Roles of cytokines and T cells in the pathogenesis of myasthenia gravis

Activated T cells, B cells, plasma cells, and related cytokines play central roles in the production of pathogenic autoantibodies in myasthenia gravis (MG). T helper 17 (Th17) cells, follicular Th (Tfh) cells, and related cytokines are upregulated, whereas regulatory T (Treg) cells and related cytokines are downregulated. Chronic inflammation by Th17 cells, the promotion of autoantibody production from B cells and plasma cells by Tfh cells or B‐cell‐related cytokines, and the activation of the immune response by dysfunction of Treg cells may be involved in the pathogenesis of MG.

Summary

Myasthenia gravis (MG) is characterized by muscle weakness and fatigue caused by the presence of autoantibodies against the acetylcholine receptor (AChR) or the muscle‐specific tyrosine kinase (MuSK). Activated T, B and plasma cells, as well as cytokines, play important roles in the production of pathogenic autoantibodies and the induction of inflammation at the neuromuscular junction in MG. Many studies have focused on the role of cytokines and lymphocytes in anti‐AChR antibody‐positive MG. Chronic inflammation mediated by T helper type 17 (Th17) cells, the promotion of autoantibody production from B cells and plasma cells by follicular Th (Tfh) cells and the activation of the immune response by dysfunction of regulatory T (T_reg) cells may contribute to the exacerbation of the MG pathogenesis. In fact, an increased number of Th17 cells and Tfh cells and dysfunction of T_reg cells have been reported in patients with anti‐AChR antibody‐positive MG; moreover, the number of these cells was correlated with clinical parameters in patients with MG. Regarding cytokines, interleukin (IL)‐17; a Th17‐related cytokine, IL‐21 (a Tfh‐related cytokine), the B‐cell‐activating factor (BAFF; a B cell‐related cytokine) and a proliferation‐inducing ligand (APRIL; a B cell‐related cytokine) have been reported to be up‐regulated and associated with clinical parameters of MG. This review focuses on the current understanding of the involvement of cytokines and lymphocytes in the immunological pathogenesis of MG, which may lead to the development of novel therapies for this disease in the near future.

Introduction

Myasthenia gravis (MG) is an autoimmunological disorder of the neuromuscular junction and is clinically characterized by muscle weakness and fatigability [1]. Most patients with MG have autoantibodies against the muscle nicotinic acetylcholine receptor (AChR), and some have autoantibodies against muscle‐specific tyrosine kinase (MuSK) or lipoprotein receptor‐related protein 4 (LRP4) [1]. Although anti‐LRP4 antibodies block the agrin–LRP4 interaction and thereby inhibit AChR clustering in the membrane [1], the pathogenicity of anti‐LRP4 antibodies in MG is not yet established. MG is divided into subgroups: early‐onset MG (age at onset ≤ 49 years without thymoma), late‐onset MG (age at onset ≥ 50 years without thymoma) and thymoma‐associated MG. Patients with early‐onset MG often show thymic follicular hyperplasia and respond to thymectomy; however, patients with late‐onset MG rarely show thymic hyperplasia. Nearly all patients with thymoma‐associated MG (a paraneoplastic disease) have anti‐AChR antibodies. MG can be also divided into ocular or generalized MG, according to the affected muscles [1]. B cells and plasma cells, depending on T helper (Th) cells sensitized to AChR or MuSK, play central roles in the production of pathogenic autoantibodies, which act upstream of the immunological pathogenesis of MG [1, 2]. The complement‐mediated destruction of the neuromuscular junction by anti‐AChR antibodies has gathered increasing attention, and is currently considered to be the main cause of dysfunction in neuromuscular transmission in MG [3]. It has been reported that various cytokines and lymphocytes are involved in the production of pathogenic autoantibodies and inflammation at the neuromuscular junction in MG [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. Chronic inflammation by T helper type 17 (Th17) cells, the promotion of autoantibody production from B cells and plasma cells by follicular Th (Tfh) cells and the activation of immune responses by dysfunction of regulatory T (T_reg) cells may exacerbate the pathological condition in MG (Fig. 1 and Tables 1 and 2). Novel treatment strategies targeting cytokines and lymphocytes are expected to provide great benefits for patients with refractory MG. In this paper, we review the roles of cytokines and lymphocytes in the immunological pathogenesis of MG.

Fig. 1.

