Autoimmune diseases can be triggered and modulated by various molecular and cellular characteristics. The mechanisms of autoimmunity and the pathogenesis of autoimmune diseases have been investigated for several decades. It is well accepted that autoimmunity is caused by dysregulated/dysfunctional immune susceptible genes and environmental factors. There are multiple physiological mechanisms that regulate and control self-reactivity, but which can also lead to tolerance breakdown when in defect. The majority of autoreactive T or B cells are eliminated during the development of central tolerance by negative selection. Regulatory cells such as Tregs (regulatory T) and MSCs (mesenchymal stem cells), and molecules such as CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) and IL (interleukin) 10 (IL-10), help to eliminate autoreactive cells that escaped to the periphery in order to prevent development of autoimmunity. Knowledge of the molecular basis of immune regulation is needed to further our understanding of the underlying mechanisms of loss of tolerance in autoimmune diseases and pave the way for the development of more effective, specific, and safer therapeutic interventions.

Introduction

One of the most important functions of the immune system is to distinguish between self and non-self substances. Upon detecting foreign invaders, innate and then adaptive immunity will be activated to eliminate pathogens. However, the immune system also recognizes that not all foreign substances are dangerous. The concept in which certain foreign substances are allowed to coexist within us without eliciting an immune reaction is termed as ‘tolerance’. With tolerance, homeostatic processes ensure that the immune system only targets dangerous pathogens and not anything else [1]. However, the complex network that maintains tolerance can be broken and enable autoimmunity [24]. Our understanding of the immune system has grown exponentially in recent years. A large number of molecules and their roles in autoimmunity are being elucidated, but our understanding is still incomplete [58].

Autoimmune diseases can be described as an abnormal immune attack against normal body part(s), characterized by seemingly unprovoked, pathological activation of the innate immune system, as well as the development of pathogenic autoantibodies or autoreactive T cells, which ultimately lead to tissue or organ damage [9]. The general understanding is that autoimmunity is a consequence of susceptible genes, environmental exposure, and failed immune regulation [10,11].

A common feature of autoimmune diseases is their tendency to appear in families, which suggests an underlying genetic susceptibility [12]. The most potent genetic influence on susceptibility to autoimmunity is the MHC, which has been known for over two decades to affect susceptibility for a variety of autoimmune diseases. Since MHC works at the level of antigen presentation by the APCs (antigen-presenting cells) for T-cell recognition, an antigen cannot become an autoantigen or elicit a response if it is not presented by the host’s MHC [1315]. In addition, lower expression levels of the proper MHC molecules may contribute to an increased threshold for recognition of antigens by immune cells and immune responses. There are many other identified non-MHC genes that contribute to the mechanisms mediating disease pathogenesis. Knowledge of these genes may help to identify new targets for the development of therapeutic strategies [16].

Environmental factors have gained much attention for their role in triggering autoimmunity. These factors include infection, gut microbiota, and physical or environmental agents [12,17]. Current data suggest that environmental factors contribute up to 70% to the loss of tolerance [18,19]. Gut microbiota, for example can be influenced by the motility of the gastrointestinal tract, smoking, and intake of alcohol and pharmaceutical medications, including antibiotics, non-steroidal anti-inflammatory drugs. On other hand, the gut microbiome interacts not only with the host but also with other organisms and environmental factors, and acts as a barrier to enteropathogenic infections. The function of the gut microbiome may be disrupted by malnutrition or perturbations in immune system function [20].

Under physiological conditions, self-components are tolerated through several types of control mechanisms. Efficient central and peripheral tolerance are induced by activation-induced cell death, anergy, clonal ignorance and a network of peripheral regulatory cells that prevent the activation of self-reactive lymphocytes [21]. Regulatory cells and molecules help to regulate autoimmunity by cell-cell contact with autoreactive T or B cells, or by soluble mediators such as anti-inflammatory cytokines [21].

T-cell negative selection

Negative selection of autoreactive T and B cells is essential to maintain a functional immune system that can defend against foreign pathogens but tolerate components of self at the same time [22]. T-cell tolerance is induced in the thymus. After positive selection by cortical thymic epithelial cells (cTECs), thymocytes migrate and interact with mTECs (medullary thymic epithelial cells) and thymic DCs (dendritic cells,) which express and present TSAs (tissue-specific Ags). Autoreactive T cells, which recognize and bind TSAs with a high affinity, are eliminated via clonal deletion, functional inactivation, or clonal deviation [2325]. The differentiation and function of TECs (thymic epithelial cells) require activation of the tumor necrosis factor (TNF) receptor superfamily members RANK, CD40, and LTβR (Figure 1). These can trigger both the classical and the alternative NF-kB pathways leading to the activation of high amounts of RelB protein, which is important for the development of sufficient mTECs to guarantee self-tolerance [2629].

Regulation of TSA expression on TECs in AIRE-dependent or -independent mechanisms

Figure 1
Regulation of TSA expression on TECs in AIRE-dependent or -independent mechanisms

Expression of TSAs on TECs is vital for development of T-cell central tolerance. Transcription factor AIRE, whose structural characteristic enables it to bind to other factors, targets specific TSA gene loci and regulate gene transcription, plays a key role in promoting expression of TSAs specifically on TECs. Regulation by factors including NF-κB and Jmjd6 also controls the level of AIRE itself. Besides, AIRE-independent mechanisms such as Prdm1 and Fezf2 take part in the regulation of TSA expression. ① represents proteins with LXXLL domain that interact with AIRE; ② represents ATF7pi/MBD1 complex. Abbreviation: AIRE, autoimmune regulator.

Figure 1
Regulation of TSA expression on TECs in AIRE-dependent or -independent mechanisms

Expression of TSAs on TECs is vital for development of T-cell central tolerance. Transcription factor AIRE, whose structural characteristic enables it to bind to other factors, targets specific TSA gene loci and regulate gene transcription, plays a key role in promoting expression of TSAs specifically on TECs. Regulation by factors including NF-κB and Jmjd6 also controls the level of AIRE itself. Besides, AIRE-independent mechanisms such as Prdm1 and Fezf2 take part in the regulation of TSA expression. ① represents proteins with LXXLL domain that interact with AIRE; ② represents ATF7pi/MBD1 complex. Abbreviation: AIRE, autoimmune regulator.

TSAs include peripheral tissue antigens that are normally present only in specialized peripheral organs and are not required for the direct functioning of mTECs [24,30]. The mechanisms that lead to the expression of self-antigen on TECs remain unclear. The most studied key molecule is the transcriptional regulator AIRE (short for autoimmune regulator), which regulates the expression of many peripheral antigens including insulin, IRBP (interphotoreceptor retinoid-binding protein; also known as RBP3) 10 and myelin protein zero 11 [3133]. AIRE mutations cause autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) syndrome in humans, by allowing for autoantibodies specific to multiple self-antigens that enable lymphocytic infiltration of endocrine glands [3436]. AIRE-deficient mice, in which only a fraction of the whole TSA repertoire are expressed on mTECs, develop similar autoimmune symptoms as a result of mononuclear cell infiltration and autoantibody production specific for multiple peripheral tissues [31,3742].

