Targeting T-bet expressing B cells for therapeutic interventions in autoimmunity

Summary

Apart from serving as a Th1 lineage commitment regulator, transcription factor T-bet is also expressed in other immune cell types and thus orchestrates their functions. In case of B cells, more specifically, T-bet is responsible for their isotype switching to specific IgG sub-classes (IgG2a/c in mice and IgG1/3 in humans). In various autoimmune disorders, such as systemic lupus erythematosus and/or rheumatoid arthritis, subsets of T-bet expressing B cells, known as age-associated B cells (CD19⁺CD11c⁺CD21⁻T-bet⁺) and/or double-negative B cells (CD19⁺IgD⁻CD27⁻T-bet⁺), display an expansion and seem to drive disease pathogenesis. According to data, mostly derived from mice models of autoimmunity, the targeting of these specific B-cell populations is capable of ameliorating the general health status of the autoimmune subjects. Here, in this review article, we present a variety of therapeutic approaches for both mice and humans, suffering from an autoimmune disease, and we discuss the effects of each approach on T-bet⁺ B cells. In general, we highlight the importance of specifically targeting T-bet⁺ B cells for therapeutic interventions in autoimmunity.

Targeting of ABCs/DN, in mice models of autoimmunity and/or humans suffering from autoimmune disorders, leads to diminished levels of T-bet expression in B cells and thus improves the general health status of the subjects.

Graphical Abstract

Graphical Abstract.

Introduction

Transcription factor T-bet, encoded by TBX21 gene, is known to immunologists as a master regulator of Th1 lineage commitment. Its expression, however, is also present in immune cell types other than CD4+ T lymphocytes, such as dendritic cells, natural killer cells, and B lymphocytes [1]. In B lymphocytes, more specifically, T-bet seems to regulate their isotype switching to specific IgG sub-classes (IgG2a/c in mice and IgG1/3 in humans) [2].

A newly discovered B-cell subset, characterized by the expression of CD11c and the lack of expression of CD21 surface markers, highly expresses T-bet. These cells display an expansion continuously with age, thus termed age-associated B cells (ABCs) [3]. ABCs also expand in infections and/or autoimmune diseases, in an independent of age manner, and seem to play a major role for the humoral immune responses, during these two conditions [3]. In the case of autoimmunity, for instance, data derived from mice models of autoimmune disorders indicate that ABCs serve as drivers of disease pathogenesis [4]. As far as T-bet is concerned, its elevated expression in ABCs has been associated with autoantibodies’ production, enhanced antigen presentation, and facilitation of spontaneous germinal centers’ formation [5]. Due to these facts, the targeting of T-bet-expressing B cells has been proposed as a potential therapeutic approach for autoimmune diseases [5].

Apart from ABCs, whose subset is defined by CD11c and CD21 surface markers, elevated expression of T-bet is also present in a B-cell population lacking expression of both CD27 and IgD markers. Due to their immunophenotype, these latter cells are known in the literature as double-negative (DN) B cells [6]. Similar to ABCs, DN constitute a heterogeneous population that expands in infections and autoimmune diseases. Actually, ABCs and DN share common functions and also display strong overlaps in terms of their immunophenotype. Thus, it is not clear whether these two populations are distinct or relatives [6, 7]. Depending on the expression of CXCR5 chemokine, which serves as a germinal center homing marker, as well as the expression of CD11c, DN are being categorized into four subsets [6]. Among these subsets, the extrafollicular DN2 subset (CD19⁺IgD⁻CD27⁻CD11c⁺CXCR5⁻) is the most dominant—in terms of expansion—in autoimmunity [8].

Despite the so far available data, the exact role and functions of ABCs/DN in autoimmunity are yet to be completely understood. Moreover, the importance of T-bet for ABC/DN biology has been questioned, as murine ABCs had been generated, both in vivo and in vitro, in the absence of the transcription factor’s expression in B cells [9]. In conjunction with these observations, loss of T-bet had conferred survival advantage to mice with post-influenza bacterial superinfection, thus indicating that targeting of T-bet in B cells may enhance the humoral immune responses and bring benefits to infected subjects [10].

Although these observations cannot be ignored, we present here various therapeutic approaches for mice and/or humans with autoimmune diseases, that happen to coincide with diminished ABC/DN percentages following the interventions. Taking into account this fact, we consider T-bet+ B cells as a novel target for the treatment of autoimmune diseases and we also highlight the importance of specifically depleting these pathogenic cells, so as to bring the best possible benefits to the autoimmune patients.

