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Plasma cell
Plasma cell
Plasma cell
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Plasma cell
Micrograph of malignant plasma cells (plasmacytoma), many displaying characteristic "clockface nuclei", also seen in normal plasma cells. H&E stain.
Micrograph of a plasma cell with distinct clear perinuclear region of the cytoplasm, which contains large numbers of Golgi bodies.
Details
SystemLymphatic system
Identifiers
Latinplasmocytus
MeSHD010950
THH2.00.03.0.01006
FMA70574
Anatomical terms of microanatomy

Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells[1] and secrete large quantities of proteins called antibodies in response to being presented with specific substances called antigens. These antibodies are transported from the plasma cells by the blood plasma and the lymphatic system to the site of the target antigen (foreign substance), where they initiate its neutralization or destruction. B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell.[2]

Structure

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Plasma cells with Dutcher and Russell bodies (H&E stain, 100×, oil)

Plasma cells are large lymphocytes with abundant cytoplasm and a characteristic appearance on light microscopy. They have basophilic cytoplasm and an eccentric nucleus with heterochromatin in a characteristic cartwheel or clock face arrangement. Their cytoplasm also contains a pale zone that on electron microscopy contains an extensive Golgi apparatus and centrioles. Abundant rough endoplasmic reticulum combined with a well-developed Golgi apparatus makes plasma cells well-suited for secreting immunoglobulins.[3] Other organelles in a plasma cell include ribosomes, lysosomes, mitochondria, and the plasma membrane.[citation needed]

Surface antigens

[edit]

Terminally differentiated plasma cells express relatively few surface antigens, and do not express common pan-B cell markers, such as CD19 and CD20. Instead, plasma cells are identified through flow cytometry by their additional expression of CD138, CD78, and the Interleukin-6 receptor. In humans, CD27 is a good marker for plasma cells; naïve B cells are CD27−, memory B-cells are CD27+ and plasma cells are CD27++.[4]

The surface antigen CD138 (syndecan-1) is expressed at high levels.[5]

Another important surface antigen is CD319 (SLAMF7). This antigen is expressed at high levels on normal human plasma cells. It is also expressed on malignant plasma cells in multiple myeloma. Compared with CD138, which disappears rapidly ex vivo, the expression of CD319 is considerably more stable.[6]

Development

[edit]

After leaving the bone marrow, the B cell acts as an antigen-presenting cell (APC) and internalizes offending antigens, which are taken up by the B cell through receptor-mediated endocytosis and processed. Pieces of the antigen (which are now known as antigenic peptides) are loaded onto MHC II molecules, and presented on its extracellular surface to CD4+ T cells (sometimes called T helper cells). These T cells bind to the MHC II-antigen molecule and cause activation of the B cell. This is a type of safeguard to the system, similar to a two-factor authentication method. First, the B cells must encounter a foreign antigen and are then required to be activated by T helper cells before they differentiate into specific cells.[7]

Upon stimulation by a T cell, which usually occurs in germinal centers of secondary lymphoid organs such as the spleen and lymph nodes, the activated B cell begins to differentiate into more specialized cells. Germinal center B cells may differentiate into memory B cells or plasma cells. Most of these B cells will become plasmablasts (or "immature plasma cells"), and eventually plasma cells, and begin producing large volumes of antibodies. Some B cells will undergo a process known as affinity maturation.[8] This process favors, by selection for the ability to bind antigen with higher affinity, the activation and growth of B cell clones able to secrete antibodies of higher affinity for the antigen.[9]

Immature plasma cells

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Plasmablast, Wright stain.

The most immature blood cell that is considered of plasma cell lineage is the plasmablast.[10] Plasmablasts secrete more antibodies than B cells, but less than plasma cells.[11] They divide rapidly and are still capable of internalizing antigens and presenting them to T cells.[11] A cell may stay in this state for several days, and then either die or irrevocably differentiate into a mature, fully differentiated plasma cell.[11] Differentiation of mature B cells into plasma cells is dependent upon the transcription factors Blimp-1/PRDM1, BCL6, and IRF4.[9]

Function

[edit]

Unlike their precursors, plasma cells cannot switch antibody classes, cannot act as antigen-presenting cells because they no longer display MHC-II, and do not take up antigen because they no longer display significant quantities of immunoglobulin on the cell surface.[11] However, continued exposure to antigen through those low levels of immunoglobulin is important, as it partly determines the cell's lifespan.[11]

