Thymic hyperplasia in myasthenia gravis: a narrative review

Introduction

Background

Thymic hyperplasia (TH) refers to an increase in the number of thymic cells, which may or may not result in enlargement of the thymus gland. TH is classified into three recognized forms: (I) true TH, (II) rebound hyperplasia and (III) thymic follicular hyperplasia (TFH). True hyperplasia occurs in newborns and children as a simple enlargement of the thymus beyond the standard norms with retained thymic architecture (1). Rebound hyperplasia is observed as a response to a variety of insults, such as infections and cancer, or treatments including chemotherapy and checkpoint inhibitors. Here again, the microscopic architecture remains normal (2). TFH is characterized by the presence of ectopic lymphoid follicles in the medulla and perivascular spaces. Although seen in other autoimmune diseases, TFH is the hallmark pathology of early-onset MG (EOMG) with initiation of disease prior to the age of 50 years, although also appreciated in older ages. Here, we provide a synopsis of TFH associated with MG.

MG is a T cell-dependent, B cell-mediated disease characterized by the production of autoantibodies that target the neuromuscular junction (NMJ) which lead to muscle weakness (3). The majority of patients have antibodies against acetylcholine receptor (AChR) and a smaller population of patients have antibodies against muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4) or have no detectable autoantibodies, so-called seronegative (SN) MG (4). MuSK and LRP4 MG are not associated with TH; however, some SN have been found to have TFH (5). AChR-MG can be further classified based on disease onset. EOMG, defined as onset before the age of 50 years, predominantly affecting women, whereas late-onset (LOMG), with onset after the age of 50 years, more commonly affects men (6). Approximately 10–30% of MG patients have thymoma associated MG, typically occurring in men over the age of 50 years, although both genders age groups can be affected (4).

Pathogenic antibodies that target the AChR mediate reduction in AChR activity at the NMJ through several mechanisms, including complement activation, blockade of AChR channel function, and antigenic modulation, in which antibodies cross-link AChR and promote their internalization. The specific mechanism of AChR loss depends on the IgG isotype, the affinity for the receptor, and the binding location of binding to the AChR. Due to the polyclonal nature of the autoimmune response, these antibodies can act synergistically to elicit a pathological outcome. This concept is well evident in the lack of correlation between antibody titers and disease severity (7). As well, not all patients respond to complement inhibitors (8,9), suggesting that alternative mechanisms may have a more significant role.

The production of AChR antibodies by B cells is dependent on T cells to help their differentiation into plasma cells. Several subsets of T helper cells (Th) are implicated, including Th1 and Th17 cells which produce proinflammatory cytokines that promote activation of autoreactive B cells and development into long-lived plasma cells (10). T regulatory cells (Tregs), which play a critical role in modulating the immune response, are thought to be imbalanced and functionally impaired in MG, contributing to the breakdown of peripheral tolerance (11). Given the importance of T cells driving MG, the site of maturation of these cells is implicated in the initiation and maintenance of autoimmunity.

Rationale and knowledge gap

The thymus plays a central role in the pathogenesis of AChR-MG as the primary site of immune dysregulation and autosensitization. Thymic abnormalities, including TFH or thymoma, are identified in approximately 80% of AChR-MG subjects (12). TFH is most commonly associated with early-onset cases, occurring in 50–60% of patients with EOMG (13,14). TFH is characterized by the presence of lymphoid follicles containing germinal centers (GCs), specialized structures typically found in secondary lymphoid organs that support the development of memory B cells and antibody secreting cells (ASCs). The association of the degree of TH and AChR anitbody levels, and therapeutic benefit of thymectomy, supports a critical role for the the thymus in the pathogenesis of EOMG (15,16). However, the mechanisms underlying the development of TH are not fully understood.

Objective

The aim of this review is to examine the role of the normal thymus and provide an overview of current knowledge regarding thymic changes associated with TFH in EOMG. We explore key factors contributing to the pathogenesis of TFH, including immune dysregulation, and sex-related influences, such as hormones. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-25-12/rc).

