In OSADs, autoantigens are a specific component of an organ, and the pathological damage and dysfunction of tissue are limited to the organ targeted by antibodies or lymphocytes. Multiple sclerosis (MS) is an autoimmune disease that demyelinates the white matter of the central nervous system. Although the specific pathogenesis remains unclear, circRNAs have been found to participate in the progression of MS (55). Cardamone et al. indicated that the abnormal metabolism of circRNAs is a potential characteristic of MS (26). Moreover, Iparraguirre et al. found two downregulated circRNAs and considered them potential biomarkers of MS (25). Among ncRNAs, miRNAs and lncRNAs are currently popular issues in MS, while circRNAs are relatively less studied; thus, more research is needed to supplement the regulatory network of ncRNAs in MS (56).

In addition to MS, circRNAs play an important role in many other OSDAs. For example, circRNAs showed promise as candidate biomarkers of primary biliary cholangitis (27), and plasma circRNA_002453 could be used as a novel biomarker of lupus nephritis (28). Researchers also found that circSnx5 control the immunogenicity of dendritic cells as a miRNA sponge, thereby alleviating experimental autoimmune myocarditis (29). Although the participation of circRNAs has further increased the complexity of the mechanism of OSAD, current research is still very simple, and it is difficult to promote the understanding of this type of disease and the therapeutic application of circRNAs.

Systemic autoimmune disease is a type of systemic multiple organ damage caused by the extensive deposition of antigen and antibody complexes on the vascular wall, and systemic lupus erythematosus (SLE) is a common disease. The exact cause of SLE is still unclear, but circRNAs have recently been regarded as vital molecules in SLE. Li et al. compared the different circRNA profiles in T cells from healthy and ailing patients and then revealed the biofunction of hsa_circ_0045272 (30). Currently, many circRNAs have been identified as biomarkers of SLE (31–34). Recently, Zhang et al. retrieved the GEO database and obtained a regulatory network, providing novel insight into the role of circRNAs in SLE (57).

Another common type of systemic autoimmune disease is rheumatoid arthritis (RA), whose pathogenesis has not been fully elucidated thus far. Currently, in the research field of circRNAs in RA, research mainly focuses on expression profile analyses, biomarker research and the proliferation and migration of fibroblast-like synovial cells. Wen et al. constructed a network of differentially expressed circRNAs and miRNAs and eventually revealed the expression profile of peripheral blood mononuclear cells (PBMCs) in patients with RA (35). Yang et al. used RNA sequencing technology to uncover the circRNA expression profiles of PBMCs in experimental and control groups and found that circRNAs are novel diagnostic markers of RA (36). Regarding the proliferation and migration of fibroblast-like synovial cells, Zhong et al. found that hsa_circ_0088036 promoted the proliferation and migration of fibroblast-like synovial cells via the miR-140-3p/SIRT1 axis in RA (37). In addition to SLE and RA, circRNAs are of great concern in some SADs. For example, Su et al. reported that hsa_circ_001264 might be a biomarker of primary Sjögren’s syndrome (pSS) (38). Although circRNAs are closely connected to SADs such as SLE, RA and pSS, research concerning SADs, such as scleroderma, dermatomyositis and polymyositis, currently mainly focuses on miRNAs. Consequently, there is substantial untapped potential in research investigating the mechanisms of circRNAs and SADs.

Currently, the study of tumor immunology focuses on the body’s immune response to tumors, the mechanism of tumor immune escape tumor immune diagnosis and immune prevention. Over years of research, scientists have discovered that circRNAs are very important molecules in various tumors, playing a variety of immunological functions. The hottest research area is the competing endogenous RNA (ceRNA) network and its regulatory molecules. Sun et al. constructed ceRNA networks based on 133 laryngeal squamous cell carcinoma (LSCC) patients and found that hsa_circ_001569 and hsa_circ_001859 might regulate the expression of CD274, IL-10 and FOXP3, thus intervening in the immune escape of LSCC (39). In another study on ceRNA networks in pancreatic adenocarcinoma (PAAD), Zhao et al. reported that CXCR4 and ZEB1 were regulated by the circUBAP2-mediated ceRNA network, inhibiting antigen presentation and promoting tumor immune escape (40). Among studies investigating ceRNA networks, research focusing on the circRNA/miRNA/mRNA axis is especially plentiful. The effects on cell phenotypes are mainly reflected in the ability to drive tumor immune escape and promote proliferation and metastasis via different axes (41, 42). In addition, studies related to anti-PD-1 therapy are included in these reports (43, 44).

