The μ heavy chain pairs with surrogate light chains—VpreB and λ5 (also known as Igll1)—along with Igα and Igβ signaling molecules, forming the pre-BCR on the cell surface. Pre-BCR signaling promotes proliferative expansion and allelic exclusion, ensuring monoallelic IgH expression, while initiating light chain gene rearrangement (V-to-J joining, first κ then λ loci). Successful light chain pairing with μ yields a complete immunoglobulin M (IgM) receptor, allowing immature B cells to exit the bone marrow as precursors to naive B cells.^[11]^[13] The bone marrow niche provides critical support for these early stages through interactions with stromal cells, cytokines, and chemokines. Stromal cells, including mesenchymal progenitors, secrete IL-7, which binds the IL-7 receptor on pro- and pre-B cells to activate JAK-STAT5, PI3K-Akt, and other pathways that enhance survival, proliferation, and transcription factor expression (e.g., EBF1 and Pax5). Chemokines such as CXCL12, produced by stromal cells, interact with CXCR4 on progenitors to guide their retention and migration within endosteal and perivascular niches, optimizing access to growth factors. This orchestrated microenvironment ensures efficient progression to the naive B cell state prior to export to peripheral lymphoid organs.^[11]^[13]

Maturation Stages

The maturation of B cells progresses through distinct stages following V(D)J recombination in the bone marrow, culminating in the generation of naive B cells capable of participating in adaptive immune responses. In the immature B cell stage, newly generated cells express surface IgM as the B cell receptor (BCR), marking the first checkpoint for central tolerance. Immature B cells that bind self-antigens with high affinity undergo negative selection mechanisms, primarily receptor editing—where secondary light chain rearrangements alter BCR specificity to reduce autoreactivity—or clonal deletion via apoptosis to eliminate strongly self-reactive clones.0029-1) These processes ensure that only B cells with low or no self-reactivity advance, preventing autoimmunity while preserving a diverse repertoire.^[14] Upon exiting the bone marrow, immature B cells enter the spleen as transitional B cells, divided into T1 and T2 stages, where peripheral tolerance mechanisms further refine the pool. T1 transitional B cells are short-lived and susceptible to apoptosis if they encounter self-antigens, serving as an initial filter for autoreactive clones through BCR-mediated signaling that promotes cell death or anergy.^[15] Progression to the T2 stage involves survival signals and additional negative selection against strong self-antigen binding, with non-autoreactive cells selected for maturation; this checkpoint is critical for establishing self-tolerance in the periphery, as defects here can lead to autoimmune disease.^[16] The hierarchical nature of these selections prioritizes deletion of high-affinity autoreactive cells in T1, followed by finer tuning in T2.^[17] Fully mature naive B cells emerge from the T2 stage with co-expression of IgM and IgD on their surface, signifying a stable BCR configuration ready for antigen encounter without further rearrangement. This co-expression arises from alternative splicing of the heavy chain transcript, allowing dual isotype display while maintaining allelic exclusion.^[18] Concurrently, downregulation of RAG1 and RAG2 expression, initiated in late immature stages and completed by the naive phase, halts V(D)J recombination to lock in the BCR specificity and prevent secondary edits that could disrupt tolerance.00611-9) This final maturation step yields long-lived, recirculating naive B cells that populate secondary lymphoid organs.^[15]

Phenotypic Characteristics

Surface Markers

Naive B cells are characterized by a distinct set of surface markers that distinguish them from other B cell subsets, such as memory or activated B cells, and facilitate their identification in experimental settings like flow cytometry. These markers include pan-B cell antigens, B cell receptor (BCR) isotypes, complement receptors, major histocompatibility complex (MHC) molecules, co-stimulatory receptors, and chemokine receptors, reflecting their mature but antigen-inexperienced state.^[19] Key pan-B cell surface proteins are highly expressed on naive B cells, including CD19, a signaling molecule that amplifies BCR responses, and CD20, which regulates calcium influx and cell cycle progression. Additionally, CD21 (also known as CR2), the complement receptor 2, is expressed at high levels, enabling naive B cells to bind complement-opsonized antigens and lower the threshold for activation. In contrast, naive B cells lack expression of CD27, a tumor necrosis factor receptor family member associated with memory B cells and plasma cell differentiation.^[20]^[21]^[21] The BCR on naive B cells predominantly consists of IgM and IgD isotypes co-expressed on the surface, serving as the primary antigen recognition structures, while other isotypes like IgG or IgA are present at low or negligible levels. MHC class II molecules, specifically HLA-DR in humans, are constitutively expressed to support antigen presentation to T cells, and CD40, a member of the TNF receptor superfamily, is present to mediate interactions with CD40 ligand on T helper cells, promoting survival and proliferation signals.^[20]^[20] For trafficking to secondary lymphoid organs, naive B cells express chemokine receptors such as CXCR5, which binds CXCL13 to direct migration into B cell follicles. They also exhibit an absence of activation markers, including high levels of CD27 and CD38, underscoring their quiescent phenotype prior to antigen encounter.^[22]^[23] In flow cytometry, naive B cells are typically identified by the profile CD19+ IgM+ IgD+ CD27-, often combined with CD21+ and low CD38, allowing precise gating within peripheral blood mononuclear cells or lymphoid tissues after initial lymphocyte selection and exclusion of other lineages. This phenotypic signature is widely used to quantify naive B cell frequencies, which range from 50-70% of circulating B cells in healthy adults.^[24]^[19]

