The Proportion of Regulatory T Cells in Patients with Rheumatoid Arthritis: A Meta-Analysis.
BACKGROUND
Regulatory T cells (Tregs) have important functions in peripheral immune tolerance. Dysfunction of Tregs is considered to be a pivotal cause of autoimmune diseases, including rheumatoid arthritis (RA). However, previous reports describing the proportion of Tregs among CD4+ T cells in RA patients were controversial because a range of markers are used to identify Tregs with little consensus. To clarify the status of Tregs in RA, we investigated the proportion of Tregs with focusing on the definitions of them.


METHODS
We identified the studies reporting the proportion of Tregs in RA patients using PubMed and Google Scholar. We performed a systematic review of them and a meta-analysis to evaluate the proportion of Tregs (FOXP3-positive and/or CD25-positive) among CD4+ T cells in peripheral blood (PB) and synovial fluid (SF) of RA patients and control subjects.


RESULTS
A total 31 studies were selected. The proportion of Tregs defined by all definitions among CD4+ T cells in PB was not significantly different between RA patients and control subjects (-0.65, [-1.30, 0.01]). Then we performed sub-analyses based on individual definitions. The proportion of Tregs defined by either CD25 or FOXP3 alone did not differ between RA patients and control subjects. The proportion of Tregs defined by both FOXP3 and CD25 was lower in RA patients than that in control subjects (-2.42 [-3.49, -1.34]). The proportion of Tregs defined by both FOXP3 and CD25 was higher in SF than that in PB among RA patients (3.27 [0.40, 6.14]).


CONCLUSIONS
The status of Tregs varied according to the definition system. The proportion of Tregs defined by stricter and functionally validated methods decreased in PB and increased in SF among RA patients. If the proportion of Tregs differs in RA, accurate and functionally relevant definitions of Tregs are necessary to elucidate their status in RA.
Department of Respiratory Medicine, Allergy and Rheumatic diseases, Osaka University Graduate School of Medicine, Osaka, Japan.|Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Takayoshi
T
Morita
Department of Respiratory Medicine, Allergy and Rheumatic diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
Yoshihito
Y
Shima
Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
James Badger
JB
Wing
Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.|Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Shimon
S
Sakaguchi
Department of Respiratory Medicine, Allergy and Rheumatic diseases, Osaka University Graduate School of Medicine, Osaka, Japan.|Division of Allergy, Rheumatology and Connective tissue disease, NTT west Osaka Hospital, Osaka, Japan.
Atsushi
http://orcid.org/0000-0003-3944-3442
A
Ogata
Department of Respiratory Medicine, Allergy and Rheumatic diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
Atsushi
A
Kumanogoh
D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology* / Q000473:pathology; D018791:CD4 Lymphocyte Count; D051858:Forkhead Transcription Factors / Q000097:blood / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology* / Q000473:pathology
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit