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If autoimmunity is defined by the generation of a variety of autoantibodies against the self, SLE is the only disease to qualify. Identification of the SLE-causing factor must fulfill the following criteria: (i) the factor induces SLE, (ii) the factor is operating in active SLE and (iii) SLE heals after removal of the factor. All candidate factors are reviewed from this viewpoint in this review. As to the cause of SLE, high levels of interferon \u03b1 can induce SLE; however, interferon \u03b1 in most patients did not reach this high level. BAFF (B cell activating factor of the TNF family) is increased in SLE. BAFF itself induced some manifestation of SLE, whereas removal of interferon \u03b1 or BAFF by an antibody (Ab) did not heal SLE. BXSB male mice with a duplicated TLR7 gene develop SLE; however, the gene Sle1 is also required for the development of SLE. In addition, sanroque mice develop a variety of autoantibodies and SLE; the sanroque mutation, which disrupts one of the repressors of ICOS, results in increased CCR7lo CXCR5+Tfh cells, IL-21 and SLE. ICOS+T follicular helper (Tfh) cells increase in SLE and SLE-model (NZBxNZW)F1 mice, and the blockade of Tfh development ameliorated SLE, indicating the importance of Tfh cells in the pathogenesis of SLE. Self-organized criticality theory shows that SLE is caused by repeated infection, wherein SLE-inducing pathogens can vary individually depending on one\u2019s HLA; however, the pathogen presented on HLA stimulates the T cell receptor (TCR) strongly beyond self-organized criticality. This stimulation generates TCR-revised, autoreactive DOCK8+Tfh cells, which induced a variety of autoantibodies and SLE. The SARS-CoV-2 virus is an example pathogen because SLE occurs after SARS-CoV-2 infection and vaccination. DOCK8+Tfh cells and SLE decreased after conventional or anti-DOCK Ab therapies. Thus, DOCK8+Tfh cells newly generated after repeated infection fulfill the criteria (i), (ii) and (iii) as the cause of SLE.<\/jats:p>","DOI":"10.3390\/cells14141080","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T11:52:58Z","timestamp":1752580378000},"page":"1080","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Pathogenesis of Autoimmunity\/Systemic Lupus Erythematosus (SLE)"],"prefix":"10.3390","volume":"14","author":[{"given":"Shunichi","family":"Shiozawa","sequence":"first","affiliation":[{"name":"Institute for Rheumatic Diseases, 60-14 Okuikeminamicho, Ashiya 659-0004, Japan"},{"name":"Department of Medicine, Matsubara Mayflower Hospital, 944-25 Fujita, Katoshi 673-1462, Japan"},{"name":"Department of Rheumatology, Graduate School of Medicine and Health Sciences, Kobe University, 7-10-2 Tomogaoka, Sumaku, Kobe 654-0142, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1136\/annrheumdis-2020-218272","article-title":"Update \u03bfn the diagnosis and management of systemic lupus erythematosus","volume":"80","author":"Fanouriakis","year":"2021","journal-title":"Ann. 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