Transcriptional Profile

Naive B cells display a transcriptional profile that underscores their quiescent state, with elevated expression of the transcription factor Bach2, which represses genes associated with plasma cell differentiation, such as Prdm1 (encoding Blimp-1), thereby preventing premature activation and maintaining B cell identity.^[25] This high Bach2 level contrasts with its downregulation in activated or memory B cells, where reduced repression allows for differentiation potential.^[25] Additionally, naive B cells express proliferation-inhibitory genes like p21/WAF-1 and tumor suppressors such as BIN-1, reinforcing their non-proliferative, resting phenotype while keeping immediate early genes (e.g., c-jun) poised for rapid response upon antigen encounter.^[26] Metabolically, the transcriptome of naive B cells is enriched for genes supporting oxidative phosphorylation (OXPHOS), such as those encoding components of the electron transport chain (e.g., Sdhb, Atp5g2), which sustain low-energy demands in their quiescent state, in contrast to the glycolytic shift observed in proliferating activated B cells.^[27] This reliance on OXPHOS over glycolysis aligns with minimal oxygen consumption rates in naive B cells, ensuring metabolic homeostasis without the high ATP turnover required for proliferation or effector functions.^[27] Epigenetically, naive B cells feature open chromatin configurations at immunoglobulin heavy chain (Igh) loci, marked by active histone modifications including H3K4me3, H3K36me3, and various acetylations (e.g., H2BK5ac, H3K9ac), which poise BCR-related regions for swift transcriptional activation and class-switch recombination upon stimulation.^[28] These permissive marks coexist with genome-wide hypermethylation and repressive modifications (e.g., H3K27me3) at non-B cell genes, safeguarding lineage fidelity.^[28] Single-cell RNA sequencing (scRNA-seq) studies consistently identify naive B cells as distinct clusters in UMAP projections, characterized by high Pax5 and Bach2 expression, separating them from activated germinal center-like B cells (enriched in IRF8 and BCL6) or antibody-secreting cells (high IRF4, XBP1, Prdm1).^[29] Pax5 serves as a master regulator, activating over 170 B cell-specific genes (e.g., Cd19, Blnk) to sustain mature B cell identity throughout the naive stage.^[30] Complementing this, a balanced low-to-moderate expression of IRF4 and IRF8 in naive B cells promotes readiness by fine-tuning receptor editing, tolerance, and positioning in lymphoid niches without driving differentiation.^[31]

Localization and Trafficking

Circulation Patterns

Naive B cells are released from the bone marrow into the bloodstream as mature, antigen-inexperienced lymphocytes ready to survey peripheral tissues for foreign antigens.^[32] Once in circulation, these cells exhibit a brief residence time in peripheral blood, reflecting their rapid transit through the vascular compartment before homing to lymphoid structures.^[33] This brief residence in blood ensures efficient recirculation without prolonged exposure to systemic environments, maintaining the pool's homeostasis through continuous influx from the bone marrow. These cells actively recirculate between the blood, spleen, and lymph nodes, primarily entering lymph nodes via specialized high endothelial venules (HEVs) that facilitate lymphocyte extravasation from the bloodstream.^[34] In the spleen, naive B cells localize to both the marginal zone, where they can interact with blood-borne antigens, and the follicular regions, positioning them for potential antigen encounters.^[35] Within lymph nodes, they scan the subcapsular sinus area, often in proximity to macrophages that capture lymph-derived antigens, allowing for initial surveillance without activation.^[36] This dynamic movement supports constant immune monitoring across secondary lymphoid organs. The recirculation and adhesion processes are tightly regulated by adhesion molecules, including the integrin LFA-1 (lymphocyte function-associated antigen 1), which mediates firm arrest on endothelium following chemokine signaling, and selectins that enable initial rolling along vessel walls.^[37] In humans, this results in a daily turnover where approximately 10^8 new naive B cells enter lymphoid organs from the bone marrow, balancing production rates with peripheral maintenance.^[38] Chemokine gradients briefly guide this homing to ensure targeted distribution.^[39]

