Transient depletion of <scp>CD</scp>4<sup>+</sup> <scp>CD</scp>25<sup>+</sup> regulatory <scp>T</scp> cells results in multiple autoimmune diseases in wild‐type and B‐cell‐deficient <scp>NOD</scp> mice

Ellis, Jason S.; Wan, Xiaoxiao; Braley‐Mullen, Helen

doi:10.1111/imm.12065

Cited by 42 publications

(48 citation statements)

References 52 publications

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“…They were fixed in formalin, sectioned and stained with H&E. The extent of lymphocyte infiltration inthe salivary glands was scored by counting the number of foci/lymphocyte aggregates consisting of >50 lymphocytes (9, 21, 22). All scoring was done in a blinded manner using the microscope and MetaMorph software indicated below.…”

Section: Methodsmentioning

confidence: 99%

“…Absence of CD28 signaling can lead to anergy or apoptosis of T cells in response to TCR stimulation (6, 7). However in several models of spontaneous autoimmune disease, including iodine-facilitated spontaneous autoimmune thyroiditis (I-SAT) (8), diabetes (9–12) and pancreatitis (13), disease is accelerated when CD28 is absent. Development of earlier and/or more severe autoimmune disease in mice lacking CD28 is due primarily to reduced numbers of functional Tregs (14).…”

Section: Introductionmentioning

confidence: 99%

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New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

Kayes

Weisman

Camden

et al. 2016

The Journal of Immunology

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60–70 % of IFN-γ−/− NOD.H-2h4 mice given NaI-supplemented water develop a slow onset autoimmune thyroid disease, characterized by thyrocyte epithelial cell hyperplasia/ proliferation (TEC H/P). TEC H/P develops much earlier in CD28−/− mice and nearly 100 % (both sexes) have severe TEC H/P at 4 months of age. Without NaI supplementation, 50% of 5–6 month old CD28−/−IfFN-γ−/− mice develop severe TEC H/P, and 2–3 weeks of NaI is sufficient for optimal development of severe TEC H/P. Mice with severe TEC H/P are hypothyroid and normalization of serum thyroxine (T4) levels does not reduce TEC H/P. Activated CD4+ T cells are sufficient to transfer TEC H/P to SCID recipients. Thyroids of mice with TEC H/P have infiltrating T cells and expanded numbers of proliferating thyrocytes that highly express CD40. CD40 facilitates, but is not required for development of severe TEC H/P, as CD40−/−IFN-γ−/−CD28−/− mice develop severe TEC H/P. Accelerated development of TEC H/P in IFN-γ−/− CD28−/− mice is a result of reduced Treg numbers as CD28−/− mice have significantly fewer Tregs, and transfer of CD28-positive Tregs inhibits TEC H/P. Essentially all female IFN-γ−/− CD28−/−NOD.H-2h4 mice have substantial lymphocytic infiltration of salivary glands and reduced salivary flow by 6 months of age, thereby providing an excellent new model of autoimmune exocrinopathy of the salivary gland. This is one of very few models where autoimmune thyroid disease and hypothyroidism develop in most mice by 4 months of age. This model will be useful for studying the effects of hypothyroidism on multiple organ systems.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

Kayes

Weisman

Camden

et al. 2016

The Journal of Immunology

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“…Strategies that rely on depletion of Treg cells, even transiently, usually lead to serious systemic side effects and signs of severe autoimmune disease [84]. Not surprisingly, Ipilimumab, the anti-CTLA-4 antibody alluded to earlier, has potentially fetal autoimmune side effects and is only used in advanced non-resectable cases of melanoma [83].…”

Section: Epac1 In T-cell Function: Implications For Anti-cancer Immunmentioning

confidence: 99%

The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention

Almahariq

Mei

Cheng

2016

ABBS

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The pleiotropic second messenger adenosine 3′,5′-cyclic monophosphate (cAMP) regulates a myriad of biological processes under both physiological and pathophysiological conditions. Exchange protein directly activated by cAMP 1 (EPAC1) mediates the intracellular functions of cAMP by acting as a guanine nucleotide exchange factor for the Ras-like Rap small GTPases. Recent studies suggest that EPAC1 plays important roles in immunomodulation, cancer cell migration/metastasis, and metabolism. These results, coupled with the successful development of EPAC-specific small molecule inhibitors, identify EPAC1 as a promising therapeutic target for cancer treatments.

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“…Treg controls autoreactive T cells in the periphery to maintain self-tolerance [18][19][20][21]. Defects in Treg function can contribute to autoimmunity [20,21].…”

Section: Activation and Negative Regulatory Mechanisms Of Immune Systemmentioning

confidence: 99%

Role of X-Chromosome encoded miRNAs in Autoimmunity: Suppressing the suppressor and Female Predisposition

Hewagama

2013

Rheumatol Curr Res

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Role of skewed X inactivation may in part explain high prevalence of autoimmune diseases in women. Human X chromosome encodes approximately 7% of the total microRNAs identified. Recent studies have implicated over expression of X-linked miRNA in women affected by the autoimmune diseases. Potential biological targets of them include critically important genes such as FOXP3, CTLA-4, PDCD1 and, members of CBL and SOCS family ubiquitin ligases, which play an important role in the immune suppressive mechanisms and maintenance of tolerance. X-linked miRNA mediated post transcriptional suppression of immunosuppressive genes is an open area of study with potential to better understand why women develop many autoimmune disorders more often than men.

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Transient depletion of CD4⁺ CD25⁺ regulatory T cells results in multiple autoimmune diseases in wild‐type and B‐cell‐deficient NOD mice

Cited by 42 publications

References 52 publications

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention

Role of X-Chromosome encoded miRNAs in Autoimmunity: Suppressing the suppressor and Female Predisposition

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Transient depletion of CD4+ CD25+ regulatory T cells results in multiple autoimmune diseases in wild‐type and B‐cell‐deficient NOD mice

Cited by 42 publications

References 52 publications

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention

Role of X-Chromosome encoded miRNAs in Autoimmunity: Suppressing the suppressor and Female Predisposition

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Transient depletion of CD4⁺ CD25⁺ regulatory T cells results in multiple autoimmune diseases in wild‐type and B‐cell‐deficient NOD mice