The involvement of the immune system in sIBM is supported by the presence of endomysial immune cell infiltration and circulating autoantibodies. Although the role of inflammation in the pathogenesis of sIBM has been under discussion for a long time, many studies have provided data to support the involvement of both innate and adaptive immunity in the disease.

Infiltrating immune cells are mostly represented by cytotoxic CD8⁺T cells that surround non-necrotic muscle fibers and are often localized in proximity to MHCI-expressing myofibers [17]. It has been estimated that CD8⁺ T cells are about fivefold more abundant than CD4⁺ T cells in sIBM muscle [152]. Several studies have shown that CD8⁺ T cells have restricted expression of T cell receptor (TCR) Vα/Vβ genes in the blood and muscle of sIBM patients and are clonally expanded, suggesting that muscle-specific antigen drives the inflammatory response in the disease [153,154,155,156,157,158,159,160,161]. Interestingly, the expression of Vβ genes was found to be different in muscle-infiltrating lymphocytes and peripheral blood, indicating that T cells expand in situ in response to antigens presented by MHCI-expressing muscle cells, or they are selectively recruited to the muscle [156,157]. Identical T cell clones have been found in different muscles and persist for years, indicating that they continuously react to muscle antigens, perpetuating the inflammatory response over time [155,162].

T cell activation requires antigen presentation via MHC and the interaction between CD28 on T cells with costimulatory molecules on antigen-presenting cells (APCs). Expression of the costimulatory molecules BB-1, ICOS, and B7-H3 by muscle fibers has been demonstrated in sIBM and suggests that myofibers may present the antigen and activate T cells expressing the appropriate TCR [163,164,165,166].

Regarding phenotypic and functional features, infiltrating CD8⁺ T cells express markers of highly differentiated effector cells, have proinflammatory and cytotoxic features, and have minimal or no proliferative ability [158,167,168,169,170]. Specifically, expression of the cytolytic molecules perforin, granulysin, and granzyme B, and natural killer (NK) markers CD16 or CD56, have been detected in CD8⁺T cells invading skeletal muscle, indicating they share functional and phenotypic features of NK cells [165,171,172,173]. The occurrence of Th1 immune response has been supported by increased expression levels of the cytokines and chemokines CXCL-9, CXCL-10, IL-12, CCL-2, and IL-1RA and by a higher number of IFN-γ expressing CD8⁺CD28⁻ T cells in the blood of patients with sIBM [169]. These findings indicate that cytotoxic T cells respond to yet unknown muscle antigen/s and contribute to the myofiber damage that occurs in sIBM [9].

On the other hand, several observations show that, in sIBM, T cells are highly differentiated and have reduced effector functions. In this regard, it has been found that peripheral blood and muscle infiltrating T cells are effector memory T (T_EM) cells and terminally differentiated effector memory T (T_EMRA), as indicated by the lack of expression of CD28 and by the acquisition of CD224 and CD57 expression [9,169,174]. Loss of CD28 and gain of CD57 in T cells are known to be associated with decreased proliferative capacity, terminal differentiation, senescence, and clonal exhaustion, a state occurring with chronic antigen stimulation [175,176]. Exhausted T-cells have decreased ability to respond to cytokines, have lost their effector functions, and have upregulated inhibitory receptors (IRs) such as programmed cell death protein1 (PD-1), lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin domain and mucin domain-3 (TIM-3), and T-cell immune receptor with Ig and ITIM domains (TIGIT) [174,177,178]. The main function of IRs is to negatively regulate the activation and the effector functions of T cells and are responsible for fine-tuning T cell activity [178]. IRs have a key role in controlling immune responses and establishing T cell tolerance [178]. The expression of PD-1 has been reported on T cells infiltrating sIBM muscle [179]. PD1 ligands PD-L1 and PD-L2 have been detected on infiltrating macrophages and on myofibers, respectively, and possibly form immunologic synapses with PD1 expressed by lymphocytes [179]. In support of an exhausted phenotype of T cells in sIBM, the mRNA levels of the exhaustion markers PD1, EOMES, TBX21, LAG3, CD244, TIM3, and KLRG1 were found to be increased in sIBM muscle [179]. Taken together, these data indicate that, in sIBM, persistent exposure to antigens drives muscle infiltrating T cells toward a state of exhaustion characterized by reduced or absent effector functions and proliferation ability. These observations suggest that the T cell-mediated cytotoxic damage of muscle fibers likely plays a role in the early stages of the disease before T cell exhaustion occurs.