As a transcriptional factor, AIRE contains several functional domains often found in nuclear proteins and transcriptional regulators, including (i) the CARD (caspase activation and recruitment domain), which is critical for the formation of AIRE homo-oligomers, in particular homodimers and tetramers [4345], (ii) the SAND (Figure 1) domain, which interacts with the ATF7ip/MBD1 repression complex to bring AIRE to the specific TSA-encoding loci [45], (iii) two PHD zinc fingers, which enable AIRE to recognize the status of histone modifications [46,47], and (iv) the four interspersed LXXLL motifs, which mediate interactions with other proteins with LXXLL motifs, such as transcriptional co-activators promoting gene transcription [48] (Figure 1). In addition, AIRE appears to facilitate the release of stalled RNA polymerase II to regulate the elongation steps of TSA gene transcription [4951]. Most importantly, AIRE promotes the development of a subset of Foxp3 (forkhead box P3+) Treg (T regulatory) cells, which can harness peripheral autoreactive T cells [33,52].

Distributed almost exclusively within the mature mTEC population, AIRE is expressed under strict control. NF-κB signaling pathway has been proven necessary for the development of a normal mTEC compartment, and also assists in regulation of AIRE expression [53,54]. In this pathway (Figure 1), a highly conserved non-coding sequence 1 (CNS1) located in the proximal AIRE promoter serves as a critical enhancer. The specific deletion of CNS1 element results in loss of AIRE expression in mTECs [55,56]. Furthermore, Jmjd6, a member of the JmjC-domain containing proteins, is a dioxygenase that catalyzes the lysyl hydroxylation of splicing intron 2 of AIRE, and influences the production of mature AIRE protein in mTECs as well as the spontaneous development of multiorgan autoimmunity in mice [57]. Since the Sirt1 target gene signature overlaps with AIRE target genes, Sirt1 can prevent acetylation of AIRE by lysine-deacetylase activity and is essential for AIRE-driven TSA expression [58]. Recently, miR-200b [59] and MAPK (mitogen-activated protein kinase) pathway [60,61] have been shown to regulate the expression of AIRE in CD4+ T cells and leukemia cells, although their function in regulating immune tolerance remains unclear. By analyzing the gene profile of AIRE expressing cells, many other putative regulators including Irf (interferon regulatory factor) 4, Irf8, Tbx21, and Tcf7 have been identified [62].

On the other hand, there are TSA genes that are induced in the absence of AIRE [30], suggesting that other regulating factors also take part in inducing self-antigens on mTECs. Transcription factor Fezf2 directly regulates various TSA genes in mTECs independently of AIRE. Fezf2 expression is regulated by the LTβR pathway but not by the RANK/CD40–Aire axis. Reduction in Fezf2 expression leads to severe autoimmune symptoms, including the production of autoantibodies and inflammatory cell infiltration targetting peripheral organs [63]. As a transcription factor that controls gene expression and chromatin structure in several embryonic and adult tissues, Prdm1 (Blimp1) influences B-cell proliferation, maturation, and terminal differentiation [64,65]. Deletion of Prdm1 in mTECs causes multisymptom autoimmune pathology. In addition, Prdm1 expression in mTECs regulates the production of autoantibodies [66] (Figure 1).

B-cell selection and autoantibody production

Recognition of the role of B cells in autoimmune disease dates back to the discovery of autoantibodies over 50 years ago [67]. Since then, it has been clear that B cells are not simply the subordinate foot soldiers of an immune response but may be just as important as T cells. The greatest evidence for the essential role of B cells in human autoimmunity is that immunotherapies involving B-cell depletion are very effective for many systemic autoimmune diseases, such as RA (rheumatoid arthritis) and SLE (systemic lupus erythematosus) [6870], and also for some organ-specific autoimmune diseases including pemphigus [71,72].

B cells form in the bone marrow (BM). The B-cell repertoire is created by random V(D)J gene recombination in B-cell precursors within the BM, which produces a population of newly formed B cells with a highly diverse set of BCRs (B-cell receptors), but also generates large numbers of potentially harmful B cells expressing autoreactive BCRs. Though the majority (55–75%) of all antibodies expressed by early immature B cells display self-reactivity, including polyreactive and antinuclear specificities, most of these autoantibodies are removed due to autoreactive B-cell population depletion at two discrete checkpoints during B-cell development [73].

The first checkpoint is in the BM where polyreactive and autoreactive immature B cells are eliminated, most likely through deletion and receptor editing [74,75]. B cells with strong BCR signals are deleted by apoptosis; secondary recombination at the Ig L chain locus also edits its BCR to decrease self-reactivity. In addition, self-reactive B cells are induced to become anergic or ignorant, before the cells are allowed to leave the BM [7678]. The second checkpoint is in the periphery when immature B cells become mature B cells, where B cells co-express IgM and IgD, acquire the capacity to be fully activated, and are able to respond productively with T cells and antigens to produce high-affinity antibodies [79]. The mechanisms of peripheral tolerance includes the induction of anergy, antigen receptor desensitization, or tolerance to antigens that co-engage sialic acid-binding Ig-like lectin (Siglec) inhibitory receptors [77,8082].

The mechanisms by which B-cell central tolerance becomes defective and autoimmune diseases develop are still not completely clear. Many genes and proteins are involved in regulating B-cell central tolerance and receptor editing [79,83]. A deficiency in these genes and proteins through mutation or abnormal activation may lead to an altered naive BCR repertoire and the generation of autoantibody-producing B cells [84,85]. Non-treated SLE and RA patients show elevated frequencies of autoreactive B cells in the naive B-cell compartments, suggesting an early break in B-cell tolerance, even before antigen-mediated activation and differentiation into antibody-secreting cells [86,87]. Similarly, elevated autoantigen-specific plasmablasts are present in patients with PBC (primary biliary cholangitis) [88,89].

T1D (type 1 diabetes) patients show abnormalities in the early checkpoints of B-cell tolerance. Treatment with rituximab, an anti-CD20 mAb, can reduce the severity of autoimmunity but cannot alter the frequencies of autoreactive and polyreactive B cells [90]. Studies from transgenic mice show that CD4+ T cells may play an important role in the elimination of peripheral autoreactive B cells through MHC II/TCR (T-cell receptor), CD40/CD40L, and Fas/FasL interactions [91,92]. Mature, naive B cells from CD40L-deficient and MHC II deficient patients consistently express a high proportion of autoreactive antibodies but not new emigrant B cells, indicating that CD40/CD40L interactions and antigen presentation are essential to establish peripheral naive B-cell tolerance [93].

B-cell lineages are conventionally classified into T-dependent memory and antibody-secreting B cells. Antibody-secreting B cells first appear as short-lived plasmablasts and become long-lived plasma cells if they find a survival niche that provides the essential survival mediators [94,95]. BAFF (B-cell activating factor) and its closely related homolog APRIL (a proliferation-inducing ligand) are key determinant cytokines in the establishment of tolerance and BM long-lived plasma cells [96]. After binding with their receptors including BAFFR, TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B-cell maturation antigen), these two cytokines regulate the development and survival of B2 and marginal zone B cells, CD40-independent class switching and promote plasma cell survival and maintenance [97]. BAFF transgenic mice develop a SLE-like syndrome, and immunological disorders with expanded peripheral B-cell compartment, enlarged B-cell follicles, high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin deposition in the kidneys [98]. Overproduction of BAFF by DCs and macrophages may play a crucial role in the pathogenesis of experimental arthritis by suppressing B-cell apoptosis and promoting production of anti-collagen antibodies in a mouse model of collagen-induced arthritis[99]. Increased levels of BAFF have also been reported in patients with various autoimmune conditions [100,101]. Drugs targetting BAFF associated pathway have been investigated or applied in treating autoimmune diseases. For example, Belimumab, an anti-BAFF antibody, has been approved by the U.S. FDA (Food and Drug Administration) for the treatment of adult SLE patients [102,103].

