Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome
Yao syndrome (YAOS) is a systemic autoinflammatory disease (SAID), formerly termed nucleotide-binding oligomerization domain-2 (NOD2)-associated autoinflammatory disease. Due to the recent identification of YAOS, the molecular mechanisms underlying its disease pathogenesis are unclear. With specific...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-02-01
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| Series: | Autoimmunity |
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| Online Access: | http://dx.doi.org/10.1080/08916934.2018.1442442 |
| _version_ | 1797684734006919168 |
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| author | Christine McDonald Min Shen Erin E. Johnson Amrita Kabi Qingping Yao |
| author_facet | Christine McDonald Min Shen Erin E. Johnson Amrita Kabi Qingping Yao |
| author_sort | Christine McDonald |
| collection | DOAJ |
| description | Yao syndrome (YAOS) is a systemic autoinflammatory disease (SAID), formerly termed nucleotide-binding oligomerization domain-2 (NOD2)-associated autoinflammatory disease. Due to the recent identification of YAOS, the molecular mechanisms underlying its disease pathogenesis are unclear. With specific NOD2 variants as characteristic genotypic features of YAOS, our study examined NOD2 expression, transcript splicing, signaling pathway activation, and cytokine profiles in peripheral blood mononuclear cells (PBMCs) from 10 YAOS patients and six healthy individuals. All participants were genotyped for NOD2 variants; all YAOS patients were heterozygous for the NOD2 IVS8+158 variant (IVS8+158) and four patients also carried a concurrent NOD2 R702W variant (IVS8+158/R702W haplotype). Resembling other SAIDs, plasma levels of TNFα, IL-1β, IL-6, IFNγ, and S100A12 were unaltered in YAOS patients. Intron-8 splicing of NOD2 transcripts was unaffected by carriage of NOD2 IVS8+158. However, NOD2 transcript level and basal p38 mitogen-activated protein kinase (MAPK) activity were significantly elevated in PBMCs from IVS8+158 YAOS patients. Moreover, these patients’ cells had elevated basal IL-6 secretion that was enhanced by muramyl dipeptide (MDP) stimulation. Tocilizumab treatment of a YAOS IVS8+158 patient resulted in marked clinical improvement. In contrast, MDP-stimulated NF-κB activity was uniquely suppressed in haplotype IVS8+158/R702W patients, as was TNFα secretion. Our study demonstrates for the first time that NOD2 expression and pathway activation are aberrant in YAOS, and specific NOD2 genotypes result in distinct NOD2 expression and cytokine profiles. These findings may also help select therapeutic strategies in the future. |
| first_indexed | 2024-03-12T00:35:03Z |
| format | Article |
| id | doaj.art-550a1eb8ba4d4ed7afb8498a0a326460 |
| institution | Directory Open Access Journal |
| issn | 0891-6934 1607-842X |
| language | English |
| last_indexed | 2024-03-12T00:35:03Z |
| publishDate | 2018-02-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autoimmunity |
| spelling | doaj.art-550a1eb8ba4d4ed7afb8498a0a3264602023-09-15T10:01:07ZengTaylor & Francis GroupAutoimmunity0891-69341607-842X2018-02-01512536110.1080/08916934.2018.14424421442442Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndromeChristine McDonald0Min Shen1Erin E. Johnson2Amrita Kabi3Qingping Yao4Lerner Research Institute, Cleveland ClinicOrthopaedic and Rheumatologic Institute, Cleveland ClinicJohn Carroll University, University HeightsLerner Research Institute, Cleveland ClinicOrthopaedic and Rheumatologic Institute, Cleveland ClinicYao syndrome (YAOS) is a systemic autoinflammatory disease (SAID), formerly termed nucleotide-binding oligomerization domain-2 (NOD2)-associated autoinflammatory disease. Due to the recent identification of YAOS, the molecular mechanisms underlying its disease pathogenesis are unclear. With specific NOD2 variants as characteristic genotypic features of YAOS, our study examined NOD2 expression, transcript splicing, signaling pathway activation, and cytokine profiles in peripheral blood mononuclear cells (PBMCs) from 10 YAOS patients and six healthy individuals. All participants were genotyped for NOD2 variants; all YAOS patients were heterozygous for the NOD2 IVS8+158 variant (IVS8+158) and four patients also carried a concurrent NOD2 R702W variant (IVS8+158/R702W haplotype). Resembling other SAIDs, plasma levels of TNFα, IL-1β, IL-6, IFNγ, and S100A12 were unaltered in YAOS patients. Intron-8 splicing of NOD2 transcripts was unaffected by carriage of NOD2 IVS8+158. However, NOD2 transcript level and basal p38 mitogen-activated protein kinase (MAPK) activity were significantly elevated in PBMCs from IVS8+158 YAOS patients. Moreover, these patients’ cells had elevated basal IL-6 secretion that was enhanced by muramyl dipeptide (MDP) stimulation. Tocilizumab treatment of a YAOS IVS8+158 patient resulted in marked clinical improvement. In contrast, MDP-stimulated NF-κB activity was uniquely suppressed in haplotype IVS8+158/R702W patients, as was TNFα secretion. Our study demonstrates for the first time that NOD2 expression and pathway activation are aberrant in YAOS, and specific NOD2 genotypes result in distinct NOD2 expression and cytokine profiles. These findings may also help select therapeutic strategies in the future.http://dx.doi.org/10.1080/08916934.2018.1442442autoinflammatory diseasenod2yao syndromeanti-cytokine therapygenetics |
| spellingShingle | Christine McDonald Min Shen Erin E. Johnson Amrita Kabi Qingping Yao Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome Autoimmunity autoinflammatory disease nod2 yao syndrome anti-cytokine therapy genetics |
| title | Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome |
| title_full | Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome |
| title_fullStr | Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome |
| title_full_unstemmed | Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome |
| title_short | Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome |
| title_sort | alterations in nucleotide binding oligomerization domain 2 expression pathway activation and cytokine production in yao syndrome |
| topic | autoinflammatory disease nod2 yao syndrome anti-cytokine therapy genetics |
| url | http://dx.doi.org/10.1080/08916934.2018.1442442 |
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