Requirements for the induction of T-bet in B cells

The elevated expression of T-bet in ABCs/DN derives from the synergistic triggering of a variety of receptors (Fig. 1). B-cell receptor (BCR), despite having no effect when applied alone, is a receptor of high importance for ABCs/DN, as it synergizes with other receptors, such as Toll-like receptors (TLRs) and/or CD40 [5]. TLRs act as nucleic acid sensors and mediate ABC/DN activation. Actually, these cells respond well to TLR7 and/or TLR9 (DN2 are considered as hyper-responsive to TLR7 signaling) and thus contribute to pathogenic responses in autoimmunity [5, 8, 11]. In the context of TLR engagement and BCR triggering, further signals are required for the induction of T-bet in ABCs/DN. These signals stem from IFNγ and IL-21 cytokines [5, 12]. The cooperation of these two cytokines drives ABC/DN expansion and also induces their differentiation into plasma cells [8, 13].

Figure 1.

T-bet expression in B cells results from the synergistic triggering of BCR, TLR7 or TLR9, and IFNγR and/or IL-21R. Other signals that contribute to the induction of T-bet expression in B cells derive from CD40, BAFF, IL-12, IL-18, IFNα, etc. Contrary, IL-4 serves as a repressor of the transcription factor.

Regulation of T-bet expressing B-cell populations

Manni et al. [14, 15] unraveled a molecular mechanism according to which ABCs are being regulated by SWEF proteins, a two-membered family of proteins that serve as Rho-guanine exchange factors. The SWEF family, more specifically, includes SWAP-70 and DEF-6 proteins. The scientists used animal models, lacking both two SWEF, and noticed that a lupus-like disease was being developed, as a result. Moreover, the mice used displayed an ABC expansion [14, 15]. Further analyses revealed that ABC expansion is being regulated by IL-21 and interferon regulatory factor 5 (IRF5). Actually, in the absence of SWEF, IRF5 gets deregulated in response to IL-21 [15]. Of note, DEF-6 is considered as a genetic risk variant for human lupus, thus indicating that SWEF are probably involved in autoimmunity pathogenesis in humans, as well [16].

Another regulatory mechanism of ABCs refers to Epstein-Barr virus (EBV) infection, as EBV is considered as one of the environmental factors that trigger autoimmune diseases [17]. In more detail, data derived from mice models of rheumatoid arthritis and multiple sclerosis, respectively, revealed that the latent form of EBV is mechanistically required for the modification of ABCs, so as to function pathogenically in both diseases [18, 19]. EBV infects B cells via binding to CD21 surface marker, which actually is a complement receptor [20]. Taking into account the fact that CD21 expression is absent from ABCs and/or DN2 cells [5, 8, 11], the most plausible scenario suggests that the virus modifies these specific B-cell populations in an indirect manner [17]. It is worth mentioning that, in the aforementioned autoimmunity suffering mice, targeting of ABCs has ameliorated the general health status of the mice, only in the case of a pre-infection with an EBV analog (known as gammaherpesvirus 68) [18, 19]. This phenomenon indicates that both ABCs and EBV are potential therapeutic targets for autoimmunity [17].

The subunit α1 of IL-13 receptor (IL-13Rα1) also plays a role in the regulation of ABCs in autoimmunity [21]. This receptor transmits signals via IL-4/IL-13 [22]. Of note, the gene encoding for IL-13Rα1, similar to the gene encoding for TLR7, is an X-linked gene [22, 23]. The fact that TLR7 induces ABCs [11], in conjunction with the fact that IL-4 is a repressor of T-bet [12], made the scientists interested in investigating the role of IL-13Rα1 in ABC regulation. The study conducted involved female mice lacking both SWEF and/or male mice hyper-expressing TLR7. In both two cases, the mice developed a lupus-like disease and also displayed high percentages of ABCs [21]. Knocking out of IL-13Rα1, however, led to diminished ABC percentages, reduced levels of autoantibodies, and low differentiation to plasma cells. In addition, the survival rate of the mice was considered as better and the development of inflammation was strongly delayed [21]. It is important to note that the reduction of ABCs, following the knocking out of IL-13Rα1, was IL-21 mediated, a fact that suggests that this specific receptor may be involved in IL-21 signaling [21].