Regulatory cells

Autoimmunity exists in every individual, including healthy ones: from the basic physiological level where self-activity exists for lymphocyte selection and immune homeostasis, to the intermediate state where a low titer of autoantibodies and a small quantity of autoreactive T cells circulate, and lastly to the pathogenic level in which autoimmunity causes tissue injury [9]. The fact that immunization with special self-antigens or associated proteins can induce autoimmune diseases in mice, such as collagen-induced arthritis [104], experimental Sjögren’s syndrome [105], EAE (experimental autoimmune encephalomyelitis) [106], and epidermolysis bullosa acquisita [107], proves that autoreactive lymphocytes with pathogenic potential can evade the regulatory processes of central tolerance and exist in the periphery of normal individuals [108]. Besides central tolerance, peripheral tolerance also plays a crucial role in maintaining the homeostasis of autoimmunity. Peripheral mechanisms of tolerance are able to suppress autoreactive T cells through certain subsets of cells.

Foxp3+ Treg cells

Amongst the various suppressive cells involved in immune regulation, Treg cells are thought to be the most relevant and powerful subset, for their ability to regulate both the innate and adaptive immune systems, targetting almost all types of cells [109,110]. Treg cells develop from the thymus, and are referred to as tTreg (thymus-derived Treg) or nTreg (natural Treg) cells. Tregs can also be induced by peripheral molecules such as TGF-β (transforming growth factor-β) and IL (interleukin) 2 (IL-2). These are called iTreg (induced Treg) or pTreg (peripheral Treg) cells [111,112]. Blockage of both TGF-β and IL-2 signaling impedes Nrp-1 (Neurophilin-1+) Treg cell and Tfh (follicular regulatory T-cell) development [113]. tTreg cells are thought to be mainly responsible for preventing autoimmune diseases [114]. It has been reported that thymic B cells contribute to the generation of thymic Treg cell precursors as well as the maintenance and proliferation of thymic Treg cells in an MHC and CD40/CD80/CD86-dependent manner [115]. The pivotal role of TCR signaling in the origin and differentiation of tTreg cells by TCR transgenic cells has been previously demonstrated [116119]. It is thought that Treg cells develop when the TCR avidity for self-antigens lies between the TCR avidities that drive positive selection and negative selection [110,120], since the TCR repertoire of conventional T cells and Treg cells do not overlap much and tTreg cells are generated through high-avidity MHC II/TCR interactions [118,121123].

Foxp3

Foxp3 is the transcription factor that specifies the Treg cell lineage and is essential for the development and function of Treg cells. Mutation of the gene-encoding Foxp3 protein leads to the scurfy phenotype in mice and IPEX syndrome (immunodysregulation, polyendocrinopathy, enteropathy) in humans [124,125]. Moreover, mice models with attenuated Foxp3 expression in Treg cells show similar aggressive autoimmune syndromes with a subverted suppressive function of Treg cells and conversion of Treg cells into effector cells [126]. Foxp3 is also induced in other type of cells besides Tregs [127]. Tregs can lose their Foxp3 expression under certain circumstances such as in inflammatory or lymphopenic environments [128130]. Thus, expression of Foxp3 is determined and regulated precisely by a combination of TCR signals, transcription factors, enhancers, and epigenetic marks [131135] (Figure 2). Acting as both transcriptional activator and repressor, Foxp3 is thought to be able to bind many genomic sites and regulate gene expression associated with Treg development and function [136,137].

Regulation of transcription factor Foxp3
Figure 2
Regulation of transcription factor Foxp3

Foxp3 is the specific transcription factor for the development and function of Treg cells. Expression of Foxp3 is regulated precisely by a combination of TCR signals, transcription factors, enhancers, and epigenetic marks. And regulation of target genes, such as inhibitory surface molecules and cytokines, by Foxp3 together with other cofactors determine how Tregs work.

Figure 2
Regulation of transcription factor Foxp3

Foxp3 is the specific transcription factor for the development and function of Treg cells. Expression of Foxp3 is regulated precisely by a combination of TCR signals, transcription factors, enhancers, and epigenetic marks. And regulation of target genes, such as inhibitory surface molecules and cytokines, by Foxp3 together with other cofactors determine how Tregs work.

Cofactors, including transcriptional factors and chromatin-modifying factors, take part in the target gene regulation of Foxp3 [138]. In a murine model of autoimmune diabetes, the NFAT (nuclear factor of activated T) cellinteracts with Foxp3 and represses expression of IL2, up-regulates expression of the Treg markers CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) and CD25, and confers suppressor function [139] (Figure 2). Interaction between Foxp3 and AML1 (acute myeloid leukemia 1)/Runx1 (Runt-related transcription factor 1) suppresses IL-2 and IFN-γ (interferon-γ) production, up-regulates Treg-associated molecules, and exerts suppressive activity by binding to the promotor region of Foxp3 target genes [140]. UXT (ubiquitously expressed transcript) associates with Foxp3 in the nucleus by interacting with the proline-rich domain in the N-terminus of Foxp3 and promotes Foxp3 transcriptional activity as well as regulates Treg-stimulated gene expression [141]. In addition, Foxp3 regulating gene expression depends on its ability to facilitate epigenetic remodeling at its target loci. After TCR stimulation, Foxp3 binds to the IL-2 and IFN-γ genes and induces active deacetylation of histone H3, which inhibits chromatin remodeling and opposes gene transcription (Figure 2).

Conversely, binding of Foxp3 to the GITR (glucocorticoid-induced TNFR family related protein), CD25, and CTLA-4 genes results in increased histone acetylation and expression [142] (Figure 2). Another cofactor highly expressed by Tregs, EOS, interacts directly with Foxp3, preventing histone trimethylation and acetylation while promoting the methylation of histone and CpG dinucleotides at the IL2 promoter, resulting finally in gene silencing [143]. A group of cofactors, including Helios, Xbp1, Eos, IRF4, Satb1, Lef1, and GATA-1, have been shown to act in synergy with Foxp3 to activate expression of most of the Treg cell signature, including key transcription factors, thereby enhancing occupancy by Foxp3 at its genomic targets [144] (Figure 2).

Mechanisms of Treg suppression

The functional mechanisms of human and mouse Treg cells have been studied using in vitro systems, and the molecular mechanisms of suppression of Treg cells has been discussed in many reviews [21,111,145148]. Autoimmune responses result from the capture and presentation of self-antigen by APCs, leading to the recognition and interaction of self-reactive T or B cells, the expansion of these autoreactive lymphocytes, and ultimately to tissue injury caused by cell infiltration and production of autoantibodies.

Tregs target DCs directly by modulating maturation and functions of DCs, including antigen presentation and co-stimulatory signals. Direct spatial proximity and interaction between DCs and Tregs in vivo has been demonstrated using intravital microscopy, in which Nrp-1, LAG3 (lymphocyte activation gene 3), adhesion molecules such as LFA-1 (lymphocyte function associated antigen 1), and co-stimulatory molecules provide the basic structure [123,146,149] (Figure 3). For example, increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells due to sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, thereby promoting the polarization of DCs toward the Treg cell adhesion zones [147]. Furthermore, with IL-2 stimulation, Tregs suppress antigen-specific T conv–DC interactions in a contact-dependent and MHC II-independent manner to impair T-cell priming, which does not require concomitant antigen recognition of Treg itself [150]. Tregs have been shown in vitro to breakdown ATP into adenosine via CD39, attracting DCs by activating Epac1-Rap1-dependent pathways, and rendering DCs less stimulatory [151]. Recently, it has been demonstrated that DCs facilitated Treg induction in the presence of elevated IL-2 in an experimental model of autoimmune encephalomyelitis [152].