Assumed networks of lymphocytes and cytokines in the pathogenesis of MG. Activated T cells, B cells, plasma cells and related cytokines play central roles in the production of pathogenic autoantibodies in myasthenia gravis (MG). Antigen‐presenting cells (APCs) present the acetylcholine receptor (AChR) or muscle‐specific tyrosine kinase (MuSK) to naive CD4⁺ T cells. Subsequently, T helper type 7 (Th17) cells, follicular Th (Tfh) cells and related cytokines are up‐regulated, whereas regulatory T (T_reg) cells and related cytokines are down‐regulated. Chronic inflammation by Th17 cells, the promotion of autoantibody production from B cells and plasma cells by Tfh cells or B cell‐related cytokines (B cell‐activating factor (BAFF) and a proliferation‐inducing ligand [APRIL]), and the activation of the immune response by dysfunction of T_reg cells may be involved in the pathogenesis of MG.

Table 1.

Key cytokines in MG

Cytokines (axis)	Change	Refs.	Correlation factor
IL‐17 (Th17)	Up‐regulated	[7]	QMG (especially in EOMG and non‐thymoma)
	Up‐regulated	[8]	AChR antibody titer
	Up‐regulated	[17, 18]
	No change	[14]
IL‐21 (Tfh)	Up‐regulated	[10]	QMG, AChR antibody titer, decrease after Tx
	Up‐regulated	[17]
IL‐10 (Treg or Breg)	Up‐regulated	[31]	In ocular MG
	Up‐regulated	[40]	Increase after Tx, treatment response
	Down‐regulated	[41]
BAFF (B)	Up‐regulated	[12]	AChR antibody titer
	Up‐regulated	[55]	in MuSK MG
	No change	[13]
APRIL (B)	Up‐regulated	[13]	Especially in LOMG
IL‐6 (Th17, Tfh, B)	Up‐regulated	[14, 46, 47]
	No change	[8]
IL‐37	Down‐regulated	[50]
IL‐23 (Th17)	Up‐regulated	[20]
IFN‐β	Up‐regulated	[53]

AChR antibody = acetylcholine receptor antibodies; B_reg = regulatory B cell; EOMG = early‐onset MG; LOMG = late‐onset MG; MG = myasthenia gravis; QMG = quantitative MG score; Tfh = follicular helper T; T_reg = regulatory T cell; Tx = treatment; BAFF = B cell‐activating factor; APRIL = a proliferation‐inducing ligand; IFN = interferon; IL = interleukin.

Table 2.

Key lymphocytes in MG

Lymphocytes (axis)	Change	Refs.	Correlation factor
Th17 (Th17)	Up‐regulated	[6]	QMG, AChR antibody titer (in TAMG)
Tfh (Tfh)	Up‐regulated	[9]	AChR antibody titer, plasma cell (in generalized MG)
	Up‐regulated	[25]	Severity, decrease after Tx
	Up‐regulated	[26]	In TAMG
Treg (Treg)	Down‐regulated	[11]	Especially in TAMG
	Down‐regulated	[30]	QMG, increase after Tx
	Down‐regulated	[31]	Generalized > ocular MG
	Down‐regulated	[66]	Increase after RTX, refractory MG
	No change	[32]
Memory B (B)	Up‐regulated	[31]	Generalized > ocular MG
Breg (B)	Up‐regulated	[31]	In ocular MG
	Down‐regulated	[64]	Restored after thymectomy, decrease after steroid Tx
	Up‐regulated	[65]
	Down‐regulated	[66]	Refractory MG
B10 (B)	Down‐regulated	[65]	In TAMG
	Down‐regulated	[55]	In MuSK MG
Th22, Tc22 (Th22)	Up‐regulated	[49]	Decrease after thymectomy
CD4+CXCR3+T (Th1)	Down‐regulated	[51]	Increase after Tx
IFN‐γ+CD4+ T (Th1)	Up‐regulated	[52]

AChR antibody = acetylcholine receptor antibodies; B_reg = regulatory B cell; MG = myasthenia gravis; QMG = quantitative MG score; RTX = rituximab; TAMG = thymoma‐associated MG; Tfh = follicular T helper cell; T_reg = regulatory T cell; Tx = treatment; IFN = interferon.