The lifespan, class of antibodies produced, and the location that the plasma cell moves to also depends on signals, such as cytokines, received from the T cell during differentiation.[12] Differentiation through a T cell-independent antigen stimulation (stimulation of a B cell that does not require the involvement of a T cell) can happen anywhere in the body[8] and results in short-lived cells that secrete IgM antibodies.[12] The T cell-dependent processes are subdivided into primary and secondary responses: a primary response (meaning that the T cell is present at the time of initial contact by the B cell with the antigen) produces short-lived cells that remain in the extramedullary regions of lymph nodes; a secondary response produces longer-lived cells that produce IgG and IgA, and frequently travel to the bone marrow.[12] For example, plasma cells will likely secrete IgG3 antibodies if they matured in the presence of the cytokine interferon-gamma. Since B cell maturation also involves somatic hypermutation (a process completed before differentiation into a plasma cell), these antibodies frequently have a very high affinity for their antigen.[citation needed]

Plasma cells can only produce a single kind of antibody in a single class of immunoglobulin. In other words, every B cell is specific to a single antigen, but each cell can produce several thousand matching antibodies per second.[13] This prolific production of antibodies is an integral part of the humoral immune response.[citation needed]

Long-lived plasma cells

[edit]
Main article: Long-lived plasma cell

The current findings suggest that after the process of affinity maturation in germinal centers, plasma cells develop into one of two types of cells: short-lived plasma cells (SLPC) or long-lived plasma cells (LLPC). LLPC mainly reside in the bone marrow for a long period of time and secrete antibodies, thus providing long-term protection. LLPC can maintain antibody production for decades or even for the lifetime of an individual,[14][15] and, unlike B cells, LLPC do not need antigen restimulation to generate antibodies. Human LLPC population can be identified as CD19– CD38hi CD138+ cells.[16]

The long-term survival of LLPC are dependent on a specific environment in the bone marrow, the plasma cell survival niche.[17] Removal of an LLPC from its survival niche results in its rapid death. A survival niche can only support limited number of LLPC, thus the niche's environment must protect its LLPC cells but be able to accept new arrivals.[18][19] The plasma cell survival niche is defined by a combination of cellular and molecular factors and though it has yet to be properly defined, molecules such as IL-5, IL-6, TNF-α, stromal cell-derived factor-1α and signalling via CD44 have been shown to play a role in the survival of LLPC.[20] LLPC can also be found, to a lesser degree, in gut-associated lymphoid tissue (GALT), where they produce IgA antibodies and contribute to mucosal immunity. Recent findings suggest that plasma cells in the gut do not necessarily need to be generated de novo from active B cells but there are also long-lived PC, suggesting the existence of a similar survival niche.[21] Tissue specific niches that allow for the survival of LLPC have been also described in nasal-associated lymphoid tissues (NALT), human tonsillar lymphoid tissues and human mucosa or mucosa-associated lymphoid tissues (MALT).[22][23][24][25]

Originally it was thought that the continuous production of antibodies is a result of constant replenishment of short-lived plasma cells by memory B cell re-stimulation. Recent findings, however, show that some PC are truly long-lived. The absence of antigens and the depletion of B cells does not appear to have an effect on the production of high-affinity antibodies by the LLPC. Prolonged depletion of B cells (with anti-CD20 monoclonal antibody treatment that affects B cells but not PC) also did not affect antibody titres.[26][27][28] LLPC secrete high levels of IgG independently of B cells. LLPC in bone marrow are the main source of circulating IgG in humans.[29] Even though IgA production is traditionally associated with mucosal sites, some plasma cells in bone marrow also produce IgA.[30] LLPC in bone marrow have been observed producing IgM.[31]

Clinical significance

[edit]

Plasmacytoma, multiple myeloma, Waldenström macroglobulinemia, heavy chain disease, and plasma cell leukemia are cancers of the plasma cells.[32] Multiple myeloma is frequently identified because malignant plasma cells continue producing an antibody, which can be detected as a paraprotein. Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia characterized by the secretion of a myeloma protein into the blood and may lead to multiple myeloma.[33]

