Allergic Aspects of IgG4-Related Disease: Implications for Pathogenesis and Therapy

Michailidou, Despina; Schwartz, Daniella M.; Mustelin, Tomas; Hughes, Grant C.

doi:10.3389/fimmu.2021.693192

Cited by 23 publications

(13 citation statements)

References 156 publications

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“… 1 The activated Th2 cells produce an inflammatory cytokine milieu that promotes the maturation from B cells into plasma cells and the isotype switch towards IgG4. 4 Among the Th2-secreted cytokines, interleukin-13 (IL-13) plays a crucial role in the progression of allergic diseases and has been found to be significantly elevated in the serum and affected tissues of the patients suffering from many autoimmune diseases, such as Sjögren’s syndrome, rheumatoid arthritis, and systemic sclerosis. 5 Notably, the number of IL-13-positive cells in the submandibular glands (SMGs) of IgG4-RS patients is much higher than that of submandibular sialolithiasis and normal controls.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

et al. 2022

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Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.

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Section: Introductionmentioning

confidence: 99%

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

et al. 2022

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“…Recently, patterns of RF reactivity to Fc epitopes have been associated with particular diseases [26]. In addition, elevated levels of IgG4 have been associated a rare fibroinflammatory illness [38]. However, although the pre-existing responses in one study population bound to an epitope on human IgG4, the autoantibodies were not themselves IgG4.…”

Section: Discussionmentioning

confidence: 97%

Pre-existing Reactivity to an IgG4 Fc-Epitope: Characterization and Mitigation of Interference in a Bridging Anti-drug Antibody Assay

Chen

Karayusuf

Sirimanne

et al. 2022

AAPS J

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Twenty percent of baseline patient samples exhibited a pre-existing response in a bridging anti-drug antibody (ADA) assay for a human IgG4 monoclonal antibody (mAb) therapeutic. In some cases, assay signals were more than 100-fold higher than background, potentially confounding detection of true treatment-emergent ADA responses. The pre-existing reactivity was mapped by competitive inhibition experiments using recombinant proteins or chimeric human mAbs with IgG4 heavy chain regions swapped for IgG1 sequences. These experiments demonstrated that the majority of the samples had reactivity to an epitope containing leucine 445 in the CH3 domain of human IgG4. The pre-existing reactivity in baseline patient samples was mitigated by replacing the ADA assay capture reagent with a version of the drug containing a wild type IgG1 proline substitution at residue 445 without impacting detection of drug-specific, treatment-emergent ADA. Finally, purification on Protein G or anti-human IgG (H + L) columns indicated the pre-existing response was likely due to immunoglobulins in patient samples. Graphical abstract

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“…The relationship between IgG4-RD and allergy is both intriguing and controversial. As IgG4-RD and allergy both engage similar Type2 immune pathways and share certain immunopathological features, it is thought that allergy plays a significant role in the pathogenesis of IgG4 ( 20 ). However, eosinophilia and elevated IgE concentrations have also been observed in IgG4-RD patients without allergic diseases ( 21 – 23 ), indicating that Th2 immune activation is not necessarily allergy-mediated and may be driven by immune processes inherent to IgG4-RD itself.…”

Section: Discussionmentioning

confidence: 99%

A rare case of IgG4-related disease masquerading as periurethral malignancy and review of the literature

Zeng

Gao²,

Liu

2023

Front. Immunol.

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Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease that typically manifests as mass lesions affecting almost any organ including the pancreas, lacrimal and salivary glands, liver, lung and kidney. However, IgG4-RD with urethra involvement is scarce. We describe a rare case of IgG4-RD involving the urethra mimicking urethral carcinoma and review the published literature. A 64-years-old female presented with progressive dysuria for more than 2 months. Pelvic gadolinium-enhanced magnetic resonance imaging revealed a huge mass encasing the urethra which showed obvious enhancement in the arterial phase. And contrast-enhanced ultrasound showed that the entire mass was heterogeneously enhanced and displayed a fast-forward and fast-out pattern, which was highly suggestive of malignant tumor. The diagnosis of IgG4-RD was finally established by ultrasound-guided transvaginal mass needle biopsy. The patient was treated with methylprednisolone and cyclophosphamide and dysuria disappeared in the first week of therapy. She has been followed up in our clinic for 1 year without recurrence. The diagnosis of IgG4-RD should be considered in the differential diagnosis of a periurethral mass. Ultrasound-guided transvaginal mass needle biopsy is a safe and well-established tissue sampling method and should be performed in order to avoid unnecessary surgery.

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Allergic Aspects of IgG4-Related Disease: Implications for Pathogenesis and Therapy

Cited by 23 publications

References 156 publications

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis

Pre-existing Reactivity to an IgG4 Fc-Epitope: Characterization and Mitigation of Interference in a Bridging Anti-drug Antibody Assay

A rare case of IgG4-related disease masquerading as periurethral malignancy and review of the literature

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