Methods

We conducted a literature search between December 19, 2024 and February 13, 2025 using PubMed as the primary database. The search strategy is summarized in Table 1. Articles were screened for inclusion if they met at least one of the following criteria: (I) discussed thymic pathology in MG; (II) examined TH, specifically in EOMG; or (III) focused on cellular or molecular mechanisms underlying TFH in EOMG.

Content review

Normal thymus

The thymus is a specialized primary lymphoid organ responsible for the development of mature, self-tolerant T cells. The thymus is organized into two anatomically distinct regions: the outer cortex and the inner medulla, which are connected by the corticomedullary junction. This junction contains vasculature and perivascular spaces populated by macrophages, dendritic cells, and B cells. Both the cortex and medulla consist of highly organized networks of thymic stromal cells, including both cortical and medullary thymic epithelial cells (cTECs and mTECs, respectively) alongside smaller populations of other lymphoid cells, such as macrophages, dendritic cells, and B cells, which support thymocyte development at various stages. The cortex is densely packed with immature thymocytes surrounded by cTECs. Macrophages are also present in the cortex, where their primary role is to remove apoptotic thymocytes (17,18). In contrast, the medulla is less dense and primarily consists of more mature thymocytes and mTECs. Additional cell types contribute to the medullary microenvironment to establish T cell tolerance, such as epithelial cells that comprise Hassal’s corpuscles, macrophages, dendritic cells, B cells and rare myoid cells.

B cells constitute a small proportion of the total lymphocytes of the thymus, primarily residing in medulla and cortico-medullary junctions (19,20). Although GCs are absent in normal thymic tissue, plasma cells accumulate in perivascular space with age. These plasma cells can produce antibodies without additional stimulation. These antibodies appear not to be pathogenic and primarily target viral proteins, suggesting a protective immune function rather than a contribution to autoimmunity (21,22).

The thymus plays a crucial role in immune homeostasis by continuously generating naïve T cells throughout life. Thymopoiesis is most active at the time of birth and progressively declines with age. Thymic involution, characterized by a reduction in TECs and accumulation of adipose tissue (23,24), leads to decreased thymic function and output (25). This decline contributes to age-related immunosenescence and increases the risk of diseases associated with aging such as autoimmunity, cancer, and infection (26). Immunosenescence is generally characterized by reduced naïve T cell output, accumulation of memory T cells, and heighted systemic inflammation. Studies of thymectomy underscore the role of the thymus in maintaining immune balance. Infants who undergo thymectomy show immune-related changes similar to those seen in aging, including reduced naïve T cell numbers and increased memory T cells, and diminished T cell diversity (27,28). While neonatally thymectomized subjects also show increased levels of autoantibodies, these children did not develop autoimmune disease in the first decade of life, suggesting peripheral tolerance mechanisms remain intact (29). In adults, thymectomy is warranted in several diseases. One study associated thymectomy with increases risk of death and development of cancer (30); however, this study has been criticized for methodological flaws (31). Thymectomy for AChR antibody-positive MG has been proven to be beneficial (32).

Thymopoiesis

Progenitor cells migrate from the bone marrow into the subcapsular region of the thymic cortex, when they begin a journey toward the inner medulla, undergoing a series of maturation and selection steps before exiting the thymus to populate peripheral lymphoid organs (33) (Figure 1). Throughout development, thymocyte functionality and autoreactivity are tested through a series of interactions between T cell receptors (TCRs) and self-peptides presented on major histocompatibility complexes (MHCs) expressed on thymic stromal cells.