Common variable immunodeficiency is thought to be due to a problem in the differentiation from lymphocytes to plasma cells. The result is a low serum antibody level and risk of infections.[citation needed]

Primary amyloidosis (AL) is caused by the deposition of excess immunoglobulin light chains which are secreted from plasma cells.[citation needed]

See also

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References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Plasma cell

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from Grokipedia
A plasma cell is a terminally differentiated B lymphocyte, a type of , that serves as the primary producer of antibodies in the humoral , secreting thousands of immunoglobulin molecules per second to combat pathogens and maintain long-term immunity. These cells arise from activated B cells following antigenic stimulation, undergoing a maturation process driven by transcription factors such as Blimp-1, , and XBP-1, which reprogram the cell to prioritize antibody synthesis over proliferation. Morphologically, plasma cells are larger than typical s (14–20 micrometers in diameter), featuring an eccentric nucleus with a characteristic "clock-face" pattern, abundant rough for protein production, and a prominent perinuclear Golgi apparatus, often marked by surface expression of and CD138. Beyond antibody secretion, plasma cells exhibit diverse functions, including the production of immunomodulatory cytokines like IL-10, IL-35, and IL-17, which regulate , inflammation, and even hematopoiesis in various tissues. Long-lived plasma cells, capable of persisting for decades in survival niches such as the and gut mucosa, ensure sustained serological against infections and vaccines, with the majority residing in niches supported by stromal cells, while others persist in mucosal tissues like the gut. Dysregulation of plasma cells contributes to immunodeficiencies (e.g., agammaglobulinemia from impaired differentiation) and pathologies like or autoimmune diseases, where autoreactive plasma cells drive chronic antibody-mediated damage. Plasma cells were first described in by Wilhelm Waldeyer, with their role as the primary antibody-producing cells confirmed experimentally in the mid-20th century; they remain central to understanding adaptive immunity and therapeutic targeting in disorders.

Structure

Morphology

Plasma cells are ovoid or round cells typically measuring 9 to 20 μm in diameter, with a mean of approximately 14 μm, making them larger than naive B cells which are around 7-10 μm. Under light microscopy, they exhibit a characteristic basophilic cytoplasm due to the abundance of rough endoplasmic reticulum (RER) involved in protein synthesis, an eccentric nucleus, and a perinuclear halo corresponding to the Golgi apparatus region. The nucleus is round or oval, positioned off-center, and features coarse heterochromatin arranged in a distinctive clock-face or cartwheel pattern, with clumps of chromatin distributed along the nuclear periphery. Electron microscopy reveals further ultrastructural details that underscore their specialization for antibody production. The cytoplasm is dominated by extensive arrays of RER, appearing as parallel stacks of flattened cisternae studded with ribosomes, often containing granular material within the lumen. A prominent Golgi apparatus occupies the perinuclear halo, consisting of vesicles, tubules, and dense globules for processing and packaging proteins. The nucleus shows a higher nucleo-cytoplasmic ratio in immature forms with well-developed nucleoli, while mature plasma cells have a denser, eccentric nucleus with less prominent nucleoli. Occasionally, cytoplasmic inclusions such as Russell bodies—dilated RER sacs filled with dense material—may be observed, reflecting accumulated immunoglobulins.

Surface antigens

Plasma cells are distinguished from other immune cells by a unique profile of surface antigens that reflect their terminal differentiation from B lymphocytes. The primary identifier is CD138 (also known as syndecan-1), a highly expressed on the surface of mature plasma cells, which facilitates their adhesion to components in survival niches. Co-expression of , a multifunctional ectoenzyme, at high levels further characterizes plasma cells, enabling their robust detection in both normal and pathological contexts. In contrast, B cell-associated markers such as and are downregulated or absent; CD19 expression is low or negative on mature plasma cells, while CD20 is typically not expressed, marking the loss of identity. During differentiation from activated B cells, plasma cells undergo significant changes in surface antigen expression, including the loss of major histocompatibility complex class II (MHC II) molecules and the . MHC II, which is highly expressed on B cells for , is progressively downregulated as plasmablasts mature into long-lived plasma cells, correlating with their reduced role in T cell interactions. Similarly, surface BCR (membrane-bound immunoglobulin) is lost or markedly reduced, shifting the cell's focus from recognition to antibody secretion; this is particularly evident in IgG-producing plasma cells, though some IgA- and IgM-secreting cells may retain low levels. These alterations begin in plasmablasts, which often retain partial B cell marker expression (e.g., CD19 positive, CD138 low), and culminate in mature plasma cells with a streamlined profile dominated by CD138 and CD38. Adhesion molecules like , a hyaluronan receptor, are upregulated on plasma cells to support their homing to niches, where interactions with stromal cells promote survival. This homing is critical for long-lived plasma cells, which express high CD44 levels to facilitate retention in supportive microenvironments. In diagnostics, these surface antigens are essential for identifying plasma cells via and . panels typically gate on CD38high CD138+ populations, with absence of and confirming maturity and distinguishing normal from neoplastic cells, such as in where aberrant expression (e.g., CD19- CD56+) aids in detecting . relies heavily on CD138 for visualizing plasma cells in tissue biopsies, offering high specificity for plasmacytic infiltrates. These markers' expression patterns also correlate with morphological features, such as the eccentric nucleus in CD138+ cells observed in aspirates.

