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Primary Sjögren's syndrome (SS) and primary SS–like disease in mice are associated with increased levels of interleukin-7 (IL-7) in salivary glands and serum, correlating with parameters of disease and inflammation. Through gain- and loss-of-function studies in both human and mouse experimental models, it has been demonstrated that IL-7 plays a critical role in the immunopathologic pathways observed in primary SS. IL-7 can contribute to the development and onset of primary SS by enhancing T cell responses and T cell–dependent activation of glandular epithelial cells and immune cells, such as B cells, dendritic cells (DCs), and macrophages. Furthermore, IL-7–driven immune activation is associated with disease phenomena characteristic of primary SS, including increased apoptosis of epithelial cells, increased lymphocyte infiltration and neogenesis, production of antinuclear antibodies (ANAs), and reduced salivary output. These data justify careful evaluation of the clinical benefits potentially achieved by interference with this pathway.

IL-7 and its receptor—potential therapeutic targets in primary SS

  1. Top of page
  2. IL-7 and its receptor—potential therapeutic targets in primary SS
  3. Ectopic lymphoid aggregates/germinal centers (GCs) in primary SS are associated with morbidity and mortality—targeting by IL-7/IL-7R blockade
  4. Conclusion
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Primary SS is associated with massive infiltration and activation of T and B lymphocytes in salivary and lacrimal glands. A hallmark of primary SS is production of autoantibodies directed toward RNA-binding nuclear antigens (SSA and SSB). Enhanced B cell activity is associated with increased morbidity, including extraglandular manifestations and pathology of salivary and lacrimal exocrine glands, finally leading to oral and ocular dryness typical of primary SS. In association with B cell overstimulation, 5–10% of patients with primary SS develop B cell non-Hodgkin's lymphoma (NHL), which increases their mortality rate. Although depletion of B cells by anti-CD20 antibody shows promising results in the treatment of primary SS, the long-term efficacy is still unclear ([1]). In addition, depletion of B cells may not sufficiently block the prominent activity of autoreactive T cells, plasma cells, and/or DC subsets, all of which have been shown to play an important role in primary SS. Besides B cell depletion, several biologic agents (e.g., anakinra, etanercept) aimed at restoring immune tolerance in primary SS have been evaluated without any success. Hence, there is a great unmet need to broaden the therapeutic armamentarium for the treatment of primary SS and thereby improve patient morbidity and mortality.

In this issue of Arthritis & Rheumatism, Jin et al ([2]) demonstrate that IL-7–mediated immune activation plays a critical role in a T cell–driven experimental model of SS. IL-7, an IL-2 family member, is a potent immunostimulatory cytokine expressed by stromal cells in primary lymphoid organs that plays a pivotal role in T cell homeostasis ([3]). IL-7 principally acts on T cells that abundantly express the high-affinity IL-7 receptor α-chain (IL-7Rα), but it also induces a strong T cell–dependent activation of macrophages, DCs, and B cells. Hence, IL-7 strongly boosts T cell–driven immune activation in cancer and during infection. IL-7 is overexpressed in the inflamed tissues of patients with different autoimmune diseases, and its expression levels correlate with parameters of disease and inflammation ([4]). Several triggers of IL-7 production have been identified, such as activated T cells, Toll-like receptor (TLR) ligands, and various proinflammatory mediators, which could arise from infectious agents and environmental factors that were previously suggested to play a role in the pathology of primary SS. We have yet to elucidate the exact mechanisms underlying IL-7 induction in autoimmune diseases, including primary SS.

Jin and colleagues demonstrate that primary SS–like disease in C57BL/6.NOD-Aec1Aec2 mice is associated with increased levels of IL-7 in salivary glands and serum, replicating the findings in primary SS patients ([5]). Through gain- and loss-of-function studies, they also elegantly demonstrate that IL-7 plays a critical role in the development and onset of primary SS by enhancing Th1 responses and interferon-γ (IFNγ)–dependent expression of CXCR3 ligands by glandular epithelial cells. IL-7–driven immune activation was found to be associated with disease phenomena characteristic of primary SS, including increased apoptosis of epithelial cells, increased lymphocyte infiltration and neogenesis, production of ANAs, and reduced salivary output, all of which were reversed by IL-7Rα blockade ([2]).

