**3. Innate Immune Cells**

#### *3.1. Dendritic Cells*

Considering that SS is characterized by overstimulation of the immune system and IFN signature, the role of DCs in SS has been the subject of considerable study [33]. DCs can be subdivided into three main types: conventional or myeloid DCs (mDCs), which are the most potent antigen presenting cells (APCs) of the immune system; plasmacytoid DCs (pDCs), the foremost IFN-α producing cell; and follicular dendritic cells (fDCs), which are not from the hematopoietic lineage and are critically involved in B cell development in germinal centers (GCs) [34,35]. DCs are one of the first cell types to infiltrate the minor SG of patients and submandibular glands of NOD mice [36,37]. Their prevalence is negatively correlated with lesion severity, whereas fDC frequency is unaffected by lesion severity. fDCs are organized into networks within GCs in severe lesions within the glands [38].

mDCs are cells of hematopoietic origin and include a number of tissue specific subtypes, such as Langerhan's cells. Immature DCs disseminate through the blood to inhabit peripheral tissues where they sample the local environment through endocytosis. DCs that have encountered antigen migrate to the secondary lymphoid tissue and develop into mature DCs [39]. They are unique in their capacity to both prime T cells and participate in peripheral tolerance [40]. Immature DCs have reduced frequency in primary and secondary SS patient blood, while mature DCs are found at increased frequency within the SGs [41,42]. DCs isolated from NOD mouse SGs lacked the expression of the regulatory chemokine receptor CCR5. The absence of CCR5 on DCs contributes to an increased expression of the T helper (Th) 1 cytokine IL-12, thereby enhancing the activity of the adaptive cellular response through Th1 cells and establishing a more proinflammatory environment [43]. Patient monocyte derived DCs (moDCs) were reported to express increased HLA-DR compared control moDCs, suggesting more antigen presenting activity. moDCs from SS patients secreted higher levels of IL-12p40 than moDCs from control patients both upon TLR7/8 stimulation [44] and under basal conditions [45].

pDCs are a rare subset of DC best known for their production of T1-IFN upon stimulation of TLR 7 and 9 [46]. pSS patients exhibit low levels of serum T1-IFN but have elevated levels in the minor SG (mSG) [47], and reduced circulating pDC within peripheral blood [48]. However, while diminished in number, pDCs of pSS patients present in peripheral blood expressed high levels of CD40 and CD86 [49]. Microarray analysis of mSGs biopsies showed significant activation of both T1 and T2-IFN pathways with elevated numbers of pDCs [50]. Analysis of pSS pDCS has revealed dysregulated miRNAs relating to apoptosis, antigen presentation, and cytokine production [51]. Furthermore, pDCs from pSS patients demonstrated increased pro-inflammatory cytokine production [52]. Finally, it has been suggested that pDC recognition of apoptotic cell debris drives the loss of immune tolerance in SS [7].

fDCs are stromal cells within GCs that lack MHC-II expression and instead present antigen-antibody complexes to B cells via complement and Fc receptors [35]. fDCs attract B cells with CXCL13 and promote positive and negative selection, isotype switching, and development of high affinity B cell receptors [53]. About 20–25% of SS patients develop ectopic GCs containing B cells, T cells, and fDC networks within the mSGs [54]. Expression of the enzyme activation-induced cytidine deaminase is critical for B cells to perform class switch recombination and somatic hypermutation, driving affinity maturation within GCs of secondary lymphoid organs. Proliferating B cells found within fDC networks in ectopic GCs express AID, indicating that these GCs are functional and a source of local antibody production and B cell expansion within the SGs of SS patients [55].
