Systemic lupus erythematosus therapeutic strategy: From immunotherapy to gut microbiota modulation

Abstract

Systemic lupus erythematosus (SLE) is characterized by a systemic dysfunction of both the innate and adaptive immune systems, leading to an attack on healthy tissues of the body. During the development of SLE, pathogenic features, such as the formation of autoantibodies against self-nuclear antigens, cause tissue damage including necrosis and fibrosis, with increased expression levels of the type Ⅰ interferon-regulated genes. Standard treatments for lupus with immunosuppressants and glucocorticoids are not effective enough but cause side effects. As an alternative, more effective immunotherapies have been developed, including monoclonal and bispecific antibodies that target B cells, T cells, co-stimulatory molecules, cytokines or their receptors, and signaling molecules. Encouraging results have been observed in clinical trials with some of these therapies. Furthermore, a chimeric antigen receptor T cell therapy has emerged as the most effective, safe, and promising treatment option for SLE, as demonstrated by successful pilot studies. Additionally, some emerging evidence suggests that gut microbiota dysbiosis may significantly contribute to the severity of SLE, and the normalization of the gut microbiota through methods such as fecal microbiota transplantation presents new opportunities for effective treatment of SLE.

Keywords: bispecific antibodies; chimeric antigen receptor T cell; fecal microbiota transplantation; immunotherapy; monoclonal antibodies; systemic lupus erythematosus.

Figure 1

Targeted therapy of systemic lupus erythematosus. The figure shows the sites of action using biological agents with a focus on therapeutic monoclonal antibodies and CAR-T cells. Abbreviations: APC, antigen-presenting cell; APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BDCA2, blood dendritic cell antigen 2; CAR-T cell, chimeric antigen receptor T cell; ICOS, inducible T-cell costimulator; ICOSL, inducible T-cell costimulator ligand; TNF, tumor necrosis factor.

Figure 2

Potential pathophysiological mechanisms of gut microbiota therapy for systemic lupus erythematosus treatment. A: Gut microbiota dysbiosis is characterized by a decreased Firmicutes/ Bacteroidetes ratio, a reduced synthesis of SCFAs and BCAAs, lower levels of anti-inflammatory cytokines, and increased levels of LPS and pro-inflammatory cytokines. B: A healthy microbiome in a state of homeostatic balance. Ideally, after gut microbiota modulation procedures in SLE, including probiotic or prebiotic therapy, oral antibiotic therapy, glucocorticoid therapy, vaccination, and FMT, the imbalance should shift towards a homeostatic balance characterized by the restoration of the composition of microorganisms, the profile of metabolites and cytokines characteristic of a healthy body. Abbreviations: BCAAs, branched-chain amino acids; FMT, fecal microbiota transplantation; LPSs, lipopolysaccharides; SCFAs, short-chain fatty acids.