Accumulating evidence originating from both ex vivo and in vitro experiments in humans previously indicated that IL-7 plays an important role in the pathogenesis of primary SS. For instance, IL-7 levels are increased in the saliva and salivary glands of primary SS patients as compared to those in their healthy counterparts ([5, 6]). At the site of inflammation, a number of cell subsets, including fibroblasts, endothelial cells, macrophages, and DCs, were shown to secrete IL-7. In addition, IL-7 expression levels correlated with peripheral and local disease activity parameters. Consistent with these observations, IL-7 stimulated the production of cytokines (including IL-12 and IL-15) by immune cells from primary SS patients that induce proinflammatory T cells, which typically display Th1 (IFNγ-producing), Th17 (IL-17–producing), and/or Th22 (IL-22–producing) profiles ([5]). Moreover, IL-7 induces chemokines that facilitate migration of such T cells (CCL3/macrophage inflammatory protein 1α, CXCL9/monokine induced by IFNγ, and CXCL10/IFNγ-inducible 10-kd protein). These latter observations clearly are consistent with the predominance of Th1 and Th17 cell activity in primary SS patients ([7, 8]).

In contrast to the large amount of data on IL-7–induced T cell activation, the effect of IL-7–driven activation of mature B cells has not been subjected to similar scrutiny. Very recently, however, it was documented that IL-7 caused T cell–dependent B cell activation (proliferation) and strongly stimulated antigen-induced antibody production by B cells from primary SS patients, which was critically dependent on small percentages of monocytes ([9]). In addition, it was documented that IL-7–activated T cells strongly potentiated TLR-7–stimulated B cell activation (and vice versa) in the presence of monocytes, leading to robust secretion of T cell cytokines (IFNγ, IL-17, IL-22, and IL-10) and IgM and IgG antibodies and production of free light chain. Consistent with this capacity of IL-7 to potentiate B cell activation and immunoglobulin secretion, glandular-expressed IL-7 has been shown to correlate with serum IgG levels as well as with increases in IgM- and IgG-producing plasma cells in the salivary gland (resulting in a decreased percentage of IgA-producing plasma cells) ([5]).

In men, the role of the IL-7 axis in primary SS is further substantiated by the observation that IL-7Rα–positive cells were markedly increased in labial salivary gland (LSG) specimens from primary SS patients compared to those from non-SS patients with sicca syndrome ([10]). IL-7Rα–positive cells were associated with IL-7 expression and strongly correlated with lymphoid neogenesis, numbers of CD3+ T cells, and numbers of CD1a- and CD208-expressing myeloid DCs. In addition, IL-7R–positive T cells correlated with enhanced numbers of CD20+ B cells and IgM- and IgG-producing plasma cells, as indicated by decreased percentages of IgA+ plasma cells. Analysis of isolated cells from LSGs demonstrated increased percentages of IL-7Rα–positive CD3+ T cells in primary SS patients as compared to non-SS patients, showing abundant IL-7Rα expression on both CD4+ and CD8+ T cells. Other CD45-expressing leukocytes and CD45-lacking tissue cells did not express IL-7Rα. Again, the percentages of IL-7Rα–positive T cells correlated significantly with glandular inflammation.

In support of the role of these findings, it was demonstrated that IL-7Rα–positive T cells are highly proliferating effector T cells that respond strongly to IL-7 by Th1 and Th17 cytokine production despite an increased number of Treg cells. In corroboration of these data, it was observed that IL-7 expression was strongly associated with increased numbers of Ki-67–expressing proliferating lymphocytes, strongly enhanced in primary SS patients. Taken together, the data provided by Jin et al and data from primary SS patients not only support a role for targeting the IL-7 axis in primary SS, but also underscore the role of IL-7 in development of ectopic lymphoid structures, the blocking of which might provide an interesting therapeutic advantage in addition to symptom relief.

