Immune cells such as T cells, B cells, and macrophages have been found in the skin and blood of SSc patients and SSc model mice
[59][60][61], and these immune cells have often been observed preceding the fibrotic process
[62]. In SSc, B cells cause the production of autoantibodies and the secretion of pro-inflammatory and pro-fibrotic cytokines such as TGF-β, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). B cells also cooperate with fibroblasts, endothelial cells (ECs), and T cells
[61], and B cells are associated with EC apoptosis, fibroblast activation, the upregulation of type I collagen synthesis, and regulate the progression of fibrosis and vascular dysfunction in SSc
[63][64]. T cells produce various cytokines such as IL-4, IL-5, IL-6, IL-10, and IL-13
[64], and T cell-produced cytokines regulate macrophage activation. In contrast, dermal fibrosis progression is induced in the bleomycin-administrated T and B cell-deficient severe combined immune deficiency (SCID) mice
[65][66]. T cells contribute to macrophage activation, but T and B cells may not be essential for the development of fibrosis. Classically (M1) and alternatively (M2) activated macrophages induce pro-fibrotic cytokines such as TGF-β and IL-6 and TIMPs production, fibroblast activation, and collagen production and collagen deposition, and macrophages play a pivotal role in the development of fibrosis in SSc
[63][67]. In particular, M2 macrophages are elevated in SSc patients
[68]. M2 macrophages are known to be induced by IL-4 and IL-13
[69], and the blockade of IL-4 and IL-13 signaling by IL-4Rα neutralizing antibodies attenuates the progression of fibrosis in SSc model mice
[66]. The increase in pro-fibrotic cytokine expression caused by these immune cells is associated with myofibroblast conversion from tissue-resident fibroblast and bone marrow-derived mesenchymal stem cells (MSC), epithelial-to-mesenchymal transition (EMT), and EndoMT. Myofibroblast deposition subsequently promotes excessive ECM production
[70][71]. On the other hand, autoantibodies such as anti-MMP-1, anti-MMP-3, and anti-fibrin bound tPA antibodies have been identified in SSc patients, and TIMPs are elevated in SSc
[58][72][73][74][75][76], and these factors suppress ECM degradation. Over-production and suppressed degradation of ECM cause fibrosis. Thus, these immune cells are associated with the overproduction of ECM and suppression of ECM degradation and have a major role in the onset of fibrosis in SSc. The correlation between fibrosis progression and the existence of specific autoantibodies such as anti-centromere antibodies and anti-Scl70 antibodies in SSc patients is unknown.
α2AP induces inflammatory cytokine production such as IL-1β and TNF-α
[38][39], and α2AP deficiency affects neutrophil recruitment, lymphocyte infiltration, and IgE production
[16][77][78]. In addition, PAP causes an increase in IgG and IgM secretion
[79]. The blockade of α2AP by α2AP neutralizing antibodies attenuates anti-Scl70 antibody production in SSc model mice
[18]. On the other hand, plasmin directly and indirectly regulates cell migration, cell proliferation, cell adhesion, monocyte chemotaxis, macrophage phagocytosis, neutrophil aggregation, monocyte/macrophage infiltration into tissues, and the release of cytokines, growth factors, and other inflammatory mediators
[43][80][81][82][83][84][85][86]. In addition, plasmin can activate protease-activated receptor (PAR), platelets, factors V, VIII, and X, and mediate inflammation response
[9][48][49]. Furthermore, plasmin effectively cleaves complement factors C3 and C5, thereby releasing the respective chemotactic anaphylatoxin fragments
[87], which results in potentiation of TLR4 signaling
[88]. α2AP contributes to inflammatory response, immune modulation, antibody production, and plasmin inhibition, and may play an important role as a mediator of inflammation and the immune system in SSc.