Homing to Secondary Lymphoid Organs

Naive B cells, upon release from the bone marrow, rely on specific chemokine receptors and adhesion molecules to home to secondary lymphoid organs such as lymph nodes, spleen, and Peyer's patches, where they position themselves for antigen surveillance. This process involves a multistep adhesion cascade initiated at high endothelial venules (HEVs), where L-selectin (CD62L) on naive B cells mediates initial tethering and rolling by binding to sulfated glycoprotein ligands like peripheral node addressin (PNAd) on HEV endothelium.^[40] This interaction facilitates subsequent firm adhesion and transmigration, enabling entry into the lymphoid tissue parenchyma.^[41] Within lymph nodes and Peyer's patches, naive B cells express CXCR5, which binds the chemokine CXCL13 produced by follicular stromal cells, guiding their migration into B cell follicles for compartmentalized positioning.^[42] This CXCR5-CXCL13 axis is essential for follicle entry, as demonstrated by studies showing that CXCL13 deficiency or CXCR5 blockade impairs B cell accumulation in these structures.^[43] Concurrently, CCR7 on naive B cells responds to CCL19 and CCL21 gradients in the T cell zone, directing them to the T-B cell border for potential interactions with T cells, although expression levels of CCR7 are lower on B cells compared to T cells.^[44] In the spleen, similar chemokine cues, including CXCR5-mediated signals, support follicular localization, while egress from these organs is regulated by the S1P1 receptor sensing sphingosine-1-phosphate (S1P) gradients, which promote exit into the bloodstream and recirculation.^[45] Disruptions in these homing pathways highlight their criticality; for instance, CXCR5 knockout mice exhibit defective B cell migration into follicles, resulting in disorganized splenic white pulp and impaired lymphoid architecture in Peyer's patches and lymph nodes.^[43] Similarly, deficiencies in S1P1 lead to retention of mature B cells within the bone marrow and spleen, underscoring the role of S1P signaling in balancing retention and release for effective immune patrolling.^[46] These molecular mechanisms ensure naive B cells are strategically positioned in secondary lymphoid organs to initiate adaptive responses upon antigen encounter.

Activation Process

Antigen Recognition

Naive B cells recognize antigens primarily through their B cell receptor (BCR), a membrane-bound immunoglobulin that exhibits low affinity for antigens, allowing initial signaling even with weak interactions. This low-avidity binding threshold enables naive B cells to respond to a broad range of antigens, with dissociation constants (KD) as high as 3.9 × 10⁻⁷ M sufficient to induce BCR signaling components such as CD79a, Syk, BLNK, and PLCγ phosphorylation, unlike germinal center B cells that require higher affinity (KD ≈ 2.4 × 10⁻⁹ M).^[47] This threshold supports the diverse repertoire of naive B cells in surveying potential threats without stringent specificity.^[48] Upon antigen binding, naive B cells capture and internalize the antigen-BCR complex via clathrin-coated pits, a process driven by Src-family kinases like Lyn within lipid rafts, leading to trafficking into multivesicular bodies for processing.^[49] Internalized antigens are proteolyzed by cathepsins, and antigenic peptides are loaded onto major histocompatibility complex class II (MHC II) molecules after removal of the invariant chain-derived CLIP peptide by HLA-DM, facilitating presentation to CD4+ T cells.^[49] Naive B cells efficiently internalize both soluble antigens, which diffuse into lymphoid follicles or arrive via conduits, and cell-bound antigens presented on follicular dendritic cells (FDCs).^[50] FDCs play a critical role in trapping opsonized immune complexes through complement receptors CR1/CR2 and FcγRIIb, retaining native antigens for extended periods (up to weeks) to ensure availability for rare cognate naive B cells.^[51] Activation of naive B cells requires antigens that promote BCR clustering, with multivalent antigens preferred as they enhance avidity and microcluster formation, lowering the signaling threshold compared to monovalent ligands.^[52] For instance, nanoscaffolded multivalent antigens induce robust BCR activation at lower stoichiometries (e.g., 19:1 antigen:BCR), while monovalent antigens demand higher occupancy and structural rigidity to achieve similar effects.^[52] This preference for multivalency ensures efficient responses to pathogen-derived repetitive epitopes. The mechanism of BCR-mediated antigen recognition in naive B cells is evolutionarily conserved across jawed vertebrates, from cartilaginous fish expressing IgM+ primary B cells to mammals, where immunoglobulin-based receptors initiate adaptive humoral immunity.^[53]

