The Involvement of Alarmins in the Pathogenesis of Sjögren’s Syndrome

Abstract

Sjogren’s syndrome (SS) is a chronic autoimmune disease that affects exocrine glands, primarily the salivary and lachrymal glands. It is characterized by lymphoplasmacytic infiltration of the glandular tissues, ultimately leading to their dysfunction and destruction. Besides classic dry eyes and dry mouth defined as sicca syndrome, patients affected by the disease also typically display symptoms such as fatigue, pain and in more than 50% of cases, systemic manifestations such as arthritis, interstitial lung involvement, neurological involvement and an increased risk of lymphoma. The pathophysiological mechanisms underlying SS still remain elusive. The crucial role of innate immunity has been advocated in recent years regarding the pathogenesis of pSS, especially in the initiation and progression toward autoimmunity. Alarmins are endogenous molecules that belong to the large family of damage associated molecular pattern (DAMP). Alarmins are rapidly released, ensuing cell injury and interacting with pattern recognition receptors (PRR) such as toll-like receptors (TLR) to recruit and activate cells of the innate immune system and to promote adaptive immunity responses. This review highlights the current knowledge of various alarmins and their role in the pathogenesis of pSS.

Network pharmacology identifies the inhibitory effect of Yiqiyangyinquyu prescription on salivary gland inflammation in Sjögren’s syndrome

“…Additionally, IFN-γ prompts SGECs to discharge alarmins into the extracellular environment, perpetuating a harmful auto-inflammatory cycle contributing to local and systemic damage. [21,22]…”

Damage-associated molecular patterns in vitiligo: igniter fuse from oxidative stress to melanocyte loss

“…In healthy individuals, DAMPs exert important intracellular roles by regulating DNA transcription, calcium homeostasis, cell proliferation, and differentiation. However, high extracellular DAMP levels are present in several pathologies and are related to disease severity in autoimmune conditions and inflammatory disorders, such as sepsis, psoriasis, traumatic brain injury, acute lung injury, inflammatory bowel disease, and arthritis [ 7 , 18 , 20 ]. In this review, we outline the relationships between different DAMPs and vitiligo pathogenesis.…”

A Temporal Comparative RNA Transcriptome Profile of the Annexin Gene Family in the Salivary versus Lacrimal Glands of the Sjögren’s Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mouse

“…For more than a decade, we have utilized temporal global genome-wide transcriptome analyses in a variety of mouse models of SS to identify molecular entities and signal transduction pathways associated with the cellular autoimmunity and pathological responses underlying the onset and progressive development of SS disease per se [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. It is now well accepted that one of the earliest bioprocesses underlying inflammation and a subsequent autoimmune response involves functional activation of molecules known as alarmins [ 23 , 24 , 25 , 26 ] that are rapidly released from injured, dying and/or activated immune cells in response to recognition of PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) [ 27 , 28 , 29 ]. While there are multiple molecular entities that can be classified as an alarmin, one critical family of alarmins is the proteins known as annexins [ 27 , 28 , 29 ].…”

“…Annexins are calcium (Ca 2+ ) and phospholipid binding proteins characterized by their rapid translocation in cells from the cytosol to intracellular and plasma membranes where their specific binding affinities for a wide range of different phospholipids define their novel specificities as alarmins in regulating cellular activities (excellently reviewed in [ 30 ]). Furthermore, annexins undergo post-translational modifications that expand their capacity to interact with a variety of cellular components, thereby diversifying their interactions with and regulations of cellular products and functions that include vesicle trafficking, cell growth, cell division, cell differentiation, cell function, stress and programmed cell death [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Not surprising, therefore, that annexins are found ubiquitously throughout various phyla from microorganisms to plants and animals.…”

“…Multiple studies have reported associations between annexins and autoimmune/auto-inflammatory pathologies [ 25 , 26 , 29 , 31 , 32 , 33 , 34 , 35 , 36 ], including the development of anti-annexin autoantibodies [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ], but especially toward Anxa1, Anxa2, Anxa5, Anxa7, and Anxa11. Both over- and under-expressions of annexins are found in development and organ systems as well as pathological conditions ranging from cancers to auto-immune diseases, especially Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS).…”