Th17 cells and related cytokines in MG

Th17 cells express the transcription factor retinoic acid‐related orphan receptor gamma t (RORγt), release several related cytokines, such as interleukin (IL)‐17 and IL‐22, and act on various cells, thus leading to the enhancement of inflammation via the activation of immune cells (e.g. neutrophils) and their infiltration into lesions [15]. It has been reported that Th17 cells are strongly associated with tissue‐specific autoimmune inflammatory disorders, such as multiple sclerosis, inflammatory bowel disease and psoriasis [15]. IL‐17 cannot directly induce antibody production by B cells, although it is indirectly involved in immunoglobulin production by other immune cells [16]. Regarding MG, the number of Th17 cells is increased in the peripheral blood and is positively correlated with the quantitative MG (QMG) score and anti‐AChR antibody titers in thymoma‐associated MG [6]. Plasma IL‐17A levels are increased and exhibit a correlation with the QMG score in anti‐AChR antibody‐positive MG, especially in patients with early‐onset, female, or non‐thymoma [7]. IL‐17A production from CD4⁺ T cells is increased in anti‐AChR antibody‐positive MG [17]. In addition, serum IL‐17 levels are increased in generalized anti‐AChR antibody‐positive MG and are correlated with anti‐AChR antibody titers [8], although a paper by Uzawa et al. does not support serum IL‐17 elevation [14]. Autoreactive T cells from MG patients (including thymoma‐associated MG and seronegative MG patients) produced IL‐17, interferon (IFN)‐γ and granulocyte–macrophage colony‐stimulating factor (GM‐CSF), but reduced IL‐10 production [18]. Th17 cells affect the production of autoantibodies through their influence on the Th1‐ and Th2‐related cytokine balance in MG patients (including thymoma‐associated MG patients) [19]. Activation of the IL‐23/Th17 pathway in the hyperplastic thymus of MG leads to inflammation and germinal center maintenance [20]. Taken together, Th17 cells and related cytokines are associated with chronic inflammation of the neuromuscular junction and play important roles in the immunological pathogenesis of MG.

Tfh cells and related cytokines in MG

Previously, Th2 cells were considered to be mainly involved in antibody production from B cells; currently, however, Tfh cells are thought to play a central role in antibody production from B cells and plasma cells [21]. Tfh cells are distributed in the germinal center of lymphoid follicles, express the chemokine receptors C‐X‐C motif chemokine receptor 5 (CXCR5) and programmed cell death‐1 (PD‐1) on their surface, produce related cytokines (such as IL‐21) and induce B cell class‐switching [21]. The importance of Tfh cells in the pathogenesis of antibody‐mediated autoimmune diseases, such as systemic lupus erythematosus, Sjögren’s syndrome and neuromyelitis optica, has been reported [22, 23, 24]. Regarding MG, the number of CD4⁺CXCR5⁺PD‐1⁺ Tfh cells is increased in generalized non‐thymomatous anti‐AChR antibody‐positive MG and is strongly correlated with the number of plasma cells and anti‐AChR antibody titer [9], suggesting the existence of a relationship between Tfh cells and antibody production from B cells and plasma cells in MG. Another study revealed that the number of CD4⁺CXCR5⁺ Tfh cells is increased in anti‐AChR antibody‐positive MG (including thymoma‐associated MG), is correlated with the severity of the disease and decreases after treatment [25]. A higher percentage of thymic Tfh cells is found in thymoma‐associated MG, suggesting that Tfh cells might be involved in the pathogenesis of MG [26]. In addition, it has been reported that serum IL‐21, a Tfh cell‐related cytokine, is elevated in MG. IL‐21 levels are correlated with the QMG score in MG patients with hyperplasia [10] and anti‐AChR immunoglobulin (Ig)G1 antibody titers [27], and decreases after steroid treatment in non‐thymomatous anti‐AChR antibody‐positive MG [27]. IL‐21 production from CD4⁺ T cells is increased in anti‐AChR antibody‐positive MG [17]. IL‐21 is reportedly produced mainly from activated Tfh1 and Tfh17 cells [9]. Based on these results, Tfh cells and related cytokines are likely to be correlated with autoantibody production from B cells and plasma cells in MG.