Co-Stimulation and Signaling

Upon engagement of the B cell receptor (BCR) by antigen, signaling in naive B cells is initiated through phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) on the cytoplasmic tails of CD79a and CD79b by the Src-family kinase Lyn, which recruits and activates the tyrosine kinase Syk to propagate downstream cascades.^[54] Syk then phosphorylates adaptor proteins such as BLNK, facilitating the recruitment and activation of phospholipase Cγ2 (PLCγ2), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).^[54] IP3 binds to receptors on the endoplasmic reticulum, triggering calcium (Ca2+) release into the cytosol, which is sustained by store-operated Ca2+ entry via STIM1 and Orai channels, ultimately activating transcription factors like NFAT essential for B cell activation.^[54] Co-receptors modulate this BCR signaling to fine-tune activation thresholds in naive B cells. The CD19/CD81 complex, associated with CD21, lowers the BCR activation threshold by enhancing signal amplification upon antigen binding; CD81 facilitates the partitioning of coligated BCR-CD19/CD21 complexes into lipid rafts, promoting efficient signaling.^[55] This complex recruits PI3K, leading to the production of PIP3 and subsequent activation of the Akt pathway, which supports B cell survival, proliferation, and metabolic reprogramming during early activation stages.^[55] In the periphery, B cell-activating factor (BAFF, also known as BLyS) binding to its receptor BAFF-R provides tonic survival signals to naive B cells, independent of but complementary to BCR engagement.^[56] BAFF-R signaling activates non-canonical NF-κB pathways, upregulating anti-apoptotic proteins like Bcl-2 to maintain naive B cell homeostasis and prevent deletion of low-affinity self-reactive clones.^[56] Negative regulation prevents excessive or autoreactive responses in naive B cells. CD22 (Siglec-2), an inhibitory co-receptor, binds sialic acid ligands and, upon BCR crosslinking, recruits the phosphatase SHP-1 via its ITIM motifs to dephosphorylate key signaling molecules, thereby dampening Lyn, Syk, and PLCγ2 activities and inhibiting Ca2+ mobilization to enforce peripheral tolerance.^[57] Deficiency in CD22 leads to hyperresponsive B cells and autoantibody production, underscoring its role in suppressing auto-reactivity.^[57] These integrated signaling pathways prepare naive B cells for differentiation by upregulating activation-induced cytidine deaminase (AID) expression through NF-κB and other transcription factors, priming the cells for potential class-switch recombination and somatic hypermutation upon full activation.^[58] AID remains undetectable in resting naive B cells but is induced via BCR and co-stimulatory signals, marking a key outcome of threshold-modulated transduction.^[58]

Differentiation Pathways

Germinal Center Entry

Upon activation by antigen in the follicles of secondary lymphoid organs, naive B cells undergo an initial positional shift, migrating to the T-B cell border where they present antigen to T follicular helper (Tfh) cells. This migration is facilitated by chemokine gradients, including CXCL13 in the follicles and CCL19/CCL21 at the border.^[59] At the T-B border, activated B cells receive essential licensing signals from Tfh cells through the interaction between CD40 ligand (CD40L) on Tfh cells and CD40 on B cells, which promotes B cell survival, proliferation, and differentiation into germinal center-competent cells. This CD40L-CD40 signaling is critical for enabling B cells to enter the germinal center (GC), as its absence leads to impaired GC formation. Licensed B cells then enter the nascent GC structure, initially clustering at the T-B border before migrating into the dark zone (DZ) of the GC. This entry into the DZ is guided by the chemokine receptor CXCR4, which responds to CXCL12 produced by stromal cells in the DZ, directing high-affinity B cell clones toward proliferative niches. Upon DZ entry, these B cells differentiate into centroblasts and undergo rapid proliferation, dividing approximately every 6-8 hours to expand clones with favorable antigen-binding properties.^[60] This proliferative burst is driven by transcription factors such as MYC and is essential for generating a diverse pool of B cell variants through somatic hypermutation. Within the GC, particularly during the transition to the light zone (LZ), B cells face stringent selection for high-affinity clones through competition for limited Tfh cell help and antigen availability. Only B cells that effectively capture and present antigen to Tfh cells receive survival signals, establishing a competitive niche where superior affinity confers a proliferative advantage. B cells failing this selection—predominantly those with low affinity—undergo apoptosis, with up to 50% of GC B cells dying every 6 hours, resulting in the vast majority of activated B cells that enter the GC response not surviving to differentiate further.^[61] This high attrition rate ensures the enrichment of high-affinity antibody-producing clones.^[62]

