**3. Abnormalities related to apoptosis in SLE**

50 Apoptosis and Medicine

a. Anti-cell-surface molecules

b. Anti-intracellular molecules

2. Systemic autoimmune diseases a. Anti-cell-surface molecules

b. Anti-intracellular molecules

**Table 1.** Examples of autoantibodies.

syndrome).

response.

1. Organ or tissue-specific autoimmune diseases

**Anti- Target molecule Disease**

TSH receptor\* TSH receptor Graves' disease NMDA N-methyl-D-aspartate receptor Encephalitis

mitochondria mitochondria PBC

phospholipid\* phospholipid APS

 dsDNA\* dsDNA SLE Sm Smith SLE

 Jo-1 histidyl-tRNA synthetase DM PR3-ANCA\* proteinase 3 WG MPO-ANCA\* myeloperoxidase MPA, AGA

\*: The titer of the Ab is correlated with the disease activity in a proportion of patients.

GAD glutamic acid decarboxylase Diabetes mellitus type I Ach\* Acetylcholine Myasthenia gravis myelin associated protein myelin Multiple sclerosis ganglioside ganglioside Neuropathy

thyroid microsomal thyroid microsomal Hashimoto's thyroiditis thyroid peroxidase thyroid peroxidase Hashimoto's thyroiditis thyroglobulin thyroglobulin Hashimoto's thyroiditis

PDGF receptor PDGF receptor Systemic sclerosis

 SS-B La/SS-B Sjögren's syndrome centromere centromere Systemic sclerosis topoisomerase-I topoisomerase-I Systemic sclerosis

TSH: thyroid stimulating hormone; PBC: Primary biliary cirrhosis; PDGF: Platelet-derived growth factor; APS: Antiphospholipid syndrome; dsDNA: double-stranded DNA; SLE: systemic lupus erythematosus; DM: dermatomyositis; WG: Wegener's granulomatosis; MPA: microscopic polyarteritis; AGA: allergic granulomatous angiitis (Churg–Strauss

or form novel epitopes, and may contribute to bypassing tolerance to autoantigens [5]. Normally, apoptotic cells are quickly eliminated by professional phagocytes. Delay of apoptotic cell clearance not only increases the time of exposure of intracellular molecules to the immune system but also changes the degree of modification of these molecules, which alters their antigenicity. When clearance fails, apoptotic cells enter the stage of secondary necrosis. The ability to cause inflammation depends on the stage of cell death [6]. Damageassociated molecular patterns (DAMPs), such as HMGB1, SAP130, etc., are released from late apoptotic/necrotic cells into the extracellular space [7-9]. DAMPs activate Toll-like receptors and act as intrinsic adjuvants, resulting in inflammation and initiation of the host immune system. Thus, delay of apoptotic cell clearance increases the risk of an autoimmune There are many lupus autoantibodies that bind to autoantigens of apoptotic cells [10]. In SLE, defective clearance of apoptotic cells has been reported. As a result, high levels of circulating early apoptotic cells are found in SLE [11]. T-lymphocytes [12], macrophages/monocytes [13,14], neutrophils [15], and endothelial cells [16] are included among the increased numbers of apoptotic cells. Monocytes and granulocytes, which take up autoantibody remnants of secondary necrotic cell complex, secrete inflammatory cytokines in SLE [17]. These phenomena threaten self-tolerance and are likely involved in the production of lupus autoantibodies [18,19]. The reason for defective apoptotic cell clearance in SLE has yet to be elucidated. It has been suggested that the efficacy of clearance is affected by the cell death trigger, but there have been no reports related to SLE from this viewpoint [20]. Anti-class A scavenger receptor autoantibodies from patients with SLE impair the clearance of apoptotic debris by macrophages [21]. However, the mechanism of autoantibody production is not yet known.

In SLE, the response to early apoptotic cells is also abnormal. Under normal conditions, macrophages secrete antiinflammatory cytokines (IL-10, TGF-, PGE2, etc.) to send "tolerate me" signals after ingestion of apoptotic cells [22]. Monocytes from healthy controls showed prominent TGF- secretion and minimal TNF- production, but monocytes from SLE patients show prominent TNF- production and diminished TGF- secretion [23]. The authors speculated that this abnormal response may be an intrinsic property of lupus monocytes.

Recent studies have highlighted the role of neutrophils in the pathogenesis and manifestations of SLE [24]. NETosis is a process characterized by the formation of neutrophil extracellular traps (NETs) [25]. NETs become not only a source of intracellular molecules but also immunogens for lupus autoantibodies [26]. Low-density granulocytes (LDGs), an abnormal subset of neutrophils, were identified among the PBMCs derived from patients with SLE [27]. LDGs secrete type I interferons (INFs), have endothelial cytotoxicity, and have higher capacity to form NETs [28]. Degradation of NETs is impaired in patients with SLE [29]. NETs activate complement and deposited C1q inhibits NET degradation [30]. These phenomena increase NETs and may contribute to the production of autoantibodies, including anti-DNA Abs.

It has recently been demonstrated that the source of intracellular molecules is microparticles (MPs), which are small membrane-bound vesicles [31]. MPs, which emerge from the cell membrane during cell activation and apoptosis, contain a variety of cellular components, including nucleic acids [32]. MPs become antigenic targets of anti-DNA Abs, form huge immune complexes in the plasma of patients with SLE, and induce complement activation [33,34].