Figure 1 Schematic of T cell development in the thymus. Early thymic progenitors arrive from the bone marrow into the thymus and differentiate into CD4⁻ CD8⁻ DN thymocytes. DN T cells undergo TCR arrangement and develop into CD4⁺ CD8⁺ DP thymocytes. DP thymocytes interact with cTECs expressing self-peptide on MHC molecules. DP T cells express functional TCRs capable of recognizing self-antigen with appropriate affinity undergo positive selection. Positively selected DP migrate to the medulla, where they undergo negative selection through interactions with mTECs to eliminate strongly self-reactive T cells, ultimately differentiating into CD4⁺ or CD8⁺ SP T cells. Mature, self-tolerant cells then exit the thymus and populate the peripheral lymphoid organs. cTEC, cortical thymic epithelial cell; DN, double negative; DP, double positive; MHC, major histocompatibility complex; mTEC, medullary thymic epithelial cell; SP, single negative; TCR, T cell receptor.

cTECs guide early T cell development by producing factors that promote thymocyte differentiation (34,35). Thymocyte maturation stages are defined based on the expression of co-receptors CD4 and CD8. Early thymocytes exhibit a double negative (DN) phenotype. As thymocytes begin TCR gene rearrangement and TCR expression, they develop into CD4⁺ CD8⁺ double positive (DP) T cells, which comprise 60–80% of total thymocytes (36). DP T cells undergo positive selection, where TCRs interact with MHC molecules expressed by cTECs. T cells that express a functional TCR and bind to self-peptides with sufficient affinity to MHC receive survival signals and further mature into CD4⁺ and CD8⁺ single positive (SP) T cells (37). Thymocytes that fail to generate a functional TCR undergo apoptosis.

Chemokines produced by thymic epithelial cells direct SP thymocytes to the medulla (38), where thymocytes undergo negative selection, a process that removes autoreactive T cells and establishes central tolerance (39-41). During negative selection, TCRs are tested against self-antigen presented by mTECs and antigen presenting cells, including dendritic cells and B cells (42-44). SP thymocytes that bind self-peptides with high affinity are eliminated through apoptosis, preventing the escape of highly autoreactive clones. However, a subset of self-reactive SP T cells survives and differentiates into Tregs, which migrate to the periphery to maintain peripheral tolerance (45,46).

The expression of peripheral tissue-restricted self-peptides in mTECs is regulated by the transcription factors AIRE and forebrain-expressed zinc finger 2 (Fezf2) (47,48). The critical roles of AIRE and Fezf2 is demonstrated by the development of autoimmunity in Aire- and Fezf2-deficient mice (49). In humans, AIRE deficiency causes the autoimmune disorder polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which results in multi-organ autoimmunity (50). In addition to mTECs, AIRE is expressed in thymic B cells, which contribute to negative selection by presenting a distinct set of self-antigens not expressed by mTECs (19). Another mechanism for presenting peripheral tissue antigens involves a specialized subset of mTECs known as mimetic cells, which express lineage-specific transcription factors and adopt molecular and morphological characteristics of peripheral cells (51). The interplay of these diverse mechanisms highlights the complexity of thymic selection and underscores its essential role in preventing autoimmunity. Upon completing thymic selection, mature, self-tolerant T cells exit the thymus and populate secondary lymphoid organs, where they participate in immune surveillance and immune response.

TH in MG

TH occurrence in MG subjects is characterized by the presence of lymphoid follicles and GC formation within the medulla (52,53). The degree of TH, defined by the number of lymphoid follicles with GCs that appear across thymic tissue, correlates with circulating AChR antibodies (15), which decline following thymectomy (54,55). These findings suggest that the thymus serves as a key site for the generation of autoreactive immune cells and production of AChR antibody. The active role of the thymus in MG pathogenesis is further supported by a randomized clinical trial demonstrating that thymectomy results in significantly greater clinical improvement compared to treatment with prednisone alone (16). Another hallmark of TFH in MG is the increased presence of high endothelial venules (HEVs) (56), specialized blood vessels typically found in secondary lymphoid organs and chronically inflamed tissues (57), which facilitate the recruitment of immune cells to the thymus.

Pathology of the MG thymus

The current model of thymic pathology in EOMG postulates a complex interplay of immune mechanisms, involving the development of autoreactive T cells that create a proinflammatory environment, facilitating the infiltration and activation of peripheral B cells. The subsequent orchestration of the GCs promotes the maturation of the B cells to produce disease-causing autoantibodies. While the exact mechanisms underlying this process are not fully understood, both innate and adaptive immune pathways are thought to contribute to the initiation and persistence of a proinflammatory milieu.

