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The role and mechanism of IL‑35 in myasthenia gravis (Review)

  • Authors:
    • Jing Mao
    • Lin-Ming Zhang
    • Yan-Lin Zhu
    • Shu-Ji Gao
    • Ming-Wei Liu
  • View Affiliations / Copyright

    Affiliations: Department of Neurology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Department of Emergency, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Department of Emergency, Dali Bai Autonomous Prefecture People's Hospital, Dali, Yunnan 671000, P.R. China
    Copyright: © Mao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 98
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    Published online on: February 17, 2026
       https://doi.org/10.3892/ijmm.2026.5769
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Abstract

Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by impaired neuromuscular junction transmission, leading to fluctuating muscle weakness and fatigue. This condition is driven primarily by autoantibodies targeting the acetylcholine receptor at the neuromuscular junction. These antibodies are predominantly generated through a T‑cell‑dependent pathway, initiating immunomodulatory responses via complement activation. Cytokines and inflammatory mediators also play pivotal roles in the pathogenesis of MG. Recently, increasing attention has been given to the involvement of cytokines in autoimmune diseases. Interleukin‑35 (IL‑35), an immunoregulatory cytokine, is critical in various inflammatory and autoimmune conditions. It modulates immune responses by promoting Treg proliferation, enhancing their immunosuppressive functions, inhibiting Th17 cell differentiation, and reducing proinflammatory cytokine levels. IL‑35 is thus pivotal in the onset and progression of MG. The present review outlines the key functions of IL‑35 in MG pathogenesis and the impact of IL‑35 on the treatment and prognosis of myasthenia gravis, explores its therapeutic potential, and assesses its prognostic value, offering insights into its mechanisms and implications for treatment.
View Figures

Figure 1

IL-35 producer and effector cells.
IL-35 modulates immune responses by regulating the functions of
various immune cells (such as Tregs, Bregs, macrophages, T cells,
and B cells). i) Regulation of immune cells: Tregs: IL-35 promotes
Treg proliferation and enhances their immunosuppressive function.
Breg: IL-35 induces Breg expansion and increases the secretion of
the anti-inflammatory cytokines IL-10 and IL-35. iTr35: IL-35
induces the generation of iTr35 cells, which exhibit a CD11b+
phenotype, secrete IL-10, and downregulate antigen-presenting
molecules (MHC I/II, CD40/CD86), further suppressing immune
responses. ii) Regulation of macrophage polarization: IL-35
inhibits the activation and function of M1 macrophages. IL-35
promotes the differentiation of M2 macrophages (anti-inflammatory
type), enhancing tissue repair and immunosuppression. iii)
Inhibition of B-cell proliferation and antibody (IgG) production:
IL-35 reduces humoral immune responses by attenuating B-cell
activity. iv) Effects on CD8+ T cells: IL-35 increases the number
of CD8+ T cells by inhibiting apoptosis or promoting cell survival.
IL-35 reduces the proliferative capacity and secretion of Th1-type
cytokines (such as IFN-γ). Increased expression of exhaustion
markers (LAG-3, TIM-3, and PD-1) leads to T-cell exhaustion. v)
Effects on CD4+ T cells: IL-35 inhibits the differentiation and
proliferation of Th1, Th2, and Th17 subsets. IL-35 reduces the
expression of related cytokines (IFN-γ, IL-17, IL-4 and IL-12) and
key transcription factors (T-bet, GATA-3, and RORγt). p35 + Ebi3:
These two subunits of IL-35 together form the functional cytokine
IL-35. IL-35: The core regulatory molecule that induces an
immunosuppressive microenvironment through multiple pathways. '↑'
indicates upregulation or promotion. '↓' indicates downregulation
or inhibition. iTr35, inducible inhibitory T cells; Tregs,
regulatory T cells; Bregs, Regulatory B cells; DC, dendritic cell;
MHC-II, major histocompatibility complex class II; LAG3, lymphocyte
activation gene 3; TIM-3, T cell immunoglobulin and mucin domain-3;
PD1, programmed cell death 1; T-bet, T-box expressed in T cells;
ATA-3, GATA binding protein 3; RORYt, transcription factors
retinoic acid related orphan receptor gamma transcription; EBI3,
Epstein-Barr virus-induced gene 3; IFN-γ, interferon-gamma; IL,
interleukin; Th, T-helper type; P35, cyclin-dependent kinase 5
regulatory subunit 1.

