**5. Conclusions**

SS is a heterogeneous disease with a wide spectrum of severity. Both human and mouse studies of SS indicate an involvement of multiple cell types in producing local inflammation in pSS and SS-like disease as summarized in Table 1. The innate immune response is crucial for the pathogenesis of SS and is implicated in disease initiation, contributing to starting the immune cascade and guiding adaptive immune responses. The activation of innate immune cells is considered to be indicative of disease onset while T and B cell infiltrates indicate driving responses in more severe cases that is reflected in glandular tissue destruction. Both cellular and cytokine repertoires that mediate the skewing, activation, and differentiation of different cell types in peripheral blood and exocrine tissue initiate the epithelial cell activation and in turn the innate immune response as illustrated in Figure 1. This process ultimately leads to chronic autoimmune responses resulting from adaptive immune cells. To date, numerous studies have been performed to identify the cells relevant to autoimmune disease and to understand the individual contributions of all interacting cell types. As a result, comprehending contributions of individual cell types and their interactions is of great importance for elucidating disease pathogenesis and the development of effective therapeutic interventions.


**Table 1.** Immune cells and their functions involved in SS.


#### **Table 1.** *Cont.*


**Table 1.** *Cont.*

**Figure 1.** Proposed functions of different cell types in the pathogenesis of Sjögren's syndrome (SS). (1) The initiating events in the development of SS remain unclear, but evidence suggests the disease proceeds following an environmental trigger on a susceptible genetic background, likely a viral infection. (2) Salivary gland epithelia cells (SGECs) experience increased apoptosis and act as sources of inflammatory cytokines and chemokines within the salivary gland (SG). (3) CD8<sup>+</sup> T cells are poorly understood in SS, but may contribute to tissue destruction in the glands. (4) Macrophages participate in tissue destruction through the release of proteases and cytokines and display reduced efferocytosis

allowing unremoved apoptotic cells to act as sources of self-antigen. (5) Type I interferon (T1-IFN) both initiates antiviral activity and exerts an activating effect on cells of the immune system. T1-IFN is produced by multiple cell types but is closely associated with plasmacytoid DCs (pDCs). (6) Myeloid dendritic cells (mDCs) are the dominant antigen presenting cells to T cells, however, macrophages and SGECs also participate. (7) Antigen presentation allows for activation of CD8<sup>+</sup> T cells and the Th1, Th2, and Th17 CD4<sup>+</sup> T cell subsets, which can then contribute to various aspects of the disease pathology. Th1 cells enter the glands and compose much of the early infiltrates and exacerbate the inflammatory environment with the production of type II interferon, while Th17 cells play an increasingly well recognized role in SS as sources of cytokines including IL-17. Conflicting evidence has caused the roles of regulatory T cells (Tregs) remain indistinct in SS. Th2 cells support the humoral autoimmune response through cytokines incusing IL-4. (8 and 9) T follicular helper (Tfh) cells support B cell development in germinal centers (GC) that include follicular dendritic cell (fDC) networks. Germinal centers exist in the spleen, but about 25% of SS patients develop ectopic germinal centers in the SG containing Tfh and fDC. B cells in the germinal center undergo proliferation, somatic hypermutation and affinity hypermutation in the dark zone of the germinal center. (10) B cells then proceed to germinal center selection by fDCs in the light zone and either leave the germinal center as memory B cells or antibody producing plasma cells (Fate 1), or return to the dark zone for further affinity maturation (Fate 2). (11) The MZ B cells function as part of the adaptive immune system carrying antigens to the germinal centers for more efficient generation of memory B cells and glandular MZB cells are proliferative, activated, and produce autoantibodies. Lastly, (12) plasma cells exhibit hyperactivity and are responsible for the production of pathogenic autoantibodies. Created with BioRender.com.

**Author Contributions:** R.W. and S.G. conceptualized, prepared, and edited the manuscript. R.W. and S.G. created the table, and S.G. made the figure. C.Q.N. conceptualized, reviewed, and revised the manuscript and provided suggestions. All authors have read and agreed to the published version of the manuscript.

**Funding:** CQN was supported financially in part by Public Health Service (PHS) grants AI130561, DE026450, and DE028544 from the National Institutes of Health. RW is supported by the T90/R90 Comprehensive Training Program in Oral Biology (NIDCR, T90 DE21990). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

**Conflicts of Interest:** The authors declare no conflict of interest.
