Extended abstract: cancer and autoimmunity: survivin as a driver of sustaining autoreactive cells and its role in neoplasia

Myasthenia gravis (MG), an autoimmune disease, involves autoreactive T cells that support the maturation of B cells, leading to the production of autoantibodies. These autoantibodies predominantly target nicotinic acetylcholine receptors (AChRs) on the post synaptic membrane of the neuromuscular junction (NMJ) (1). The self-recognition of these lymphocytes demonstrates the dysregulation of the adaptive immune response and the breakdown in tolerance. While the mechanism causing the breakdown in tolerance is unknown, evidence suggests that the anti-apoptotic pathway may have a role (2).

The recognition of specific antigens by B and T lymphocytes begins at the site of central tolerance. Antigen-specific receptors on these cells enable immune activation, with T cells generating T cell receptors (TCRs) and B cells producing surface-bound immunoglobulins to recognize the antigen (3). As the repertoire pool expands, the immune system protects self-antigens by directing self-reactive lymphocytes to undergo apoptosis. The failure in this highly regulated process of self-tolerance leads to autoimmunity (2). The active immune process initiates with the presentation of the antigen, proceeds by the proliferation of lymphocytes, and terminates as the lymphocytes undergo apoptotic removal. In various autoimmune disorders, including MG, the inability to eliminate or control autoreactive lymphocytes and autoantibodies results in the main pathology (2).

The thymus serves as the selection and maturation site for T cells. The migration of precursor double-negative (CD4⁻CD8⁻) T cells from the bone marrow to the thymus initiates a shift to double-positive (DP) (CD4⁺CD8⁺) expression. Selection is critical for tolerance, allowing DP cells to shift further to single-positive CD4⁺ or CD8⁺ T cells (3). This process generates a pool of T follicular helper cells and T cytotoxic T cells for the adaptive immune response.

In MG, negative selection is impaired, leading to the generation of autoreactive T cells (1). Additionally, the thymus transforms into a site of hyperplasia, forming germinal centers that recruit B cells. B cells undergo multiple rounds of interaction with T follicular helper cells to fine-tune the antibody repertoire and class switch (4). As the B cell population expands, the selection of autoreactive plasma cells and memory B cells generates autoantibodies to AChR and a persistent population of sensitized B cells.

The ability of autoreactive cells to escape apoptosis may involve the action of survivin, a member of the inhibitor of apoptosis proteins (IAPs). Survivin (BIRC5) contains one baculovirus IAP repeat (BIR) domain which is characteristic of the family proteins, making it one of the smallest members. The BIR domain regulates the inhibition of apoptosis as well as directing proliferation. The protein is highly regulated by modifications, containing phosphorylation sites on serine and threonine residues, as well as, several lysine residues that can be modified by ubiquination and acetylation (5).

During proliferation, survivin identifies phosphorylated histone H3, recruits proteins to the chromosomal passenger complex, and binds DNA to mitotic spindles for proper chromosome orientation. The function of survivin in proliferation is demonstrated by an increased expression during embryonic and fetal development but is absent in differentiated tissue. Survivin’s proliferative role is also evident in increased expression in most cancers, leading to drug resistance (6).

With localization to the mitochondria, survivin functions in the inhibition of apoptosis through the association with other IAPs. Although survivin contains only one BIR domain, the protein will form complexes with other IAPs to stabilize their expression. The complex will inhibit caspase activity, specifically caspase 3 and 7 (7).

The immune system incorporates survivin in various immune cells. T cells in the thymus require survivin for the transition from double-negative to DP cells and the formation of memory T cells. B cells also use survivin for proliferative functions, immunoglobulin isotype switching, somatic hypermutation, and differentiation into plasma cells (8,9). Due to its diverse roles in immune cells, survivin’s involvement in autoimmunity has been investigated in diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) (10,11).

To investigate the role of survivin expression in MG, studies on circulating lymphocytes were assessed along with non-autoimmune controls. The results revealed increased survivin expression in CD20⁺ B cells from MG patients compared to non-autoimmune controls (12,13). This expression was also observed on the outer membrane of B cells exposed to the extracellular space (13). Taking information from the cancer field which found secreted survivin in vescicles that promoted the tumor microenvironment (14,15) we propose that the expression of survivin on the outer membrane comes from this pool due to the known secretion of vesicles from lymphocytes (16). Survivin expression in autoreactive cells may contribute to the evasion of tolerance mechanisms. The capacity of survivin to transfer to other cells in an autoimmune context could enable additional autoreactive cells to bypass checkpoints and evade elimination. The expression of survivin on the outer surface of CD20⁺ B cells suggests a potential role for survivin in cell-cell signaling.

To assess survivin’s potential role in driving autoimmunity in the thymus, thymus sections from early-onset MG patients were analyzed for survivin through immunostaining. Survivin expression was detected in germinal centers in hyperplastic thymus samples (12). As seen as survivin’s role in B cell development, the high level of expression may be suggestive of an active germinal center that is expanding the autoreactive B cell population, generating immunoglobulin G (IgG) class switching and producing plasma cells.

The expression of survivin in lymphocytes from MG patients suggests a role in the continued expansion of autoreactive cells and the potential to target the protein for elimination. Survivin has been implicated in other autoimmune conditions such as RA and MS, therefore survivin may play a key role in the dysregulation of the immune system. Ongoing investigations are required to determine the divergent roles it may play and the potential as a therapeutic target.

Acknowledgments

Funding: This work was supported by the Myasthenia Gravis Foundation of America.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Malgorzata Szolkowska, Chul Kim, Mohammad Ashraghi, and Claudio Silva) for “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” published in Mediastinum. The article has undergone external peer review.

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-23-69/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-69/coif). “The Series Dedicated to the 13th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2023)” was commissioned by the editorial office without any funding or sponsorship. L.L.K. has declared consultation with Mimivax. The author has no other conflicts of interest to declare.

Ethical Statement: The author is 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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