Mechanisms of Foxp3+ Treg-mediated immune regulation
Figure 3
Mechanisms of Foxp3+ Treg-mediated immune regulation

Foxp3+ Tregs regulate autoimmune mainly through the following mechanisms: suppressing T-cell activation by directly modulating the maturation and functions of DCs; mediating target cell death including effector T cells, monocytes, B cells and DCs; expression of inhibitory molecules such as CTLA-4, LAG3, and TIGIT, and cytokines as TGF-β and IL-10.

Figure 3
Mechanisms of Foxp3+ Treg-mediated immune regulation

Foxp3+ Tregs regulate autoimmune mainly through the following mechanisms: suppressing T-cell activation by directly modulating the maturation and functions of DCs; mediating target cell death including effector T cells, monocytes, B cells and DCs; expression of inhibitory molecules such as CTLA-4, LAG3, and TIGIT, and cytokines as TGF-β and IL-10.

In addition, Tregs suppress autoimmune responses by mediating target cell death through cytolysis and apoptosis. Human adaptive Treg cells produce granzyme B, and activated human CD4+CD25+ nTreg cells express primarily granzyme A with very little granzyme B. Treg cells exhibit perforin-dependent cytotoxicity against autologous target cells, including activated CD4+ and CD8+ T cells, CD14+ monocytes, and both immature and mature DCs. Using antibodies against CD18, it was demonstrated the cytotoxicity function is dependent on CD18 interactions but is independent of Fas/FasL [153]. Granzyme A shows a significantly lower expression at the protein level of Tregs in GVHD (graft versus host disease) patients, and further studies have shown that Tregs require granzyme A to rescue hosts from murine GVHD by inducing cytolysis in a perforin-dependent, Fas/FasL-independent manner [154].

B-cell proliferation can also be inhibited by activated CD4+CD25+ Tregs which up-regulate expression of perforin and granzymes [155]. On the other hand, apoptosis of target cells is induced by different mechanisms. IL-2 is a key cytokine for T-cell survival, expansion, and activation as well as the generation and maintenance of Tregs, although Tregs barely produce IL-2 by themselves [156159]. Several studies have shown that IL-2 signaling through the high-affinity IL-2R is essential for the immunosuppressive function by cytokine deprivation through CD25 expression [160]. In a mouse model of IBD (inflammatory bowel disease), Tregs induce effector CD4+ T-cell death through the pro-apoptotic protein Bim, accompanied by reduced activation of the prosurvival kinase Akt and lower levels of phosphorylated pro-apoptotic protein Bad in target cells [161]. Activated Treg cells can also induce apoptosis of effector T cells through the up-regulation of the TRAIL-DR5 (TNF-related apoptosis inducing ligand-death receptor 5) pathway or galectin-1 [162,163].

Tregs express many other inhibitory molecules which contribute to the suppression of effector cells, such as CTLA4, TIGIT, and LAG3. Though several in vitro studies have demonstrated direct suppression of Tregs by Teff cells without APCs, no evidence has demonstrated that direct contact between Tregs and Teffs is required for suppression in vivo [150].

Another mechanism by which Tregs act is through suppression by inhibitory cytokines. Inhibitory cytokines, such as IL-10 and TGF-β, are thought to be important mediators of Treg-induced suppression, and are also able to stimulate the development of induced Treg cells [145,164] (Figure 3). However, studies show contrasting results about the importance of Treg-derived IL-10 and TGF-β [165]. TGF-β can induce naive CD4+ T cells from human peripheral blood to develop powerful, contact-dependent suppressive activity against CD8+ T cells proliferation in response to alloantigens, preventing the development of cytotoxic effector cells. This suppression is not prevented by anti-TGF-β or anti-IL-10 mAbs [166]. In mice, TGF-β plays a role in the conversion of CD4+CD25 naive/responder into CD4+CD25+Foxp3+ anergic/suppressor T cells, which can suppress ovalbumin (OVA)-specific T-cell proliferation and prevent HDM (house dust mite) induced allergic pathogenesis in vivo [167].

OX40 signals strongly antagonize this process [168]. Studies show that Tregs function in a contact-dependent manner by neutralizing antibodies of inhibitory cytokines [169,170]. In contrast, IL-10 plays a non-redundant role in the functioning of regulatory T cells (Tregs) that controls inflammatory responses toward intestinal antigens [171]. In allergy and asthma models, which are characterized by active T helper (Th) 2 (Th2) responses, both naturally occurring CD4+CD25+ Treg cells and antigen-driven IL-10-secreting CD4+ Treg cells can control the disease [172]. Furthermore, intratracheal administration of naive lung CD4+CD25+ T cells can reduce allergen-induced airway hyperresponsiveness (AHR) and inflammation [173].

IL-35 is also thought to be an inhibitory cytokine in Treg-mediated suppression [163,174]. In all, while there appear to be many different mechanisms in regulating autoimmune responses, the overall picture of how Tregs co-ordinate this suppression is unclear [145] (Figure 3).

Tregs in autoimmune diseases

It has been shown that Treg cells are implicated in development of many autoimmune diseases such as T1D [175], autoimmune hemolytic anemia (AHA) [176], autoimmune thyroid disease (ATD) [155], RA [156], SLE [154], Sjögren’s syndrome [177], and systemic sclerosis [178]. Initially identified in the secondary lymphoid tissues of mice and the peripheral blood of humans, Tregs express a dizzying array of adhesion molecules and chemoattractant receptors targetting both lymphoid and non-lymphoid sites [157]. For example, Tregs migration and retention within the skin are dependent on the ability to generate carbohydrate ligands for P-selectin and e-selectin by the action of the α-(1,3)-fucosyltransferase vII enzyme, deletion of which on Treg cells results in the development of skin-specific autoimmunity [179]. Moreover, deficiency of CCR7 blocks Treg cell migration to the lymph nodes and inhibits Treg cell function in an experimental model of colitis [180].

Another important phenotype is that Treg cells acquire distinct characteristics, tailoring them to the response to be regulated [157]. For example, Treg cells up-regulate expression of the transcription factor T-bet, which is required for suppression of Th1 responses [158], IRF4 for suppression of Th2 responses [159], STAT3 for suppression of Th17 responses [161], and GATA-3, important for control of effector T cells [162]. Thus, identifying and characterizing the cellular and molecular mechanisms that underlie the functional specialization of Treg cells, as well as developing methods for selectively isolating and expanding different Treg cell subsets may be the key to Treg-associated therapy in autoimmune diseases.

Other regulatory cells

Though Tregs are powerful and widely implicated in regulating autoimmunity, other types of regulatory cells should not be ignored, including myeloid-derived suppressor cells (MDSCs), regulatory B (Breg) cells, regulatory macrophages, CD8+ Tregs, MSCs (mesenchymal stem cells), and so on (Table 1).

