IgG4‐related disease: Association with a rare gene variant expressed in cytotoxic T cells

Abstract Background CD4+ T cells play critical roles in the pathogenesis of IgG4-related disease (IgG4-RD). The aim of this study was to investigate the TCR repertoire of peripheral blood CD4+ T cells in IgG4-RD. Methods The peripheral blood was collected from six healthy controls and eight IgG4-RD patients. TCR β-chain libraries of CD4+ T cells were constructed by 5′-rapid amplification of cDNA ends (5′-RACE) and sequenced by Illumina Miseq platform. The relative similarity of TCR repertoires between samples was evaluated according to the total frequencies of shared clonotypes (metric F), correlation of frequencies of shared clonotypes (metric R), and total number of shared clonotypes (metric D). Results The clonal expansion and diversity of CD4+ T cell repertoire were comparable between healthy controls and IgG4-RD patients, while the proportion of expanded and coding degenerated clones, as an indicator of antigen-driven clonal expansion, was significantly higher in IgG4-RD patients. There was no significant difference in TRBV and TRBJ gene usage between healthy controls and IgG4-RD patients. The complementarity determining region 3 (CDR3) length distribution was skewed towards longer fragments in IgG4-RD. Visualization of relative similarity of TCR repertoires by multi-dimensional scaling analysis showed that TCR repertoires of IgG4-RD patients were separated from that of healthy controls in F and D metrics. We identified 11 IgG4-RD-specific CDR3 amino acid sequences that were expanded in at least 2 IgG4-RD patients, while not detected in healthy controls. According to TCR clonotype networks constructed by connecting all the CDR3 sequences with a Levenshtein distance of 1, 3 IgG4-RD-specific clusters were identified. We annotated the TCR sequences with known antigen specificity according to McPAS-TCR database and found that the frequencies of TCR sequences associated with each disease or immune function were comparable between healthy controls and IgG4-RD patients. Conclusion According to our study of CD4+ T cells from eight IgG4-RD patients, TCR repertoires of IgG4-RD patients were different from that of healthy controls in the proportion of expanded and coding degenerated clones and CDR3 length distribution. In addition, IgG4-RD-specific TCR sequences and clusters were identified in our study.

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Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease

International Immunology ◽

10.1093/intimm/dxz073 ◽

2019 ◽

Vol 32 (3) ◽

pp. 163-174

Author(s):

Takanori Sasaki ◽

Taiki Yajima ◽

Tatsuro Shimaoka ◽

Shuhei Ogawa ◽

Takashi Saito ◽

...

Keyword(s):

T Cells ◽

Synergistic Effect ◽

Plasma Cells ◽

Synergistic Effects ◽

Lymphoid Tissues ◽

Irreversible Damage ◽

Tissue Specific ◽

Related Disease ◽

Igg4 Related Disease ◽

Igg4 Antibody

Abstract IgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we established a mouse model that enabled us to evaluate the pathogenic function of IgG4 antibodies in response to a tissue-specific autoantigen using recombinant ovalbumin (OVA)-specific human IgG4 monoclonal antibody (rOVA-hIgG4 mAb) and the mice expressing OVA of the pancreatic islets (RIP-mOVA mice). We found no inflammatory effect of rOVA-hIgG4 mAb transfer alone; however, co-transfer with OVA-specific CD8 CTLs (OT-I T cells) induced tissue damage with dense lymphocytic inflammation in the pancreas of RIP-mOVA mice. rOVA-hIgG4 mAb caused accumulation of conventional DC1 cells (cDC1s) in the lymphoid tissues, and the dendritic cells (DCs) activated the OT-I T cells via cross-presentation. We also revealed that the synergistic effects of CTLs and antibodies were observed in the other subclasses including endogenous antibodies if they recognized the same antigen. The transfer of OVA-specific CD4 helper T cells (OT-II T cells) into RIP-mOVA mice induced the production of anti-OVA antibody, which had a synergistic effect, through acquisition of a T follicular helper (TFH) phenotype. Moreover, using OT-II T cells deficient in Bcl6 caused lower anti-OVA antibody production and inflammation with OT-I T cells. Our results indicated that autoreactive IgG4 antibodies play an important role of the tissue-specific CTL response in IgG4-RD.