With the deepening of understanding, researchers have discovered the potential of circRNAs as therapeutic targets and biomarkers with abilities to assist with diagnosis and prognosis and their function in the immune regulation of exosomes. Wang et al. showed that circSPARC might conceivably act as a possible biomarker for diagnosis and prognosis and a target for therapy in colorectal cancer (CRC) (45). In another study concerning hepatocellular carcinoma (HCC), scientists reported that the upregulated level of plasma exosomal circUHRF1 decreased NK-cell tumor infiltration, curbing the function of NK cells (44).

Generally, from the laboratory to the clinical level, current research focusing on circRNAs in tumor immunology is proceeding in an orderly manner. Therefore, the application of circRNAs in the future may have a very positive impact on many aspects of tumor immunotherapy, such as diagnosis, treatment, and prognosis.

Infectious diseases refer to diseases in which bacteria, viruses, fungi, parasites, and other infectious agents, invade, grow, and reproduce in the body, causing damage to the normal metabolic functions of the tissue structure. Thus far, circRNAs have been found to be used as biomarkers of many infectious diseases in most cases, while emergent corroboration indicates that a small number of circRNAs are verified to directly impact the regulatory network of infectious diseases (58). By regulating the NF-κB pathway, the potential miRNA targets of hsa_circ_001937 exert effectiveness in antibacterial immune responses in patients with tuberculosis (46, 48). In a bioinformatics analysis experiment, Zhuang et al. found that hsa_circ_0005836 could be a novel biomarker for diagnosis and prognosis and a target for therapy of active pulmonary tuberculosis (47). In a similar experiment, Yang et al. performed a circRNA transcription analysis of primary human brain microvascular endothelial cells infected with meningeal Escherichia coli and preliminarily constructed a potential regulatory network that enhanced our understanding of the mechanisms of bacterial meningitis (49). Additionally, in Marinov et al.’s study focusing on an LPS-inducible circRNA called circRasGEF1B, the authors assumed that inducible RasGEF1B circular RNA may play an essential role in protecting cells against microbial infection by preserving the constancy of the mature mRNA of ICAM-1 in LPS-activated cells (53), providing a new idea for antimicrobial infection therapies. CircRNAs are of vital importance to the infection of viruses because the abnormal expression of circRNAs may promote or suppress the infection progress of viruses, and vice versa. Studies have shown that when infected with viruses, circRNAs are rapidly degraded by RNase L, releasing PKR (dsRNA-activated protein kinase) linked to circRNAs and participating in innate cellular immune responses (35, 59). Notably, circRNAs initiate innate immunity by combining with K63, which links ubiquitin chains, and RIG-I (retinoic acid-inducible gene I). Exogenous circRNAs without m6A modification can attach to K63 and RIG-I. This complex can promote the polymerization and activation of RIG-I, affect the aggregation of downstream mitochondrial antiviral signals, guide the dimerization and activation of interaction regulating factor 3 (IRF3), and finally induce the expression of autoimmune-related pathway genes (50, 60, 61). The antiviral dsRNA-binding protein NF90/110 can stabilize the secondary structure of intronic RNA, thereby promoting the biogenesis of circRNAs. NF90/110 can also act as global regulators of circRNA biogenesis by reducing their nuclear levels during viral infection (51, 62).

Since the end of 2019, the world has experienced several rounds of outbreaks caused by variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and improper anti-epidemic measures. Omicron, a newly discovered SARS-COV-2 variant with high transmission, is causing unease and uncertainty. Therefore, whether focusing on the present or the future, it is particularly important to develop new treatment technologies on the basis of existing epidemic prevention measures such as drug development and vaccination (63). CircRNAs, molecules closely associated with viral infection, is one option. A differential host circRNA expression profile analysis in human lung epithelial cells infected with SARS-CoV-2 was completed (64), and two circRNA profile analyses revealed abundant and diverse information regarding the identification and characterization of the circRNAs encoded by SARS-CoV-1, SARS-CoV-2 and MERS-CoV (65, 66), facilitating future studies concerning on COVID-19 infection and pathogenesis. Arora et al. identified a circRNA/lncRNA-miRNA–mRNA ceRNA network involving two circRNAs in SARS-CoV-2-infected cells, enhancing the current understanding of the mechanisms associated with coronavirus disease 2019 (COVID-19) (52). Specific segments of the SARS-CoV-2 5’-untranslated region can be expeditiously accessed by particular antisense circRNAs, resulting in bringing an approximately 90% cutback in virus proliferation in cell culture with a minimal duration of 2 days, which is attractive and promising (67). Briefly, relevant research focused on expression profile analyses, ceRNA construction and therapeutic target seeking. Although circRNAs are in the initial stage in the prevention and treatment of novel coronavirus, with the development of cross-discipline and the emergence of more advanced technology, it is believed that there will be opportunities for circRNAs to display their clinical talents in the future.

