The produced macrophage monocytes and cytokines deserve special attention among many immune cells and mediators involved in the pathogenesis of autoimmune diseases. Macrophages are one of the leading links in the pathophysiology of atherosclerosis.

In patients with atherosclerosis and animal models, the number of circulating monocytes is related to the stage and size of the atherosclerotic plaque [20, 21]. Monocytes can further differentiate into macrophages, which, after lipid accumulation, become foamy cells [14].

An imbalance between macrophage phenotypes is considered to be a reason that SSc develops. Macrophages are important in the immunopathogenesis of systemic lupus erythematosus (SLE) since they produce cytokines that support inflammation by recruiting new immune cells (monocytes, neutrophils), polarizing T cells, and activating fibroblasts [16].

Activated macrophages are classified as M1 and M2 depending on the nature of the inflammatory response. M1 macrophages contribute to the development of inflammation, while M2 macrophages promote tissue repair by producing profibrotic cytokines [22].

There is strong evidence that abnormal macrophage activation is involved in developing SSс [23]. Since the 1990s, many studies have established the presence of monocyte/macrophage activation in SSс. High numbers of macrophages were observed in the skin of SSс patients. At the same time, cells positive for cluster of differentiation 163 (CD163), a possible M2 macrophage marker, were found in the serum of SSc patients [24]. A recent study showed that the level of interleukin (IL)-34 in serum is elevated in SSc [25].

IL-34 promotes the survival and proliferation of monocytes and their differentiation into profibrotic macrophages [26]. A number of studies have shown increased expression of monocyte/macrophage-related genes (e.g., IL-8, vascular endothelial growth factor (VEGF), and epiregulin) in mononuclear cells in patients with SSc [24]. Macrophages are also a major source of transforming growth factor-beta (TGF-$\beta$) [27], a potent inducer of fibrosis [28, 29]. R.B. Christmann et al. [28] showed that macrophage activation and the increased expression of genes regulated by TGF-$\beta$ and interferon (IFN) were important in the progression of pulmonary fibrosis in SSс.

Sequencing of the skin transcriptome has shown that M2-type macrophages are involved in molecular processes in the skin of SSc patients, leading to the activation of IFN, adaptive immunity, extracellular matrix remodeling, and cell proliferation [30]. The cytokines IL-4 and IL-13 are involved and essential in the pathogenesis of fibrotic disorders [31]. In unchanged fibroblasts, IL-4 promotes proliferation, chemotaxis, and collagen synthesis, increasing TGF-$\beta$ and connective tissue growth factor. In mesenchymal cells, TGF-$\beta$ is a powerful stimulator of fibrogenesis, increasing collagen synthesis, proliferation, migration, adhesion, and differentiation into myofibroblasts [32].

Previous studies have shown that profibrotic phenotypic M2 macrophages are found in the skin and peripheral blood of SSc patients and contribute to developing ILD in SSc [25, 33, 34].

Interestingly, the gene expression profile of profibrotic macrophages differed between skin and lung. This suggests that although the role of macrophages in the immunopathogenesis of fibrosis in both skin and lung in SSc seems similar, there may still be differences [35].

Recent studies in a mouse model have found that skin fibrosis with knockout of the conditional regulatory factor IFN 8 (specific for myeloid cells) leads to increased mRNA levels of extracellular matrix components and enhanced bleomycin-induced skin fibrosis [36]. Higher circulating mixed M1/M2 monocytes/macrophages levels are associated with ILD, systolic pressure in the pulmonary artery, and positive antibodies for topoisomerase I [32]. Notably, single-cell ribonucleic acid sequencing identified the presence of secreted phosphoprotein 1+ (SPP1+), pulmonary macrophages, or Fc$\gamma$-region-receptor III-A-positive (FCGR3A+) skin macrophages in SSc. A defect in the insoluble capacity of macrophages may also be involved in autoimmune disorders in SSc [37].

D. Toledo and P. Pioli [38] presented an important model of SSс pathogenesis involving macrophages. Here, activation of the Wnt, JAK/STAT, and Sonic hedgehog (SH) cell differentiation signaling pathways under the influence of genetic and environmental factors led to the increased expression of fibrosis mediators, including TGF-$\beta$ and IL-6. Following monocytic recruitment to the target tissues, profibrotic macrophages are activated, and various inflammatory mediators are released, including profibrotic cytokines. Fibrosis in SSc is aggravated by TGF-$\beta$-mediated stimulation of profibrotic platelet-derived growth factor (PDGF) production [39]. At the end of the fibrosis process, collagen deposition, extracellular matrix production, and the development of chronic fibrosis occur, which also exacerbates atherosclerotic vascular damage in SSc.

