Type 2 hypersensitivity disorders, including systemic lupus erythematosus, Sjögren’s syndrome, Graves’ disease, myasthenia gravis, immune thrombocytopenia, autoimmune hemolytic anemia, dermatomyositis, and graft-versus-host disease, are THαβ-dominant autoimmune diseases

ABSTRACT

The THαβ host immunological pathway contributes to the response to infectious particles (viruses and prions). Furthermore, there is increasing evidence for associations between autoimmune diseases, and particularly type 2 hypersensitivity disorders, and the THαβ immune response. For example, patients with systemic lupus erythematosus often produce anti-double stranded DNA antibodies and anti-nuclear antibodies and show elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 throughout the disease course. These cytokines and antibody isotypes are associated with the THαβ host immunological pathway. Similarly, the type 2 hypersensitivity disorders myasthenia gravis, Graves’ disease, graft-versus-host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjögren’s syndrome have also been linked to the THαβ pathway. Considering the potential associations between these diseases and dysregulated THαβ immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferon α/β could be explored for effective management.

Introduction

The TH17 host immunological pathway contributes to protection against extracellular microorganisms, such as bacteria, fungi, and protozoa. Research on systemic lupus erythematosus (SLE), a relatively common autoimmune disorder, has demonstrated a potential association with the TH17 host immunological pathway; however, the relationship is still not clearly established. In particular, SLE autoantibodies typically target anti-double stranded DNA and anti-nuclear antibodies, suggesting that the disease is linked to viral infections, rather than the TH17 pathway [1]. There are literature evidences showing that virus infection can induce anti-ds DNA autoantibodies [2,3]. Although it is possible to extracellularly release of DNA by dying extracellular bacteria, it is still not reasonable that anti-ds DNA antibody is induced by extracellular bacteria. TLR9 sensing CG rich DNA is located in the endosomal location of cells. Thus, extracellular DNA cannot successfully induce TLR9 activation pathway. Only virus infection can induce TLR3, TLR7, and TLR9 to induce THαβ immune reaction. TLR7, TLR8, and TLR9 can induce TH1 immune reaction against intracellular bacteria like Mycobacterium tuberculosis. However, it is still not extracellular DNA released by dying extracellular bacteria to induce TH17 immune reaction. Besides, antibodies need to attack on pathogen surface in order to eliminate the pathogen. Thus, it is more reasonable that host antibodies attack extracellular bacteria cell walls to destroy these pathogens instead of inducing anti-DNA antibodies. The development of autoimmunity in SLE is thought to involve molecular mimicry, particularly through viral infections, such as Epstein-Barr virus (EBV) [4]. We suggest that the THαβ immune response, involved in defense against viruses and prions, is connected to the pathophysiology of SLE and other type 2 hypersensitivity disorders.

In type 2 hypersensitivity, an excessive type 1 interferon response plays a pivotal role in pathophysiology [5,6]. Antibody-mediated cytotoxicity is the hallmark of type 2 hypersensitivity. Several type 2 hypersensitivity disorders, including Sjögren’s syndrome, Graves’ disease, autoimmune hemolytic anemia, immune thrombocytopenia, graft-versus-host disease, dermatomyositis, and myasthenia gravis, do not align with TH1, TH2, or TH17 inflammatory disorders, creating uncertainty regarding their immunopathogenesis. In this context, we present evidence suggesting that these disorders are linked to antiviral THαβ-dominant autoimmune reactions, possibly triggered by viral infections through molecular mimicry. The presence of anti-nuclear antigens in the above-mentioned diseases further supports the notion that these type 2 autoimmune conditions can be classified as THαβ-dominant immune disorders. This perspective adds to our understanding of the immunological mechanisms underlying these diseases and their potential connection to viral infections.

