What is the evidence that mycobacteria are associated with the pathogenesis of Sjogren’s syndrome?

Abstract

Sjogren’s syndrome (SS) is a common, systemic autoimmune disorder primarily affecting the exocrine glands resulting in xerostomia and xerophthalmia. SS may also manifest with polyarthralgia, polyarthritis, polymyalgia, cutaneous/other organ vasculitis, interstitial lung disease, and/or various other disorders. The primary autoantibodies associated with SS and used as adjuncts to diagnosis are anti-Ro (SSA) and anti-La (SSB). The pathogenesis of SS is considered to involve genetic susceptibility and environmental triggers. An identified genetic susceptibility for SS lies in variants of the tumor necrosis factor alpha inducible protein 3 ( TNFAIP3 ) gene, the product of which is known as A20. Deficiency or dysfunction of A20 is known to induce macrophage inflammatory response to mycobacteria, potentially increasing the repertoire of mycobacterial antigens available and predisposing to autoimmunity via the paradigm of molecular mimicry; i.e. , providing a mechanistic link between genetic susceptibility to SS and exposure to environmental non-tuberculous mycobacteria (NTM). Mycobacterium avium ss. paratuberculosis ( MAP ) is an NTM that causes Johne’s disease, an enteritis of ruminant animals. Humans are broadly exposed to MAP or its antigens in the environment and in food products from infected animals. MAP has also been implicated as an environmental trigger for a number of autoimmune diseases via cross reactivity of its heat shock protein 65 (hsp65) with host-specific proteins. In the context of SS, mycobacterial hsp65 shares epitope homology with the Ro and La proteins. A recent study showed a strong association between SS and antibodies to mycobacterial hsp65. If and when this association is validated, it would be important to determine whether bacillus Calmette-Guerin (BCG) vaccination (known to be protective against NTM likely through epigenetic alteration of innate and adaptive immunity) and anti-mycobacterial drugs (to decrease mycobacterial antigenic load) may have a preventive or therapeutic role against SS. Evidence to support this concept is that BCG has shown benefit in type 1 diabetes mellitus and multiple sclerosis, autoimmune diseases that have been linked to MAP via hsp65 and disease-specific autoantibodies. In conclusion, a number of factors lend credence to the notion of a pathogenic link between environmental mycobacteria and SS, including the presence of antibodies to mycobacterial hsp65 in SS, the homology of hsp65 with SS autoantigens, and the beneficial effects seen with BCG vaccination against certain autoimmune diseases. Furthermore, given that BCG may protect against NTM, has immune modifying effects, and has a strong safety record of billions of doses given, BCG and/or anti-mycobacterial therapeutics should be studied in SS.

Cutaneous Mycobacterium chelonae in a Patient with Sjogren’s Syndrome

“…It has been reported that exposure to mycobacteria may be related to the pathogenesis of SS; thus, it is hypothesized that the bacilli Calmette-Guerin (BCG) vaccine and antimycobacterial drugs may contribute to the prevention and treatment of SS. 9 According to Chao et al, a correlation exists between NTM infection and SS, and this correlation is very high in postmenopausal and nonbronchiectasis subjects. 10 The mechanism of this correlation may be related to type I interferon and sex hormones.…”

Mycobacterium paratuberculosis zoonosis is a One Health emergency

“…To date, MAP has been causally associated with granulomatous diseases: Crohn’s (Kuenstner et al 2017 ), sarcoidosis (Celler BG 2018 ; Reid and Chiodini 1993 ) and Blau syndrome (Dow and Ellingson 2010 ). Through molecular mimicry from mycobacterial heat shock protein (hsp65) (Dow 2012 ), MAP induces autoantibodies in autoimmune diabetes (T1D) (Naser et al 2013 Jun), multiple sclerosis (Cossu et al 2013 ; Ekundayo et al 2022 ), autoimmune thyroiditis (Sisto et al 2010 ), lupus (Dow 2016 ), rheumatoid arthritis (Bo et al 2019a , 2018 ) and possibly, Sjogren’s syndrome (Dow and Chan 2021 ). The causal association of three diseases will be further featured: T1D, multiple sclerosis and rheumatoid arthritis.…”

Neglected Facts on Mycobacterium Avium Subspecies Paratuberculosis and Type 1 Diabetes

“…Dow and Chan [ 88 ] recently reported that BCG has shown benefit in T1D mellitus and multiple sclerosis, autoimmune diseases that have been linked to MAP via Hsp65 and disease-specific autoantibodies. Obviously, a number of factors lend credence to the notion of a pathogenic link between environmental mycobacteria and Sjogren’s syndrome (SS), including the presence of antibodies to mycobacterial Hsp65 in SS, the homology of Hsp65 with SS autoantigens, and the beneficial effects seen with BCG vaccination against certain autoimmune diseases.…”

“…Obviously, a number of factors lend credence to the notion of a pathogenic link between environmental mycobacteria and Sjogren’s syndrome (SS), including the presence of antibodies to mycobacterial Hsp65 in SS, the homology of Hsp65 with SS autoantigens, and the beneficial effects seen with BCG vaccination against certain autoimmune diseases. Furthermore, given that BCG may protect against NTM, has immune modifying effects, and has a strong safety record of billions of doses given, BCG and/or antimycobacterial therapeutics should be studied in SS [ 88 ].…”