Recently, several studies have focused on the possible activation of the coagulation pathway in SSc and its influence on the inflammatory and fibrotic response through the involvement of PDGF and protease-activated receptor 1 (PAR-1) [39, 40, 41]. PDGF is a well-described mediator of fibrosis, whose individual epitopes, stimulated by autoantibodies in SSc, cause activation of intracellular signaling and collagen gene overexpression [40]. The IgG antibody fraction detected in patients with SSc modulates signaling through PAR-1 and affects IL-6 secretion by human endothelial cells (ECs) [41].

B- and T- cells interactions are essential in adaptive immune responses and significantly impact the physiopathology of autoimmune diseases. Cellular immunity requires the activation of B cells, which occurs due to the increased CD19${}^{\mathrm{+}}$ gene expression and the appearance of T- and B-lymphocytes, which are hypersensitive to their antigens. Under the influence of mediators and cytokines, B cells differentiate into various subtypes with diverse functions and may be significantly involved in the immunopathogenesis of SSc. Activated B cells produce autoantibodies that appear even before the development of fibrosis. Some of them have a direct profibrotic effect, whereas others cause microvasculopathy.

Various cells with innate or adaptive immunity, which have been infiltrated by B- and plasma cells, have been identified in the skin, lungs, and gastrointestinal tract of SSс patients [42, 43, 44, 45, 46]. B cells are involved in various regulatory immune processes in SSс, such as antigen presentation, cytokine synthesis, T cell development and differentiation, and structural disorganization of lymphoid organs [46]. The upregulation of costimulatory molecules CD80/86–CD28 contributes to the activation of autoreactive T cells and the increased secretion of profibrotic cytokines in SSс [47].

At the same time, the possibility of B cells generating IL-10, which is involved in the suppression of regulatory B cells (Breg), changes [48]. B cells express many molecules on their surfaces, which are involved in the activation or surviving pathways while also reducing levels of co-receptor inhibitors. They also express the co-receptors necessary for interference with T cells. B cells react with different immune cells (macrophages, fibroblasts, and ECs) through direct and indirect exposure. Moreover, they all participate in profibrotic and proinflammatory processes, vascular remodeling, and impaired immune regulation [46].

B effector cells stimulate macrophages by synthesizing the granulocyte–macrophage colony-stimulating factor (GM-CSF), causing inflammatory and fibrotic lesions. These cells belong to the memory B cell subgroup and actively produce IL-6 and tumor necrosis factor-alpha (TNF-$\alpha$) [49]. TNF$\alpha$ initiates and accelerates acute inflammation, while IL-6 is another important cytokine in inflammatory conditions [50]. Hyperactive B cells accumulate in the affected organs, react locally with various immune cells, and may play a key role in the production of proinflammatory and profibrotic cytokines (IL-6 and TGF-$\beta$). B cells with high affinity for topoisomerase I antibodies produce the proinflammatory cytokine IL-6 and induce fibrosis. While B cells with low affinity for topoisomerase I produce anti-inflammatory cytokine IL-10 and suppress fibrosis [46].

T cells are apparently able to influence the autoimmune response through the co-stimulatory activity of B cells in the interaction of B–T cells [51]. The importance of CD4${}^{+}$ T cells in the immunopathogenesis of SSс has been proven [52]. In particular, antigen presentation and co-stimulation of B cells by T cells are significant for CD4${}^{+}$ T cells during sensitization with small amounts of the antigen, which seems to play an important role in the development of ARDs.

CD8${}^{+}$ effector T cells, T helper (Th)17 cells, and regulatory T cells (Treg) are involved in the synthesis of proinflammatory and profibrotic cytokines (IL-4, IL-5, IL-9, IL-13, IL-17, TGF-$\beta$, and TNF-$\alpha$) in SSc [53]. Recent studies suggest that the activation of CD4${}^{+}$ and, consequently, interferon-$\gamma$, IL-2, IL-12, TNF-$\alpha$, orphan retinoic acid receptor gamma (ROR-$\gamma$), and IL-17, alongside suppressing the production of regulatory T cell cytokines (IL-4, IL-6, and IL-13) and forkhead box P3 (Foxp3) (IL-10 and TGF-$\beta$) in vivo and in vitro can produce both stimulatory and inhibitory effects on the immune system response [54].