Framework of host immunological pathways

Host immunological pathways can be classified into two primary categories: IgG-dominant eradicable immune reactions and IgA-dominant tolerogenic immune reactions [7–9]. Follicular helper T cells play a crucial role in facilitating the development of eradicable immunity by promoting an antibody class switch from IgM to IgG. Four distinct types of eradicable immune responses (i.e. TH1, TH22, TH2, and THαβ) correspond to different pathogenic entities. TH1 immunity, for instance, specifically combats intracellular microorganisms, including intracellular bacteria, protozoa, and fungi. This categorization improves our understanding of the intricate and specialized roles of different immune pathways in responses to diverse types of pathogens [10]. TH1 immunity involves M1 macrophages, IFNγ CD4 T cells, iNKT1 cells, CD8 T cells (Tc1, EM4), and IgG3 B cells [11,12]. It is linked to type 4 delayed-type hypersensitivity, which results in a delayed immune response. In contrast, TH2 immunity is specifically tailored to combat parasites. Notably, TH2 immunity includes two distinct subtypes, TH2a induced in response to endoparasites (helminths) and TH2b induced in response to ectoparasites (insects), emphasizing the nuanced and specialized nature of the immune response against parasitic invaders [13]. TH2a immunity involves inflammatory eosinophils (iEOS), interleukin-4/interleukin-5 CD4 T cells, mast cell tryptase (MCt), iNKT2 cells, and IgG4 B cells [14–17]. TH2b immunity includes basophils, interleukin-13/interleukin-4 CD4 T cells, mast cells-tryptase/chymase (MCtc), iNKT2 cells, and IgE B cells [18–20]. The TH2 immunological pathway is intricately associated with type 1 allergic hypersensitivity, representing a specific immune response to allergens. In contrast, TH22 immunity serves as the host’s specialized immune reaction targeting extracellular microorganisms (broadly including extracellular bacteria, protozoa, and fungi). The components of TH22 immunity are diverse and include neutrophils (N1), CD4 T cells that produce interleukin-22, iNKT17 cells, and IgG2 B cells [21,22]. TH22 immunity is associated with type 3 immune complex-mediated hypersensitivity. THαβ immunity is the host immunological pathway against infectious particles (viruses and prions) [23–25]. THαβ immunity involves NK cells (NK1), interleukin-10-producing CD4 T cells, iNKT10 cells, CD8 T cells (Tc2,EM1), and IgG1 B cells [26]. THαβ immunity is associated with type 2 antibody-dependent cytotoxic hypersensitivity. CXCR3 and its ligands are associated in THαβ immunity [27].

The immunological pathways classified as tolerogenic are characterized by the dominance of IgA-mediated immune reactions, which are further subdivided into four distinct groups tailored to address different pathogens. Regulatory T cells play a pivotal role in facilitating the development of tolerogenic immune reactions by activating the antibody class switch to IgA [7]. TH1-like immunity is a tolerogenic immune reaction against intracellular microorganisms (intracellular bacteria, protozoa, and fungi). TH1-like immunity involves M2 macrophages, TGF/IFNγ CD4 T cells, iNKT1 cells, CD8 T cells (EM3), and IgA1 B cells [28]. TH1-like immunity is associated with type 4 delayed hypersensitivity. TH9 immunity is a tolerogenic immune reaction against parasites (insects and helminths). TH9 immunity involves regulatory eosinophils (rEOS), basophils, interleukin-9 CD4 T cells, iNKT2 cells, IL-9 related mast cells (MMC9), and IgA2 B cells [29,30]. TH9 immunity is associated with type 1 allergic hypersensitivity. TH17 immunity is a tolerogenic immune reaction against extracellular microorganisms (extracellular bacteria, protozoa, and fungi). The TH17 immune reaction involves neutrophils (N2), interleukin-17 producing CD4 T cells, iNKT17 cells, and IgA2 B cells. TH17 immunity is associated with type 3 immune complex-mediated hypersensitivity [31,32]. TH3 immunity is a host immune reaction to infectious particles (viruses and prions). TH3 immunity involves NK cells (NK2), interleukin-10/TGFβ CD4 T cells, iNKT10 cells, CD8 T cells (EM2), and IgA1 B cells [33,34]. TH3 immunity is associated with type 2 antibody-dependent cytotoxic hypersensitivity.