The expansion of ABCs in lupus seems to be mediated by ribonuclease A family member 2 (RNase2), as well, through monocyte-derived IL-10 [24]. RNase2 is strongly expressed in the peripheral blood mononuclear cells of lupus patients and its expression correlates with T-bet+ B-cell percentages [24]. The in vitro silencing of the gene encoding for RNase2 in monocytes, via small interfering RNA (siRNA), has led to the reduction of ABC percentages, as well as reduced levels of total IgG and IL-10. Interestingly, the exogenous administration of IL-10 in cocultures of B cells and monocytes managed to restore ABC percentages [24].

In lupus, once again, the axis of IL-12-STAT4 seems to be of high importance for the regulation of ABCs/DN [25]. Actually, this pathway is considered as one of the strongest inducers of IFNγ and IL-21 by human CD4+ T lymphocytes and these two cytokines, as mentioned above, play a major role in the induction of T-bet in B cells [8, 12, 13].

Lastly, some interesting preliminary data have derived from in vitro and in vivo observations in both mice and humans, regarding the role of transcription factor Zeb2 in ABC/DN biology [26]. In more detail, Zeb2 seems to repress transcription factor Mef2b and, as a result, acts as an obstacle to the formation of germinal centers, while, at the same time, promotes the expression of genes such as Itgax, that encodes for CD11c marker. Additionally, Zeb2 regulates the distinct biological features of ABCs and governs ABC/DN differentiation by having an effect on Jak-Stat signaling [26].

Therapeutic interventions in autoimmunity and their effects on T-bet+ B cells

Up to this day, there is no cure for autoimmune disorders. Current therapies, which are assistive but do not lead to disease treatment, are mostly based on immunosuppressive drugs that affect the whole immune system and thus inevitably increase the risk of infections and cancer [27]. Targeted approaches need to be introduced to the clinical practice, so as to bring the maximum benefits to the patients. To this end, various studies have been conducted, with a focus on the specific targeting of pathogenic B-cell populations, such as ABCs/DN.

The effects of knocking out the IL-13Rα1 on ABCs, in lupus-prone mice, have already been mentioned [21]. The effects of siRNA-mediated silencing of the gene encoding for RNase2 on human ABCs, cocultured with monocytes from lupus patients, have been presented, as well [24]. Similarly, interesting data regarding the targeting of ABCs in mice models of rheumatoid arthritis and multiple sclerosis, respectively, pre-infected with an EBV analog, have also been discussed [18, 19]. These data, in total, indicate that targeting T-bet expressing B cells is capable of attenuating the symptoms of various autoimmune diseases.

This point of view is further strengthened by additional data. In mice models of lupus, conditional knockout targeting of T-bet in B cells has generally improved the health status of the mice, as better function of kidneys, better survival rate, reduced production of antibodies, and reduced titers of IgG2α in the serum have been reported [28]. Moreover, taking into account the pathway of SWEF proteins and their regulatory role for ABCs, some ABC-based therapeutic interventions for lupus have been proposed. In more detail, an indirect targeting of ABCs can probably be achieved by SWEF enhancers, IRF5 inhibitors, and/or IL-21 inhibitors [29]. Truly, in accordance with these proposals, genetic and/or chemical inhibition of IRF5 turned out to be successful in suppressing preexisting lupus-like disease in mice [30].

Prompted by the IL-12-STAT4 pathway, it can be hypothesized that JAK inhibitors and/or IL-12 inhibitors may reduce ABC/DN percentages and thus bring benefits to patients with autoimmune disorders (Fig. 2). Truly, in vitro observations revealed that the treatment of mouse- or human-isolated cells with baricitinib or tofacitinib, which refer to JAK1/2 and JAK1/3 inhibitors, respectively, has led to strong reduction of ABC/DN percentages [26]. Further, as far as tofacitinib is concerned, according to in vivo observations in patients with rheumatoid arthritis, its administration has reduced DN percentages, 4 weeks after the treatment initiation. The drug also managed to reduce the levels of C-reactive protein and, as a result, relieve inflammation [26]. As far as lupus is concerned, we note that the efficacy of JAK inhibitors is yet to be determined (although, some agents have shown merit as potential treatments of the disease and thus are under investigation in clinical trials) [31]. Similarly to JAK inhibitors, other pharmaceutical agents that target IL-12 signaling, such as ustekinumab that binds to p40 subunit of IL-12Rβ1 and is used in clinical practice for autoimmune diseases such as Crohn’s disease [32], may also lead to the reduction of ABCs/DN. To our knowledge, however, this scenario is yet to be confirmed.

