B cells play an important role in the development of SLE, including the presentation of antigens, activation of T cells, and production of autoantibodies (13), reducing the persistence of autoantibody-secreting plasma cells and memory B cells in SLE patients is therefore a key to treating SLE. In 2021, Jin et al (17) demonstrated in a mouse model of SLE that administration of CD19-targeted CAR-T therapy resulted in depletion of B-cells, interruption of autoantibody production, and reversal of glomerulonephritis and other organ damage in mice. In September 2022, Prof. Georg Schett’s team at the University of Erlangen-Nuremberg, Germany, reported in Nature Medicine the results of CAR-T therapy in five patients with refractory SLE (15). The five patients who were treated with CAR-T had no anti-dsDNA antibodies and an overall reduction in autoantibodies; they did not relapse during the 17-month follow-up period, and all of them achieved drug-free DORIS (the definitions of remission in SLE) remission without receiving any medication related to SLE during the treatment period (16). The results showed that all SLE patients achieved DORIS remission at 6 months post-treatment, with significant clinical responses in patients with idiopathic inflammatory myopathies and reduced disease activity in patients with systemic sclerosis. Grade 1 cytokine release syndrome (CRS) occurred in 10 patients, and 1 patient was hospitalized with grade 2 CRS, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia (Table 1).

MG is an autoimmune disease characterized by autoantibody-mediated impairment of acquired neuromuscular junction (NMJ) transmission, mainly caused by anti-acetylcholine receptor (AChR) antibodies (31). B cells play a crucial role in the pathologic process of MG (32). Descartes-08 is a CAR ⁃T therapy that expresses CAR from mRNA, transiently rather than permanently, thereby reducing the risks inherent in traditional CAR ⁃T cell therapy, and targets BCMA for the treatment of generalized myasthenia gravis (gMG). Recently, Tahseen Mozaffar et al. published the results of a phase Ib/IIa clinical trial of Descartes ⁃08 in patients with gMG (18), in which the first cohort of three patients with gMG showed significant disease improvement and tolerated the drug well, with no CRSs or other serious adverse effects. The second cohort 11 gMG patients had no dose-limiting toxicity, CRS, or neurotoxicity at a median follow-up of 5 months (range, 3 to 9 months) and showed significant improvement in MG clinical performance at up to 9 months post-infusion.

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic B-cells are damaged by a variety of factors (autoimmunity, genetics, viral infections, etc.) and fail to secrete insulin normally. A variety of abnormal autoantibodies can be produced in patients, such as anti-glutamic acid decarboxylase antibodies, insulin antibodies, islet cell antibodies, etc. The most common treatment for T1D is the injection of artificial insulin preparations, but this does not provide a cure. Zhang et al. (19) used mAb287 chimeric antigen receptor T (287⁃CAR⁃T) cells and found that they could temporarily inhibit autoimmunity against pancreatic islet cells and delay the onset of T1D in untreated mice by about 6 weeks. They found that insulin autoantibodies were detectable in both control mice at week 10, but not in the 287⁃CAR⁃T cell-treated mice. However, they found that the efficacy of 287-CAR-T cell therapy was not long-lasting, and the 287-CAR-T cells in the mice gradually decreased over time, becoming undetectable by 25 weeks. This suggests that the current single-injection CAR-T cell therapy can only delay the progression of diabetes, but not stop it.

