A new perspective of frozen shoulder pathology; the interplay between the brain and the immune system

Abstract

Frozen shoulder (FS), also known as adhesive capsulitis of the shoulder (FS), is a fibrotic inflammatory process of unknown etiology whose main symptoms are pain, stiffness and the loss of joint mobility. These symptoms may be associated with pathologies such as diabetes, Dupuytren's syndrome and the prevalence of today's sedentary lifestyle. This literature review provides an overview of the epidemiology and pathogenesis of this pathology, as well as the mechanisms of lowgrade chronic inflammation and infection, insulin resistance, and omics-science associated with it. We also propose a new hypothesis related to the possibility that the GABAergic system could play a decisive role in the development of frozen shoulder and that therefore diabetes type 1, endocrinological autoimmune disorders and frozen shoulder are connected by the same pathophysiological mechanisms. If that is true, the combined presence of psycho-emotional stress factors and pathogenic immune challenges could be the main causes of frozen shoulder syndrome. Finally, we propose a series of possible intervention strategies based on a multifactorial etiological and mechanistic concept.

Keywords: autoimmune disorder; endocrinological disease; frozen shoulder (adhesive capsulitis); low grade inflammation; psychosocial factors; shoulder condition; shoulder pain.

FIGURE 1

Social defeat and psycho-emotional distress lead to increased presentation of brain super autoantigens, which are presented to pro-inflammatory T lymphocytes present in the meninges of the brain. Immune challenges such as virus, bacteria and leaky gut, sedentary lifestyle, and obesity, produce a LGI and activity of both the innate and acquired immune system. The heightened activity of the T lymphocytes increases the susceptibility for the development of Teffector cells primed for multiple super autoantigens like GAD65. Active Teffector cells respond to GAD65 (antigen) presented by antigen presenting cells in the meninges inducing the primus movens of a possible autoimmune reaction. Teffector cells primed for GAD65, migrate to the peripheral body and specifically the pancreas, where they find a high level of GAD65 inducing a severe auto-immune response that ultimately leads to diabetes type 1. Antigen spreading to specific sites attract Teffector cells into the susceptible shoulder (non-dominant neglected), the thyroid gland, and the hand muscles, whereas immune activity in the brain causes a neuroinflammation, leading to depression, fear and anxiety.