Histological studies of thymic specimens from individuals with EOMG have revealed significant heterogeneity in the degree of hyperplasia and involution (58). Epidemiological factors, including age, sex, lifestyle, the duration of disease, and treatments such as corticosteroid use, strongly influence the extent of hyperplasia and involution (15). These factors also parallel the clinical heterogeneity observed in MG subjects. The varied histological patterns observed may reflect different stages of disease progression, distinct pathogenic pathways, or environmental influences, underscoring the complexity of EOMG pathogenesis (58).

Accumulation of B cells in thymus and presence of GCs

GCs are specialized structures within B cell follicles that form in secondary lymphoid organs. Within GCs, B cells undergo proliferation, differentiation, and antibody diversification through processes such as somatic hypermutation and class switching, ultimately leading to the production of memory B cells and ASCs. This maturation is supported by other key cell types within the B cell follicle, including follicular dendritic cells and T follicular helper cells, which secrete signals that shape B cell fate.

In EOMG, histological analyses reveal the presence of GCs and infiltrating B cells in the medulla and perivascular space, correlating with AChR antibody levels (59). These findings suggest that AChR antibodies originate from GC responses within the thymus. Transcriptional studies show higher expression of B cell-related genes such as CD20, CD19, and CD79A in MG thymic tissue (60), with phenotypic analyses providing additional evidence of B cell activation and isotype switching (61,62). Immunohistochemical analyses further demonstrate that activated B cells primarily localize in GCs, rather than the medulla (63). Antibodies derived from thymic B cells are polyclonal and exhibit features of somatic hypermutation and clonal diversity (64-66), consistent with ongoing antibody diversification within the thymus. Thymic extracts confirm the presence of AChR antibodies in the thymus (67), and functional assays show that a subset of thymic B cells produce AChR antibodies both spontaneously and in response to stimulation in vitro (61,68-70). Collectively, these findings underscore the GCs in the thymus as a critical site for autoantibody production and B cell-driven pathology in EOMG.

Due to the accumulation of B cells in the MG thymus, several mechanisms driving infiltration of B cells in the hyperplastic thymus have been identified. Enhanced vascularization supports the trafficking of peripheral lymphocytes, with abnormal development of HEVs and lymphatic endothelial vessels (LEVs) facilitating B cell migration (56,71) by promoting expression of chemokines. Gene expression analyses have revealed increased production of B cell-attracting chemokine CXCL13 in the MG thymus compared to non-MG thymic tissue, implicating CXCL13 in GC formation (60,72). Spatial transcriptomics studies have further confirmed a dysregulated chemokine profile in the hyperplastic thymus, including elevated expression of CXCL13, CCR4, CXCR5, and CXCL16 (73). CCL21, a chemokine critical for recruitment of T cells in secondary lymphoid organs (74), was found to be overexpressed around HEVs, suggesting a role in promoting lymphocyte recruitment to GCs (61,63). While the factors leading to chemokine overexpression in the thymus are unclear, microRNA (miRNA) analyses suggest a regulatory role. Downregulation of miR-548k inversely correlates with CXCL13 expression in the MG thymus (75) and miR-7 inversely correlates with CCL21 (76). These findings highlight a role for miRNAs in regulating expression of specific chemokines that facilitate peripheral lymphocyte recruitment to the thymus in EOMG.

Autosensitization process

The presence of autoreactive B and T cells, along with autoantigen in the thymus, has led to the hypothesis that the thymus serves as the site where autoimmune response is initiated (77). AChR subunits are expressed in mTECs and at higher levels in muscle-like cells known as myoid cells (78). Myoid cells are located near GCs surrounded by infiltrating T cells and B cells (79-81). While mTECs and myoid cells are well-recognized sources of AChR autoantigen in the thymus, recent findings suggest that muscle-mimetic cells may also contribute (51). Although their role in MG pathogenesis remains speculative, their presence in the human thymus raises the possibility that they participate in autosensitization.