Regulatory T cells (Tregs) represent a subpopulation of CD4⁺T cells which have the main function to suppress immune responses [180]. Their immune suppressive activity is crucial for keeping immune reactions against invading pathogens under control and maintaining immune tolerance toward self-antigens [180]. The decreased number and function of Tregs have been associated with loss of tolerance and autoimmune diseases [181]. Studies have demonstrated that Tregs are able to control local immune responses during regeneration after skeletal muscle injury [182,183]. Although Tregs suppression activity in sIBM was found to be normal, a reduction in their number was observed in the blood and skeletal muscle of sIBM patients and proposed as a factor contributing to the autoimmune response to skeletal muscle in this disease [169].

Several studies have provided evidence for a muscle antigen-driven B- and plasma cell-mediated immune response and humoral immunity in sIBM. Differentiated CD138⁺ plasma cells, but not CD19⁺ or CD20⁺ B cells, and increased expression of immunoglobulin gene transcripts were detected in the skeletal muscle of patients with sIBM [184]. Analysis of the variable region of Ig H chain gene transcript obtained from sIBM muscles demonstrated that B cells and their descendent plasma cells undergo oligoclonal expansion, isotype switching, and accumulate somatic mutations [185]. These processes usually occur in secondary lymphoid organs where B cells migrate after exposure to antigens to maturate and differentiate into antibody-producing plasma cells [185]. Interestingly, it has been observed that in sIBM muscles, inflammatory infiltrates of T cells, B cells, plasma cells, and myeloid dendritic cells assemble in lymphoid structures that could support the in situ maturation of B cells into antibody-secreting plasma cells [186]. Furthermore, increased serum levels of B-cell activating factor (BAFF), a cytokine involved in the survival, maturation, and differentiation of B cells, were detected in the serum of patients with sIBM [187]. These findings indicate that local maturation of B cells to antibody-producing plasma cells occurs in the muscle of sIBM patients in response to muscle antigen/s [185]. In agreement with these observations, a recent study revealed the sIBM muscle B cell receptor (BCR) repertoire and showed that it has distinct features from those of other IIMs, indicating that it may originate from exposure to disease-specific antigens [188].

The presence of a humoral immune response in sIBM was further supported by the detection of antibodies against cN1A, as described previously in this manuscript. The pathogenic role of the anti-cN1A was supported by the finding that mice immunized with anti-cN1A IgG isolated from patients show increased sarcoplasmic aggregation of p62 and LC3, degenerative features of sIBM muscle [30].

Overall, these findings support that in sIBM, B cells become activated and mature into plasma cells that produce antibodies directed against a muscle antigen.

Macrophages and myeloid dendritic cells (DCs) have also been detected in sIBM muscle [152,189]. Proteomic studies have shown that CD74, CD163, and STAT1 are increased in sIBM muscle, and immunohistochemical analysis revealed these molecules are enriched in macrophages [190]. Specifically, CD74 was found to be expressed in CD68⁺ macrophages and the sarcolemma. CD163 was detected in endomysial macrophages, and STAT1 was found in macrophages that displayed phagocytic activity [190]. The interferon-induced protein ISG15 and IRF8 were found to be strongly expressed on MHCII⁺ macrophages, indicating that these cells are in an activated state [190].

DCs are also infiltrating the sIBM muscle. A study of the two populations of DCs, namely myeloid DC (mDCs) and plasmacytoid DC (pDCs), revealed that mDCs surround and invade healthy myofibers [191,192]. The close colocalization of mDCs with T cells has been interpreted as a possible role of mDCs in antigen presentation to T cells [191,192].

These studies show that, despite the expression of MHC on muscle fibers of sIBM patients and their possible contribution to antigen presentation, professional antigen-presenting cells (APCs) also play a role in the pathogenesis of sIBM [193,194,195]. However, further efforts are needed to better characterize the phenotype and function of macrophages and dendritic cells in sIBM.