There is a misleading belief that almost all the autoimmune disorders link to TH17 immunological pathway. For example: asthma is a type 1 autoimmune illness, but it is related to TH2 or TH9 immunological pathway. Multiple sclerosis is a type 4 autoimmune illness, but it is related to TH1 immunological pathway. Thus, it is also reasonable that some autoimmune diseases belong to TH17 immunological pathway and others belong to THαβ immunological pathway. TH17 or TH22 immune reaction is against the infections of extracellular micro-organisms including extracellular bacteria, fungi, and protozoa. THαβ immune reaction is against infectious particles including viruses and prions. The main immune effector cells are neutrophils with cytokines including TNFα, IL-1, and IL-6 in TH17 or TH22 immune response. The main effector cells are NK cells and CTLs with cytokines including IL-10, IL-27, and type 1 interferons in THαβ immune response. Thus, when neutrophils and TNFα play major roles in the pathogenesis of certain autoimmune diseases. These autoimmune diseases are TH17 or TH22 immune related disorders. For example, rheumatoid arthritis is a TH17 or TH22 immune disorder which is related to hyper-activity of neutrophils and TNFα [35]. Thus, we can use Humira, the TNFα inhibitor, to treat rheumatoid arthritis patients and get promising results. However, we cannot to treat SLE, dermatomyositis, and other type 2 hypersensitivities with Humira because they have different pathophysiology. These diseases are THαβ immune responses.

Relationship between the THαβ immunological pathway and SLE

While several previous studies have suggested that the TH17 immune response is related to SLE, this association has not been verified. The TH17 immunological pathway has been proposed to be linked to nearly all autoimmune disorders; however, this concept is flawed. Conditions such as asthma, atopic dermatitis, and allergic rhinitis fall into the category of type 1 autoimmune disorders and are associated with the TH2 or TH9 immunological pathways. In contrast, multiple sclerosis, contact dermatitis, and type 1 diabetes mellitus are classified as type 4 autoimmune diseases and are related to the TH1 immunological pathway. Consequently, the TH17 immunological pathway cannot comprehensively explain the mechanisms underlying all autoimmune disorders. It is crucial to recognize that the TH17 immunological pathway primarily serves as the host defense against extracellular microorganisms, including extracellular bacteria, protozoa, or fungi. The existence of disease-specific anti-nuclear antibodies in SLE is correlated with the host immune response against viruses. The THαβ immunological pathway, which is responsible for host eradicable immunity against viral infections, plays a role in this context. The relationship between SLE and the THαβ immune reaction will be explored further in this article.

The initiation of THαβ immune response involves innate lymphoid cells, specifically ILC10. Additionally, plasmacytoid dendritic cells (DCs) serve as antigen-presenting cells that initiate the THαβ immunological pathway. A previous study established the significance of plasmacytoid dendritic cells in the initiation of SLE [36]. Type 1 interferons (interferons alpha and beta) are mainly produced by plasmacytoid DCs. These cytokines are the first line of defense against viral pathogens invading the host. Type 1 interferons play key roles in the pathogenesis of SLE [37–39]. Monoclonal antibodies against type 1 interferons have been tested in patients with SLE in several clinical trials [40,41]. Type 3 interferons, such as interferon lambda, have similar cellular functions to those of type 1 interferons. Previous studies have also pointed out the relationship between type 3 interferons and the pathogenesis of SLE [42,43].

In addition, we examined the roles of Toll-like receptor (TLR) patterns in initiating antiviral immune reactions. TLR3, TLR7, and TLR9 are the major subtypes that trigger antiviral immune responses. TLR3 is activated by double-stranded RNA. TLR7 and TLR9 are activated by single-stranded RNA. TLR3, TLR7, and TLR9 are located in the endosomal compartments of cells. Their activation can lead to the production of type 1 interferons (interferon alpha and beta) by DCs, especially plasmacytoid DCs. TLR3, TLR7, and TLR9 are all related to the pathophysiology of SLE [44–50]. Thus, TLRs may be therapeutic targets for controlling SLE [44,51].

The central THαβ immunity-related cytokine is interleukin-10, which can activate the immune activities of NK cells and CTL and cause the B cell antibody isotype switch to IgG1. The serum level of interleukin-10 is elevated in patients with SLE [52,53]. Furthermore, anti-interleukin-10 monoclonal antibodies can alleviate symptoms and disease progression in patients with SLE [54–57]. These findings indicate that the THαβ immune reaction plays a key role in the pathogenesis of SLE. Levels of IgG1, the primary antibody used against viral infection, are elevated in patients with SLE. These findings support the hypothesis that SLE is a THαβ immune disorder. CXCR3, IRF5, and IRF7 are also related to SLE pathogenesis [58,59].

In addition to the THαβ eradicable host immunological pathway, TH3 tolerogenic immunity contributes to the response to viral infection [33]. This type of immunity is usually observed during the chronic stage of SLE. A component of the TH3 immunological pathway, serum antibody IgA1 is elevated in patients with chronic SLE [60]. Additionally, the TH3 immunological pathway with Treg cells and TGFβ production can cause kidney fibrosis and eventually lead to renal failure, a common complication of chronic SLE. Thus, TH3 immunity plays a vital role in the pathophysiology of SLE.