Figure 2

The IL-12 cytokine family and its
heterodimeric receptors. The IL-12 family members are heterodimers
formed by different combinations of an α subunit (p19, p28, p35)
and an α β subunit (p40, Ebi3): IL-12 (p35/p40), IL-23 (p19/p40),
IL-27 (p28/Ebi3), and IL-35 (p35/Ebi3). The α subunits share the
four-helix bundle structure characteristic of the IL-6 superfamily,
whereas the β subunits are structurally related to the
extracellular domains of type I cytokine receptors. IL-12, IL-23,
IL-27, and IL-35 can stimulate binding to their respective
receptors to activate JAK/STAT signaling. Activated JAK
phosphorylates and dimerizes STAT, and the dimerized STAT is
transferred to the nucleus to regulate the transcription and
expression of genes, stimulating further inflammatory release.
IL-12 and IL-23 function primarily as
pro-inflammatory/pro-stimulatory cytokines, amplifying inflammatory
signals and being crucial for immune balance and inflammatory
responses. IL-27 has dual pro- and anti-inflammatory properties: it
promotes Th1 differentiation while inhibiting Th17 cell
development. Since IL-27 signals through a receptor complex
involving gp130, it is also often classified within the IL-6
family. IL-35, which is secreted mainly by regulatory T cells, has
anti-inflammatory functions. The upward arrow (↑) indicates an
increase; the downward arrow (↓) indicates a decrease. TYK2,
tyrosine kinase 2; JAK1, Janus kinase 1; RORC, RAR-related orphan
receptor C; STAT, signal transducer of activation; CDK5R1,
cyclin-dependent kinase 5 regulatory subunit 1; EBI3, Epstein-Barr
virus-induced gene 3; TBX21, T-box transcription factor 21; GATA3,
GATA binding protein 3; IFN, interferon; P, phosphorylation.

Figure 3

IL-35 signaling pathways in B
lymphocytes and T lymphocytes. IL-35 signaling pathway in B cells:
IL-35 binds to the IL-12Rβ2/IL-12Rβ1 receptor on the B-cell
surface, activating JAK, which subsequently leads to the
phosphorylation of STAT1 and STAT3 (forming pSTAT1 and pSTAT3).
Phosphorylated STAT proteins translocate into the nucleus, regulate
gene expression and prompt B cells to produce IL-35 and IL-10,
which participate in immune regulation. IL-35 signaling pathway in
T cells: IL-35 binds to receptors on the T-cell surface, including
the IL-12Rβ2/IL-27Rα, IL-12Rβ2/gp130 and gp130/gp130 homodimers.
This activates JAK, leading to the phosphorylation of STAT1 and
STAT4 (forming pSTAT1 and pSTAT4). Phosphorylated STAT proteins
enter the nucleus, driving the expression of IL-35-related genes in
T cells and exerting immunoregulatory functions (such as
suppressing excessive immune responses). STAT, signal transducer of
activation; p, phosphorylation; JAK, Janus kinase.

Figure 4

Anti-inflammatory effects of IL-35
and IL-37 on immune system cells. IL-35, which is derived primarily
from Tregs and Bregs, exerts its anti-inflammatory effects mainly
through the regulation of adaptive immune cells. In T cells, IL-35
potently suppresses the activation and function of Th1 and Th17
cells. Th1 cells block the STAT4 signaling pathway, reducing the
production of IFN-γ. Th17 cells inhibit the STAT3/RORγt pathway,
decreasing the secretion of IL-17A and IL-12. Concurrently, IL-35
promotes proliferation and enhances the function of Foxp3+ Tregs,
establishing a positive feedback regulatory loop. In B cells, IL-35
inhibits plasma cell differentiation and antibody production while
also inducing the differentiation of Bregs. These Bregs further
mediate immunosuppression by secreting anti-inflammatory cytokines
such as IL-10. Additionally, IL-35 acts on dendritic cells,
downregulating the expression of MHC class II molecules and
costimulatory molecules, thereby attenuating their
antigen-presenting capacity. STAT, signal transducer of activation;
RORC, RAR-related orphan receptor C; IFN, interferon; Neu,
neutrophil; MQ, macrophages; DC, dendritic cell; RORYt,
transcription factors retinoic acid related orphan receptor gamma
transcription; Mono, monocyte; Tregs, regulatory T cells; Bregs,
Regulatory B cells; MHC-II, major histocompatibility complex class
II; iTr35, inducible inhibitory T cells; TGF-β, transforming growth
factor β; FOXP3, factor forkhead box protein 3.

Figure 5

Regulation of
inflammatory/anti-inflammatory signaling pathways by IL-35 and
IL-37. Under inflammatory conditions, the MAPK and NF-κB pathways
are activated through inflammatory cytokine receptors (especially
IL-18R), TLR ligands, and cellular environmental stress. The
precursor IL-35 is subsequently generated. Mature IL-35 binds to
the cell surface receptor complex gp130/IL-12Rβ2, thereby
inhibiting p38 MAPK. IL-35 reduces the production of
proinflammatory cytokines by suppressing inflammatory signaling
pathways. IL-37 inhibits the TLR/MyD88 pathway by blocking IL-18
signal transduction. The black and purple arrows indicate
positive/activating effects, whereas the red lines and blunt ends
indicate negative/inhibitory effects. IL, interleukin; IL-18R,
IL-18 receptor; TLR, Toll-like receptor; MyD88, Myeloid
differentiation primary response 88; IRAK, interleukin-1
receptor-associated kinase; TRAF, TNF receptor-associated factor 6;
NF-κB, Nuclear factor kappa-B; IκB, Inhibitor of NF-κB; IKK, IκB
kinase; MAPK, Mitogen-activated protein kinase; AP-1, Activator
protein-1; MKK, MAP kinase kinase; P, phosphorylation; Ub,
Ubiquitination.

