Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria

Bo, Marco; Jasemi, Seyedesomaye; Uras, Giuseppe; Erre, Gian Luca; Passiu, Giuseppe; Sechi, Leonardo Antonio

doi:10.3390/microorganisms8101459

Cited by 34 publications

(29 citation statements)

References 187 publications

(239 reference statements)

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“…Several studies have indicated that immune-inflammatory responses to Mtb, as well as non-tuberculous mycobacteria (NTM), can drive the pathogenesis of IMIDs and signaling via toll-like receptors (TLRs) plays an important role in this process [ 10 , 11 ]. Cell membrane-associated glycolipids and lipoproteins of Mtb serve as microbe-associated molecular patterns (MAMPs) recognized by the pattern-recognition receptors (PRRs, including TLRs) of innate immune cells [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…The pro-inflammatory cytokines produced by these cells, besides orchestrating innate immunity against the invading microbe, can trigger pathogenesis of RA and other IMIDs [ 6 ]. Antigenic constituents of Mtb membrane (MtM) are also potent inducers of adaptive immunity which, in turn, may contribute to the pool of pro-inflammatory cytokines [ 10 , 12 ]. Mtb ‘immunoproteome’ is rich in membrane-associated and secreted proteins [ 13 ] and certain MtM-associated proteins identified by us [ 14 ] and others [ 15 ] were found capable of inducing strong T cell responses in persons with LTBI.…”

Section: Introductionmentioning

confidence: 99%

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Patterns of T and B cell responses to Mycobacterium tuberculosis membrane-associated antigens and their relationship with disease activity in rheumatoid arthritis patients with latent tuberculosis infection

et al. 2021

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This study was aimed at exploring whether latent tuberculosis infection (LTBI) contributes to the pathogenesis of immune-mediated inflammatory diseases in a TB endemic setting. We screened 198 rheumatoid arthritis (RA) patients with tuberculin skin test (TST) and studied 61 (median DAS28-ESR = 6.3) who were positive. Whole blood T cell proliferative responses to Mycobacterium tuberculosis (Mtb) membrane (MtM) antigens, including the latency-induced protein alpha crystallin (Acr), were determined by flow cytometry using Ki67 expression as the marker for nuclear proliferation. Serum antibody levels were determined by ELISA. Follow-up investigations (at 3–6, 9–12 and 15–18 months after baseline) were performed in 41 patients who were classified empirically as ‘high’ (HR-T/HR-B) or ‘low’ (LR-T/LR-B) responders based on their dynamic T cell or antibody responses. Significant correlations were seen between baseline T cell responses to MtM and Acr, and between IgG, IgA and IgM antibody responses to MtM. However, no correlation was seen between T and B cell responses. At all time points during the follow-up, T cell responses to both antigens (except for MtM at one point) were significantly higher in HR-T (n = 25) than LR-T (n = 16) patients. Levels of IgA and IgM (but not IgG) antibodies to MtM were also significantly higher in HR-B (n = 13) than LR-B (n = 28) at all time points. Importantly, HR-T patients exhibited significantly higher baseline and follow-up DAS28 scores than LR-T. Ten (of 61) patients had a history of TB and developed RA 6 years (median) after contracting TB. Three new TB cases (1 from TST-positive and 2 from TST-negative groups) emerged during the follow-up. Our results suggest that persistently elevated T cell responses to Mtb antigens may contribute to disease activity in RA.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Patterns of T and B cell responses to Mycobacterium tuberculosis membrane-associated antigens and their relationship with disease activity in rheumatoid arthritis patients with latent tuberculosis infection

et al. 2021

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“…In the same region, nearly 31% of 28,291 humans tested positive for MAP as well [ 81 ]. MAP has also been implicated in the pathogenesis of rheumatoid arthritis – which not uncommonly co-exist and has overlapping features with SS [ 82 ]. More specifically, supporting evidence for the link between mycobacteria and rheumatoid arthritis include the finding of mycobacterial antigens in the joints of rheumatoid arthritis patients and of increased level of anti-mycobacterial antibodies in their sera [ 82 ].…”

Section: Discussionmentioning

confidence: 99%

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

Dow

Chan

2021

Journal of Translational Autoimmunity

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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.

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“…Recent studies have suggested that mucosal surfaces, specifically the periodontium, the gut, and the lungs, might be privileged sites of autoimmunity initiation in RA [ 5 ] ignited by a humoral and cytotoxic immune response against mucosal-associated pathogens [ 6 ]. Accordingly, there is convincing evidence that immunity against mucosal microbial pathogens such as Porphyromonas gingivalis ( P. gingivalis) and Aggregatibacter actinomycetemcomitans ( A. actinomycetecomitans ) may be linked to RA development [ 7 , 8 , 9 , 10 ]. RA-related autoantibodies against these pathogens are stimulated in different ways.…”

Section: Introductionmentioning

confidence: 99%

Humoral Response to Microbial Biomarkers in Rheumatoid Arthritis Patients

Jasemi

Erre

Cadoni

et al. 2021

JCM

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Background/Objective: Chronic humoral immune response against multiple microbial antigens may play a crucial role in the etiopathogenesis of rheumatoid arthritis (RA). We aimed to assess the prevalence and magnitude of antibody response against various bacterial and viral immunogen peptides in the sera of RA patients compared with the general population. Methods: Polyclonal IgG antibodies (Abs) specific for peptides derived from Porphyromonas gingivalis (RgpA, Kpg), Aggregatibacter actinomycetemcomitans (LtxA1, LtxA2), Mycobacterium avium subsp. paratuberculosis (MAP4027), Epstein–Barr virus (EBNA1, EBVBOLF), and human endogenous retrovirus (HERV-W env-su) were detected by ELISA in serum samples from 148 consecutive RA patients and 148 sex and age-matched healthy controls (HCs). In addition, the presence of a relationship between the positivity and the titer of antibodies and RA descriptors was explored by bivariate correlation analysis. Results: RA patients exhibit a higher prevalence of humoral immune response against all tested peptides compared to HCs with a statically significant difference for MAP4027 (30.4% vs. 10.1%), BOLF (25.7% vs. 8.1%), RgpA (24.3% vs. 9.4%), HERV W-env (20.3% vs. 9.4%), and EBNA1 (18.9% vs. 9.4%) peptides. Fifty-three (35.8%) out of 148 RA serum and 93 (62.8%) out of 148 HCs were negative for all pathogen-derived peptides. There was a significant correlation between OD values obtained by ELISA test against all peptides (p < 0.0001). We also found an increased titer and prevalence of Abs against LtxA1 and LtxA2 in seropositive vs. seronegative RF (p = 0.019, p = 0.018). Conclusion: This study demonstrates a significantly increased humoral response against multiple pathogens in patients with RA and implies that they could be an important factor in the pathogenesis of the disease. Therefore, the role of each individual pathogen in RA needs to be further investigated.

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Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria

Cited by 34 publications

References 187 publications

Patterns of T and B cell responses to Mycobacterium tuberculosis membrane-associated antigens and their relationship with disease activity in rheumatoid arthritis patients with latent tuberculosis infection

Patterns of T and B cell responses to Mycobacterium tuberculosis membrane-associated antigens and their relationship with disease activity in rheumatoid arthritis patients with latent tuberculosis infection

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

Humoral Response to Microbial Biomarkers in Rheumatoid Arthritis Patients

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