Akt Signaling Pathway Is Activated in the Minor Salivary Glands of Patients with Primary Sjögren's Syndrome.

Ioanna E Stergiou,Loukas Chatzis,Efstathia K Kapsogeorgou,Asimina Papanikolaou,Stavroula Giannouli,Athanasios G Tzioufas,Michael Voulgarelis

doi:10.3390/ijms222413441

Ioanna E Stergiou, Loukas Chatzis + Show 5 more

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https://doi.org/10.3390/ijms222413441

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Primary Sjögren’s syndrome (pSS) is an autoimmune exocrinopathy of mainly the salivary and lacrimal glands associated with high prevalence of lymphoma. Akt is a phosphoinositide-dependent serine/threonine kinase, controlling numerous pathological processes, including oncogenesis and autoimmunity. Herein, we sought to examine its implication in pSS pathogenesis and related lymphomagenesis. The expression of the entire and activated forms of Akt (partially and fully activated: phosphorylated at threonine-308 (T308) and serine-473 (S473), respectively), and two of its substrates, the proline-rich Akt-substrate of 40 kDa (PRAS40) and FoxO1 transcription factor has been immunohistochemically examined in minor salivary glands (MSG) of pSS patients (n = 29; including 9 with pSS-associated lymphoma) and sicca-complaining controls (sicca-controls; n = 10). The entire and phosphorylated Akt, PRAS40, and FoxO1 molecules were strongly, uniformly expressed in the MSG epithelia and infiltrating mononuclear cells of pSS patients, but not sicca-controls. Morphometric analysis revealed that the staining intensity of the fully activated phospho-Akt-S473 in pSS patients (with or without lymphoma) was significantly higher than sicca-controls. Akt pathway activation was independent from the extent or proximity of infiltrates, as well as other disease features, including lymphoma. Our findings support that the Akt pathway is specifically activated in MSGs of pSS patients, revealing novel therapeutic targets.

Highlights

Primary Sjögren’s syndrome is a chronic systemic autoimmune disease with multiple clinical phenotypes extending from mild, limited to exocrine glands, to severe multi-systemic and occasionally life-threatening disease
The entire and phosphorylated forms of Akt and its substrates were found to be strongly expressed in the epithelial and mononuclear cells of the positive control tissue, the stomach biopsies from patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated with Helicobacter pylori infection (Figure 1)
Strong cytoplasmic staining was detected in the epithelial and all infiltrating mononuclear cells (MNC) at the minor salivary glands (MSG) of all Primary Sjögren’s syndrome (pSS) patients and it was not found to associate with the extent of infiltrates, their organization into ectopic germinal centers (GCs), the predominating immune cell type response, or lymphoma (Figure 1)

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Introduction

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease with multiple clinical phenotypes extending from mild, limited to exocrine glands, to severe multi-systemic and occasionally life-threatening disease. Severe MSG inflammatory responses have been associated to NHL development, suggesting a link between local immune responses and the clinical picture of the disease [3,4,5,6,7,8]. It appears that salivary gland epithelial cells (SGEC) studied in MSG biopsies and long-term cultures are the target of autoimmune responses, and the initiators and key regulators of the autoimmune lesion, holding a central role in disease pathogenesis (reviewed in [9]). The pathways underlying epithelial cell activation in pSS, as well as the mechanisms regulating the interaction between epithelial and immune cells and B-cell transition to lymphoma, are still elusive

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