In addition to bacteria and viruses, circRNAs function in many other infectious diseases, such as chlamydia infection (54). In addition to modulating the human body, circRNAs can play a regulatory role in other organisms during infectious diseases, such as parasite infection. Broadbent et al. identified developmentally regulated lncRNAs and circRNAs by strand-specific RNA sequencing in Plasmodium falciparum malaria (68), but currently, there is no clinical significance.

Overall, current research concerning circRNAs in infectious diseases mostly focuses on viral and bacterial infections, but in addition to research as biomarkers, these results are still a long way from clinical application.

Thus far, we mentioned that circRNAs are of great significance in autoimmune diseases, tumors, and bacterial and viral infections. In addition, expanding the perspective to the whole area, circRNAs perform effectively in hypersensitivity, immunodeficiency diseases and transplantation immunity, namely, the pathological changes caused by immune defense function. However, because the contents and categories of current related studies are relatively similar, there are only a few examples, which are no longer explained in detail here. For instance, circHIPK3 was proven to modulate the proliferation of airway smooth muscle cells by the miR-326/STIM1 axis in asthma (69), a group of ample circRNAs and ceRNA networks were found to likely contribute to acquired immune deficiency syndrome (AIDS) (70), and a two-circular RNA signature of donors was thought to be a biomarker of early allograft dysfunction after liver transplantation (71). In addition to the above diseases, circRNAs play vital roles in a variety of immunological diseases and immune cells. Under stimulation by different pathological factors, the way that circRNAs are involved in the activation of macrophages is a large subject (53, 72–74). In addition, a variety of circRNAs have been identified to influence various immune cells, such as intestinal immune cells (75), lung immune cells poisoned by Nd2O3 (76), CD4+ T cells in asthma (77) and immune cells in periodontitis (78). In addition to these effects on different immune cells, there are also some studies focusing on innovative technologies. Recently, Wesselhoeft et al. showed that unmodified exogenous circRNA can bypass cellular RNA sensors, thereby avoiding immune responses in RIG-1- and Toll-like receptor (TLR)-competent cells and mice, suggesting that RNA circularization reduces immunogenicity and can prolong the translation time in vivo ( 61).

Studies concerning circRNAs in immune-related diseases are miscellaneous, but the core functions and mechanisms are constant. The discovery of circRNAs has further deepened researchers’ understanding of the intricate immune regulatory network. Generally, the immune system has three major functions, namely, immune defense, immune surveillance and immune homeostasis, and circRNAs realize immune-related mechanisms as follows: 1) during immune defense functions, circRNAs can assist the body in removing pathogenic microorganisms and other antigens in various ways; however, hypersensitivity or immune deficiency occurs when the immune response is too high or too low; 2) when immune surveillance operates regularly, circRNAs can help the body remove mutant cells and virus-infected cells through various pathways; if this function is abnormal, it could lead to tumor occurrence and persistent virus infection; and 3) when immune homeostasis occurs naturally, circRNAs can aid the body in removing damaged or senescent cells in various ways, but imbalance could lead to autoimmune diseases. Therefore, the balance between the immune system and circRNAs plays a key role in whether the body is in a healthy or pathological state.

The regulatory mechanism of circRNAs in immune-related diseases can be summarized into the following two aspects: the regulatory effects of circRNAs on immune-related signaling pathways ( Figure 3 ), such as the MAPK signaling pathway, endocytosis signaling pathway, JAK-STAT signaling pathway, mTOR signaling pathway, and Wnt signaling pathway, and the regulatory effects of circRNAs on immune cells, such as the regulation of macrophages, etc.

Immunotherapy refers to a treatment technique that artificially heightens or represses the immune function of the body to treat immune-related diseases in accordance with the low or hyperactive immune state of the body. Because of their unique structure and various functions, circRNAs have broad application prospects in the treatment of immune-related diseases.

At the current stage, most studies investigating the functions of circRNAs are still in the laboratory stage, and only a few theories have been developed for technical applications in clinical treatment, such as gene therapy. Tens of thousands of studies have proven circRNAs to be substantially considerable in the advancement of many immune-related diseases, suggesting the roles of circRNAs as therapeutic agents and targets (50, 62, 147, 155–157). To date, there are four main approaches to realizing gene therapy as follows: inducing or inhibiting the expression of the target circRNA upstream, chemically modifying key molecules, designing analogs of the target circRNA and designing downstream molecular analogs of the circRNA, i.e., miRNA.

