Physiological and pathological roles of the thymus and value of thymectomy in myasthenia gravis: a narrative review

Abstract

Background and objective: Myasthenia gravis (MG) is a well-elucidated autoimmune disorder affecting the neuromuscular junction. Given the relationship between MG and thymic pathologies, with T cell and antibody-mediated pathogenesis, surgical (i.e., thymectomy) and non-surgical approaches remain a mainstay of management of the disease. This review seeks to outline the involvement of the thymus in the development of lymphocytes leading to MG.

Methods: Different databases were searched exploring the role of thymectomy in treatment and outcomes in various MG patient subpopulations, including in ocular versus generalized disease, different age groups, and antibody status.

Key content and findings: Overall, the findings of multiple studies and reviews provide evidence to support the efficacy and long-term success of thymectomy in the management of MG; outcomes have included remission status, symptom severity, and need for adjunctive therapy. However, the heterogeneity in the MG population suggests that there are multiple factors that may confound the results of thymectomy and still need further examination. Separately, other autoimmune diseases develop following thymectomy, and further research is required to elucidate this susceptibility. Finally, our review will discuss the different surgical approaches for thymectomy, including their advantages, limitations, and perioperative complications.

Conclusions: Overall, in light of the known pathogenesis and association of the thymus with MG, thymectomy remains an extremely effective approach for long-term management and improved clinical outcomes.

Keywords: Myasthenia gravis (MG); T cell development; thymectomy; thymic pathologies.

Figure 1

Journey of T cells. Hematopoietic pluripotent stem cells originating in the yolk sac, fetal liver, or bone marrow differentiate into T cell precursor-producing LPCs, which move to thymus for antigen independent T cells maturation. Naive T cells then migrate to secondary lymphoid organs for antigen dependent differentiation and activation. They then leave into the lymph and return to the blood via the thoracic duct. HPC, hemopoietic precursor cell; MPC, myeloid progenitor cell; LPC, lymphoid progenitor cell; MHC, major histocompatibility complex; Treg, regulatory T cell.

Figure 2

T cell development in thymus. Thymic progenitors within the thymus undergo different maturation phases that can be identified by the expression of several cell surface markers. After receiving Notch signaling from cTEC at the corticomedullary junction, DN thymocytes migrate outward in the thymic cortex. Positive selection occurs as DP thymocytes migrate back to the cortico-medullary interface and interact with MHC expressed on cTECs. Thymocytes that have been positively chosen move into the medulla. SP thymocytes are subjected to negative selection within the medulla by being evaluated for reactivity to tissue-restricted self-antigens expressed by mTECs or dendritic cells. Mature T cells leave the thymus through blood or lymph. pTα, pre-T cell receptor alpha; TCR, T cell receptor; V/D/J, variable/diversity/joining; RAG, recombination activating gene; DN, double negative; DP, double positive; cTEC, cortical thymic epithelial cells; MHC, major histocompatibility complex; AIRE, autoimmune regulator; mTEC, medullary thymic epithelial cell; Fezf2, forebrain embryonic zinc finger-like protein 2; TRA, tissue-restricted self-antigen; SP, single-positive; Treg, regulatory T cell.

Figure 3

Pathogenesis of thymic lymphocytic hyperplasia related MG. Excessive NAs released from necrotic cells, exacerbated by impaired macrophage clearance in the thymus, as well as infections via TLRs on thymic epithelial cells, result in chronic over-expression of IFN-β. IFN-β upregulation is the primary orchestrator of thymic alterations: sensitization to AChR by selectively expressing α-AChR expression in TECs; promotes the expression of CXCL13 and CCL21 in the thymus, two chemokines involved in germinal center formation; causes BAFF overexpression; promotes the growth of pathogenic Th17 cells in the thymus. These modifications transform the thymus into a tertiary lymphoid organ with germinal center formation and the production of anti-AChR antibodies, resulting in neuromuscular junction failure. The autoimmune process triggered by the thymus can also disseminate to the periphery, explaining why disease activity persists even after thymectomy. PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; PRRs, pattern recognition receptors; TLR, toll-like receptor; NA, nucleic acid; TEC, thymic epithelial cell; IFN-β, interferon beta; BAFF, B-cell activating factor; IL-23, interleukin 23; CXCL, chemokine family of ligands; HEV, high endothelial venule; AChR, acetylcholine receptor; Treg, regulatory T cell; GC, germinal center; APC, antigen presenting cell; IgG, immunoglobulin; VGSC, voltage-gated sodium channels; SR, sarcoplasmic reticulum; Kv1.4, voltage-gated potassium channel subfamily A member 4; MAC, membrane attack complex; MG, myasthenia gravis.

Figure 4

Pathogenesis of thymoma related MG. The absence of thymic architecture in thymoma, which is required for T-cell maturation and development, contributes to the formation of self-reactive T helper cells via biased positive selection and impaired negative selection. After being appropriately activated, self-reactive T helper cells results in the generation of autoantibodies against native AChR outside of the thymoma. MHC, major histocompatibility complex; AIRE, autoimmune regulator; Treg, regulatory T cell; AChR, acetylcholine receptor; APC, antigen presenting cell; MG, myasthenia gravis.

Figure 5

Pathogenesis of thymic Atrophy related MG. Inflammaging (because to defective negative selection and imbalanced generation of Treg TCR repertoire) and immunosenescence (due to diminished thymopoiesis and the proliferation of oligo-clonal T cells) both contribute to an increase in self-reactive T cells. These self-reactive T cells upon activation in the periphery leads to the generation of pathogenic AChR antibodies and late onset MG. MG, myasthenia gravis; TEC, thymic epithelial cell; MHC, major histocompatibility complex; AIRE, autoimmune regulator; Treg, regulatory T cell; TCR, T cell receptor; AChR, acetylcholine receptor; APC, antigen presenting cell.