An important pathologic aspect of IL-34-induced macrophages is their participation in transforming memory T cells into Th17 cells [26]. Indeed, increased amounts are found in the skin and peripheral blood of patients with high SSс activity [55]. In addition, Th17 cytokine levels of IL-17 and IL-23 in the peripheral blood and exhaled air condensate are associated with ILD severity in SSc patients [56]. At the same time, Th1 and Th17 cells have a stimulatory effect on the formation of atherosclerosis. However, Treg also performs a protective function in the process of atherosclerosis. Thus, the ratio of helper Th17 cells to Treg cells plays an important role in the formation of atherosclerosis.

Lipid deposition in the arterial wall is the initiating event in atherosclerosis. Lipids, under the action of oxidative enzymes produced by cells in the vascular wall, subsequently become oxidation-specific epitopes (OSEs), such as ECs and smooth muscle cells. OSEs can activate vascular cells and produce adhesion molecules, cytokines, and chemokines, which subsequently attract circulating monocytes and T cells to the vessel wall [18]. More recent studies have shown that antibodies to OSEs can inhibit the uptake of oxidized-low-density lipoprotein (OxLDL), which supports the hypothesis that the B-cell component has a functional role in the development of atherosclerosis [57]. Neoantigens, including OSEs, can interact with Toll-like receptors (TLRs), further enhancing the inflammatory response in macrophages and T cells [58].

The importance of the B cell response in atherogenesis is emphasized by genome-wide association and transcriptomic data, indicating the status of B cell activation and proliferation as significant risk factors for cardiovascular disease [59]. Antigen-presenting B cells enter into antigen-specific interactions with T cells through signals transmitted by co-stimulatory molecules such as CD40, CD80, and CD86, which are recognized by peptides in the major histocompatibility complex (MHC). Therefore, T cell activation occurs through an interaction with the T cell receptor, whereby the antigen-presenting cell presents the MHC class II and antigen.

In recent years, an important role for B cells has been shown in atherosclerosis [60]. Available studies emphasize the strong specific effects of B1, follicular, and marginal zone B cells, Breg, and innate response activator B cells [42]. Inflammation further stimulates the recruitment of B cells to atherosclerotic plaques and leads to the subsequent formation in vessels of arterial tertiary lymphoid tissues. A recent study showed that CD19${}^{+}$–CD11b${}^{+}$ B cells contribute to disrupting the T cell antigen receptor (TCR) signaling and promote TCR suppression by inhibiting the T cell response [61].

Different types of chemokines and chemokine receptors, such as C-X-C motif ligand (CXCL)13/C-X-C motif receptor (CXCR)5, C-C motif ligand (CCL)19/CCL21/C-C motif receptor (CCR)7, allow for the direct migration of B cells into lymphoid and non-lymphoid tissues, supporting the return of B cells to lymphoid structures. CXCL13 and CCL21 have been identified as chemokines, which are critical for the presence of B cells in adventitial tertiary lymphoid organs [62]. Recently, an additional role of CCR6 was discovered in the recruitment of B cells to the atherosclerosis-prone aorta under the control inhibitor of differentiation-3 [63].

Dendritic cells (DCs) are predominantly involved in T cell activation. Thus, they are closely involved in the low-grade inflammation in both SSс and atherosclerosis. DCs are involved in major events in the pathogenesis of SSc. The maturation of DCs is induced by activated B cells, CD83, CD80, CD86, CD40, and HLA-DR, via the B cell receptor and B cell activation factor receptor (BAFF). B cell-matured DCs have a secondary effect on the polarization and activation of naive CD4${}^{+}$ T cells into Th2 cells, with a subsequent increase in IL-4, IL-5, and IL-13 production, which stimulates autoimmune reactions [64].

There are two major types of DCs: Conventional and plasmacytoid. Plasmacytoid DCs (pDCs) are specialized cells whose activation increases IFN production. A recent study showed that activation of pDCs, which infiltrates the skin of SSc patients, is accompanied by the production of large amounts of IFN-$\alpha$ and CXCL4 [65, 66]. CXC ligand 4 (CXCL4) is upregulated in pDCs isolated from SSc patients and can also be detected at elevated levels in the plasma of SSc patients. Furthermore, these correlate with disease severity, meaning CXCL4 is a potential biomarker for SSc [65]. Recently, it was observed in a mouse model that pDCs depletion prevented the development of SSc and resulted in reduced fibrosis in mice that developed the disease [67]. In contrast, the disease was more severe in TLR8 transgenic mice, with pDCs recruited to fibrotic skin, thereby suggesting that TLR8 is a key RNA-sensitive TLR involved in fibrosis. Similar data were shown in the biotic ligand model, whereby more pDCs were found in the affected skin and lungs, compared to wildtype mice [68]. The pDCs express the BAFF ligand, which may support interactions between B cells and pDCs in the SSc [69].