T_reg cells and related cytokines in MG

T_reg cells express forkhead box protein 3 (FoxP3), release inhibitory cytokines [such as transforming growth factor β (TGF‐β) and IL‐10] and are responsible for suppressing the immune response by inhibiting the function of other effector T cells and antigen‐presenting cells [28]. Autoimmune disease, including multiple sclerosis and systemic lupus erythematosus, can develop when the immune balance is disrupted by the dysfunction of T_reg cells [29]. In MG, the T_reg cell count is also reportedly lower than in normal controls, especially in patients with thymoma‐associated MG or those without immunotherapy [11]; moreover, the number of CD4⁺CD25⁺FoxP3⁺ T_reg cells is decreased during the active phase of anti‐AChR antibody‐positive MG and increases after immunotherapy, and the change rate of T_reg cells is correlated with the QMG score [30]. The proportion of T_reg cells is significantly lower in generalized anti‐AChR antibody‐positive MG without thymoma group than in the ocular MG and control groups [31]. T_reg cells are suggested to be involved in the clinical condition of MG (including thymoma‐associated MG) [19]. Moreover, a paper by Thiruppathi et al. claims that there is no alteration in the relative numbers of T_reg cells (CD4, CD25^high and CD127^low/− expression) within the peripheral T cell pool in MG patients [32]. We should take care in the interpretation of T_reg data, which may vary due to the isolation method of T_reg cells (e.g. some studies isolated T_reg cells based on CD127^low/− [31, 32], whereas others included FoxP3 [20, 30, 33, 34, 35, 36, 37]). The thymus plays a pivotal role in the pathogenesis of anti‐AChR antibody‐positive MG. The immunoregulatory defects observed in MG patients are assumed to be caused by defective T_reg cells in MG patients with hyperplasia and thymoma [20, 33, 34, 35, 36, 37, 38]. Chronic inflammation, over‐expression of inflammatory cytokines, T and B cell activation, germinal center formation and Th17/T_reg imbalance characterize hyperplastic MG thymus. In thymoma‐associated MG, there is considerable evidence regarding T_reg cells dysfunction and B cells infiltration [35, 36, 38]. Imbalance between effector and regulatory T cells in thymoma‐associated MG may be involved in the disease pathogenesis [36]. Generally, dysfunction of the T_reg cells, both in the periphery and thymus, is related to MG, whereas low numbers of T_reg cells in the thymus are mainly related to thymoma‐associated MG [32, 39]. The serum levels of IL‐10, which is considered to be a T_reg cell‐related cytokine, are increased after plasma exchange and the rate of IL‐10 increase is correlated with the treatment response in MG (including thymoma‐associated MG patients) [40], which cannot be necessarily related to T_reg cell increase, because many factors are associated with IL‐10 production. B cell‐derived IL‐10 is also reportedly decreased in MG (irrespective of autoantibody type or production) [41]. These findings suggest that down‐regulated levels of IL‐10 are associated with the pathogenesis of MG.

Other cytokines and lymphocytes in MG

IL‐6 has various biological activities associated with inflammation, including potent B cell stimulation and differentiation, antibody production, T cell activation, inhibition of T_reg differentiation and differentiation of Th17 and Tfh cells; moreover, it is involved in the pathogenesis of several inflammatory disorders [42, 43, 44]. Many cells, including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells and T and B cells, are associated with the production of IL‐6 [45]. Regrading MG, serum levels of IL‐6 are reported to be increased in anti‐AChR antibody‐positive MG (including thymoma‐associated MG) [14, 46, 47], whereas another study mentions that they are not measurable [8]. However, it has been reported that administration of anti‐IL‐6 antibodies suppresses experimental autoimmune MG, decreases anti‐AChR antibody titers, reduces the number of B cells and down‐regulates several Th17‐related genes, indicating that IL‐6 is an important target for modulation of autoimmune responses in MG [48]. Th22 cells and cytotoxic T 22 (Tc22) cells, which secrete IL‐22 and tumor necrosis factor‐alpha (TNF‐α) and are reportedly involved in the pathogenesis of autoimmune thyroid diseases and systemic lupus erythematosus, are also increased in MG (including thymoma‐associated MG and seronegative MG) and decrease after thymectomy, suggesting a link between these factors and the pathogenesis of MG [49]. Down‐regulated serum levels of IL‐37, a newly identified immune‐suppressive cytokine, is confirmed in non‐thymomatous anti‐AChR antibody‐positive MG patients and is associated with the severity of MG and higher Tfh/Tfh17 and B cell numbers [50]. Regarding the role of Th1 cells in MG, CD4⁺CXCR3⁺T cells are decreased in anti‐AChR antibody‐positive MG patients (including thymoma‐associated MG patients) and increase after the initiation of therapy [51]; conversely, IFN‐γ‐positive CD4⁺ T cells are up‐regulated in MG (including thymoma‐associated MG) [52]. Therefore, the role of Th1 cells in MG remains under debate. Further investigations of these lymphocytes and cytokines in the context of MG are required. IFN‐β also strongly associates with the pathogenesis of MG: the over‐expression of intrathymic IFN‐β relates to thymic events leading to non‐thymomatous MG by triggering the expression of AChR [53], and suggests that MG could be triggered by pathogen infections [54].