Development and Lifespan

Differentiation from B cells

Plasma cells differentiate from mature B cells through activation pathways that initiate the transition to antibody-secreting cells. In T cell-dependent activation, which occurs primarily in germinal centers of secondary lymphoid organs, naive B cells recognize antigens via their (BCR) and receive co-stimulatory signals from CD4+ helper T cells, leading to proliferation and differentiation into plasmablasts. T cell-independent activation, in contrast, involves direct stimulation of B cells by antigens with repetitive structures, such as , bypassing T cell help and resulting in more rapid but lower-affinity responses, often producing IgM-secreting plasmablasts. Key signals driving this differentiation include CD40 ligand (CD40L) expressed on activated T cells, which binds CD40 on to promote survival and proliferation, synergizing with cytokines such as interleukin-4 (IL-4) and IL-21. IL-4 supports growth and class switching to IgG and IgE, while IL-21 potently induces plasmablast formation and immunoglobulin secretion by upregulating terminal differentiation programs. Additionally, B cell-activating factor (BAFF, also known as BLyS) and a proliferation-inducing ligand () provide survival signals through receptors like TACI and BCMA, enhancing the commitment to the plasma cell lineage. The transcriptional program for plasma cell differentiation is orchestrated by key factors, including and (encoding Blimp-1). initiates the process by activating expression and repressing identity genes, while Blimp-1 further enforces the plasmacytic state by silencing proliferation-associated genes like and promoting immunoglobulin secretion machinery. These factors act in a dose-dependent manner, with graded levels coordinating transitions from activated to plasmablasts. Plasmablasts emerge as the immediate precursors to plasma cells, characterized by initial secretion of immunoglobulins, predominantly IgM in early responses. In germinal centers during T cell-dependent responses, B cells undergo affinity maturation through , which introduces mutations in antibody variable regions to enhance binding, followed by selection of high-affinity clones. Class-switch recombination also occurs here, diversifying isotypes from IgM to IgG, IgA, or IgE under the influence of cytokines like IL-4 or IFN-γ, preparing plasmablasts for effector functions. This differentiation process unfolds rapidly following exposure, with activated B cells proliferating and forming plasmablasts within 3–7 days , depending on the pathway and type.

Immature and short-lived plasma cells

Immature and short-lived plasma cells arise as proliferating antibody-secreting cells primarily in extrafollicular regions of secondary lymphoid organs, such as the red pulp of the and medullary cords of lymph nodes, where they expand rapidly in response to antigenic stimulation. These cells transition from plasmablasts, the immediate proliferating precursors derived from activated B cells under influences like IL-21, and are characterized by markers such as expression in humans and B220 in mice, reflecting their immature state. Their high proliferative capacity enables a swift buildup during the early phase of an , generating large numbers—often in the millions within the —to mount an immediate defense. These plasma cells exhibit a brief lifespan of approximately 3 to 5 days, constrained by limited access to survival signals in their transient niches within lymphoid tissues. Unlike more persistent counterparts, they lack robust support from stromal cells or cytokines, leading to rapid turnover and contributing to the resolution of acute responses. In terms of function, they predominantly secrete low-affinity IgM antibodies, providing essential but non-specialized humoral support to control early dissemination before affinity maturation occurs. Apoptosis in these cells is tightly regulated by the of proteins, where insufficient anti-apoptotic members like result in heightened sensitivity to intrinsic death pathways triggered by bioenergetic stress or overload from high secretory demands. They also display vulnerability to Fas-mediated in precursor stages, facilitating the elimination of excess cells post-initial response to prevent overproduction. Overall, while comprising the majority of antibody-secreting cells in the acute phase, most undergo programmed death shortly after, ensuring a controlled and temporary contribution to immunity.