Relationship between the THαβ immunological pathway and Sjögren’s syndrome

Sjögren’s syndrome is a type 2 hypersensitivity disorder that manifests as dry eyes, dry mouth, and dry mucosa, indicating an autoimmune condition. These clinical features can also be associated with various viral infections, which must be considered in the differential diagnosis. Furthermore, viral infections, notably EBV infections, have the potential to activate molecular mimicry, leading to the subsequent development of autoimmune Sjögren’s syndrome. Other viral infections, including HIV, HCV, and HTLV, can also cause dry eye, dry mouth, and dry mucosa, mimicking the clinical symptoms and signs of Sjögren’s syndrome [61]. This highlights the importance of recognizing and investigating the role of viral infections in the etiology and pathogenesis of Sjögren’s syndrome [61] and ruling out viral infections before diagnosis. It is likely that Sjögren’s syndrome is associated with the antiviral THαβ immunological pathway. Furthermore, the pathogenesis involves the destruction of cells in the salivary glands, lacrimal glands, and mucosal tissue. This destruction is characterized as type 2 antibody-dependent cytotoxic hypersensitivity that is linked to the anti-viral THαβ immune reaction. These factors collectively indicate that Sjögren’s syndrome can be classified as a THαβ immune disorder.

Sjögren’s syndrome is related to the presence of anti-Ro and anti-La autoantibodies, which are antibodies against RNA molecules (Y RNA), in the serum [62]. Thus, the anti-nucleic acid antibodies associated with Sjögren’s syndrome also support the role of antiviral THαβ immunity. Viral particles can be DNA or RNA viruses. Thus, RNA is an inherited molecule from infectious viruses. Based on the shared role of THαβ autoimmunity, SLE and Sjögren’s syndrome may overlap. TLR3, TLR7, and TLR9 activation is related to the immunopathogenesis of Sjögren’s syndrome [63,64]. These three TLRs respond to DNA and RNA molecules during viral infection. Plasmacytoid DCs, which are antigen-presenting cells that initiate THαβ immunity, are activated in Sjögren’s syndrome. Type 1 and type 3 interferons, which are responsible for THαβ antiviral immunity, are also upregulated in Sjögren’s syndrome [65]. Follicular helper T cells, follicular DCs, and plasmacytoid DCs also play a role in the pathogenesis of Sjögren’s syndrome [66,67]. Follicular DCs are associated with the upregulation of follicular helper T cells. Plasmacytoid DCs are involved in the upregulation of TLR3, TLR7, and TLR9, thereby triggering type 1 interferon responses to initiate THαβ anti-virus host immune reactions. The antiviral antibody subtype IgG1 is the major autoantibody found in Sjögren’s syndrome [62]. The THαβ cytokines interleukin-10 and interleukin-27 are also upregulated in Sjögren’s syndrome and may play key roles in its pathogenesis [68,69]. The TCR repertoire is related to the pathogenesis of Sjögren’s syndrome [70]. Cytotoxic T cells, which are the key effector cells in antiviral THαβ immunity, are also stimulated in Sjögren’s syndrome [71]. Thus, T cell-related cellular immune responses, including THαβ immune reactions, are correlated with the pathophysiology of Sjögren’s disease. STAT1 and STAT3 are the major transcription factors that mediate the antiviral THαβ immunological pathway; both are upregulated in Sjögren’s syndrome [72,73]. CXCR3 is the major chemokine receptor in THαβ-related T lymphocytes. There is also evidence that CXCR3-presenting lymphocytes are correlated with Sjögren’s syndrome [74]. Various CXCR3 ligands, including CXCL9, CXCL10, and CXCL11, are upregulated in tissues involved in Sjögren’s syndrome. NKT and CD56+ NK cells also play vital roles in the pathogenesis of Sjögren’s syndrome [75]. These findings highlight the importance of THαβ immunity in the pathogenesis of Sjögren’s syndrome.