Figure 2.

Binding of IL-12 to IL-12R leads to the phosphorylation of STAT4 by kinases (TYK2/JAK2). Afterward, the phosphorylated STAT4 enters the nucleus and initiates the transcription of genes, associated with ABC/DN biology, such as IFNγ and/or IL-21. Baricitinib, a JAK1/2 inhibitor, has been confirmed to affect ABC/DN percentages in vitro. Ustekinumab effects on ABCs/DN, on the other hand, require investigation.

Triggering of adenosine receptor 2a (A2a) has been reported to target CD11c⁺T-bet⁺ B cells in mice models of lupus, as well as mice models of bacterial infections [33]. In case of lupus, interestingly, A2a agonists seem to reduce the percentages of T-bet⁺ B cells and CD138⁺ plasma cells. In addition, there is a reduction of antinuclear antibodies and a general improvement in kidney function. Of note, these observations refer to both lupus-prone mice and after-disease-onset mice [33]. It is also important to mention that indirect targeting of A2a, by enhancing adenosine levels at inflamed sites, accounts for most of the anti-inflammatory effects of methotrexate, a pharmaceutical agent used extensively in the clinical practice against rheumatoid arthritis (and other rheumatic diseases) [34]. Whether methotrexate affects T-bet⁺ B cells or not is an issue that requires investigation. Taking into account the fact that diminished T-bet+ B-cell percentages coincide with improved health status for the autoimmune subjects [5, 18, 19, 21, 28], it is plausible to consider that this agent has an effect—to some extent—on ABCs/DN.

Some very interesting data have emerged from follow-up studies, regarding patients with systemic lupus erythematosus. According to a study that took place in Sweden, the initiation of belimumab (an anti-BAFF monoclonal antibody, approved for clinical use) has led to progressive decreases in both ABC and DN percentages. ABCs (as CD11c⁺CD21⁻) displayed a strong reduction at the time point of 3 months after the initiation of the treatment, while DN (as IgD⁻CD27⁻) required 12 months for a statistically significant reduction to be reported [35]. In another study, also conducted in Sweden, rituximab administration (refers to an anti-CD20 monoclonal antibody) in lupus patients has led to a decrease of CD11c⁺CD21⁻IgD⁻CD27⁻ B cells, during the second and fourth month after the initiation of the intervention. Interestingly, statistically significant decreases of IgD⁻CD27⁻CD11c⁺CXCR5⁻ and IgD⁻CD27⁻CD11c⁻CXCR5⁻ B cells, termed as DN2 and DN3, respectively, have also been reported during this time [36].

In an observational study regarding rheumatoid arthritis patients and healthy donors as controls, the effects of TNF inhibitors and tocilizumab (a well-known antagonist of IL-6 receptor) on B-cell populations, including DN B cells, have been evaluated [37]. According to the results of the study, both TNF inhibitors and tocilizumab decrease DN percentages, while the rest of B-cell populations remain unaffected after the interventions. Changes in the expression of some B-cell markers, including TLR9, CD5, and HLA-DR, were also detected following the treatment, but in general, no significant alterations were found in the gene expression of B cells [37].

Evobrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is a pharmaceutical agent that has been positively evaluated in clinical trials focusing on the treatment of multiple sclerosis. Interestingly, this agent seems to suppress the development of T-bet-expressing B cells [38]. Of note, multiple sclerosis is characterized by the expansion of ABCs/DN and the development of these pathogenic populations in the disease seems to be associated with the activity of BTK [38, 39]. More specifically, inducers of T-bet expression in B cells, such as IFNγ and/or TLR9 agonists, lead to enhanced BTK phosphorylation and activation [38]. The kinase has a central role in signaling pathways that govern B cells’ development. The use of its inhibitor, however, according to in vitro observations, has strong effects on ABCs/DN (Fig. 3).

Figure 3.

Naïve B cells are considered as precursors of ABCs/DN. In vitro observations, referring to co-cultures of human B cells with endothelial brain cells, indicate that evobrutinib can serve as a therapeutic agent for multiple sclerosis. In more detail, this agent has an effect on ABC/DN-related markers (T-bet, CD11c and CD21) and also interferes with ABC/DN differentiation into antibody-secreting cells (ASC), as well as with their chemokine-mediated migration to the central nervous system (CNS).