Long-lived plasma cells and survival niches

Following differentiation in germinal centers, a subset of plasma cells acquires competence for homing to the through upregulation of the CXCR4, which interacts with its ligand SDF-1 () produced by bone marrow stromal cells, directing migration and retention in survival niches. This /SDF-1 axis is essential for post-germinal center plasma cells to exit peripheral sites and establish residence in the , where they compete for limited niche space. Within the , long-lived plasma cells occupy specialized survival niches formed by interactions with stromal cells, including mesenchymal progenitors and perivascular reticular cells, which provide essential survival signals. Key factors in these niches include and BAFF, secreted by stromal cells and non-hematopoietic nurse-like cells, which bind to receptors such as and TACI on plasma cells to promote through anti-apoptotic pathways. Additionally, IL-6 signaling from niche-associated cells enhances plasma cell persistence by supporting metabolic fitness and inhibiting cell death. These extrinsic cues enable a small population of plasma cells, comprising approximately 1% of total bone marrow cells, to maintain high output despite their scarcity. Long-lived plasma cells enter a non-proliferative, quiescent state characterized by repression of the transcription factor Bach2, which facilitates terminal differentiation and suppresses proliferation genes, ensuring long-term survival without division. Elevated expression of on these cells further contributes to quiescence by mediating adhesion to components in the niche, stabilizing their position and reducing motility. This quiescent allows plasma cells to persist for decades, as evidenced by sustained tetanus-specific immunity in humans for over 10 years post-vaccination, underpinning serological memory. Recent research highlights the role of hypoxia-inducible factors (HIFs), particularly HIF-1α, in maintaining these niches under the bone marrow's low-oxygen environment (PO₂ ~2-3%), where it upregulates stromal-derived factors like to support plasma cell adhesion and survival. Metabolic adaptations driven by HIF signaling, including enhanced and mitochondrial function, enable long-lived plasma cells to meet the energy demands of continuous secretion while resisting , further promoting their longevity.

Function

Antibody secretion

Plasma cells are highly specialized for the high-rate secretion of , producing up to 10,000 immunoglobulin molecules per cell per second through an expanded (RER) and Golgi apparatus pathway. This secretory capacity arises from their morphological adaptations, including abundant RER, which supports the massive protein synthesis required for antibody production. The process begins with the of immunoglobulin heavy and light chains on polysomes associated with the RER membrane, followed by their translocation into the lumen for folding and assembly. Within the ER, heavy and light chains undergo proper folding, assisted by chaperones, and form disulfide bonds to assemble into complete immunoglobulin monomers or multimers, with N-linked glycosylation occurring to stabilize the structure and facilitate trafficking. Glycosylation patterns vary by isotype, influencing antibody function and stability during secretion. Plasma cells produce diverse isotypes—IgG, IgA, IgE, and IgM—determined by prior class-switch recombination in B cell precursors, allowing adaptation to different immune challenges. The transcription factor XBP1 plays a central role in expanding the secretory apparatus by upregulating genes for ER biogenesis, protein folding, and vesicular transport, enabling sustained high-output antibody production. To manage the resulting ER stress from this intense synthetic load, plasma cells activate a specialized unfolded protein response (UPR) that selectively engages the IRE1-XBP1 arm while suppressing the PERK branch, thereby promoting survival and secretion without triggering apoptosis. Secretion rates can be quantified ex vivo using enzyme-linked immunospot (ELISPOT) assays, which detect antibody spots formed by individual cells, revealing heterogeneity in output among plasma cell populations.