Ectopic lymphoid aggregates/germinal centers (GCs) in primary SS are associated with morbidity and mortality—targeting by IL-7/IL-7R blockade

  1. Top of page
  2. IL-7 and its receptor—potential therapeutic targets in primary SS
  3. Ectopic lymphoid aggregates/germinal centers (GCs) in primary SS are associated with morbidity and mortality—targeting by IL-7/IL-7R blockade
  4. Conclusion
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Sialadenitis in a considerable number (∼25%) of primary SS patients is associated with the formation of ectopic lymphoid T and B cell aggregates and follicular DCs (FDCs) that are spatially organized in structures that resemble GCs, which are typically found in lymphoid organs. Patients with GCs in their glandular tissue at diagnosis have a 14-fold higher risk of developing NHL compared to patients who do not have these structures ([11, 12]). Recently, we observed that similar to patients with GCs, patients who have high numbers of lymphocytic aggregates (focus scores >3) also show a comparable increased risk of developing NHL (van Roon JAG, Kruize AA, Radstake TRDJ: unpublished observations) as well as extraglandular manifestations. Data from a number of studies suggest that IL-7 plays a critical role in this lymphoid neogenesis.

Formation of ectopic GCs is not unique to primary SS patients but is typical of chronic inflammatory autoimmune diseases. In ∼15–25% of synovial tissues from rheumatoid arthritis (RA) patients and in salivary gland tissues from primary SS patients, these organized GC-like structures of T cells, B cells, and FDCs are found. The remainder of the tissues lack FDCs and show diffuse or aggregated infiltrates of T cells and B cells. Pathway analysis upon gene expression profiling revealed increased expression of genes involved in IL-7 signal transduction in the tissues with ectopic lymphoid follicles, accompanied by increased expression of IL-7Rα/IL-2Rγ chains and IL-7 ([13]). This was associated with increased JAK/STAT signaling and T cell– and B cell–specific pathways. Protein expression of IL-7 in RA tissues was localized within fibroblast-like synoviocytes, macrophages, and blood vessels and was colocalized with extracellular matrix structures around the B cell follicles. Consistent with these findings of the gene expression analysis, previous studies also demonstrated that tissues with lymphoid structures showed elevated expression of CXCL13, CCL21, CCR7, lymphotoxin α (LTα), and LTβ messenger RNA, molecules that are involved in lymphoid neogenesis. Also, a strong correlation between IL-7 and these mediators was observed ([13]).

Interestingly, IL-7R–expressing lymphoid tissue inducer cells as well as stromal cells are critical not only in the development of lymph nodes in fetal stages, but also in the development of tertiary lymphoid structures, as seen in chronic inflammatory diseases such as RA ([14]). Moreover, the attraction of lymphoid tissue inducer cells to tumors by CCL21 results in the development of a tertiary lymphoid structure–like environment and contributes to tumor development by inducing tolerance ([15]). Of note, we recently demonstrated that in RA patients, IL-7 induces the expression of not only CCL21, but also LTβ, LTα, and tumor necrosis factor α, all of which are known to be critically involved in the development of ectopic lymphoid structures (van Roon JAG, Radstake TRDJ: unpublished observations).