Ulcerative colitis is an inflammatory bowel disease characterized by mucosal inflammation that begins at the distal end, gradually expands proximally, and eventually involves the entire colon, often with recurrent episodes. The key cause of its pathogenesis is the imbalance in the dynamic balance between the intestinal flora and the body’s immune response. Reduced activity of peripheral regulatory T cells (Treg) leads to over-activation of intestinal immune responses. Elinav et al (20) proposed that natural Tregs (nTreg) can efficiently express functional, antigen-specific chimeric receptors, and they found that nTreg with a variable region of antibodies against 2, 4, 6 ⁃ Trinitrophenol (TNP) specifically inhibited effector T cells in vitro and in vivo ( 21), and in mice model of colitis, the cells significantly ameliorated the symptoms of colitis in mice. Blat et al (22) evaluated the ability of CAR⁃Treg to redirect to the inflammatory part of the colon and the regulation of CAR⁃Treg. They used carcinoembryonic antigen (CEA), which is overexpressed in colitis, as the target of CAR⁃Treg targeting, and designed a chimeric embryonic antigen receptor-regulated T cell (CEA-CAR⁃Treg) to target the inflammatory part of the colon. The results show that CEA⁃CAR⁃Treg can be redirected to the site of inflammation to suppress the immune response. This study also found that CAR⁃Treg has more potent inhibitory activity than polyclonal Treg. More importantly, CEA⁃CAR⁃Treg can inhibit the progression of colitis to colorectal cancer, and its use in the early stages of colitis significantly reduces the risk of colorectal cancer progression. These studies have shown that CAR⁃Treg is effective in animal experiments (33). It is important to note that the effects of CAR⁃Treg are also influenced by the microenvironment, and some microenvironments may even mediate the opposite effect of CAR⁃Treg. If Treg loses expression of the forehead box P3 (FOXP3) in an inflammatory environment, the immunosuppressive phenotype of Treg is altered. Treg can even exhibit effector cell properties (34), secreting proinflammatory cytokines to exacerbate inflammation. Therefore, it is necessary to design a specific CAR⁃Treg for the specific microenvironment to ensure safety and effectiveness (35).

Asthma is a common chronic inflammatory disease of the respiratory tract, and eosinophils, as the main inflammatory effector cells in asthma, and lgE, a key mediator mediating the allergic response, are one of the main targets for the treatment of asthma. Skuljec et al. (23) studied an experimentally induced asthma mouse model and found that CAR⁃Treg redirected to the lungs and aggregated in the lungs and tracheobronchial lymph nodes of the mice, significantly attenuating airway inflammation and infiltration of inflammatory cells in the lungs compared to the control group. Ward et al. (24) used the highly specific binding between Fc epsilon receptor I (FcϵRI) and IgE to design a CAR with FcϵRIα as the extracellular region of the receptor, which specifically recognizes and binds to lgE-expressing cells and produces cytotoxic effects. However, high concentrations of secreted lgE were found to inhibit the binding of these CAR⁃ T cells to target cells. To address this issue, they used CAR⁃T cells with a low affinity mutant of FcϵRIα, and found that they could tolerate high concentrations of lgE and at the same time produce cytotoxicity against mIgE-expressing myeloma cells in vitro. Low affinity mutant CAR has very high affinity for mast cells expressing membrane bound isoform of IgE (mIgE) (36).

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, and one of the major causes of its development is a decrease in the ability of Treg to block the production of interferon γ (IFN ⁃ γ) and tumor necrosis factor α (TNF ⁃ α) by CD4 + CD25 + T cells (37). Developing specific CAR⁃Tregs to induce immune tolerance in the affected synovium is also a promising treatment strategy for RA. Wright et al. (25) utilized ovalbumin (OVA)-specific Tregs to inhibit OVA-induced arthritis, including T cell receptor (TCR)-transduced primary Tregs and TCR⁃FoxP3-transduced CD4+ T cell-induced Tregs, both modified Tregs reduce the proliferative function of different antigen-specific T cells through bystander inhibition. TCR⁃Tregs and TCR⁃FoxP3-induced Tregs localized to damaged tissues, reduced the number of inflammatory Th17 cells, and significantly reduced arthritic bone destruction. Citrullinated vimentin (CV) is a modified protein found only in rheumatoid arthritis, and CV⁃CAR⁃Treg can specifically (26) recognize CV or CV+ cells in patients with RA, thus improving the specific localization of Treg. CV-CAR⁃Treg enhances the specific blocking function of Treg (27), making it a promising new treatment for RA in the future.