These observations have led to a multi-step model of intrathymic pathogenesis in EOMG, proposed by Willcox et al. (82). In the first step, infiltrating T cells localize to the perivascular space and hyperplastic medullary epithelial regions, where they may gain access to AChR-expressing mTECs (81). Although it remains unclear what drives initial T cell activation, it is proposed that T cells primed by mTECs subsequently activate B cells to produce autoantibodies. In the second step, these autoantibodies target AChR on myoid cells, leading to complement activation (81,82). Upregulation of complement components and decreased expression of complement regulators on myoid cells has been associated with complement-mediated damage and release of native autoantigen (83). Myoid cells are closely associated with T cells and dendritic cells (81,84), which are thought to cross present antigen to T cells (85). This cascade ultimately drives GC formation, promoting the expansion and diversification of autoreactive plasma cells. Ultimately, this model implicates multiple thymic cell types in the dysregulated immune response within the hyperplastic thymus, highlighting the complex process of autosensitization in EOMG.

Activation of interferons (IFNs) in the hyperplastic thymus

Several studies have linked the activation of the innate immune system to thymic pathology in MG by promoting antigen exposure, GC formation, and immune dysregulation (60,86-88). A defining feature of the hyperplastic thymus is a strong IFN signature, characterized by high expression of IFN-α- and IFN-β-regulated genes (60,89). IFN-β and IFN-γ contribute to MG pathogenesis by modulating expression of AChR in mTEC and myoid cells, thereby increasing availability of antigen for autoreactive B and T cells. In addition, IFNs enhance the production of chemokines such as CXCL13 and CCL21 by mTECs, which facilitate the recruitment of peripheral lymphocytes to the thymus (89,90).

TLR signaling and potential triggers

Additionally, the hypothesis of MG linked to an anti-viral immune response is supported by evidence of dysregulated toll-like receptor (TLR) signaling. One of the primary drivers of IFN production is the engagement of pattern recognition receptors (PRRs), such as TLRs, which recognize viral and bacterial pathogens. Studies have shown that the EOMG thymus exhibits overexpression of TLR3 and TLR4, suggesting a dysregulated immune activation. Stimulation of TLR4 on mTECs induces expression of Th17-associated cytokines and as well as chemokines CCL17 and CCL22 (88). Similarly, activation of TLR3 specifically upregulates the alpha subunit of AChR in mTECs and increases IFN-β production (91), reinforcing a link between innate immune activation and autoantigen presentation.

Epstein-Barr virus (EBV) infection may contribute to the initiation of MG through the upregulation of TLR7 and TLR9 in the MG thymus. Cavalcante et al. demonstrated that TLR7 expression correlates with levels of IFN-β in patients with latent EBV infection (92). The persistent reactivation of EBV may promote immune dysregulation through TLR signaling and increased type I IFN production. Additionally, TLR7 and TLR9 are upregulated in GC B cells and mTECs in the MG thymus. While these findings support the hypothesis of an anti-viral immune response contributing to thymic pathology, a direct causal link between viral infection and MG development is not established (93). Moreover, one study failed to detect evidence of EBV infection (94).

Beyond viral infections, an alternative mechanism has been proposed in which endogenous nucleic acids serve as ligands for innate immune activation in the thymus. Under normal conditions, apoptotic cells undergoing selection are cleared by thymic macrophages, preventing the accumulation of cellular debris that could trigger immune response (18). However, Payet et al. showed that co-culturing necrotic thymocytes with mTECs induce expression of IFN-β and the α AChR subunit, suggesting that a defective clearance of apoptotic cells may activate an IFN-I response. Decreased numbers of macrophages in the MG thymus may impair apoptotic cell clearance, leading to increased exposure of self-nucleic acids and triggering activation of PRRs (95). Supporting this idea, miR-146a, a miRNA that negatively regulates TLR signaling, was found to be downregulated in the MG thymus (96), potentially contributing to excessive activation of innate immune pathways.