Fate Decisions

Upon activation, naive B cells undergo fate decisions that direct them toward either rapid, short-lived effector responses or long-term adaptive immunity through germinal center (GC) pathways. These decisions are influenced by the strength and context of antigen stimulation, as well as signals from the microenvironment, leading to differentiation into plasma cells, memory B cells, or further proliferation within GCs.^[63] In extrafollicular responses, activated naive B cells rapidly differentiate into short-lived plasmablasts that produce early IgM antibodies, providing immediate protection against pathogens. This pathway occurs outside GCs, typically peaking 4–6 days post-activation, and involves proliferation driven by factors like BAFF via the TACI receptor, often in a T cell-independent manner. These plasmablasts have a half-life of a few days and exhibit low-affinity antibody secretion with limited somatic hypermutation, prioritizing speed over optimization.^[63] Within GCs, affinity maturation occurs through somatic hypermutation (SHM), where activation-induced cytidine deaminase (AID) deaminates cytosines in immunoglobulin variable region exons, introducing point mutations at hotspots like RGYW motifs. This process generates diversity in B cell receptors (BCRs), with subsequent selection favoring clones that bind antigen with higher affinity while eliminating those with reduced function. SHM also produces double-strand breaks, contributing to deletions in a subset of sequences, ultimately refining the antibody repertoire for enhanced pathogen recognition.^[64] Class switch recombination (CSR) enables activated B cells to shift from IgM or IgD expression to other isotypes like IgG, IgA, or IgE, diversifying antibody effector functions. AID initiates CSR by creating double-strand breaks in switch regions upstream of constant region genes, followed by repair via non-homologous end joining. Cytokines direct isotype specificity; for instance, IFNγ activates STAT1 signaling to promote switching to IgG subclasses, such as IgG2a in mice or IgG1/3 in humans, enhancing antiviral responses. Other cytokines, like IL-4 for IgG1 and IgE or TGF-β for IgA, similarly regulate accessibility of switch regions through transcription factors.^[65] Asymmetric cell division in GC B cells contributes to fate heterogeneity by unequally distributing key molecules between daughter cells. During division, proteins such as the transcriptional regulator Bcl6, the IL-21 receptor (IL-21R), and atypical protein kinase C polarize to one pole, resulting in one daughter inheriting higher levels and migrating to the light zone for antigen-mediated selection, while the other receives lower levels and returns to the dark zone for proliferation. This mechanism promotes self-renewal and diversity, integrating microenvironmental cues to balance expansion and selection.^[66] Memory B cells form primarily through GC-dependent pathways, emerging as isotype-switched, long-lived cells that carry somatic mutations from SHM and CSR. Naive B cells proliferate in GCs, undergoing ~10 divisions and accumulating mutations, with T cell help via CD40L-CD40 interactions driving AID expression. Resulting memory populations, such as CD27⁺IgG⁺ or CD27⁺IgA⁺ cells, persist for years, enabling rapid secondary responses upon re-exposure to antigen.^[67] Recent studies as of 2025 have revealed that individual naive B cells can give rise to both plasma cells and GC B cells through bifurcated differentiation, influenced by competing gene regulatory networks that differ between naive and memory B cell fates. These findings highlight the plasticity in early fate decisions and implications for memory formation.^[68]

Clinical and Research Relevance

Role in Autoimmune Diseases

In autoimmune diseases, breaches in central and peripheral B cell tolerance mechanisms allow self-reactive naive B cells to escape deletion and become activated, contributing to pathological immune responses. For instance, in systemic lupus erythematosus (SLE), immature self-reactive B cells that normally undergo receptor editing or apoptosis in the bone marrow can mature and enter the periphery due to defective anergy induction, leading to higher frequencies of activated naive B cells expressing CD69. Similarly, in rheumatoid arthritis (RA), peripheral tolerance is compromised, enabling autoreactive naive B cells to participate in germinal center reactions and produce affinity-matured autoantibodies like anti-citrullinated protein antibodies. Hyperactive B cell-activating factor (BAFF) signaling exacerbates this by promoting the survival and expansion of autoreactive naive B cells, rescuing them from apoptosis and allowing their accumulation in the naive and transitional pools. This overabundance of BAFF, observed in SLE and other autoimmune conditions, lowers the threshold for B cell activation and supports the selection of low-affinity self-reactive clones. Belimumab, a monoclonal antibody targeting soluble BAFF, selectively depletes naive and transitional B cells, thereby reducing the autoreactive pool and mitigating disease activity in SLE patients. Genetic variants, such as the PTPN22 R620W polymorphism, further impair naive B cell tolerance by interfering with negative selection during development, resulting in increased survival and export of autoreactive naive B cells to the periphery. This variant disrupts signaling pathways that normally eliminate self-reactive clones, heightening auto-reactivity and susceptibility to diseases like SLE and RA. In type 1 diabetes, islet-specific autoreactive naive B cells infiltrate pancreatic lymph nodes and islets early in pathogenesis, acting as antigen-presenting cells to prime diabetogenic T cells and amplify beta-cell destruction. These cells, accumulating as early as 4-7 weeks in non-obese diabetic (NOD) mouse models, drive insulitis and are essential for disease progression, with their depletion preventing onset. Recent single-cell RNA sequencing (scRNA-seq) studies post-2020 have identified naive-like B cell subsets with dysregulated interferon signaling and clonal expansion during autoimmune flares, such as in SLE where IL-4R-negative, IFN-β-positive naive B cells correlate with autoantibody production and disease heterogeneity.