Relationship between the THαβ immunological pathway and myasthenia gravis

Myasthenia gravis is a common type 2 hypersensitivity disorder. It is not a TH1, TH2, or TH17 disorder. We provide evidence that myasthenia gravis is closely related to the THαβ immune response, consistent with its classification as a type 2 hypersensitivity disorder. Autoantibodies for myasthenia gravis are mainly anti-acetylcholine receptor antibodies, typical IgG1 antibodies involved in THαβ immunity [76]. Because acetylcholine receptors are located in the cell membrane of neurons at the neuromuscular junction, anti-acetylcholine receptor IgG1 antibodies can cause neuronal cell antibody-dependent cellular cytotoxicity via NK cells. NK cell activity is also upregulated in patients with myasthenia gravis. After plasmapheresis for myasthenia gravis treatment, NK cell activity decreases [77]. Interleukin-10 polymorphisms are associated with myasthenia gravis, suggesting that the THαβ immune response is related to this autoimmune disorder [78]. This indicator of cellular immunity contributes to the pathogenesis of myasthenia gravis. Another study reported that interleukin-10 and Tr1 cells (THαβ CD4 T cells) are correlated and upregulated in myasthenia gravis [79]. TLR3, TLR7, and TLR9, related to THαβ immune activation, are overexpressed in the thymus of patients with myasthenia gravis [80,81]. Plasmacytoid dendritic cells and IRF5 are also correlated to the pathogenesis and clinical severity of myasthenia gravis [82,83]. Plasmacytoid dendritic cells are also associated with thymoma in myasthenia gravis. [82]

Levels of the central antiviral THαβ immune cytokine, interleukin-10, are elevated in patients with myasthenia gravis [84]. Another key THαβ cytokine, interleukin-27, which can induce the production of interleukin-10, is also upregulated in myasthenia gravis [85]. In addition, initiators of THαβ immunity and type 1 interferons are upregulated [86]. These findings suggests that the THαβ immunological pathway plays a vital role in the pathophysiology of myasthenia gravis. Thymomas are often observed in patients with myasthenia gravis. Thymomas are usually associated with the overproduction of CD4 T cells and CD8 T cells. These two lymphocytes, especially cytotoxic CD8 + T cells, are important components of the THαβ immune reaction. Anti-double-stranded RNA, another autoantibody related to viral infection, is also related to the etiology of myasthenia gravis [87]. Viral infection can usually exacerbate myasthenia gravis, highlighting the vital role of the THαβ immunological pathway in disease pathogenesis. EBV, parvovirus, and HSV infections have been reported to be associated with the pathogenesis of myasthenia gravis [88,89]. Chemokine receptors and their ligands CXCR3 and IP10, which are related to THαβ immunity, are overexpressed in T lymphocytes in myasthenia gravis [90].

Relationship between the THαβ immunological pathway and Graves’ disease

Autoimmune thyroiditis encompasses Hashimoto thyroiditis (classified as a type 4 hypersensitivity disorder) and Graves’ disease (classified as a type 2 hypersensitivity disorder). Graves’ disease is associated with hyperthyroidism, whereas Hashimoto’s thyroiditis is associated with hypothyroidism. In Graves’ disease, the presence of autoantibodies leads to thyroid hyperplasia, whereas in Hashimoto thyroiditis, these autoantibodies result in thyroid tissue destruction [91]. This explains the differences in clinical characteristics between the two autoimmune thyroiditis types [92]. Similar to SLE, anti-nuclear antibodies can be detected in autoimmune thyroiditis, especially in Graves’ disease. Anti-double-stranded DNA autoantibodies are also found in patients with Graves’ disease [93]. The chemokine receptor CXCR3 and its ligand CXCL10 are overexpressed in THαβ immune cells, and they are both overexpressed in Grave’s disease [94]. Type 1 and type 3 interferons, including interferon alpha/beta/lambda, are initiators of the THαβ immune response and are overexpressed in Graves’ disease [95]. The transcription factor IRF7, which is related to type 1 interferon expression, is also overexpressed in Graves’ disease. IgG1 is an anti-viral THαβ immune reaction antibody and is the major autoantibody IgG subtype found in Graves’ disease [96]. The central cytokine of the THαβ immunological pathway, interleukin-10, is also overexpressed in this disease [97]. Another important THαβ immunity cytokine, interleukin-27, is also related to the pathophysiology of Grave’s disease. TLR3, TLR7, and TLR9 play vital roles in sensing viral antigens to trigger THαβ immune reactions, and these TLR subtypes are also overexpressed in Graves disease [98]. NK cells are important immune effector cells against viral infections. However, the activity of NK cells is suppressed by thyroid hormones. Thus, decreased NK cell activity is noted in Graves’ disease with hyperthyroidism [99]. Plasmacytoid dendritic cells are related to Grave’s disease pathophysiology [100]. Besides, virus infections including enterovirus, HHV6, and Parvovirus link to the pathogenesis of Grave’s disease [101].