Pemphigus vulgaris (PV) is an autoimmune herpetic disease whose pathogenesis involves autoantibodies directed against pemphigus 1 and pemphigus 3 (Dsg3). These antibodies disrupt bridging granules and interfere with the cohesion between keratinocytes in the epidermis, causing damage to healthy skin function and the formation of blisters and ulcers on the skin or mucous membranes. To address this pathogenesis, Ellebrecht et al. (28) designed a CAAR⁃T cell therapy that targets B cells producing Dsg3-specific autoantibodies. In cultured cells in vitro, Dsg3-CAAR-T cells showed specific toxicity to B cells expressing the Dsg3 BCR, reducing the titer of the Dsg3 autoantibody. In addition, studies in PV mouse models have shown that Dsg3-CAAR-T cells can persist in vivo and target Dsg3-specific B cells. This Dsg3⁃CAAR⁃T cell therapy is designed to selectively target and kill Dsg3 antibody-producing B-cells while preserving healthy B-cells critical for immune function. However, data from the phase I clinical trial of Dsg3 ⁃CAAR ⁃T cells in patients with mucosal PV (NCT04422912) have not yet been published, and further research and clinical trials are needed that will help to evaluate the potential of CAAR ⁃T in the treatment of PV.

Like MG, muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness (38, 39) due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. There are some differences in the treatment of myasthenia gravis between MuSK antibody-positive and acetylcholine receptor (AchR) antibody-positive myasthenia gravis. To avoid chronic immunosuppression caused by current therapies, Sangwook et al. (29) designed T cells expressing chimeric autoantibody receptor MuSK with CD137-CD3ζ signaling structural domains (MuSK-CAART) to precisely target B cells, which expressing anti autoantibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced the IgG levels of anti-MuSK, but did not reduce B-cell levels or total IgG levels. No specific off-target interactions of MuSK-CAART were identified in vivo, in primary human cell screens, or by high-throughput human membrane proteome arrays. These data contribute to the design of new drug applications and phase 1 clinical trials for MuSK-CAART as a treatment for MuSK autoantibody-positive MG.

Lupus nephritis is one of the complications of SLE. LN is present in 40% to 60% (40, 41) of SLE patients at initial presentation, with a recurrence rate of 33% to 40% and progression to end-stage renal disease in about 20% of patients (42). Several autoantibodies, particularly against double-stranded DNA (anti-dsDNA), are believed to play an important role in inducing glomerular inflammation (30, 43, 44). Currently, glucocorticoids and immunosuppressive agents are the mainstay of LN treatment, and although traditional treatment programs based on these agents can improve the symptoms and prognosis of LN, adverse drug reactions and disease recurrence have prompted the search for new therapies (40).

To address the challenge of chronic immunosuppression associated with current therapies, Cristina et al. (45) designed T cells expressing a chimeric autoantibody receptor (DNA-CAART) that precisely targets B cells, which expressing anti-dsDNA autoantibodies. Depending on the antigenic specificity (including α-actinin, histone-1, heparan sulfate, or C1q), they transduced T cells from LN patients using six different CAAR vectors. The cytotoxicity, cytokine production and cell-to-cell contact of DNA-CAART were demonstrated in co-culture experiments with B cells (anti-dsDNA-positive and non-dsDNA-positive) isolated from patients. DNA-CAART was intensively investigated in co-culture experiments with B cells (anti-DNA-positive and non-DNA-positive) isolated from patients. Its efficacy was further evaluated in vitro immunologic renal LN organ model. Among the six proposed DNA-CAART, DNA4 and DNA6 exhibited excellent selective cytotoxic activity against anti-dsDNA⁺ B cells. In particular, DNA4-CAART ameliorated organoid morphology, apoptosis and inflammatory processes in the presence of IFNα-stimulated anti-dsDNA⁺ B cells. These findings suggest that DNA4-CAART is a promising candidate for modulating autoimmunity and may be a novel approach for the treatment of LN.