Immunoregulatory Cells in Myasthenia Gravis

Abstract

Myasthenia gravis (MG) is a T cell-dependent, B-cell mediated autoimmune disease caused by antibodies against the nicotinic acetylcholine receptor or other components of the post-synaptic muscle endplate at the neuromuscular junction. These specific antibodies serve as excellent biomarkers for diagnosis, but do not adequately substitute for clinical evaluations to predict disease severity or treatment response. Several immunoregulatory cell populations are implicated in the pathogenesis of MG. The immunophenotype of these populations has been well-characterized in human peripheral blood. CD4⁺FoxP3⁺ regulatory T cells (Tregs) are functionally defective in MG, but there is a lack of consensus on whether they show numerical perturbations. Myeloid-derived suppressor cells (MDSCs) have also been explored in the context of MG. Adoptive transfer of CD4⁺FoxP3⁺ Tregs or MDSCs suppresses ongoing experimental autoimmune MG (EAMG), a rodent model of MG, suggesting a protective role of both populations in this disease. An imbalance between follicular Tregs and follicular T helper cells is found in untreated MG patients, correlating with disease manifestations. There is an inverse correlation between the frequency of circulating IL-10-producing B cells and clinical status in MG patients. Taken together, both functional and numerical defects in various populations of immunoregulatory cells in EAMG and human MG have been demonstrated, but how they relate to pathogenesis and whether these cells can serve as biomarkers of disease activity in humans deserve further exploration.

Keywords: circulating; follicular; myasthenia gravis; regulatory B cells (Breg); regulatory T cells (Treg).

Figure 1

Suppressive Mechanisms of Immunoregulatory Cells. (A) Tregs secrete anti-inflammatory cytokines IL-10, transforming growth factor beta (TGF-β), and IL-35, thus inhibiting target effector T (Teff) cells. Production of perforin and granzyme causes Teff cell apoptosis. Constitutively high expression of CD25 depletes IL-2, which attenuates Teff cell proliferation. Interaction with dendritic cells (DCs) via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte-activation gene 3 (LAG-3) downregulates CD80/CD86 expression, which induces upregulation of indoleamine 2,3-dioxygenase (IDO). This enzyme expressed by DCs converts tryptophan to kynurenine, leading to Teff cell exhaustion. Surface expression of CD39 and CD73 converts extracellular adenosine triphosphate (ATP) to immunosuppressive adenosine and adenosine monophosphate (AMP). Tregs can also suppress autoreactive B cells via programmed death (PD) ligands 1 and 2 (PD-L1/2). (B) In germinal centers (GCs), both follicular helper T (Tfh) and follicular regulatory T (Treg) cells express transcription factor B cell lymphoma 6 (BCL6), surface marker PD-1, and C-X-C motif chemokine receptor 5 (CXCR5). Tfh cells produce IL-4, IL-21, and interferon gamma (IFNγ). They provide help signals to GC B cells and promote their differentiation into antibody-secreting plasma cells and memory B cells. Tfr cells regulate GC responses by inhibiting both Tfh and B cells via anti-inflammatory IL-10 and TGF-β. Tfr cells can also directly suppress GC B cells via CTLA-4. (C) Myeloid-derived suppressor cells (MDSCs) produce high levels of inducible nitric oxide synthase (iNOS), arginase-1 (ARG1), and reactive oxygen species (ROS). iNOS generates nitric oxide (NO), which reacts with ROS to produce peroxynitrite (PNT). ARG1 converts L-arginine to L-ornithine. IDO expressed by MDSCs sequesters cysteine. All of these can inhibit Teff cells. MDSCs also induce Treg expansion via IL-10 and TGF-β. In addition, MDSCs suppress maturation, migration, and antigen presentation of DCs. (D) Regulatory B cells (Bregs) inhibit activation and differentiation of pro-inflammatory target cells, including Teff cells, DCs and monocytes via secretion of IL-10, IL-35, and TGF-β. Bregs can also directly suppress Teff cells via CTLA-4 and CD80/CD86 interaction. On the other hand, Bregs induce expansion and differentiation of Tregs and invariant natural killer T (iNKT) cells. (Suppressive mechanisms in this figure refer to general contexts, including homeostasis and all inflammatory conditions.)