Role in humoral immunity

Plasma cells serve as the primary effectors of the by secreting antibodies that neutralize and facilitate opsonization, thereby marking infectious agents for by immune cells such as macrophages and neutrophils. These antibodies bind to specific epitopes on , preventing their attachment to host cells and inhibiting replication, while opsonization enhances the efficiency of pathogen clearance through Fc receptor-mediated uptake. In the context of immunological memory, long-lived plasma cells provide sustained by continuously producing long after the initial encounter, operating independently of T cell support following their differentiation from B cells. This autonomy ensures persistent protection against reinfection without the need for ongoing antigenic stimulation or T cell activation. Different isotypes produced by plasma cells contribute to site-specific defense mechanisms; for instance, IgG antibodies dominate systemic circulation, providing broad protection against blood-borne pathogens, whereas IgA antibodies are secreted at mucosal surfaces to reinforce barriers in the respiratory, gastrointestinal, and urogenital tracts. Once migrated to survival niches such as the or mucosal tissues, plasma cells exhibit minimal direct interactions with other immune cells, instead delivering protection primarily through the release of soluble into the bloodstream or local secretions. Beyond antibody production, plasma cells can secrete immunomodulatory cytokines such as interleukin-10 (IL-10), IL-35, and IL-17, which contribute to regulatory functions in immunity. IL-10 and IL-35 from regulatory plasma cells promote and suppress excessive , while IL-17 production by certain plasma cell subsets may enhance responses against extracellular pathogens or contribute to autoimmune pathology. The functional role of plasma cells in is evolutionarily conserved across jawed vertebrates, where B cell-derived plasma cell-like effectors generate adaptive responses to combat diverse pathogens. Quantitatively, these cells maintain lifelong serum levels, as exemplified by measles-specific IgG titers with an estimated half-life exceeding 3,000 years, ensuring durable protection against reinfection.

Clinical Significance

Plasma cell neoplasms and disorders

Plasma cell neoplasms represent a group of disorders characterized by the uncontrolled proliferation of clonal plasma cells, leading to excessive production of monoclonal immunoglobulins or chains. , the most common plasma cell , involves the clonal expansion of malignant plasma cells in the , often exceeding 10% of cellularity, which disrupts normal hematopoiesis and . This proliferation results in the classic CRAB symptoms: hypercalcemia due to osteolytic , renal failure from chain cast nephropathy or hypercalcemia, from infiltration and cytokine-mediated suppression, and bone lesions manifesting as lytic lesions, fractures, or . Related premalignant and malignant disorders include (MGUS), , and . MGUS is an asymptomatic precursor condition defined by a serum monoclonal protein less than 3 g/dL, clonal plasma cells less than 10%, and absence of end-organ damage or myeloma-defining events. features an IgM monoclonal protein produced by lymphoplasmacytic cells in the , often causing , , and due to IgM-mediated effects. In , misfolded light chains secreted by clonal plasma cells deposit as amyloid fibrils in organs, particularly the heart and kidneys, leading to and . Dysfunction or overactivity of plasma cells also contributes to autoimmune diseases through the persistent production of pathogenic autoantibodies. In systemic lupus erythematosus (SLE), autoreactive plasma cells secrete antibodies such as anti-double-stranded DNA and anti-Smith, driving immune complex deposition and tissue in organs like the kidneys and skin. Similarly, in , long-lived plasma cells in the synovium produce and anti-citrullinated protein antibodies, perpetuating chronic and via autoantibody-mediated complement and immune cell . Plasma cell deficiencies underlie certain immunodeficiencies, resulting in impaired antibody production and recurrent infections. (CVID) involves defective B-cell differentiation into plasma cells, leading to , reduced switched memory B cells, and paucity of plasma cells in tissues, which predisposes to sinopulmonary infections and . Agammaglobulinemia, often X-linked, features an absence of mature B cells and thus plasma cells due to mutations in the BTK gene, causing profound and susceptibility to bacterial infections from early infancy. Diagnosis of plasma cell neoplasms typically relies on laboratory and histopathological findings. identifies monoclonal proteins (M-spikes) in over 80% of cases, while confirms the immunoglobulin type; urine protein electrophoresis detects light chains (Bence Jones proteins). is essential, revealing clonal plasma cells often positive for CD138, with a threshold of 10% or greater (≥10%) clonal cells supporting a diagnosis of when combined with myeloma-defining events. Post-2020 research has identified prolonged production, such as antinuclear and antiphospholipid antibodies, in survivors, contributing to symptoms like and neurological dysfunction. This immune dysregulation may stem from SARS-CoV-2-induced B-cell hyperactivity, with new-onset autoantibodies persisting beyond 12 months in a subset of patients.