Figure 6

Bregs mediate immune responses
through IL-10, TGF-β, and/or IL-35. IL-10 secreted by Bregs
inhibits the differentiation of Th1/Th17 cells and enhances Th2
polarization. IL-10 from Bregs also suppresses the activation of
macrophages and dendritic cells. IL-35 secreted by Bregs inhibits
Th1/Th17 activation and promotes the expansion of Tregs. TGF-β
secreted by Bregs inhibits Th1 activation and facilitates the
expansion of Tregs. TGF-β, transforming growth factor-β; IL,
interleukin; Tregs, regulatory T cells; Bregs, regulatory B cells;
Th, T-helper type.

Figure 7

Immunosuppressive mechanisms mediated
by Tregs. Tregs modulate immune responses by suppressing the
functions of Teffs and APCs through multiple mechanisms, including
i) interactions between CTLA-4 and LAG-3 expressed by Tregs and the
CD80/86 costimulatory molecules and MHC class II molecules
expressed by DCs, respectively, to inhibit DC function and
maturation, thereby inducing IDO generation and suppressing Teff
cell activation. ii) Metabolic disruption: Tregs can disrupt
metabolic processes by expressing the ectoenzymes CD39/CD73,
leading to the generation of adenosine, which binds to the A2AR
exposed on effector T cells, or by IL-2 deprivation. iii)
Production and secretion of the anti-inflammatory cytokines IL-10,
IL-35, and TGF-β, which inhibit Th1 and Th17 immune responses and
the production of IFN-γ and IL-17, respectively. iv) Direct
cytotoxicity: Tregs can also directly kill effector cells by
releasing granzyme A, granzyme B, and perforin, thereby inducing
target apoptosis. APC, antigen-presenting cell; TGF-β, transforming
growth factor-β; A2AR, adenosine A2A receptor; IL, interleukin;
IFN, interferon; Teff, effector T cell; Treg, regulatory T cell;
CD, cluster of differentiation; IDO, indoleamine 2,3-dioxygenase;
DC, dendritic cell; CTLA-4, cytotoxic T-lymphocyte antigen 4; LAG3,
lymphocyte-activation gene 3; MHC, major histocompatibility
complex.
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Copy and paste a formatted citation
Spandidos Publications style
Mao J, Zhang L, Zhu Y, Gao S and Liu M: The role and mechanism of IL‑35 in myasthenia gravis (Review). Int J Mol Med 57: 98, 2026.
APA
Mao, J., Zhang, L., Zhu, Y., Gao, S., & Liu, M. (2026). The role and mechanism of IL‑35 in myasthenia gravis (Review). International Journal of Molecular Medicine, 57, 98. https://doi.org/10.3892/ijmm.2026.5769
MLA
Mao, J., Zhang, L., Zhu, Y., Gao, S., Liu, M."The role and mechanism of IL‑35 in myasthenia gravis (Review)". International Journal of Molecular Medicine 57.4 (2026): 98.
Chicago
Mao, J., Zhang, L., Zhu, Y., Gao, S., Liu, M."The role and mechanism of IL‑35 in myasthenia gravis (Review)". International Journal of Molecular Medicine 57, no. 4 (2026): 98. https://doi.org/10.3892/ijmm.2026.5769
Copy and paste a formatted citation
x
Spandidos Publications style
Mao J, Zhang L, Zhu Y, Gao S and Liu M: The role and mechanism of IL‑35 in myasthenia gravis (Review). Int J Mol Med 57: 98, 2026.
APA
Mao, J., Zhang, L., Zhu, Y., Gao, S., & Liu, M. (2026). The role and mechanism of IL‑35 in myasthenia gravis (Review). International Journal of Molecular Medicine, 57, 98. https://doi.org/10.3892/ijmm.2026.5769
MLA
Mao, J., Zhang, L., Zhu, Y., Gao, S., Liu, M."The role and mechanism of IL‑35 in myasthenia gravis (Review)". International Journal of Molecular Medicine 57.4 (2026): 98.
Chicago
Mao, J., Zhang, L., Zhu, Y., Gao, S., Liu, M."The role and mechanism of IL‑35 in myasthenia gravis (Review)". International Journal of Molecular Medicine 57, no. 4 (2026): 98. https://doi.org/10.3892/ijmm.2026.5769
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