Relationship between the THαβ immunological pathway and graft-versus-host disease

Graft-versus-host disease is classified as a type 2 hypersensitivity reaction and is a THαβ-dominant autoimmune disorder. In the context of transplantation, activated NK cells and cytotoxic CD8 T cells originating from the graft target the recipient tissues that possess mismatched MHC molecules, leading to the development of graft-versus-host disease [102]. Antibody-dependent cellular cytotoxicity is over-activated and CD8 + T cell perforins are overexpressed in this disease. Interleukin-10, the central cytokine in THαβ immunity, is related to the severity of graft-versus-host disease [103]. The THαβ immunity-related chemokine receptor CXCR3 and the cytokines interleukin-15 and interleukin-27 are overexpressed in this disease [104–106]. Type 1 interferons, vital THαβ immunity initiators, are also upregulated in graft-versus-host disease [107]. Transcription factors related to type 1 interferons, IRF3 and IRF7, are also upregulated in graft-versus-host disease [108,109], and STAT1 and STAT3 are activated [110,111]. TLR7 and TLR9, which sense viral nucleic acid antigen, are also upregulated in graft-versus-host disease [112,113]. Signaling factors downstream of these TLRs, including MyD88 and TRIF, are also vital to the pathogenesis of the disease [114]. Antigen-presenting cells for antiviral THαβ immunity, plasmacytoid DCs, are activated in graft-versus-host disease [115]. CXCR3 and anti-DNA IgG1 autoantibody also participate in the pathogenesis in graft-versus-host disease [104,116].

Relationship between the THαβ immunological pathway and immune thrombocytopenia

Immune thrombocytopenia, formerly known as idiopathic thrombocytopenia, is characterized by the immune-mediated destruction of platelets. It can be caused by viral infection and thus is a THαβ-related immune disorder. Anti-nuclear autoantibodies are found in immune thrombocytopenia, particularly in patients with chronic immune thrombocytopenia. B and T cells play important roles in the pathogenesis of immune thrombocytopenia. Additionally, cytotoxic T lymphocytes and plasmacytoid DCs, both of which are important effector cells in the THαβ immunological pathway, play key roles in the pathophysiology [117].

Key cytokines in the THαβ immunological pathway also play key roles in the pathophysiology of immune thrombocytopenia. Genetic polymorphisms in interleukin-10 are related to immune thrombocytopenia [118]. Interleukin-10 is closely associated with disease development and progression [119]. Another important THαβ immunity cytokine, interleukin-27, is elevated in patients with immune thrombocytopenia [120]. Furthermore, interleukin-27 polymorphisms are also associated with the risk of immune thrombocytopenia [121]. Type 1 interferons, initiators of THαβ immunity, are also important in the pathogenesis [122], and many interferon-regulated genes are upregulated in patients with immune thrombocytopenia. IgG1, the antiviral THαβ immunity antibody subtype, is over-expressed in immune thrombocytopenia [123,124].

Signaling pathways involved in THαβ immune reactions are upregulated in immune thrombocytopenia. There is evidence for the upregulation of TLR7 [123], the type 1 interferon signaling-related transcription factor IRF3 and adaptive immunity-related transcription factor NFκB [125], and the master THαβ immune transcription factors STAT1 and STAT3 [126,127]. These results shows that the THαβ immune reaction is important in the pathophysiology of immune thrombocytopenia. NK cells and CXCR3 with its ligand CXCL11 are associated with the pathogenesis of immune thrombocytopenia [128–130]. Many viruses like VZV, rubella, EBV, influenza, and HIV also link to the pathophysiology of immune thrombocytopenia [131].