In addition to gene therapy, with the discovery of the function of encoding proteins, circRNAs are speculated to have the potential to be novel drug delivery carriers. Wesselhoeft et al. produced a protein with high quality and stable expression in eukaryotic cells after the circularization of mRNA in vitro and indicated that RNA circularization can reduce immunogenicity and extend translational duration in vivo (61, 158, 159), providing insight into the treatment of immune-related diseases. In addition, circRNAs have the potential to function as appropriate biomarkers of immune-related diseases. In case of immune-related diseases, it is usually difficult for patients to determine whether they fell ill by the clinical symptoms in the early stage so that they will not go to the hospital until their symptoms worsen (9). Therefore, circRNAs can function as ideal biomarkers due owing to the four main characteristics mentioned above. Thus far, numerous circRNAs have been found in exosomes, and changes in the content of circRNAs in exosomes can reflect the process of diseases (159). However, the current problem that has blocked the application of circRNAs as biomarkers in the clinic is that with the continuous improvement of the circRNA database in immune-related diseases, the expression of the same circRNA in different diseases may have the same trend, which may interfere with the judgment. Therefore, a more refined database needs to be established.

Unparalleled strides have been made in cancer treatment with the use of immune checkpoint blockade (ICB), but ICB resistance hinders the efficacy of cancer immunotherapies (160). Based on existing research, regulating gene expression at the transcriptional level, acting as miRNA sponges, binding functional proteins and encoding proteins are the four major biological functions of circRNAs, and these functions can play a vital role in regulating immune diseases, such as immune escape, immune tolerance, and antitumor and anti-infection effects, either independently or in combination (7, 12, 161–167). Moreover, circRNAs can achieve cross-cellular regulation via exosomes. Recent studies have certified the potential role of exosomes in tumor immunity and resistance to ICB (160). For instance, Lu et al. suggested that immuno-repression and anti-PD1 resistance were caused by exosomal circTMEM181 by increasing the expression of CD39, and suppressing the ATP-adenosine signaling pathway by targeting CD39 on macrophages could rescue anti-PD1 therapy resistance in HCC (168). Therefore, via exosomes, circRNAs may yield unusually brilliant clinical results in ICB.

Considering that specially designed antisense circRNAs can effectively access the SARS-CoV-2 5’-untranslated region and inhibit the proliferation of most viruses for a time, circRNAs also an option for the clinical treatment of COVID-19, which is a major achievement that uses of the unique structure of circRNAs and artificial assistance for modification, showing many advantages. The best advantage is that the antisense sequence of circRNAs is better than the corresponding linear configuration and modified antisense oligonucleotides, and antisense circRNAs have strong activity against point mutations in the target sequence. This approach manifests the function of circRNAs as nucleic acid binders, starting novel applications for designing circRNAs and hopeful therapeutic strategies for COVID-19 (67). Fortunately, Qu et al. designed a circular RNA vaccine encoding the receptor domain (RBD) of the spike protein of SARS-CoV-2 for the very virus and its mutants and found that the circRNARBD-Delta vaccine designed for the SARS-CoV-2 Delta mutant was a candidate vaccine for COVID-19 with broad-spectrum protection in rhesus monkeys. A series of comparative evaluations showed that compared with mRNA vaccines, circRNA vaccines have higher stability and a higher proportion of neutralizing antibodies, which can effectively reduce the potential side effects of vaccine-associated respiratory diseases (VAERD) (169).

Despite numerous studies, research focusing on circRNAs is still limited, and many problems remain to be solved. Although the structure of circRNAs can help attenuate off-target effects, this problem cannot be avoided. Moreover, a specific circRNA may have different functions in different cells and may cause uncontrollable side effects. In addition, if an exogenous circRNA is synthesized without protein-binding partners, it may be recognized by RIG-I as a virus-derived circRNA and thus induce innate immunity (7–9, 62).

CircRNAs perform the functions of sponging miRNAs, binding specific proteins and regulating gene transcription, and some can even encode proteins. Meanwhile, circRNAs are widely distributed in cells, the internal environment and exosomes, coupled with stable ring structures; thus, they have application potential in the diagnosis, treatment and prognosis of immune-related diseases. However, current research investigating related diseases mainly focuses on tumor immunity, bacterial and viral infections, and some autoimmune diseases, while relatively uncommon diseases are rarely studied. The hotspots of the roles of circRNAs in immune-related diseases include expression profile analyses, potential biomarker research, ncRNA axis/network construction, impacts on phenotypes, therapeutic target seeking, maintenance of nucleic acid stability and protein binding research. In addition, the study of the mechanism of circRNAs in immune regulation only occupies the tip of the iceberg in immunology. Currently, few studies on the regulation of circRNAs in the establishment of the immune system and the regulation of the immune system in the normal physiological state. A representative study showed that the structure and decomposition of circRNAs modulate PKR activation in innate immunity (4). At present, this field also faces some unsolved problems, such as off-target effects and unpredictable side effects. Therefore, continuing to supplement the regulatory network of circRNAs, attempting to explore new mechanisms, and developing new functions will be crucial for the entire field in the future, and the birth of new technologies will further contribute to the complete unveiling of the roles of circRNAs in immunity and immune-related diseases.