Taken together, these findings highlight the critical role of innate immune activation in shaping TFH in MG, involving contributions from IFN signaling, complement activation, PRR engagement, and defective clearance of apoptotic cells (Figure 2). Although current evidence suggests that viral infections or endogenous nucleic acid accumulation could serve as potential disease triggers, further studies are needed to establish causality and determine whether targeting innate immune pathways represents a viable therapeutic strategy for MG.

Figure 2 Mechanisms of thymic pathology in MG thymus. The EOMG thymus is characterized by a strong IFN signature. Upregulation of TLRs promote IFN expression, as well as induction of chemokines and AChR subunit expression by mTEC. TLRs in the thymus are thought to be activated by either viral infection or impaired clearance of apoptotic thymocytes, resulting from reduced macrophage numbers in the MG thymus. Increased chemokine expression and HEVs promote infiltration of peripheral T cells and B cells into the thymus. By mechanisms that remain unclear, infiltrating T cells become activated and are primed by AChR-expressing mTECs. Autoreactive T cells then activate B cells to produce antibodies against AChR. Autoantibodies target AChR-expressing myoid cells, leading to complement activation. Damaged myoid cells release autoantigen, which is taken up by surrounding dendritic cells that internalize antigen–antibody complexes. The accumulation of autoreactive T cells, B cells, and dendritic cells promote the formation of GCs. The GC reaction drives B cell affinity maturation, somatic hypermutation, and the generation of production of plasma cells that produce pathogenic AChR antibodies. AChR, acetylcholine receptor; EOMG, early-onset myasthenia gravis; GC, germinal center; HEV, high endothelial venule; IFN, interferon; MG, myasthenia gravis; mTEC, medullary thymic epithelial cell; TLR, toll-like receptor.

Role of sex hormones

Approximately 80% of EOMG patients with TFH are women (15), implicating biological sex as an important factor in the development of thymic pathology. Hormonal influences, particularly estrogen, appear to contribute to this female predominance by influencing both immune regulation and central tolerance within the thymus (97-99). Estrogen exerts its effects through estrogen receptors (ER-α and ER-β), which plays a role in modulating immune responses (100). Notably, expression of ER-α is increased in the thymus and both ER-α and ER-β in the peripheral blood mononuclear cells (PBMCs) of MG subjects compared to controls, with a pro-inflammatory cytokine environment potentially supporting this upregulation (97). Heightened ER signaling may enhance B cell activity and alter T cell responses, promoting an immune environment that favors autoimmunity. In addition to ER-mediated effects, estrogen itself has also been shown to suppress the expression of AIRE in mTECs, a key factor necessary in promoting self-tolerance (98). Reduced AIRE expression may impair negative selection of autoreactive lymphocytes, thereby contributing to autoimmunity in MG. Together, these findings suggest that estrogen promotes autoimmunity in MG by both enhancing immune cell activity through ER signaling and disrupting central tolerance through AIRE suppression.

Sexual dimorphism in thymic biology and the immune response

Emerging evidence suggests that sex-based differences in thymic development and immune function contribute to disease susceptibility. These differences begin early in postnatal life, influencing thymic architecture and rates of thymic involution, and may shape immune responses and disease risk later in life (101). Gene expression in the developing thymus differs between sexes, with females exhibiting higher expression of genes involved in metabolism and antigen presentation, whereas males showed increased expression of genes linked to proinflammatory signaling and adipogenesis. In addition, females have a greater abundance of DP T cells and cTECs, while males have higher numbers of mTECs and SP T cells (101). These findings suggest that sex-based variations in thymocyte development and selection may directly influence adaptive immune responses and susceptibility to MG.

A key question in immunology is whether sex-based differences in thymic biology persist into adulthood and how they shape composition of the peripheral T cell compartment, immune tolerance, and T cell function. Observed differences in thymic architecture, gene expression, and cellular composition between males and females suggest that thymic output may differ between the sexes, potentially contributing to long-term immune system differences. For example, females demonstrate higher CD4:CD8 T cell ratios and lower numbers of Tregs compared to males (102), supporting the hypothesis that thymic selection mechanisms influence circulating T cell populations. Sex hormones have significant impact on shaping the differences in T cell development (103), with testosterone promoting AIRE expression and estrogen having an inverse effect (98,104). Additionally, murine models suggest sex hormones may also impact the TCR repertoire, thereby impacting T cell diversity and immune responses (103).