Finally, it was demonstrated that enhanced expression of IL-7 in transgenic mice resulted in accumulation of lymphoid tissue inducer cells by promoting their survival ([14]). Enhanced IL-7 availability led to a 5-fold increase in Peyer's patch numbers, resulting from lymphoid tissue inducer–stimulated de novo formation of stromal tissue organizer cells. Overexpression of IL-7 also led to the formation of multiple organized ectopic lymph nodes, which after immunization, developed normal T cell–dependent B cell responses and GCs. Consistent with the formation of tertiary lymphoid tissues in patients with autoimmune diseases, naive IL-7–transgenic mice spontaneously developed tertiary lymphoid follicles in target organs for autoimmune reactions, such as the pancreas and salivary gland ([14]). Therefore, by controlling IL-7Rα–positive lymphoid tissue inducer cell numbers, IL-7 regulates the formation of both normal and ectopic lymphoid organs. In light of these observations, it is tempting to speculate that IL-7 might play a more general role in chronic inflammatory conditions, a concept that in our opinion, deserves further attention.

Conclusion

  1. Top of page
  2. IL-7 and its receptor—potential therapeutic targets in primary SS
  3. Ectopic lymphoid aggregates/germinal centers (GCs) in primary SS are associated with morbidity and mortality—targeting by IL-7/IL-7R blockade
  4. Conclusion
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES

Taken together, a large body of evidence supports a significant role of the IL-7 axis in primary SS, driving T cell–dependent immunopathology and lymphoid neogenesis (Figure 1). This justifies careful evaluation of the clinical benefits potentially achieved by interference with this pathway. Consistent with this, the first initiatives for IL-7/IL-7R blocking strategies in humans are ongoing. In this regard, primary SS patients with a high frequency of IL-7R–positive cells and/or IL-7, either in the salivary glands or the circulation, might be the most promising patients for such a treatment. Given the role of IL-7 in T cell activation, clinical studies blocking the IL-7 pathways should be undertaken with special attention to T cell homeostasis.

image

Figure 1. The interleukin-7 (IL-7) axis as the driver of T cell–dependent immunopathology in primary Sjögren's syndrome (SS). In primary SS, (self) antigen–specific T cell activation (trigger “X”), resulting in cytokine production (IL-17, interferon-γ [IFNγ]) and cell–cell contact (including CD40L), could initiate the production of IL-7 by activated myeloid cells, such as macrophages and dendritic cells (DCs), and tissue cells, such as fibroblasts and endothelial cells (1). Alternatively, “Y” triggers (e.g., Toll-like receptors [TLRs]) that activate macrophages and stromal cells such as fibroblasts can induce IL-7 production (2). Increased IL-7 not only augments the initiating antigen-driven responses, but also induces cell contact–dependent cytokine-activated T cells responsive to less dominant epitopes (3). This provokes a diversification of the T cell repertoire associated with autoantigenic recognition. In contrast, IL-7 cannot directly affect Treg cells that lack IL-7 receptor (IL-7R), but prevents suppression by these T cells through activation of IL-7R–positive effector T cells (4). IL-7/cytokine–activated “bystander” T cells contribute to the chronicity of the inflammatory response by stimulating myeloid cells and B cells, further enhancing immunopathology by tissue-destructive cytokines (IFNγ, tumor necrosis factor α [TNFα], granzymes) and pathogenic autoantibodies (5). In patients expressing high levels of IL-7, the capacity of IL-7 to activate IL-7R α-chain–positive (innate) lymphoid tissue inducer (LTi) cells induces spatial organization of T cells, B cells, follicular DCs (fDCs), and stromal cells, resembling germinal centers in lymphoid organs (6). The formation of these ectopic lymphoid follicles in primary SS is associated with enhanced development of lymphoma and spreading of inflammation to other organs. TGFβ = transforming growth factor β; TCR = T cell receptor; LTα/β = lymphotoxin α/β.

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REFERENCES

  1. Top of page
  2. IL-7 and its receptor—potential therapeutic targets in primary SS
  3. Ectopic lymphoid aggregates/germinal centers (GCs) in primary SS are associated with morbidity and mortality—targeting by IL-7/IL-7R blockade
  4. Conclusion
  5. AUTHOR CONTRIBUTIONS
  6. REFERENCES
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