Relationship between the THαβ immunological pathway and autoimmune hemolytic anemia

Autoimmune hemolytic anemia falls under the category of type 2 autoimmune disorders, wherein red blood cells bound to IgG antibodies are targeted and destroyed by immune cells, leading to hemolysis. This condition is also a THαβ immunological disorder. Notably, our findings provide evidence that type 1 regulatory T cells, specifically THαβ CD4 T cells, play a crucial role in the development and progression of autoimmune hemolytic anemia [132]. Anti-nuclear autoantibodies have also been observed [133,134], suggesting that certain viral-related antigens can trigger autoimmune hemolytic anemia via molecular mimicry. For example, enterovirus 71 can induce autoimmune hemolytic anemia. CD4 and CD8 T cells [135] as well as follicular helper T cells, which initiate eradicable immunity, can promote autoimmune hemolytic anemia [136]. On the other hand, regulatory T cells (Tregs), which drive the tolerogenic immune response, can control autoimmune hemolytic anemia [136]. Plasmacytoid DCs with IRF8 upregulation trigger autoimmune hemolytic anemia [36].

Key THαβ immunological pathway-related cytokines play an important role in triggering autoimmune hemolytic anemia. Interleukin-10 levels are associated with autoimmune hemolytic anemia [137]. There is a positive correlation between interleukin-10 levels and reticulocyte counts and a negative correlation between interleukin-10 and haptoglobin in hemolytic anemia [138]. Type 1 interferons, including interferon alpha and beta, can trigger autoimmune hemolytic anemia [139]. IgG1, an antiviral THαβ immune-related antibody [133], STAT1 and STAT3, [140,141], and the chemokine receptor CXCR3 are involved in the pathophysiology of autoimmune hemolytic anemia [142]. TLR7 and NK cells are also related to the pathogenesis of autoimmune hemolytic anemia [143,144].

Relationship between the THαβ immunological pathway and dermatomyositis

Dermatomyositis is a type 2 autoimmune disorder that specifically falls under the category of inflammatory myopathy. This condition is characterized by elevated interferon levels, particularly type 1 interferon, within the spectrum of inflammatory myopathies [145]. Dermatomyositis is dominated by THαβ cells. The majority of individuals with dermatomyositis exhibit the presence of the Anti-Jo1 autoantibody, which targets histidyl-tRNA synthetase [146]. Because the THαβ immune reaction fights against viruses-derived DNA and RNA molecules, dermatomyositis is associated with antiviral THαβ immunity [147]. B cells, CD4+ T cells, CD8+ T cells, and NK cells are important components of the THαβ immune reaction and are important in the pathogenesis of dermatomyositis [147–151]. The central THαβ immunity-related cytokine interleukin-10 is upregulated in dermatomyositis and is related to its pathophysiology [152–154]. Another important THαβ immune reaction-associated cytokine, interleukin-27, is also over-expressed in dermatomyositis [155]. These findings highlight the importance of THαβ immunity in the pathogenesis of dermatomyositis.

Various components in the signaling pathway of THαβ immunity are overexpressed in dermatomyositis. MHC1, an antigen-presenting molecule for CD8 T cells, is over-represented [156]. The type 1 interferon-related transcription factors IRF3 and IRF7 [157] and JAK signaling (involved in activating STAT immune master transcription factors) are important in the pathogenesis of dermatomyositis [158]. TLR9 and TLR7, which activate anti-viral THαβ immunity, are also upregulated in dermatomyositis [151,159]. CXCR3+ lymphocytes and their ligands CXCL9 and CXCL10 are correlated with the progression of dermatomyositis [160]. These chemokine ligands and receptors are important for mediating THαβ immunity. Plasmacytoid dendritic cells and IgG1 are related to the pathogenesis of dermatomyositis [161,162]. Virus infections like EBV can also link to the pathophysiology of dermatomyositis [163].

Some of these type 2 autoimmune disorders are systemic, while others are regional. The difference is depending on the autoantibodies. For example: SLE is related to ANA and anti-dsDNA antibodies which will attack on all the human cells with DNA structure that makes SLE a systemic disease [1]. On the other hand, myasthenia gravis is a regional disease. Its autoantibody is the anti-acetylcholine receptor antibody which attacks on the neuro-muscular junction only [76]. This makes myasthenia gravis a regional illness. These point out the importance of autoantibodies which will guide immune cells to attack on general or specific target cells. We made a summary of these points in Table 1 and Figure 1.

Table 1.

Summary of the relationship of THαβ related immune mediators and type 2 hypersensitivities.

