Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation

Ciecko, Ashley E.; Foda, Bardees M.; Barr, Jennifer; Ramanathan, Sheela; Atkinson, Mark A.; Serreze, David; Geurts, Aron M.; Lieberman, Scott M.; Chen, Yi-Guang

doi:10.1016/j.celrep.2019.11.010

Cited by 39 publications

(28 citation statements)

References 84 publications

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“…Several studies, including genome-wide association studies ( 63 – 65 ), demonstrate pathogenic roles of the cytokine IL-27 in T1D. Transgenic NOD IL-27 receptor knockout mice are resistant to disease and blockade of IL-27 delays T1D onset in NOD mice ( 66 , 67 ). MCP-1 is a chemokine involved in immune cell recruitment.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome

et al. 2020

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Inflammation stimulates release of a heterogeneous population of beta EV with differential expression of immunogenic substances involved in immune cell recruitment and activation. HIGHLIGHTS-Stress engenders an up to four-fold increase in the volume of the vesiculome and enhanced auto-antigen release-Cytokines are selectively sorted into EV subspecies-TLR-binding microRNAs are enriched in sEV-EV from stressed beta cells promote dendritic and macrophage cell activation.

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Section: Discussionmentioning

confidence: 99%

Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome

et al. 2020

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“…Recent investigation reported that IL-27 not only showed immunomodulatory function, but also was a compensatory effort of dendritic cells against the ongoing inflammation in T1D patients (37). On the contrary, Ciecko et al (38) reported that IL-27 contributes to the pathogenesis of T1D in NOD mice by altering the balance of Treg and T H 1 cells and enhancing the effector function of CD8 T cells, although it was reported that serum IL-27 was strongly elevated in patients with SS (39), which is inconsistent with our results. This may be because SS patients were particularly associated with interstitial lung disease complications in their study.…”

Section: Discussionmentioning

confidence: 97%

IL-27 Regulated CD4+IL-10+ T Cells in Experimental Sjögren Syndrome

Zhang

Tang

et al. 2020

Front. Immunol.

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Interleukin 27 (IL-27) plays diverse immune regulatory roles in autoimmune disorders and promotes the generation of IL-10-producing CD4 + T cells characterized by producing the immunosuppressive cytokine IL-10. However, whether IL-27 participates in pathological progress of Sjögren syndrome (SS) through regulating CD4 + IL-10 + T cells remains unknown. Here we aimed to explore the potential role of IL-27 and CD4 + IL-10 + T cells in the pathogenesis of SS. The IL-27 gene knockout non-obese diabetic (Il-27 −/− NOD) mice were generated and injected with exogenous IL-27. Exogenous injection of IL-27 and neutralization of IL-27 with anti-IL-27 antibody in NOD mice were performed. The histopathologic changes in submandibular glands, lacrimal glands and lung, salivary flow rate, and percentages of CD4 + IL-10 + T cells were determined. And, ovalbumin-immunized C57L/B6 mice were injected with IL-27 to detect the percentage of CD4 + IL-10 + T cells. In vitro, splenic naive T cells from C57L/B6 mice were cultured with IL-27 for 4 days to induce the differentiation of CD4 + IL-10 + T cells. In addition, IL-27, IL-10, and CD4 + IL-10 + T cells were determined in health control and SS patients. The results showed that Il-27 −/− NOD mice had more severe disease and lower level of CD4 + IL-10 + T cells than control mice. And IL-27 promoted the generation and differentiation of CD4 + IL-10 + T cells in vivo and in vitro significantly. In agreement with the findings in the SS-like mice, patients with SS showed lower levels of IL-27, IL-10, and CD4 + IL-10 + T cells. Our findings indicated that IL-27 deficiency aggravated SS by regulating CD4 + IL-10 + T cells. Targeting IL-27 and CD4 + IL-10 + T cells may be a novel therapy for patients with SS.

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“…Analyses were performed in a blinded manner. The wild-type male lacrimal and female salivary gland focus scores represent a subset of our recently published larger wild-type data set 21 that were chosen based on being colony-matched and temporally-matched (i.e., procured within a year of procurement of the knockout samples to which they are compared). Higher magnification representative images were captured with a 10X objective on a Leitz DM-RB research microscope with a Leica DCF700T digital camera using the Leica Application Suite X software (Leica Microsystems, Wetzlar, Germany).…”

Section: Methodsmentioning

confidence: 99%

UBASH3A deficiency accelerates type 1 diabetes development and enhances salivary gland inflammation in NOD mice

Chen

Ciecko

Khaja

et al. 2020

Sci Rep

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Recent advances in genetic analyses have significantly refined human type 1 diabetes (T1D) associated loci. The goal of such effort is to identify the causal genes and have a complete understanding of the molecular pathways that independently or interactively influence cellular processes leading to the destruction of insulin producing pancreatic β cells. UBASH3A has been suggested as the underlying gene for a human T1D associated region on chromosome 21. To further evaluate the role of UBASH3A in T1D, we targeted Ubash3a in NOD mice using zinc-finger nuclease mediated mutagenesis. In both 10-week-old females and males, significantly more advanced insulitis was observed in UBASH3A-deficient than in wild-type NOD mice. Consistently, UBASH3A-deficient NOD mice developed accelerated T1D in both sexes, which was associated with increased accumulation of β-cell autoreactive T cells in the spleen and pancreatic lymph node. Adoptive transfer of splenic T cells into NOD.Rag1-/mice demonstrated that UBASH3A deficiency in T cells was sufficient to promote T1D development. Our results provide strong evidence to further support a role of UBASH3A in T1D. In addition to T1D, UBASH3A deficiency also promoted salivary gland inflammation in females, demonstrating its broad impact on autoimmunity. Genetic susceptibility and its interaction with incompletely defined environmental factors promote the development of type 1 diabetes (T1D) 1. Human genome wide association studies (GWAS) have identified more than 50 genetic loci significantly linked to T1D 2,3. While the greatest genetic contribution is provided by certain human leukocyte antigen (HLA) haplotypes, non-HLA susceptibility genes also convey significant risk for T1D development. However, our knowledge of the underlying genes within these mapped GWAS regions is incomplete. One such region is on chromosome 21, of which UBASH3A has been indicated as the underlying gene. Recent fine mapping studies identified several T1D-associated non-coding single nucleotide polymorphisms (SNPs) in UBASH3A 3. Subsequent studies further linked UBASH3A risk alleles to its elevated expression and reduced interleukin (IL)-2 production in human CD4 T cells, providing additional evidence to support it as a causal gene in this T1D region 4,5. UBASH3A belongs to the ubiquitin-associated and Src-homology 3 domain containing (UBASH3) family that also includes a second member UBASH3B 6. Expression of UBASH3A is restricted to lymphoid tissues and primarily in T cells 7. On the other hand, UBASH3B is ubiquitously expressed 8. An earlier study indicated that T cells deficient in both UBASH3A and UBASH3B were hyperreactive to T cell receptor (TCR) stimulation and the double knockout mice were more susceptible to experimental autoimmune encephalomyelitis compared to the wild-type control 7. More recently, it was demonstrated that deficiency in either UBASH3A or UBASH3B alone had distinct effects in promoting trinitrobenzene sulfonic acid induced colitis in mice 9. UBASH3B suppresses TCR signaling by dephospho...

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Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation

Cited by 39 publications

References 84 publications

Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome

Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome

IL-27 Regulated CD4+IL-10+ T Cells in Experimental Sjögren Syndrome

UBASH3A deficiency accelerates type 1 diabetes development and enhances salivary gland inflammation in NOD mice

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