Type I Interferon Signaling Is Required for Dacryoadenitis in the Nonobese Diabetic Mouse Model of Sjögren Syndrome

Chaly, Yury; Barr, Jennifer; Sullivan, David A.; Thomas, Helen E.; Brodnicki, Thomas C.

doi:10.3390/ijms19103259

Cited by 11 publications

(23 citation statements)

References 48 publications

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“…Lacrimal gland inflammation was markedly diminished with little to no inflammation detected in the glands from male Tlr7 KO mice compared to WT male mice ( Figure 2 A,B). Neither WT nor Tlr7 KO female mice developed lacrimal gland inflammation ( Figure 2 C,D) in accordance with the known male-specific occurrence of spontaneous lacrimal gland autoimmunity in NOD mice [ 19 , 23 ]. In contrast, females developed focal sialadenitis to a similar degree regardless of the presence or absence of TLR7 ( Figure 2 E,F).…”

Section: Resultssupporting

confidence: 81%

Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Development in Male Nonobese Diabetic Mice

Debreceni

Chimenti

Serreze

et al. 2020

IJMS

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Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation. Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice. RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands. Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice.

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Section: Resultssupporting

confidence: 81%

Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Development in Male Nonobese Diabetic Mice

Debreceni

Chimenti

Serreze

et al. 2020

IJMS

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“…Other proteins like IFN inducible guanylate binding protein 1 and CD45 + cell infiltration are corelated and may be analyzed by the degree of CD45 + infiltration in the major SGs of pSS patients [ 107 ]. CCL9 and CCL19 expression is up-regulated in the salivary (SG) and LGs (LG) of NOD and C57BL/6.NOD- Aec1Aec2 mice during disease onset, inducing other potentially disease relevant genes such as Epsti1 and Ubd that show enhanced activity in the LGs of male mice [ 109 , 114 ]. IL-7, known to cause increased production of IFN-γ and CXCR3 via upregulation of Th1 cells, has been shown to accelerate the development of SS [ 115 ].…”

Section: Adaptive Immune Cellsmentioning

confidence: 99%

Contributions of Major Cell Populations to Sjögren’s Syndrome

Witas

Gupta

Nguyen

2020

JCM

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Sjögren’s syndrome (SS) is a female dominated autoimmune disease characterized by lymphocytic infiltration into salivary and lacrimal glands and subsequent exocrine glandular dysfunction. SS also may exhibit a broad array of extraglandular manifestations including an elevated incidence of non-Hodgkin’s B cell lymphoma. The etiology of SS remains poorly understood, yet progress has been made in identifying progressive stages of disease using preclinical mouse models. The roles played by immune cell subtypes within these stages of disease are becoming increasingly well understood, though significant gaps in knowledge still remain. There is evidence for distinct involvement from both innate and adaptive immune cells, where cells of the innate immune system establish a proinflammatory environment characterized by a type I interferon (IFN) signature that facilitates propagation of the disease by further activating T and B cell subsets to generate autoantibodies and participate in glandular destruction. This review will discuss the evidence for participation in disease pathogenesis by various classes of immune cells and glandular epithelial cells based upon data from both preclinical mouse models and human patients. Further examination of the contributions of glandular and immune cell subtypes to SS will be necessary to identify additional therapeutic targets that may lead to better management of the disease.

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“…In contrast, the inflammation of lacrimal and salivary glands tends to occur with more absolute sex-specificity. Moreover, evidence supports different interferon (IFN)-mediated immune pathways required for lacrimal and salivary gland disease with male-specific lacrimal gland inflammation dependent on type I IFN signaling 41 and female-specific salivary gland inflammation dependent on type II IFN signaling 42 . In T1D, the roles of IFN signaling are more complex, but neither type I nor type II IFN signaling is absolutely required for T1D development in either sex 43 .…”

Section: Discussionmentioning

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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Type I Interferon Signaling Is Required for Dacryoadenitis in the Nonobese Diabetic Mouse Model of Sjögren Syndrome

Cited by 11 publications

References 48 publications

Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Development in Male Nonobese Diabetic Mice

Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Development in Male Nonobese Diabetic Mice

Contributions of Major Cell Populations to Sjögren’s Syndrome

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

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