From our point of view, the most revolutionary approach regarding the in vivo targeting of ABCs refers to a research group that used engineered gold nanoparticles (GNPs) [40]. In more detail, polyethylene glycol-coated fluorescently labeled gold nanospheres have been injected into the flank of mice. Surprisingly, GNPs accumulated in the B cells of the spleen, after short-term exposure, and specifically interacted with ABCs, without affecting the cell viability or the cell percentages of other B-cell populations in the other organs [40]. In addition, GNPs did not impair adaptive B-cell responses in the mice and also did not activate B-cell innate-like immune responses, derived from innate-like B cells such as marginal zone B cells and/or B1 cells [40]. Such an approach can potentially serve as a therapeutic tool for ABC-mediated autoimmune diseases, such as lupus, as it seems to be effective in specifically targeting the pathogenic population of B cells, thus protecting the autoimmune patients from infections and/or cancer, as the rest of the immune system cells remain unaffected [27, 41, 42].

Lastly, taking into account the elevated metabolic profile of ABCs, in conjunction with the fact that both IFNγ and T-bet promote glycolysis in these cells, a research group decided to investigate the effects of an inhibitor of this specific metabolic pathway, on mice models of lupus [43, 44]. The elevated glycolysis in these mice models is associated with elevated ABC differentiation into ASCs. Interestingly, the administration of the glycolysis inhibitor, during the experimental procedures of the study, has led to a decrease in ABC percentages, strong reduction of autoantibodies’ levels, and general health improvement of the mice [44], thus indicating that targeting of metabolism may serve as another therapeutic approach for lupus. Further, similar data have emerged from another study, recently conducted, regarding the administration of metformin, a well-known anti-hyperglycemic agent, in mice models of lupus. According to the results of the study, the drug managed to suppress both phenotypic and functional characteristic of ABCs [45], thus strengthening the scenario of targeting metabolism for therapeutic interventions in autoimmunity.

Discussion

T-bet expressing B cells, known as ABCs and/or DN, expand in various autoimmune diseases, both in mice and humans, and play a major role in disease pathogenesis. Actually, these cells are considered as precursors of ASCs and thus as potential drivers of autoimmunity [8, 11]. Taking into account the pathogenic role of ABCs/DN in systemic autoimmune disorders, many scientific groups have focused on the targeting of these specific populations of B cells for therapeutic interventions. In this review article, we presented various in vivo and in vitro approaches for depleting ABCs/DN, mostly referring to mice models of autoimmunity, but also to some patients with autoimmune diseases.

All the approaches presented were effective in reducing ABC/DN percentages (Table 1). Among them, some such as the administration of TNF inhibitors and/or tocilizumab in rheumatoid arthritis patients, had no effect on other than ABCs/DN populations of immune cells [37]. On the other hand, approaches such as the administration of belimumab and/or rituximab in lupus patients, despite bringing benefits to the patients, globally affect the immune system [35, 36]. One of the major issues that physicians have to deal with is the fact that current therapies, used in clinical practice against systemic autoimmune diseases, affect the whole immune system and as a result increase the risks of infections and cancer [27, 41, 42]. Thus, it is of high importance for novel targeted therapies to be introduced to the clinical practice, so as to bring the maximum benefits to the patients suffering from autoimmunity.

Table 1.

The table summarizes the therapeutic approaches presented in this review article, with a focus on the effects on T-bet expressing B cells (ABCs/DN) in autoimmunity