Table 1
Functional properties of other regulatory cells
Cell typesKey featuresFunctionsReferences
Breg cells Produce IL-10, IL-35, TGF-β, IgG4 Induce Treg cells. Suppress effector CD4+ T cells, CD8+ T cells, DCs, monocytes, neutrophils, and NK cells. Suppress Th1 and Th17 cells in patients with SLE and RA. Support iNKT cell homeostasis [297302
CD8+ Treg cells Produce IL-10, TGF-β, IFN-γ and perforin. Express PD-1, TRAIL, ICOSL Target Qa-1 mediating the functions of activated T cells and APCs. Direct killing of the target cell. Secretion of soluble factors, such as immunosuppressive cytokines [303
MSCs Expressing NO (nitric oxide), IDO (indoleamine 2,3-dioxygenase), PD-L1 (programmed death ligand 1), or FasL. Produce extracellular vesicles (EVs), PGE2, HGF, HO1. Suppress T-cell activation/proliferation and induce T-cell apoptosis. Regulate or inhibit inflammation [194,195,304
Cell typesKey featuresFunctionsReferences
Breg cells Produce IL-10, IL-35, TGF-β, IgG4 Induce Treg cells. Suppress effector CD4+ T cells, CD8+ T cells, DCs, monocytes, neutrophils, and NK cells. Suppress Th1 and Th17 cells in patients with SLE and RA. Support iNKT cell homeostasis [297302
CD8+ Treg cells Produce IL-10, TGF-β, IFN-γ and perforin. Express PD-1, TRAIL, ICOSL Target Qa-1 mediating the functions of activated T cells and APCs. Direct killing of the target cell. Secretion of soluble factors, such as immunosuppressive cytokines [303
MSCs Expressing NO (nitric oxide), IDO (indoleamine 2,3-dioxygenase), PD-L1 (programmed death ligand 1), or FasL. Produce extracellular vesicles (EVs), PGE2, HGF, HO1. Suppress T-cell activation/proliferation and induce T-cell apoptosis. Regulate or inhibit inflammation [194,195,304
Breg cells

IL-10-producing Breg cells, representing 1–2% of spleen B220+ cells in mice, suppress autoimmune disease by secreting anti-inflammatory cytokine IL-10 independent of autoantibody production [181,182]. IL-35-producing B cells are also key players in the negative regulation of immunity. Mice with a B-cell-specific deficiency of IL-35 fail to recover from T cell-mediated demyelinating autoimmune disease EAE [183]. Recently, a new population of granzyme B-producing B cells was identified, and these cells negatively regulate Th1 and Th17 cells partly via down-regulating TCRζ chain and inducing T-cell apoptosis in RA [184].

CD8+ Treg cells

CD8+ Treg cells are essential for maintaining self-tolerance and preventing autoimmune disease. Genetic disruption of the inhibitory interaction between CD44+ ICOSL+ CD8+ T cells and their target Qa-1+ follicular T-helper (Th) cells results in the development of a lethal SLE-like autoimmune disease [185]. In septic patients, immune suppression such as an impaired DTH (delayed-type hypersensitivity) response is observed [186]. In the sepsis model, apoptotic cell induced CD8+ Tregs are thought to mediate CD4+ T-cell suppression by TRAIL expression [187]. TRAIL expressing CD8+ Tregs are also important in maintaining peripheral tolerance after CD4+ T-cell deletion with the same antigen specificity [188]. Furthermore, a robust induction of neuroantigen-reactive CD8+ T cells in several EAE mice models exists, which is similar to human MS (multiple sclerosis). These IFN-γ and perforin-producing CD8+ T cells are able to kill MOG (myelin oligodendrocyte glycoprotein) loaded CD4+ T cells as well as CD4-depleted APCs, exhibiting a novel and unexpected immune regulatory function through a contact-dependent or cytotoxic mechanism [189191].

MSCs

MSCs are non-hematopoietic, multipotent, stromal precursor cells resident in most adult tissues, and are increasingly recognized as capable of modulating immune responses [192,193]. It has been demonstrated that MSCs directly suppress T-cell activation/proliferation and induce T-cell apoptosis by expressing NO (nitric oxide), IDO (indoleamine 2,3-dioxygenase), PD-L1 (programmed death ligand 1), or FasL [194200]. Their therapeutic efficacy in animal models and clinical trials of Crohn’s disease, SLE, and RA is under investigation [201]. It is found that MSCs derived from mice with EAE suppress the disease and have similar biological properties with MSC from healthy donors, suggesting that the inflammatory process in EAE does not exert any deleterious effect on the functional or biological properties of the MSCs, which is important for its future clinical applications [202]. MSC based therapy has also been investigated for antifibrotic effects in murine model of systemic sclerosis [203]. On the other hand, extracellular vesicles (EVs) produced by MSCs exert their therapeutic effects in two autoimmune murine models, T1D and uveoretinitis, by inhibiting activation of APCs and suppressing development of Th1 and Th17 cells [204]. MSCs are an attractive source of EVs because they secrete a large number of therapeutic factors, including cytokines, chemokines, and miRNAs in EVs [205207]. According to the data from National Institutes of Health U.S.A., currently ~350 trials focussing on the reparative capabilities of MSC therapy, particularly in cardiac syndromes and spinal cord injury, have either been completed or are in progress, showing the great potential of MSCs in future clinical applications.

Regulatory factors

The immune system is regulated by complex cellular and molecular interactions that organize, direct, and control its functions. Many different regulatory molecules, such as Foxp3 have been found to maintain homeostasis of host immunity. Any change or alternative expression of these molecules may result in autoimmune diseases. Hence, researchers have generated a number of gene knockin, knockout, KD, transgenic or mutant mice to delineate their function and regulatory mechanisms in autoimmune diseases (Table 2).

Table 2
Functional properties of regulatory factors in autoimmunity
Regulatory factorsFunctionsPathological phenotypeReferences
PTPN22 (protein tyrosine phosphatase non-receptor 22) Acts as a brake on TCR signaling and regulates T-cell development. Mediates B-cell function, such as antibody production. Regulates innate immunity . Ptpn22−/− mice exhibit enhanced proliferation and expansion of effector/memory T cells, enhanced primary and secondary T cell-dependent Ig responses to antigen, increased size of the peripheral Treg cell, exacerbated DSS (dextran sodium sulphate) induced colitis, impaired induction of type 1 IFNs in BMDM (BM-derived macrophage) after TLR4 agonist stimulation. Ptpn22 KD (knockdown) promoted the expansion of the Treg cell; PTPN22 inhibition leads to defective human central B-cell tolerance [215217,223,227,230
CTLA-4 Inhibits function in T-cell activation as stronger binding affinity for CD80 and CD86. Induces up-regulation of LFA-1 to enhance cell adhesion and motility and override the TCR-induced stop signals. Required for Treg function . CTLA-4−/− mice exhibited a fatal autoimmune pathology such as lymphoproliferation and multiorgan lymphocyte infiltration, enlarged population of Foxp3+ Tregs, Ag-specific Tregs are unable to control disease. Tregs specific reduction in CTLA-4 expression results in an increase in the formation of antigen-specific Tfh cells, GCs (germinal centers), and plasma and memory B cells after vaccination . [234,235,240,242,250253,256
Regulatory miRNA Regulates innate and adaptive immune cell development. Alters the response to PAMPs (pathogen-associated molecular patterns) or inflammatory cytokine . miRNA-deficient mice: developed a spontaneous autoimmune disorder, blocked T- or B-cell development and function, impaired Ig class switch in B cell. [271,272,274,276,277,281,283285,291
Regulatory factorsFunctionsPathological phenotypeReferences
PTPN22 (protein tyrosine phosphatase non-receptor 22) Acts as a brake on TCR signaling and regulates T-cell development. Mediates B-cell function, such as antibody production. Regulates innate immunity . Ptpn22−/− mice exhibit enhanced proliferation and expansion of effector/memory T cells, enhanced primary and secondary T cell-dependent Ig responses to antigen, increased size of the peripheral Treg cell, exacerbated DSS (dextran sodium sulphate) induced colitis, impaired induction of type 1 IFNs in BMDM (BM-derived macrophage) after TLR4 agonist stimulation. Ptpn22 KD (knockdown) promoted the expansion of the Treg cell; PTPN22 inhibition leads to defective human central B-cell tolerance [215217,223,227,230
CTLA-4 Inhibits function in T-cell activation as stronger binding affinity for CD80 and CD86. Induces up-regulation of LFA-1 to enhance cell adhesion and motility and override the TCR-induced stop signals. Required for Treg function . CTLA-4−/− mice exhibited a fatal autoimmune pathology such as lymphoproliferation and multiorgan lymphocyte infiltration, enlarged population of Foxp3+ Tregs, Ag-specific Tregs are unable to control disease. Tregs specific reduction in CTLA-4 expression results in an increase in the formation of antigen-specific Tfh cells, GCs (germinal centers), and plasma and memory B cells after vaccination . [234,235,240,242,250253,256
Regulatory miRNA Regulates innate and adaptive immune cell development. Alters the response to PAMPs (pathogen-associated molecular patterns) or inflammatory cytokine . miRNA-deficient mice: developed a spontaneous autoimmune disorder, blocked T- or B-cell development and function, impaired Ig class switch in B cell. [271,272,274,276,277,281,283285,291