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Cholangiocarcinoma with respect to IgG4 Reaction

International Journal of Hepatology ◽

10.1155/2014/803876 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Kenichi Harada ◽

Yasuni Nakanuma

Keyword(s):

T Cells ◽

Plasma Cells ◽

Cytotoxic T Cells ◽

Immune Surveillance ◽

Intraepithelial Neoplasia ◽

Cell Switching ◽

Igg4 Related Disease ◽

Regulatory Cytokine ◽

High Risk Factor ◽

Antigen Presenting

IgG4 reactions marked by infiltration of IgG4-positive plasma cells in affected organs occur in cancer patients and in patients with IgG4-related diseases. Extrahepatic cholangiocarcinomas including gall bladder cancer are often accompanied by significant IgG4 reactions; these reactions show a negative correlation with CD8-positive cytotoxic T cells, suggesting that the evasion of immune surveillance is associated with cytotoxic T cells. The regulatory cytokine IL-10 may induce IgG4-positive plasma cell differentiation or promote B cell switching to IgG4 in the presence of IL-4. Cholangiocarcinoma cells may function as nonprofessional antigen presenting cells that indirectly induce IgG4 reactions via the IL-10-producing cells and/or these may act as Foxp3-positive and IL-10-producing cells that directly induce IgG4 reactions. Moreover, IgG4-related disease is a high-risk factor for cancer development; IgG4-related sclerosing cholangitis (IgG4-SC) cases associated with cholangiocarcinoma or its precursor lesion biliary intraepithelial neoplasia (BilIN) have been reported. IgG4-positive cell infiltration is an important finding of IgG4-SC but is not a histological hallmark of IgG4-SC. For the diagnosis of IgG4-SC, its differentiation from cholangiocarcinoma remains important.

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Intrathecal activation of CD8 + memory T cells in IgG4‐related disease of the brain parenchyma

EMBO Molecular Medicine ◽

10.15252/emmm.202113953 ◽

2021 ◽

Author(s):

Mirco Friedrich ◽

Niklas Kehl ◽

Niko Engelke ◽

Josephine Kraus ◽

Katharina Lindner ◽

...

Keyword(s):

T Cells ◽

Memory T Cells ◽

Brain Parenchyma ◽

Related Disease ◽

Igg4 Related Disease ◽

Cd8 Memory T Cells ◽

The Brain

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Faculty Opinions recommendation of Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726505895.793528692 ◽

2017 ◽

Author(s):

Daniel Hamilos

Keyword(s):

T Cells ◽

Related Disease ◽

Igg4 Related Disease ◽

Follicular Helper

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Clonally expanded cytotoxic CD4+ T cells and the pathogenesis of IgG4-related disease

Autoimmunity ◽

10.1080/08916934.2017.1280029 ◽

2017 ◽

Vol 50 (1) ◽

pp. 19-24 ◽

Cited By ~ 34

Author(s):

Hamid Mattoo ◽

John H. Stone ◽

Shiv Pillai

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Related Disease ◽

Igg4 Related Disease

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A Case Report of an Atypical Presentation of IgG4-Related Disease and Idiopathic CD4 Lymphocytopenia

Case Reports in Medicine ◽

10.1155/2015/512370 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Francesco Rapisarda ◽

Luca Zanoli ◽

Grazia Portale ◽

Salvo Scuto ◽

Pietro Castellino

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Plasma Cells ◽

Elevated Serum ◽

Serum Levels ◽

Temporal Association ◽

Related Disease ◽

Igg4 Related Disease ◽

First Case ◽

Idiopathic Cd4 Lymphocytopenia

The IgG4-related disease is a fibroinflammatory disease characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and, often but not always, elevated serum levels of IgG4. Idiopathic CD4 lymphocytopenia is a heterogenic and rare syndrome characterized by the detection of a persistent absolute CD4 T cells count <300 cells/mm3(or <20% of total T cells) in more than one occasion and no evidence of HIV infection in absence of immunodeficiency or therapy associated with depressed levels of CD4 T cells. We report the case of a 50-year-old man with a multiorgan IgG4-related disease presenting in a temporal association with a profound and symptomatic idiopathic CD4 lymphocytopenia. Both clinical pictures improved after steroid treatment. Idiopathic CD4 lymphocytopenia has been associated with a number of autoimmune conditions but, to the best of our knowledge, this is the first case in which an association with the IgG4-related disease is reported.

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