Recipient	Intervention	Outcome	Reference
Mice models of rheumatoid arthritis (collagen-induced arthritis), pre-infected with gammaherpesvirus 68 (EBV analog)	Knockingout ABCs	General health status of the mice has been ameliorated	[18]
Mice models of multiple sclerosis (experimental autoimmune encephalomyelitis), pre-infected with gammaherpesvirus 68 (EBV analog)	Knockingout ABCs	General health status of the mice has been ameliorated	[19]
Female mice lacking both SWEF and/or male mice hyper-expressing TLR7 (mice models of lupus)	Knockingout IL-13Rα1	Reduction of ABC percentages, reduced levels of autoantibodies, and low differentiation to plasma cells. In addition, better survival rate of the mice and strong delay of inflammation development	[21]
Co-cultures of B cells and monocytes, isolated from lupus patients	In vitro silencing of the gene encoding for RNase2, via siRNA	Reduction of ABC percentages, as well as reduced levels of total IgG and IL-10	[24]
Mouse- or human-isolated B cells	Treatment with baricitinib (a JAK1/2 inhibitor) or tofacitinib (a JAK1/3 inhibitor)	Strong reduction of ABC/DN percentages	[26]
Rheumatoid arthritis patients	Administration of tofacitinib, a JAK1/3 inhibitor	Reduced DN percentages, 4 weeks after the treatment initiation. Reduced levels of C-reactive protein and inflammation relief	[26]
Mice models of lupus	Conditional knockout targeting of T-bet in B cells	Improved function of kidneys, better survival rate, reduced production of antibodies, and reduced titers of IgG2α in the serum	[28]
Lupus-like disease mice models	Genetic and/or chemical inhibition of IRF5, which is required for the formation of T-bet+ B cells	Successfully suppressed lupus-like disease in the mice	[30]
Lupus-prone mice and after-disease-onset mice models	Use of A2a agonists, for the triggering of adenosine receptor 2a	Reduction of percentages of T-bet+ B cells and CD138+ plasma cells. In addition, reduction of antinuclear antibodies and general improvement of kidney function	[33]
Systemic lupus erythematosus patients	Initiation of belimumab, an anti-BAFF monoclonal antibody, and follow-up of the patients	Progressive decreases in both ABC and DN percentages	[35]
Systemic lupus erythematosus patients	Administration of rituximab, an anti-CD20 monoclonal antibody	Decrease of CD11c+CD21−IgD−CD27− B cells, during the second and fourth month after the initiation of the intervention. Statistical significant decreases of DN2 and DN3 B cells	[36]
Rheumatoid arthritis patients	Administration of TNF inhibitors and/or tocilizumab, an antagonist of IL-6 receptor	Decrease in DN percentages, while the rest of B-cell populations remain unaffected. Changes in the expression of some B-cell markers	[37]
Co-cultures of human B cells with endothelial brain cells (multiple sclerosis-like environment)	Treatment with evobrutinib, a BTK inhibitor	Reduction in the expression of ABC/DN-related markers (T-bet, CD11c, and CD21), interference with ABC/DN differentiation into ASCs, as well as with their chemokine-mediated migration (to CNS)	[38]
7- to 12-week-old female mice	GNPs injected into the flank of the mice	GNPs accumulated in the B cells of the spleen and specifically interacted with ABCs, without affecting the cell viability or the cell percentages of other B-cell populations in the other organs	[40]
Lupus-induced mouse model	Administration of a glycolysis inhibitor	Decrease of ABC percentages, strong reduction of autoantibodies’ levels, and general health improvement of the mice	[44]
Mice models of lupus	Administration of metformin	The drug suppressed both phenotypic and functional characteristic of ABCs	[45]

To this end, from our point of view, the GNP-based method that differs a lot from other (more traditional) therapeutic approaches, is considered as revolutionary and impressive, even though it refers to mice [40]. Similarly, the scenario of targeting metabolic pathways, in order to affect the functions of the immune system and even deplete pathogenic populations, as described by Han et al. [44] and Ramirez De Oleo et al. [45], is also a very interesting intervention. Of note, metabolomics are now widely used in clinical studies and drug discovery, regarding a variety of autoimmune diseases [46].

In total, independently of the method used, targeting T-bet+ B cells seems to attenuate autoimmunity. However, the positive effects derived from the depletion of these cells should be carefully considered in clinical practice, as other nondesirable effects may emerge.

Glossary

Abbreviations:

A2a

adenosine receptor 2a

ABCs

age-associated B cells

ASCs

antibody-secreting cells

BCR

B-cell receptor

BTK

Bruton’s tyrosine kinase

DN

double-negative B cells

EBV

Epstein-Barr virus

GNPs

engineered gold nanoparticles

TLR

Toll-like receptor

IL-13Rα1

subunit α1 of IL-13 receptor

IRF5

interferon regulatory factor 5

siRNA

small interfering RNA

SWEF

SWAP-70 and DEF-6 regulatory proteins

Conflict of Interests

The authors declare no conflict of interest.

Data availability

Not applicable. The manuscript refers to a mini review, thus no data have emerged.