Much earlier, the role of pDCs was studied in atherosclerotic vascular lesions. It is known that the function of pDC is impaired in atherosclerosis. Moreover, higher expression of CD83, a marker of DCs activation, has been demonstrated in plaque tissue from patients with ischemic complications [70]. In humans, pDC-mediated IFN-$\alpha$ secretion resulted in proinflammatory pDCs activation and induced apoptosis of effector T cells with subsequent vascular smooth muscle cell (VSMC) death, plaque destabilization, and increased risk of acute coronary syndrome [71].

In the last decade of research, neutrophils have been shown to accelerate atherosclerosis development and to be actively involved in inflammation and cardiovascular repair [72]. Dysregulation of cholesterol and glucose metabolism in cardiometabolic diseases determines the chronic nature of inflammation, while neutrophils activate inflammatory pathways.

Accumulation of immune cells and lipoproteins in the arterial intima promotes resorption and instability of atherosclerotic plaques. Disrupting the efflux of cholesterol into neutrophils can also enhance inflammatory activation and promote neutrophil infiltration and the release of neutrophil extracellular traps (NETs) in atherosclerotic lesions, ultimately, accelerating atherosclerotic lesion formation [73]. NETs are net-like structures composed of DNA–histone complexes and proteins (histones, enzymes, and other antimicrobial proteins) released by activated neutrophils. Activated neutrophils release granular proteins, including cathelicidin and cathepsin G, which directly or indirectly promote myeloid cell recruitment. In addition to their key role in the neutrophil innate immune response, NETs are also involved in the development of autoimmune diseases.

The occurrence of oxidative stress is associated with the pathogenesis of SSс. Polymorphonuclear neutrophils (PNN) generate a significant amount of reactive oxygen species (ROS) during the development of the disease [74]. Neutrophils from SSс patients lack several effector molecules and effector properties, including key chemokine receptors, the formation of NETs, and phagocytosis of bacterial particles [75]. Neutrophil deficiency in SSс patients may be accompanied by impaired tissue remodeling, inflammation, and neutrophil antimicrobial defenses [75]. Neutrophils are characterized by many phenotypic changes and functional impairments. Neutrophils in SSс patients are characterized by increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) and STAT6 proteins, decreased expression of CD16 and CD62L on their surface, and a number of functional abnormalities, including the absence of typical chemokine receptors CXCR1 and CXCR2, which regulate migration to the strong neutrophil chemoattractant CXCL8 [75].

Markers of neutrophil activation, such as increased levels of calprotectin in bronchoalveolar lavage fluid [76] and serum [77], are associated with increased pulmonary fibrosis and positive antitopoisomerase I tests in patients with SSc. R. Kuley et al. [78] showed increased calprotectin levels in SSc patients with vascular-related manifestations, such as cutaneous pitting scars. However, this study found no association between autoantibodies, intracellular antigens, and circulating NET levels. At the same time, neutrophil activation upon stimulation with blood plasma of SSc patients was terminated by blocking the binding sites of immune complexes on Fc$\gamma$ receptors. Moreover, the data of R. Kuley demonstrated for the first time an increased level of neutrophil activation factor - mitochondrial N-formylmethionine (fMet) in the circulation of SSc patients, which indicated that the mitochondrial component of fMet has an important role in the stimulation of neutrophil-mediated activation in SSc.

During the progression of atherosclerosis, the neutrophil granular proteins cathelicidin and $\alpha$-defensin stimulate macrophage activation toward a proinflammatory state. Neutrophils secrete myeloperoxidase, which mediates OxLDL, promoting foam cell formation. NETs stimulate pDCs to produce proatherogenic IFN-$\alpha$ and macrophages to generate IL-1$\beta$ and IL-18 [79]. The secretion of ROS and proteases by neutrophils on the luminal and intimal sides of the atherosclerotic plaque leads to activation and dysregulation of the ECs layer and the underlying extracellular matrix, which promotes leukocyte infiltration and LDL extravasation. VSMC death is also induced by neutrophil metalloproteinases through the degradation of the extracellular matrix. Degradation of the extracellular matrix and VSMC death led to fibrous cap thinning and the formation of rupture-prone vulnerable plaques [73].