Protein tyrosine phosphatase non-receptor 22

It has been more than 20 years since tyrosine phosphorylation was discovered to be a critical mechanism for TCR signaling and T-lymphocyte activation. Reversible tyrosine phosphorylation is a key regulatory mechanism for numerous physiological processes, including many that are crucial for the immune system, such as adhesion, cell migration, cell cycle control, secretion, endocytosis, and intracellular vesicle traffic. In addition, most antigen receptors, immunoglobulin receptors, co-receptors, accessory molecules, and cytokine receptors signal through tyrosine phosphorylation cascades [208].

The gene PTPN22 (protein tyrosine phosphatase non-receptor 22) encoding for the phosphatase LYP (or PEP in mice) is a strong susceptibility gene which is shared by many autoimmune diseases, such as T1D [209], SLE [210], RA [211], Graves’ disease [212], and others. An SNP (single nucleotide polymorphism) in PTPN22, 1858C>T (rs2476601), results in a single amino acid change from arginine (R) at position 620 to tryptophan (W), and is thought to convey the highest risk for disease. To explore how the polymorphism of this gene affects autoimmunity, several mice models with different genetic backgrounds have been established [213]. PEP contributes to the regulation of both innate and adaptive immune systems, and is involved in the function of multiple cell lineages [214]. First, PTPN22 acts as a brake on TCR signaling and regulates T-cell development. In research using human Jurkat T cells lines, LYP R620W (LypW) negatively regulates TCR-induced intracellular Ca2+ flux, tyrosine phosphorylation, MAPK activation, and NFAT response element transactivation [215]. PTPN22 forms a complex with SH3 domain of C-terminal Src kinase (Csk), a TCR signaling regulator, which is important for regulation of PTPN22 function [216].

Studies using ptpn22−/− mice demonstrated enhanced proliferation and expansion of effector/memory T cells in vivo and in vitro, as well as enhanced primary and secondary T cell dependent Ig responses to antigen [217,218], while in other models thymus negative selection is unaffected [219]. An increased size of the peripheral CD25+Foxp3+CD4+ T-cell compartment is observed in ptpn22−/− mice but the alteration of their suppressive function remains controversial [218,220,221]. Ptpn22 KD (knockdown) promoted the expansion of the Treg cell compartment by up-regulating the GITR and increasing associated signaling [222]. Second, in humans or mice carrying the PTPN22-R620W variant or its engineered homolog Ptpn22-R GC (germinal centers), high frequencies of autoreactive B-cell clones and increased antibody production indicate dysregulation within the B-cell compartment [223227]. In addition, PTPN22 may play a role in malignant B-cell signaling as high levels of PTPN22 are found in CLL (chronic lymphocytic leukemia) blasts [228]. Using NOD-scid-common γ chain knockout (NSG) mice engrafted with human hematopoietic stem cells expressing PTPN22 T allele, it has been demonstrated that PTPN22 inhibition leads to defective human central B-cell tolerance [229].

Third, PTPN22 regulates innate immunity. Expressed in myeloid cells, PTPN22 appears indispensable for the development of blood monocytes, CD11b+ splenocytes, and subsets of DCs in lymphoid organs [217,230]. Studies show that PTPN22 functions as a selective promoter of PRR (pattern reorganization receptor ) signaling and is the key for driving the type I IFN response in myeloid cells and inflammatory polarization in macrophages. In ptpn22−/− mice, DSS (dextran sodium sulphate) induced colitis was exacerbated and induction of type 1 IFNS by BM-derived macrophages (BMDMs) after TLR4 agonist stimulation was impaired [230,231]. However, the role of PTPN22 in NK cells is not well identified, except for its regulation of NK cell in vitro expansion [232].

Overall, evidence of altered autoimmune or inflammatory responses in individuals with the PTPN22 mutation demonstrate the role of PTPN22 in T cell-mediated peripheral tolerance and prominent dysregulation of humoral responses and myeloid-dependent immunoregulatory processes [214]. Thus, development of specific drugs targetting PTP and other protein tyrosine phosphatases may present an opportunity for the treatment of autoimmune diseases.

CTLA-4

One important mechanism by which tumors evade destruction by the immune system is through the up-regulation of immune-inhibitory molecules such as PD-1 in T cells to mediate their dysfunction or inhibition. Thus, immune checkpoint blockade therapy targetting these inhibitory molecules has been an exciting area of research for several years. The role of the checkpoint molecules in regulating autoimmunity has been extensively studied in recent years.

CTLA-4 or CD152 is a T-cell surface glycoprotein that plays a critical role in the prevention of T-cell activation induced autoimmune pathology. As a homolog of CD28, CTLA-4 is structurally and functionally related [233]. Both CTLA-4 and CD28 bind to CD80 and CD86 receptors, two B7 family members that are present on APCs [234]. Studied relatively thoroughly for decades as a co-stimulatory molecule, CD28 engagement provides the second signal for T-cell activation, which lowers the TCR signaling threshold and therefore enhances TCR-mediated T-cell proliferation, cytokine production and survival. Activated T cells also help B cells with GC response and antibody production [235239]. In contrast with CD28, CTLA-4 shows inhibitory function in T-cell activation. It has also been reported that mice with CTLA-4 deficiency exhibit fatal autoimmune pathology such as lymphoproliferation and multiorgan lymphocyte infiltration [240242].

CTLA-4 regulates T-cell responses by several mechanisms. Firstly, CTLA-4 has a stronger binding affinity than CD28 for CD86 and particularly for CD80 [243,244], thus outcompeting CD28 binding and reducing its signals. After TCR stimulation in conventional CD4+ T cells as well as Tregs, CTLA-4 previously stored in the secretory granules directly moves to the activating T cell-APC or bilayer interface and translocates to the CD3lo signaling central-supramolecular activation cluster (cSMAC) in a ligand-binding manner, even at a low density of CD80, resulting in the inhibition of CD28-PKCθ-CARD-containing MAGUK protein 1 recruitment [245].