Implications for Vaccination and Therapy

Vaccines are designed to mimic natural antigen encounters, thereby activating naive B cells to initiate primary immune responses and generate long-term immunity. By presenting antigens in a controlled manner, these vaccines stimulate naive B cells through B cell receptor recognition, often in conjunction with T cell help, leading to differentiation into antibody-secreting cells and memory B cells. For instance, conjugate vaccines, which link polysaccharides to carrier proteins, promote T cell-dependent activation of naive B cells, enhancing germinal center formation and affinity maturation for improved efficacy against encapsulated bacteria.^[69]^[70] Messenger RNA (mRNA) vaccines, such as those developed for COVID-19, potently activate naive B cells by encoding viral antigens that trigger robust humoral responses in previously unexposed individuals. These vaccines induce rapid proliferation and differentiation of naive B cells into plasmablasts and memory B cells, resulting in high-affinity antibodies and broad variant recognition, with two doses often sufficient to peak these responses in naive subjects. Studies have shown that mRNA vaccination elicits potent memory B cell formation from naive precursors, contributing to durable protection against SARS-CoV-2.^[71]^[72] Chimeric antigen receptor (CAR) B cell therapies represent an emerging preclinical approach to engineer naive B cells for targeted tumor therapies, leveraging their antigen-presenting capabilities in studies presented post-2023. In these strategies, naive B cells are modified to express CARs that recognize tumor antigens, enabling antibody production and immune orchestration against malignancies, with initial research focusing on solid tumors and B cell lymphomas. This builds on differentiation pathways by redirecting naive B cell potential toward therapeutic antibody secretion at tumor sites.^[73] Depletion therapies like rituximab, a monoclonal antibody targeting CD20 expressed on naive B cells, are widely used in treating B cell lymphomas and malignancies by inducing complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis to eliminate malignant naive and mature B cell populations. Rituximab effectively reduces CD20-positive naive B cells in circulation, achieving remission in non-Hodgkin lymphoma patients, though resistance can develop due to antigen modulation.^[74]^[75]^[76] A key challenge in leveraging naive B cells for vaccination and therapy is the age-related decline in their repertoire diversity and frequency, which diminishes vaccine efficacy in the elderly by impairing primary responses and memory formation. This thymic involution-linked reduction leads to weaker antibody titers post-vaccination, as seen in influenza and pneumococcal vaccines, necessitating adjuvants or booster strategies to compensate for the contracted naive B cell pool.^[77]^[78]^[79]