Diseases	TLRs	DCs	Cytokine	Chemokine	Transcription factor	Autoantibody	B cell	T cell	NK cell	Related Viruses
SLE	TLR3,7,9	pDC	IFNα/β/λ, IL-10	CXCR3	IRF5, IRF7	Anti-dsDNA, ANA	IgG1, IgA1	CTLs	NK cell	EBV
Sjögren’s syndrome	TLR3,7,9	pDC, FDC	IFNα/β/λ, IL-10 IL-27	CXCR3, CXCL9, CXCL10, CXCL11	STAT1, STAT3	Anti-Ro,Anti-La	IgG1	CTLs	NK cell, NKT cell	EBV, HIV, HCV,HTLV
Myasthenia gravis	TLR3,7,9	pDC	IL-10	CXCR3 IP10	IRF5	Anti-AchR, Anti-dsRNA	IgG1	CTLs, thymoma	NK cell	EBV, parvovirus, HSV
Grave’s disease	TLR3,7,9	pDC	IFNα/β/λ, IL-10, IL-27	CXCR3, CXCL10	IRF7	TSI, ANA, Anti-dsDNA	IgG1			Enterovirus, HHV6, Parvovirus
GvHD	TLR7,9 TRIF, MyD88	pDC	IFNα/β, IL-15, IL-10, IL-27	CXCR3	IRF3, IRF7, STAT1, STAT3	Anti-MHC Anti-DNA	IgG1	CTLs	NK cell
Immune thrombocytopenia	TLR7	pDC	IFNα/β, IL-10, IL-27	CXCR3, CXCL11	IRF3, STAT1, STAT3	Anti-platelet antibody, ANA	IgG1	CTLs	NK cell	VZV,rubella, EBV,influenza, HIV
Autoimmune hemolytic anemia	TLR7	pDC	IFNα/β, IL-10,	CXCR3	IRF8, STAT1, STAT3	ANA	IgG1	CTLs	NK cells	enterovirus
Dermatomyositis	TLR7,9	pDC	IFNα/β, IL-10, IL-27	CXCR3, CXCL9, CXCL10	IRF3, IRF7	Anti-Jo1	IgG1	CTLs	NK cells	EBV

Figure 1.

The anti-viral THαβ immunological pathway and its relations to type 2 hypersensitivity disorders including autoimmune hemolytic anemia, immune thrombocytopenia, systemic lupus erythematosus, Sjögren’s syndrome, grave’s disease, myasthenia gravis, graft versus host disease, and dermatomyositis.

Conclusion

Understanding that the etiologies of type 2 hypersensitivities, encompassing SLE, myasthenia gravis, Graves’ disease, graft-versus-host disease, immune thrombocytopenia, autoimmune hemolytic anemia, dermatomyositis, and Sjögren’s syndrome, are linked to the antiviral THαβ immunological pathway, paving the way for the development improved diagnosis and treatment approaches for these debilitating conditions. Current management often involves the use of steroid agents, which, while effective, pose significant risks by affecting adaptive immunity and increasing susceptibility to viral or bacterial infections. If the THαβ immune response is identified as the primary pathogenic mechanism underlying these diseases, a more targeted approach could involve blocking central THαβ cytokines, such as type 1 interferons, interleukin-10, and interleukin-27, using specific inhibitors. This strategic intervention aims to halt disease progression while circumventing infection-related drawbacks associated with steroid treatment. This innovative management strategy holds considerable promise for providing more effective and tailored therapeutic options for autoimmune disorders.

Funding Statement

This study was supported by grants from the Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation [TCRD-TPE-110-02(2/3) and TCRD-TPE-111-01(3/3)].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

YMH, LJS, KWT, TWH and WCH conducted the study and wrote the manuscript. LJS, KCL, and WCH aided in collecting the reference literature and assisted in drafting the manuscript. TWH and YMH were helpful in drafting the manuscript. YMH, LJS, MTL, and WCH handled data processing and created tables and figures. YMH, KWT, KCL, and WCH reviewed the study and edited the manuscript. WCH finally approved the manuscript. All authors have read and approved the final work.

Data availability statement

Data sharing not applicable – no new data generated

Ethical statement and consent

This review article examines the literature on type 2 hypersensitivity disorders, including THαβ-dominant autoimmune diseases such as systemic lupus erythematosus, Sjögren’s syndrome, Grave’s disease, Myasthenia Gravis, immune thrombocytopenia, autoimmune hemolytic anemia, dermatomyositis, and graft-versus-host disease. References were sourced from PubMed and Medline, obviating the need for ethical statements and informed consent for the article’s preparation and completion.