Macrophages: important players in primary Sjögren’s syndrome?

Abstract

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disorder characterized by immune-mediated destruction of the salivary and lacrimal glands with unknown etiology. Due to recent research utilizing human subjects as well as laboratory animal models, our understanding of the pathophysiological and immunological mechanisms of pSS has made great strides. As a consequence, targeted, immune-based therapies are gaining increased attention as the ideal way to conquer autoimmune diseases like pSS. Currently, however, there is no effective treatment to target specific immunological events or effector immune cells in the pathogenesis of pSS (discussed in other reviews of the current issue). Here, we summarize our current understanding and knowledge of the roles of monocytes/macrophages in the pathogenesis of pSS. Human studies, especially utilizing salivary gland biopsies, demonstrate the infiltration of macrophages and its correlation with disease severity. Moreover, animal model studies have shown the functional involvement of macrophages in promoting the ocular component of pSS.

Keywords::

• clodronate liposome
• dry eye disease
• IL-1 receptor antagonist
• IFN-γ
• IL-1β
• keratoconjunctivitis sicca
• macrophages
• primary Sjögren’s syndrome
• squamous metaplasia

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Immune cells, including CD4 T cells and macrophages, infiltrate the exocrine glands and other target organs of human patients with primary Sjögren’s syndrome (pSS), where they contribute to the destruction of tissues, such as the oral and ocular mucosa.

• Squamous metaplasia of the ocular mucosa is a process of altered lineage commitment that occurs in the setting of advanced, autoimmune-mediated aqueous-deficient dry eye.

• Currently, there are no targeted, US FDA-approved, anti-inflammatory therapies that are highly effective in managing the ocular component of pSS.

• CD4 T cells are primary effectors in the development of pSS pathogenesis, but they require infiltrating macrophages and local signaling via IL-1/IL-1R1 to provoke the ocular component of SS.

• Aire knockout mice mimic the clinical characteristics of aqueous-deficient dry eye in pSS.

• Local depletion of macrophages using clodronate liposome and topical application of IL-1R1 antagonist using anakinra effectively reduced KCS in the Aire knockout mouse model of pSS.

• Macrophages appear to serve as a link between CD4 T cells and local tissue damage.

• Targeting the signals and mediators of macrophage recruitment and activation may represent novel approaches for immunotherapy.

Notes