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The complex of enzymes that act in concert to effect somatic V(D)J recombination is termed the V(D)J recombinase. The products of the two genes RAG-1 and ...4-2. The DNA sequence... · 4-4. Rearrangement of V, D... · 4-5. The reaction that...
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Short- and long-term memory | Nature Reviews Immunology
Feb 25, 2011 · In a classical primary immune response, naive IgM+ B cells ... affinity maturation and immunoglobulin class switching. The cells ...
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Transcription factor networks in B-cell differentiation link ...
This review article focuses on the roles of transcription factors in early B-cell development and their involvement in the formation of human leukemia.Lymphoid priming in... · B-lineage commitment is... · Transiting through the pre-B...
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[PDF] B-Cell Development, Activation, and Differentiation
B cells are generated in the bone marrow. • Takes 1-2 weeks to develop from hematopoietic stem cells to mature B cells. • Sequence of expression of cell ...
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To B or not to B | Science Signaling
Jun 11, 2024 · When a self-antigen is first recognized in the bone marrow, B cell self-tolerance relies on receptor editing rather than clonal deletion to ...
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An integrated proteome and transcriptome of B cell maturation ...
Aug 23, 2023 · During B cell maturation, transitional and mature B cells acquire cell-intrinsic features that determine their ability to exit quiescence ...
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Induction of metabolic quiescence defines the transitional ... - Science
Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors.
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https://www.nature.com/articles/s41467-023-40621-2
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The promise and challenge of high-throughput sequencing ... - Nature
Jan 19, 2014 · After passage through several developmental checkpoints, newly generated mature IgM+IgD+ B cells form the naive B cell (and, therefore, naive ...
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A Guide to B Cell Markers | Biocompare
Dec 2, 2020 · These mature, yet unactivated naive B cells may be identified with the phenotype CD19+, IgD+, CD27–, CD38+/–, CD24+/–. Plasmablasts are ...
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B cell markers - Abcam
B cell markers include IgM, HLA-DR, CD19, CD20, and CD40, which help define B cell identity and function. IgM is found on mature B cells.
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Surface phenotypes of naive and memory B cells in ... - PubMed - NIH
Dec 22, 2021 · This study identified surface proteins differentially expressed between memory and naive B cells in human and mouse tissues, aiding in their ...
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Expression of chemokine receptors CXCR4, CXCR5 and CCR7 on ...
In this study, we have investigated the expression of chemokine receptors CXCR4, CXCR5 and CCR7 on lymphocyte subpopulations (naive and memory B cells; CD4+ and ...
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Distinguishing naive‐ from memory‐derived human B cells during ...
Naive B cells underwent equivalent ASC generation, but exhibited less class‐switch and modulation of CD27, CD38 and CD20 expression than memory B cells after ...
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Immunophenotyping of B Cells by Flow Cytometry | Bio-Rad
Immunophenotyping of B cells uses flow cytometry with markers like CD19, CD27, CD24, CD38, and surface immunoglobulin to identify subsets. Initial gating ...
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https://pmc.ncbi.nlm.nih.gov/articles/PMC6851823/
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Transcriptional analysis of the B cell germinal center reaction - PNAS
Here we analyzed the transcriptional changes that occur in B cells during GC transit (naïve B cells → centroblasts → centrocytes → memory B cells) by gene ...
[25]
Progressive Upregulation of Oxidative Metabolism Facilitates ... - PMC
Proliferating, activated B cells switch from glycolysis to oxidative phosphorylation as they differentiate into plasmablasts.
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Epigenetics of Peripheral B-Cell Differentiation and the Antibody ...
In B cells, epigenetic marks, such as DNA methylation, histone modifications, and miRNAs, are induced by the same stimuli that drive the antibody response ...
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Single-cell analysis reveals dynamics of human B cell differentiation ...
Mar 2, 2023 · Here, we dissected differentiation trajectories of human naive B cells into ASCs using single-cell RNA sequencing.
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IRF4 and IRF8: Governing the virtues of B Lymphocytes - PMC
In B lymphocytes, IRF4 and IRF8 have been shown to control important events during their development and maturation including pre-B cell differentiation, ...
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B Cell Receptor - an overview | ScienceDirect Topics
Mature B cells leave the bone marrow and enter the peripheral lymphocyte pool as naïve B cells. ... Some naïve B cells have a half-life of only a few days, ...
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Lymphocytes - Deranged Physiology
Aug 24, 2025 · Half life is ~ 3 days for peripheral mature B cells, but ~8 weeks ... B cell life cycle. B cells remain in the bone marrow (hence B) and ...B Cell Life Cycle · Causes Of Increased... · Drugs That Influence...
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Lymphatic endothelial cells regulate B-cell homing to lymph nodes ...
Mar 5, 2018 · Naive T and B cells extravasate through HEVs, the site of lymphocytes trafficking from the blood to the LNs, via a multistep adhesion cascade.
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Marginal Zone B-Cells, a Gatekeeper of Innate Immunity - Frontiers
Dec 12, 2011 · Two B-cell subsets, marginal zone (MZ) and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses.Abstract · Marginal Zone B-Cells · The Functions of MZ B-Cells · Human MZ B-Cells
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B cell Acquisition of Antigen in vivo - PMC - NIH
B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity ...
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Integrins in immunity | Journal of Cell Science
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Naive B Cell - an overview | ScienceDirect Topics
... B cells are relatively long-lived, with a half-life of 3–4 months. These experiments also show that, although NF B cells are produced at a rate of 107 per ...
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Immune cell migration in inflammation: present and future ... - Nature
Nov 17, 2005 · Rolling adhesions can last from seconds to minutes, depending on the type of leukocyte and the target endothelial bed. Integrins can also ...
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High endothelial venules (HEVs) in immunity, inflammation and cancer
The first interaction between naive lymphocytes and HEVs is initiated by lymphocyte L-selectin (also known as CD62L) that recognizes a family of sulfated mucin- ...
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A Novel Endothelial L-Selectin Ligand Activity in Lymph Node ...