Unfortunately, data on lymphocytes and cytokines in anti‐MuSK antibody‐positive MG are scarce, presumably because of the relative rarity of this type of MG. Higher B cell‐activating factor (BAFF) levels and lower percentages of B10 cells have been reported in patients with anti‐MuSK antibody‐positive MG [55]. IFN‐γ, IL‐17A and IL‐21 are up‐regulated by stimulating peripheral blood mononuclear cells from patients with anti‐MuSK antibody‐positive MG [56], which implies that Th1, Th17 and Tfh cells may be involved in the pathogenesis of this type of MG. There are few data on the protein levels of cytokines in anti‐MuSK antibody‐positive MG. Accordingly, further studies are required to confirm the exact role of lymphocytes and cytokines in anti‐MuSK antibody‐positive MG.

B cells and related cytokines in MG

B cells play crucial roles in MG, including autoantibody production, complement activation and cytokine release [2]. As described above, Tfh cells can induce B cells to generate antibody‐producing plasma cells and long‐lived memory B cells [21]. Autoantibody production from B cells or plasma cells is considered to be strongly involved in the pathogenesis of MG [2]. The proportion of memory B cells is elevated in MG (generalized MG > ocular MG) [31]. B cell profiles in patients with MG differ according to disease status, and may guide treatment decisions [57]. An increase in the number of CD19⁺BAFF‐R⁺ B cells in MG patients (including thymoma‐associated MG and seronegative MG patients) [58] and the efficacy of treatment with rituximab (an anti‐B cell agent) have been reported in MG [59, 60]. The proportion of regulatory B cells and the level of serum IL‐10 are higher in the ocular MG group than in the generalized MG and control groups [31]. The reduced ratios of regulatory B cells may contribute to the progression of ocular MG to generalized MG, and the increased proportion of memory B cells may be closely related to the progression of ocular MG [31]. Similarly, regulatory B cells decreased in MG and inversely correlated with disease severity [61, 62, 63]. It has been reported that the proportion of regulatory B cells is restored after thymectomy, but not restored after corticosteroid treatments in anti‐AChR antibody‐positive non‐thymomatous MG patients [64]. The percentage of regulatory B cells increases and B10 cells (a subset of regulatory B cell identified by the production of IL‐10) decrease in thymoma‐associated MG [65], and reduced B10 cell frequencies in anti‐AChR antibody positive‐MG patients inversely correlate with disease severity [63]. In refractory MG, the proportion of regulatory B cells and T_reg cells is reduced, and the expression of BAFF‐R is greater than in non‐refractory MG (including thymoma‐associated MG and seronegative MG patients) [66]. In addition, B cell‐related cytokines, BAFF and a proliferation‐inducing ligand (APRIL), play important roles in the maturation and survival of B cells [67]. Several articles have described the behavior of B cell‐related cytokines in patients with MG: serum BAFF levels are up‐regulated in anti‐AChR antibody‐positive MG (including thymoma‐associated MG) and are correlated with anti‐AChR antibody titers [12]; moreover, APRIL levels are increased in anti‐AChR antibody‐positive MG (including thymoma‐associated MG), especially in patients with non‐thymomatous late‐onset MG [13].

Therapeutic implications of cytokine and lymphocyte blockade in MG

Oral corticosteroids, immunosuppressants, thymectomy, cholinesterase inhibitors, intravenous immunoglobulin, plasmapheresis and eculizumab are currently used to treat patients with MG in clinical practice [2]. Novel treatments against lymphocytes (B, T and plasma cells) or cytokines will be useful for symptom suppression in patients with MG who cannot tolerate standard immunosuppression therapy.