Therapeutic targeting and immunomodulation

Proteasome inhibitors, such as , target the unfolded protein response (UPR) in plasma cells, which are highly sensitive due to their intense immunoglobulin synthesis and proteasomal workload. In , induces by overwhelming the proteasome's capacity to degrade misfolded proteins accumulated during UPR activation. This mechanism has established as a cornerstone therapy, improving response rates and survival in myeloma patients. Monoclonal antibodies like daratumumab target CD38, a surface antigen highly expressed on malignant plasma cells, inducing cell death through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and phagocytosis. Approved for relapsed or refractory multiple myeloma, daratumumab monotherapy yields objective response rates of around 30% in heavily pretreated patients, with enhanced efficacy in combinations. Elotuzumab, targeting SLAMF7 (CD319), promotes natural killer cell-mediated antibody-dependent cellular cytotoxicity against myeloma cells while directly activating NK cells. Expressed uniformly on plasma cells, SLAMF7 enables elotuzumab to achieve progression-free survival benefits when combined with lenalidomide and dexamethasone in relapsed myeloma. Immunomodulatory drugs like lenalidomide enhance immune surveillance by activating T cells and natural killer cells, facilitating clearance of malignant plasma cells in multiple myeloma. Lenalidomide reduces programmed death-1 expression on T and NK cells, boosts interleukin-2 and interferon-γ secretion, and degrades the transcription factor Ikaros to promote cytotoxic responses. This leads to improved overall survival in combination regimens for both newly diagnosed and relapsed disease. Post-2020 emerging therapies include BCMA-targeted chimeric antigen receptor T-cell (CAR-T) therapy, such as idecabtagene vicleucel, approved in 2021 for relapsed or refractory after at least four prior lines of therapy. Targeting (BCMA) on plasma cells, idecabtagene vicleucel achieves deep responses, with 73% overall response rates and 33% complete responses in pivotal trials. Bispecific antibodies, such as (BCMA-CD3) and (GPRC5D-CD3), redirect T cells to lyse malignant plasma cells, yielding response rates exceeding 60% in heavily pretreated patients. Recent 2025 data from real-world studies and combinations (e.g., with ) confirm response rates exceeding 70-80% in relapsed/refractory cases. Inhibitors of APRIL and BAFF disrupt survival niches in the by blocking these cytokines essential for long-lived plasma cell maintenance, leading to rapid depletion of plasma cells in preclinical models. Emerging research also investigates engineered long-lived plasma cells as a therapeutic platform for the sustained delivery of biologics. These therapies offer potential benefits, including enabling long-term or "permanent" effects through one-time or infrequent interventions, addressing lifelong needs in conditions such as autoimmune diseases, HIV, and enzyme deficiencies like hemophilia B. Preclinical studies in humanized mouse models have shown durable engraftment and functional protein secretion for over a year, with as few as 50,000 cells achieving therapeutically relevant titers. Challenges in these approaches include competition for limited bone marrow niches, requiring mild conditioning such as Busulfan to facilitate engraftment, with only about 5% of transferred cells typically retained long-term. Safety issues encompass off-target effects from gene editing tools like CRISPR-Cas9 and potential immune reactions or toxicities from persistent protein secretion. In vivo induction methods, such as via vaccines or adjuvants to promote engineered plasma cell formation, are less advanced but under exploration in preclinical models. In , B-cell depletion with rituximab indirectly reduces plasma cell precursors by targeting CD20-positive B cells, limiting replenishment of autoantibody-secreting plasma cells. This approach depletes short-lived autoreactive plasma cells in diseases like and , though long-lived plasma cells persist. Plasma exchange removes circulating pathogenic antibodies produced by plasma cells, providing rapid symptom relief in antibody-mediated autoimmune conditions such as Guillain-Barré syndrome and . By filtering plasma and replacing it with or donor plasma, this procedure reduces autoantibody levels by 50-70% per session. mRNA vaccines, such as those for SARS-CoV-2, boost the generation of long-lived plasma cells in the bone marrow to enhance humoral memory and sustained antibody production. These vaccines induce robust germinal center responses, leading to antigen-specific memory B cells that differentiate into long-lived plasma cells secreting neutralizing antibodies for months to years post-vaccination.

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