Second, upon ligation with CD80, CD86, or anti-CTLA-4 antibody, CTLA-4 mediates its effects by transducing a cell intrinsic negative signal. The CTLA-4 cytoplasmic domain contains two tyrosine sites in the YVKM and YFIP motifs [246]. Within the cytoplasmic region, the SHP-2 (SH2 domain-containing tyrosine phosphatase-2) activates the RAS pathway, and PP2A (protein phosphatase 2A) inhibits phosphorylation of Akt, both of which are dependent on the YVKM motif [247249]. Moreover, as a potent direct activator of LFA-1 adhesion, CTLA-4 induces up-regulation of LFA-1 to enhance cell adhesion and motility and override the TCR-induced stop signal required for stable conjugate formation between T cells and APCs [250,251].

Third, CTLA-4 is required for Treg function. Notably, loss of CTLA-4 expression in Treg cells alone triggers fatal lymphoproliferative disease, while activated T cell restricted CTLA-4 expression is sufficient to prevent activated T-cell accumulation in non-lymphoid organs and thereby extend the lifespan of model mice, which suggests a dual function of CTLA-4 in both conventional T cells and Treg cells to regulate autoimmunity [252,253]. Anti-CTLA-4 mAb treatment inhibits Treg function in vivo via direct effects on CTLA-4-expressing Tregs, without reducing their numbers or affecting their homing [254]. CTLA-4-deficient mice have an enlarged population of Foxp3+ Treg cells due to enhanced proliferation in the periphery, while these Ag-specific Tregs lacking CTLA-4 are unable to control disease in an adoptive transfer model of diabetes [255]. Other studies also demonstrated that Treg cell specific reduction in CTLA-4 expression results in an increase in the formation of antigen-specific Tfh cells, GCs, and plasma and memory B cells after vaccination [256]. As opposed to mice in which CTLA4 heterozygote has no obvious phenotype, human CTLA4 haploinsufficiency causes dysregulation of Foxp3+ Treg cells, hyperactivation of effector T cells, increase in predominantly autoreactive CD21lo B cells and lymphocytic infiltration of target organs [257,258].

It is worth mentioning that the immune checkpoint therapy against CTLA-4 has been investigated quite extensively and the antibody against CTLA-4, ipilimumab, has been approved in 2011 by U.S. FDA for the treatment of melanoma [259]. The possibility and application of targetting checkpoint molecules to control the over-reactive T cells in autoimmune diseases need further investigation [260,261].

Regulatory miRNA

Epigenetic factors such as histone modification and DNA methylation, which convert signals from environmental changes into dynamic and heritable alterations of transcriptional potential, are receiving increased attention by researchers in both basic and clinical studies associated with autoimmune and autoimmune diseases [262265]. Since the Human Genome Project has been declared complete for more than 10 years, we knew that genes coding for protein consist of only 1% of the mammalian genome, whereas more than 70% are primarily transcribed into RNA, whose function in biological processes are poorly understood. MiRNAs are a set of short (~22 nts) single-stranded noncoding RNAs which are critical post-transcriptional regulators of gene expression in complex life [266].

Generation of miRNAs starts from RNA transcribed in the nucleus by RNA polymerase II or III to form long preliminary transcripts, which are cleaved by Drosha, exported to the cytoplasm by exportin 5, further processed by Dicer into mature miRNA duplexes, and then strand separated and interacting with Argonaut protein at the core of the multiprotein RISC (RNA-induced silencing complex) [267]. MiRNAs function by base pairing, thus targetting the 3′-UTR of specific mRNAs for degradation or translational repression, to regulate cellular processes such as embryonic development, cell differentiation, cell cycle, apoptosis, and immune functions. Researchers suggest that the abnormal expression pattern of miRNAs may be associated with the pathogenesis of a series of autoimmune diseases; many miRNAs capable of regulating autoimmunity have been identified [268270].

MiRNAs regulate development of the immune system. Many studies reveal that miRNAs not only regulate innate immune cell development but also dramatically alter the response to PAMPs (pathogen-associated molecular patterns) or inflammatory cytokine stimulation [271274]. They also regulate development of T and B cells. The ribonuclease III enzyme Dicer is essential for processing miRNAs from dsRNA precursors. Deletion of Dicer at an early stage of T-cell development compromises the survival of αβ lineage cells, whereas γδ-expressing thymocytes are not affected [275]. Deficiency of Dicer also results in impaired T-cell development and aberrant Th cell differentiation and cytokine production [276]. Deletion of Dicer in early B-cell progenitors results in a developmental block at the pro- to pre-B-cell transition, and the pro-apoptotic molecule Bim is highly up-regulated due to up-regulation of miR-17–92 [277].

One miRNA, miR-155, is processed from an exon of its primary miRNA precursor, the noncoding RNA known as bic [278280]. Bic-deficient mice immunized with antigens or stimulated with LPS (lipopolysaccharide) are not protected as are wild-type (WT) mice, and also fail to produce significant levels of cytokines or antibodies, suggesting a diminished T- and B-cell response [281]. miR155−/− mice are highly resistant to EAE because miR-155 promotes development of inflammatory T cells including the Th17 cell and Th1 cell subsets [282]. Additionally, miR-155 is important for Ig class switching to IgG in B cells via targetted repression of activation-induced cytidine deaminase (AID) and the transcription factor PU.1 [283285].

Various miRNAs have been shown to play a critical role in the regulation of Treg development and function. nTreg cells and conventional CD4+ T cells have distinct miRNA profiles; a Dicer deficiency causes a reduction in Treg numbers and defective iTreg induction [286]. Depletion of miRNA within the Treg cell lineage results in fatal autoimmunity indistinguishable from that in Foxp3-deficient mice, implicating miRNA as a key guardian of a stable Treg cell functional program [287]. For example, miR-155 expression in Tregs is regulated by Foxp3, which promotes proliferation of Tregs and maintains Treg cell homeostasis by limiting SOCS1 (suppressor of cytokine signaling 1) protein expression [288]. Another study also demonstrated that C-type lectin receptor CD69 controls tTreg cell development and peripheral Treg homeostasis through regulation of bic/miR-155 and its target SOCS-1 [289]. In human Tregs, miR-155 is also up-regulated and regulates the susceptibility of conventional CD4+ Th cells to nTreg cell mediated suppression [290].

Another miRNA, miR-146a, is also important in Treg function. MiR-146a-deficient mice develop a spontaneous autoimmune disorder, characterized by splenomegaly, lymphadenopathy, and multiorgan inflammation due to the loss of peripheral T-cell tolerance [291]. Deficiency of miR-146a in Tregs results in increased numbers but impaired function of Treg cells and consequently, breakdown of immunological tolerance with massive lymphocyte infiltration in several organs. This is likely to be due to STAT1 activation, which is a direct target of miR-146a, and a selective ablation of SOCS1, leading to Th1-mediated pathology [292]. miR-146a has a similar role in RA patients as well [293].

Dysregulation of miRNA can promote the induction of autoimmunity. For example, mice with elevated miR-17–92 expression in lymphocytes develop lymphoproliferative disease and autoimmunity, as a result of miR-17–92 mediated repression of Bim and PTEN, which play critical roles in immune tolerance [294,295]. Other miRNAs were found altered in autoimmune diseases, depending on various cell populations and tissue specificities. In summary, it has been clearly shown that proper expression and function of miRNAs is essential for normal immune system development and function. It is therefore important that the expression of miRNA is tightly regulated to maintain immune homeostasis.