B cells play central roles in the immunological pathogenesis of MG. Rituximab, a monoclonal antibody against CD20, which is expressed on B cells but not in plasma cells, is an effective treatment for refractory MG. Treatment with rituximab appears to be effective in some patients with anti‐AChR antibody‐positive MG and in the majority of patients with anti‐MuSK antibody‐positive MG [59, 60]. Another study reveals that clinical improvement corresponded to CD20⁺ B cell depletion and memory B cell recovery is associated with exacerbation of symptoms after rituximab treatment in anti‐AChR antibody‐positive MG [68]. Rituximab exerts its effect through B cell elimination and subsequent B and T cell repopulation. There is an increased percentage of the T_reg population after rituximab treatment and is significantly correlated to the improvement of myasthenic severity in MG (including seronegative MG) [66]. Second‐ and third‐generation anti‐B cell agents (anti‐CD19 or anti‐CD20), including ocrelizumab, ofatumumab, obinutuzumab, ublituximab and ineblizumab, are more effective than first‐generation agents and may be used for the treatment of MG in the future [2]. Belimumab can suppress BAFF, which is elevated in MG and functions in promoting B cell survival and maturation [12, 13, 67]. A clinical trial of belimumab was performed in 40 patients with generalized MG (non‐thymomatous anti‐AChR/MuSK antibody‐positive MG). Unfortunately, there was no significant difference in the mean change in the QMG score at week 24 between patients who received belimumab and those who received the placebo [69]. Proteasome inhibitors, such as bortezomib, which are used to treat multiple myeloma, are currently attracting attention as a new treatment for autoantibody‐mediated disorders, including MG [70, 71]. Plasma cells are sensitive to proteasome inhibitors because they have a high protein turnover due to the constant secretion of antibodies. Therefore, proteasome inhibitors can reduce the number of plasma cells, leading to the reduction of autoantibody production, and may represent a new treatment option for MG [71]. Tocilizumab, an IL‐6 receptor antagonist, was reportedly effective in two patients with rituximab‐refractory MG [72]. Other anti‐cytokine agents, such as brodalumab, inekizumab and secukinumab (anti‐IL‐17), are candidate new treatments for MG [2].

Janus kinase (JAK) inhibitors also have potential in the treatment of MG. These agents inhibit an intracellular signaling cascade, resulting in the suppression of effector T cells and B cells [2]. In fact, treatment with a JAK inhibitor, ruxolitinib, for the management of myelofibrosis, induced the remission of MG symptoms in a patient with anti‐MuSK antibody‐positive MG [73]. Abatacept, a fusion protein of the Fc region of IgG and the cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4), suppresses T cell activation and is also a candidate treatment for MG [2]. Recently, we developed a fusion protein, AChR‐Fc, which may be a novel therapeutic agent for MG [74]. AChR‐Fc has dual activities because of its structure: the extracellular domain of the human AChR‐α1 subunit combined with human IgG1 Fc. This agent neutralizes anti‐AChR antibodies via the decoy effect of the AChR‐α1 subunit region and exhibits cytotoxicity against autoantibody‐producing B cells via the antibody‐dependent cellular cytotoxicity activity of IgG1 Fc region. Other cytokine‐ or lymphocyte‐blocking therapies will hopefully be discovered in the future.

Conclusion

Many studies have addressed the roles of cytokines and lymphocytes in relation to the pathogenesis of MG; however, they are not necessarily well established. The immunological profile may vary according to the type of MG. In addition, lymphocyte counts and cytokine concentrations in the peripheral blood may not reflect the disease status, as the lesion site of MG at the neuromuscular junction is small. Future research concerning the relationship between cytokines and lymphocytes and the pathogenesis of MG may lead to the development of novel treatments for this disease.

Disclosures

A. U., Y. O., M. Y. and T. I. report no competing interests. S. K. has received speaker honoraria from Alexion Pharmaceuticals, Teijin Pharmatheticals and CSL Behring. S. S. received personal fees from Alexion Pharmaceuticals, the Japan Blood Products Organization and Asahi Kasei Medical. H. M. has served as a paid consultant for Alexion Pharmaceuticals, argenx BVBA and Ra Pharmaceuticals and has received speaker honoraria from the Japan Blood Products Organization and research support from the Ministry of Health, Labour and Welfare, Japan. Y. N. has received speaker honoraria from Alexion Pharmaceuticals and Japan Blood Products Organization. K. U. has served as a paid consultant for argenx, Ra Pharmaceuticals and UCB Pharma and has received speaker honoraria from Alexion Pharmaceuticals and Japan Blood Products Organization.

Data Availability Statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.