These differences extend beyond thymic output. Females exhibit stronger proinflammatory responses compared to males (105), which may contribute to the initiation of thymic pathology. A more robust interferon response in females may play a role in the IFN signature observed in the hyperplastic thymus, promoting inflammation. Stronger T cell responses may result in greater thymic T cell infiltration in EOMG, increasing the risk of developing autoimmune disease. In contrast, males demonstrate a higher proportion of Tregs with greater suppressive capacity, potentially providing greater protection against autoimmunity. However, the reduced inflammatory immune response in males is associated with greater susceptibility to infection and non-reproductive cancers (105). Given that Tregs isolated from the EOMG thymus exhibit reduced functionality (11,106,107), sex may play a key role in shaping the extent of Treg dysfunction and overall disease risk.

Novel approaches to advance understanding of TFH

Studying thymic biology presents significant challenges due to the cellular complexity of the microenvironment and the lack of in vitro models. However, novel technologies offer new opportunities to dissect the thymic microenvironment in MG, allowing for more detailed characterization of cellular interactions, immune regulation, and pathology. Techniques such as single cell RNA sequencing, spatial transcriptomics, and multiplex imaging offer high resolution insights into the diversity of B and T cells infiltrating the hyperplastic thymus.

Spatial transcriptomic analysis of thymoma has characterized the medullary environment associated with GC formation in thymoma-associated MG (TAMG) (73) and revealed similarities between the thymic microenvironments of EOMG and TAMG, particularly in immune composition and chemokine expression patterns. However, a major limitation of this study is the lack of a single-cell reference dataset from the EOMG thymus, which impairs precise identification of cellular populations. Given the challenges in studying thymic biology, integrating multi-omic approaches into MG research could bridge critical knowledge gaps, providing deeper understanding of the mechanisms driving TFH and the autoimmune response.

The development of in vitro thymic organoids offers promising new tools for studying T cell development and mechanisms underlying thymic pathology. Traditional two-dimensional organoid models have faced several challenges, including limited cellular diversity, loss of functionality over time, and absence of critical elements of thymic architecture (108). Recent advancements have improved the thymic organoid models through the incorporation of multiple progenitor cell types to enhance cellular diversity, optimize culture conditions to support T cell development, and implement novel three dimensional techniques (108-110). As these models continue to evolve, they may provide crucial insights into the development of TFH in EOMG.

Conclusions

A refined understanding of TFH in MG not only highlights the complexity of the disease but also emphasizes the need for personalized therapeutic approaches. The variation in thymic histology across patients with MG and the lack of response to thymectomy in upwards of one-third of patients support a variation of disease mechanisms among individuals (16,111). The advancements in new technologies will pave the way for future research focused on elucidating the specific molecular and cellular pathways involved in the development of TFH in MG, potentially leading to more targeted and effective treatments.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Malgorzata Szolkowska) for “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” published in Mediastinum. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-25-12/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-25-12/prf

Funding: The work was supported by the MGNet a member of the Rare Disease Clinical Research Network Consortium (RDCRN) (NIH U54 NS115054).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-12/coif). “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” was commissioned by the editorial office without any funding or sponsorship. P.M.S. is supported by a career development award from the American Academy of Neurology, Myasthenia Gravis Foundation of America, and American Brain Foundation. H.J.K. is a consultant for Roche, Takeda, UCB Pharmaceuticals, Canopy Immunotherapeutics, and Merck. Argenx provides an unrestricted educational grant to George Washington University. He is an unpaid consultant for Care Constitution. H.J.K. has equity interest in Mimivax, LLC. H.J.K. is principal investigator for the Rare Disease Network, MGNet supported by NIH grant U54NS115054. L.L.K. has a 1% stock option in MimiVax which has no value. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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