Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease

Kamekura, Ryuta; Takano, Kenichi; Yamamoto, Motohisa; Kawata, Keiichiro; Shigehara, Katsunori; Jitsukawa, Sumito; Nagaya, Tomonori; Ito, Fumie; Sato, Akinori; Ogasawara, Nagahisa; Tsubomatsu, Chieko; Takahashi, Hiroki; Nakase, Hiroshi; Himi, Tetsuo; Ichimiya, Shingo

doi:10.4049/jimmunol.1601507

Cited by 62 publications

(57 citation statements)

References 25 publications

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“…Adaptive immune responses underlying the immunopathogenesis of IgG4-RD have been studied extensively. Accumulation of T helper type 2 (Th2) cells [7,8], regulatory T cells (Treg cells) [7,8], or follicular helper T (Tfh) cells [9][10][11] into peripheral blood and disease-ridden organs is observed in patients suffering from IgG4-RD. In addition to Th2 cells, Treg cells, and Tfh cells a unique population of CD4 þ cytotoxic T lymphocytes (CTLs) producing IFN-c, IL-1b, and TGF-b1 is involved in the chronic fibro-inflammatory responses in IgG4-RD [12,13].…”

Section: Introductionmentioning

confidence: 99%

Cytokines produced by innate immune cells in IgG4-related disease

Yoshikawa

Watanabe

Minaga

et al. 2018

Modern Rheumatology

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IgG4-related disease (IgG4-RD) is a newly defined multi-organ disease proposed by Japanese physicians. IgG4-RD is characterized by elevated serum levels of IgG4 and massive infiltration of IgG4-expressing plasma cells in the affected organs. Recent studies have shown that abnormal adaptive immune responses mediated by T helper type 2 cells, regulatory T cells, follicular helper T cells, cytotoxic CD4 þ T cells, and plasmablasts are involved in IgG4-RD immunopathogenesis. In addition to adaptive immune responses, innate immune responses play pathogenic roles in IgG4-RD. Plasmacytoid dendritic cells (pDCs), M2 macrophages, and basophils are activated to produce various kinds of cytokines in IgG4-RD. Recent studies highlight the importance of type I IFN and IL-33 produced by pDCs in IgG4-RD immunopathogenesis.

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Section: Introductionmentioning

confidence: 99%

Cytokines produced by innate immune cells in IgG4-related disease

Yoshikawa

Watanabe

Minaga

et al. 2018

Modern Rheumatology

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“…The switch to IgG4 has also been shown to be induced by these cytokines in the context of IgG4-related disease [39,40]. Recently, both Tfh1 and Tfh2 cells were also shown to be the main B cell helpers to produce IgG4 in the lesions of IgG4-related disease (IgG4-RD) [41,42]. Although IgG4-RD and MuSK-MG seem to have similar aspects, the results of the IL-4 measurements in a smaller subgroup did not support the effect of HLA that we observed in this study.…”

Section: Discussionmentioning

confidence: 99%

Relation ofHLA-DRB1to IgG4 autoantibody and cytokine production in muscle-specific tyrosine kinase myasthenia gravis (MuSK-MG)

Çebi

Durmuş

Yılmaz

et al. 2019

Clinical and Experimental Immunology

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A small subset of myasthenia gravis (MG) patients develop autoantibodies against muscle-specific kinase (MuSK), which are predominantly of the immunoglobulin (Ig)G4 isotype. MuSK-MG is strongly associated with HLA-DRB1*14, HLA-DRB1*16 and HLA-DQB1*05. In this study, the possible effects of these HLA associations on MuSK IgG autoantibody or cytokine production were investigated. Samples from 80 MG patients with MuSK antibodies were studied. The disease-associated HLA types were screened in the DNA samples. The IgG1, IgG2, IgG3 and IgG4 titres of the MuSK antibodies and the levels of interleukin (IL)-4, IL-6, IL-17A and IL-10 were measured in the sera. Comparisons were made among the groups with or without HLA-DRB1*14, HLA-DRB1*16 or HLA-DQB1*05. The IgG4 titres of the MuSK antibodies were higher than those of the IgG1, IgG2 and IgG3 isotypes among the whole group of patients. DRB1*14 (+) DRB1*16 (-) patients had higher levels of IgG4 antibodies than those of DRB1*14 (-) DRB1*16 (+) patients. DRB1*14 (+) DRB1*16 (+) patients also had higher levels of IgG4 antibodies than those of DRB1*14 (-) DRB1*16 (+) and DRB1*14 (-) DRB1*16 (-) patients. Higher IL-10 and lower IL-17A levels were measured in DRB1*14 (+) DRB1*16 (-) patients than in DRB1*14 (-) DRB1*16 (-) patients. The higher IgG4 titres of MuSK autoantibodies in patients carrying HLA-DRB1*14 than those in the other patients suggest a role for HLA in the production of the antibodies. The differences in IL-10 and IL-17A support the role of DRB1 in the etiopathogenesis of this autoimmune response.

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“…Higher proportions of T regulatory and Tfh cells have been detected in IgG4-RD patients compared to healthy controls, correlated with plasmablasts and serum IgG levels [ 17 ]. In support to these findings, an increased number and frequency of circulating PD-1 high Tfh cells have been detected in peripheral blood of patients, functionally effective in driving IgG4 production from autologous B cells and responsive to steroid treatment [ 15 , 16 ]. A diffuse infiltrate of Tfh expressing PD-1, ICOS, and BCL6 at high density has been described in tissue lesions [ 16 ].…”

Section: Introductionmentioning

confidence: 87%

“…In support to these findings, an increased number and frequency of circulating PD-1 high Tfh cells have been detected in peripheral blood of patients, functionally effective in driving IgG4 production from autologous B cells and responsive to steroid treatment [ 15 , 16 ]. A diffuse infiltrate of Tfh expressing PD-1, ICOS, and BCL6 at high density has been described in tissue lesions [ 16 ]. On the whole, these data suggest the possibility to use also circulating Tfh cells as biomarker of disease activity.…”

Section: Introductionmentioning

confidence: 87%

Salivary Gland Pathology in IgG4-Related Disease: A Comprehensive Review

Puxeddu

Capecchi

Carta

et al. 2018

Journal of Immunology Research

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IgG4-related disease (IgG4-RD) is a rare fibroinflammatory condition that can affect almost any organ, characterized by swollen lesions and often by eosinophilia and elevated serum IgG4 concentrations. The diagnosis of IgG4-RD is a challenging task: in fact, single or multiple organs can be affected and clinical, serological, and histological findings can be heterogeneous. In IgG4-RD, the involvement of salivary glands is observed in 27% to 53% of patients. Several organ-specific conditions, now recognized as different manifestations of IgG4-related sialadenitis (IgG4-RS), were viewed in the past as individual disease entities. The study of salivary glands may sometimes be complex, because of the number of pathological conditions that may affect them, often with overlapping clinical pictures. Integration of different imaging techniques is often required in the case of swelling of salivary glands, even though biopsy remains the gold standard for a definite diagnosis of IgG4-RS. Thus, in this review, we discuss new insights in the pathogenesis of IgG4-RD, focusing on its clinical aspects and the tools that are currently available for a correct differential diagnosis when the salivary glands are involved.

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Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease

Cited by 62 publications

References 25 publications

Cytokines produced by innate immune cells in IgG4-related disease

Cytokines produced by innate immune cells in IgG4-related disease

Relation ofHLA-DRB1to IgG4 autoantibody and cytokine production in muscle-specific tyrosine kinase myasthenia gravis (MuSK-MG)

Salivary Gland Pathology in IgG4-Related Disease: A Comprehensive Review

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