Lymphocyte homing occurs mainly in high order HEVs (3, 4). The first step is the binding of L-selectin (CD62L) to endothelial sulfated carbohydrate (CHO) ...
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Chemokine Requirements for B Cell Entry to Lymph Nodes and ...
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B cell attracting chemokine 1 (CXCL13) and its receptor CXCR5 are ...
BCA-1 was produced and accumulated in relation to peripheral dendritic elements of lymphoid follicles in Peyer's patches and normal colon, as well as in ...
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Finding the right niche: B-cell migration in the early phases of T ...
Indeed, when mice lack CXCL13, EBI2 affects naive B-cell ... lymph nodes and Peyer's patches and affects B cell trafficking across high endothelial venules.
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Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated ...
May 13, 2021 · The S1PR1/S1P axis participates in naïve B cell trafficking from bone marrow to blood, egress from secondary lymphoid organs [12], and ...
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S1P1 receptor directs the release of immature B cells from bone ...
S1P1 receptor expression is required for the egress of newly formed T cells from the thymus and exit of mature T and B cells from secondary lymphoid organs.
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Intrinsic properties of human germinal-center B cells set antigen ...
Here we show that human GC B cells have intrinsically higher affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as ...
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Apoptosis and antigen affinity limit effector cell differentiation of a ...
Feb 13, 2015 · Some studies suggest that different naïve B cell clones only produce a single effector subset, depending on BCR affinity for antigen (5–8) or ...
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Early BCR Events and Antigen Capture, Processing, and ... - Frontiers
Here, we review the sequential steps required for BCR recognition of antigen, internalization, processing, and loading onto MHC II, with special emphasis on the ...
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Role of B cells as antigen presenting cells - PMC - PubMed Central
Antigen presentation by B2 cells primarily occurs through the BCR, in which interaction with a BCR-specific antigen leads to B cell activation and proliferation ...
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Visualizing B cell capture of cognate antigen from follicular dendritic ...
Jun 8, 2009 · B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node .
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Antigen footprint governs activation of the B cell receptor - Nature
Feb 22, 2023 · Even considering the lower affinity of B1-8i B cells, these conditions should cause ~98% BCR occupancy, corresponding to ~24,500 engaged BCRs on ...
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Evolution of B Cell Immunity - PMC - PubMed Central
Here we summarize features of B cells and their predecessors in the different animal phyla, focusing the review on B cells from jawed vertebrates.
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The regulators of BCR signaling during B cell activation - PMC
In this review, we will discuss three major BCR mediated signaling pathways (the PLC-γ2 pathway, PI3K pathway and MAPK pathway) and related regulators.Missing: PLCγ2 | Show results with:PLCγ2
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https://pmc.ncbi.nlm.nih.gov/articles/PMC4203447/
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https://pmc.ncbi.nlm.nih.gov/articles/PMC8975005/
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https://doi.org/10.3389/fimmu.2018.01606
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https://doi.org/10.4049/jimmunol.1001708
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Immunoglobulin class‐switch recombination: Mechanism, regulation ...
In addition, with the help of cytokines and other immune cells, antibody CSR converts IgM to other Igs, including IgA, IgD, IgE, and IgG. Mature B cells reach a ...
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Asymmetric B Cell Division in the Germinal Center Reaction
### Extracted Details on Asymmetric Cell Division in Germinal Center B Cells
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Human memory B cells originate from three distinct germinal center ...
Aug 25, 2011 · ... mutated hot-spot in memory B cells rather than additional mutations. ... Somatically Mutated Ig VH Genes and Define a New Memory Population.
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Pneumococcal Conjugate and Plain Polysaccharide Vaccines Have ...
Mar 28, 2012 · The detection of memory B-cells following immunization with PCV7 in older adults in this study indicates that this vaccine induces a T-dependent ...
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Distinct effects of adjuvants on B cell responses to protein ... - Frontiers
Background: Protein-polysaccharide conjugate vaccines rely on the induction of T-cell-dependent responses that support germinal center (GC) reactions to ...
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Distinct antibody and memory B cell responses in SARS-CoV-2 ...
Two shots of the mRNA vaccines were needed to induce peak antibody and memory B cell responses against SARS-CoV-2 in naïve patients, whereas only one shot ...
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SARS-CoV-2 spike-reactive naïve B cells and pre-existing memory ...
Feb 14, 2024 · SARS-CoV-2 spike-reactive naïve B cells and pre-existing memory B cells contribute to antibody responses in unexposed individuals after vaccination.
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Setting the Stage for Engineered B-Cell Therapies in Cancer and ...
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[71]
CD20 as a gatekeeper of the resting state of human B cells - PNAS
Due to its B cell-specific expression, CD20 is an ideal target of B cell-depleting monoclonal antibodies, most prominently rituximab (RTX). These anti-CD20 ...
[72]
Effect of Rituximab on the Peripheral Blood and Cerebrospinal Fluid ...
It targets CD20, a transmembrane phosphoprotein expressed on most B cells, except for plasma B cells. Rituximab depletes B cells by binding to the CD20 ...<|separator|>
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The regulation and function of CD20: an “enigma” of B-cell biology ...
Rituximab is one of the most effective and widely used therapeutic monoclonal antibodies, but malignant B cells can become relatively resistant to such therapy.
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How aging impacts vaccine efficacy: known molecular and cellular ...
The reduced production of B cells from bone marrow and impaired affinity maturation of B cells contribute to the age-associated decline in vaccine efficiency.
[75]
Insights into vaccines for elderly individuals: from the impacts of ...
Apr 10, 2024 · These alterations in B cells may explain the impairment in protective humoral immunity in older individuals after vaccination. As the key ...
[76]
Aging induces B cell defects and decreased antibody responses to ...
Nov 19, 2020 · Aging is characterized by a progressive decline in the capacity of the immune system to fight influenza virus infection and to respond to vaccination.