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.

Shashi Kant Kumar,Suvrat Arya,Amita Aggarwal,Ankita Singh,Sudhir Sinha,Ramnath Misra,Leonardo A Sechi

doi:10.1371/journal.pone.0255639

Abstract

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.

Highlights

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease (IMID) caused by interplay of genetic and environmental factors that dysregulate the immune system [1]
Pulmonary TB patients show seropositivity for antibodies to citrullinated protein antigens (ACPAs) and rheumatoid factor (RF) [9] suggesting that Mycobacterium tuberculosis (Mtb) could trigger the production of these antibodies which are otherwise considered as hallmarks of RA
The indications that Mtb could serve as an environmental trigger for IMIDs, we undertook this study aimed at exploring whether the RA patients harbouring latent TB infection (LTBI) exhibit distinct T and B cell response patterns against Mtb membrane (MtM)-associated antigens and whether such patterns have any relationship with their disease activity

Summary

Introduction

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease (IMID) caused by interplay of genetic and environmental factors that dysregulate the immune system [1]. In some population-based studies [4, 5] history of TB was found associated with RA suggesting that Mtb could play a role in pathogenesis of RA which, like TB, may begin in the airways and lungs [6]. In early RA disease, germinal centre-like structures are seen in the lungs wherein activated B cells produce antibodies to citrullinated protein antigens (ACPAs). Seropositive RA patients harbour citrullinated proteins in their bronchial tissue and this abnormality was not associated with smoking [7, 8]. Pulmonary TB patients show seropositivity for ACPA and rheumatoid factor (RF) [9] suggesting that Mtb could trigger the production of these antibodies which are otherwise considered as hallmarks of RA

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