The mechanisms of pathogenesis in autoimmune diseases are complex and highly orchestrated. Numerous immune cell types, regulatory molecules, and molecular pathways have been discovered to be tightly involved in modulating and fine tuning our immune system. Dysregulation and malfunction of these molecular processes can lead to autoimmunity. The representative molecular processes in selected autoimmune diseases (Table 3) provide a glimpse of the complexity of the molecular design of our immune system and also vast opportunities of target therapy in autoimmunity.

Table 3
Representative molecular process of major autoimmune diseases
Autoimmune diseaseImmunopathological phenotypeAssociated immunological molecules and pathwaysReferences
SLE Systemic tissue damages. Elevated autoantibodies levels, immune complexes, complement activation and proinflammatory cytokines. Increased production of autoantibodies during apoptosis; decreased clearance of cellular debris and aberrant presentation Type I interferon, IRF, C-reactive protein, NFκB pathway, PD-1, MMP, BAFF [102,305310
RA Chronic inflammation, destruction of the synovial joints leading to progressive joint damage and disability, production of autoantibodies such as rheumatoid factor or anticitrullinated antibodies PTPN22, CTLA4, peptidyl arginine deaminase 4 (PADI4), NFκB pathway, TNF-α, IL-6 [311315
PBC Destruction of small bile ducts, liver fibrosis, and potentially cirrhosis. Progressive T cell predominant lymphocytic cholangitis, high level of antimitochondrial antibodies IL-12, CXCR3, CXCR5, NFκB, TNF-α [316324
T1D Chronic inflammatory infiltrates at pancreatic islets, with predominant CD8+ T cells within insulitis lesions. Immune-mediated loss of pancreatic β-cell mass consecutive insulin deficiency. Autoantibodies against insulin, glutamic acid decarboxylase (GADA), insulinoma-associated autoantigen 2 and zinc transporter 8 PTPN22, CTLA4, IL2RA, TLRs, AIRE [325328
MS Autoreactive Th 1/Th17-mediated autoimmune response against myelin chronic central nervous system inflammation and degeneration. Activation of microglia, macrophages and astrocytes, recruitment of B cells IL-1, IL-2, TNF-α, GMCSF (granulocyte macrophage colony stimulating factor), IL-6- and IL-21-induced Th17 differentiation pathways 4-galactosyltransferase 5 and 6 [329335
Autoimmune diseaseImmunopathological phenotypeAssociated immunological molecules and pathwaysReferences
SLE Systemic tissue damages. Elevated autoantibodies levels, immune complexes, complement activation and proinflammatory cytokines. Increased production of autoantibodies during apoptosis; decreased clearance of cellular debris and aberrant presentation Type I interferon, IRF, C-reactive protein, NFκB pathway, PD-1, MMP, BAFF [102,305310
RA Chronic inflammation, destruction of the synovial joints leading to progressive joint damage and disability, production of autoantibodies such as rheumatoid factor or anticitrullinated antibodies PTPN22, CTLA4, peptidyl arginine deaminase 4 (PADI4), NFκB pathway, TNF-α, IL-6 [311315
PBC Destruction of small bile ducts, liver fibrosis, and potentially cirrhosis. Progressive T cell predominant lymphocytic cholangitis, high level of antimitochondrial antibodies IL-12, CXCR3, CXCR5, NFκB, TNF-α [316324
T1D Chronic inflammatory infiltrates at pancreatic islets, with predominant CD8+ T cells within insulitis lesions. Immune-mediated loss of pancreatic β-cell mass consecutive insulin deficiency. Autoantibodies against insulin, glutamic acid decarboxylase (GADA), insulinoma-associated autoantigen 2 and zinc transporter 8 PTPN22, CTLA4, IL2RA, TLRs, AIRE [325328
MS Autoreactive Th 1/Th17-mediated autoimmune response against myelin chronic central nervous system inflammation and degeneration. Activation of microglia, macrophages and astrocytes, recruitment of B cells IL-1, IL-2, TNF-α, GMCSF (granulocyte macrophage colony stimulating factor), IL-6- and IL-21-induced Th17 differentiation pathways 4-galactosyltransferase 5 and 6 [329335

Conclusion

The important functions of the immune system are to distinguish self from non-self and to balance defense against infection with the protection of the host from its own immune system. Immune responses must therefore be precisely regulated at multiple checkpoints [296]. The mechanisms of regulating autoimmunity include immune tolerance of lymphocytes, function of regulatory cells and proteins, as well as epigenetic regulation. Understanding of the molecular basis of these regulation mechanisms is necessary to reveal the pathogenesis of autoimmune diseases and develop novel therapies.

Funding

This work was supported by the National Key R&D Program of China [grant number 2017YFA0205600]; and the National Natural Science Foundation of China [grant numbers 81430034, 91542123].

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • AIRE

    autoimmune regulator

  •  
  • APC

    antigen-presenting cell

  •  
  • BAFF

    B-cell activating factor

  •  
  • BCR

    B-cell receptor

  •  
  • BM

    bone marrow

  •  
  • Breg

    regulatory B

  •  
  • CARD

    caspase activation and recruitment domain

  •  
  • CNS1

    conserved non-coding sequence 1

  •  
  • CTLA-4

    cytotoxic T-lymphocyte associated antigen 4

  •  
  • DC

    dendritic cell

  •  
  • EAE

    experimental autoimmune encephalomyelitis

  •  
  • EV

    extracellular vesicle

  •  
  • FDA

    Food and Drug Administration

  •  
  • Foxp3

    forkhead box P3+

  •  
  • GC

    germinal center

  •  
  • GITR

    glucocorticoid-induced TNFR family related protein

  •  
  • GVHD

    graft versus host disease

  •  
  • IFN-γ

    interferon-γ

  •  
  • IL

    interleukin

  •  
  • iTreg

    induced T-regulatory cell

  •  
  • KD

    knockdown

  •  
  • LAG3

    lymphocyte activation gene 3

  •  
  • LFA-1

    lymphocyte function associated antigen 1

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MS

    multiple sclerosis

  •  
  • MSC

    mesenchymal stem cell

  •  
  • mTEC

    medullary thymic epithelial cell

  •  
  • NFAT

    nuclear factor of activated T cell

  •  
  • NF-kB

    nuclear factor kappa B

  •  
  • Nrp-1

    neurophilin-1

  •  
  • nTreg

    natural Treg

  •  
  • PTPN22

    protein tyrosine phosphatase non-receptor 22

  •  
  • RA

    rheumatoid arthritis

  •  
  • SLE

    systemic lupus erythematosus

  •  
  • SOCS1

    suppressor of cytokine signaling 1

  •  
  • STAT

    signal transducers and activators of transcription

  •  
  • TCR

    T-cell receptor

  •  
  • TEC

    thymic epithelial cell

  •  
  • Tfh

    follicular regulatory T cell

  •  
  • TGF-β

    transforming growth factor-β

  •  
  • Th

    T helper

  •  
  • TNF

    tumor necrosis factor

  •  
  • Treg

    regulatory T cell

  •  
  • TSA

    tissue-specific Ag

  •  
  • tTreg

    thymus-derived Treg

  •  
  • T1D

    type 1 diabetes

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