Meta-Analysis of Alterations in Regulatory T Cells’ Frequency and Suppressive Capacity in Patients with Vitiligo
Prashant S. Giri, Jahanvi Mistry, Mitesh Dwivedi
Abstract
Vitiligo is a noncontagious autoimmune skin depigmenting disease. Regulatory T cells (Tregs) play a key role in maintaining peripheral tolerance; however, Tregs’ number, suppressive function, and associated suppressive molecules (FOXP3, IL-10, and TGF-β) are found to be reduced in vitiligo patients. Although, the role of Tregs in vitiligo pathogenesis is well established, there are several contrary findings which suggest a controversial role of Tregs in vitiligo. Therefore, to clarify the role of Tregs in vitiligo pathogenesis, we aimed to study Tregs’ frequency, suppressive capacity, and associated suppressive molecules (FOXP3, IL-10, and TGF-β) in vitiligo patients through meta-analysis approach. A total of 30 studies involving 1223 vitiligo patients and 1109 controls were included in the study. Pooled results from our meta-analysis suggested significantly reduced Treg cells’ frequency in vitiligo patients ( <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"><a:mi>p</a:mi><a:mo>=</a:mo><a:mn>0.002</a:mn></a:math> ). Interestingly, Tregs’ suppressive capacity was also significantly reduced in vitiligo patients ( <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" id="M2"><c:mi>p</c:mi><c:mo>=</c:mo><c:mn>0.0002</c:mn></c:math> ); specifically, Treg-mediated suppression of CD8+T cells was impaired in vitiligo patients ( <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" id="M3"><e:mi>p</e:mi><e:mo><</e:mo><e:mn>0.00001</e:mn></e:math> ). Moreover, FOXP3, a key Tregs’ transcription factor, was significantly reduced in blood and skin of vitiligo patients ( <g:math xmlns:g="http://www.w3.org/1998/Math/MathML" id="M4"><g:mi>p</g:mi><g:mo><</g:mo><g:mn>0.00001</g:mn></g:math> ). Intriguingly, the FOXP3 expression was significantly reduced in the lesional skin as compared to perilesional and nonlesional skin ( <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" id="M5"><i:mi>p</i:mi><i:mo>=</i:mo><i:mn>0.007</i:mn></i:math> and <k:math xmlns:k="http://www.w3.org/1998/Math/MathML" id="M6"><k:mi>p</k:mi><k:mo>=</k:mo><k:mn>0.04</k:mn></k:math> ). Furthermore, the expression of key Treg-associated suppressive cytokines IL-10 and TGF-β were significantly reduced in vitiligo patients ( <m:math xmlns:m="http://www.w3.org/1998/Math/MathML" id="M7"><m:mi>p</m:mi><m:mo>=</m:mo><m:mn>0.0005</m:mn></m:math> and <o:math xmlns:o="http://www.w3.org/1998/Math/MathML" id="M8"><o:mi>p</o:mi><o:mo>=</o:mo><o:mn>0.01</o:mn></o:math> ). The disease activity-based analysis suggested for reduced Tregs’ frequency and FOXP3 expression in active vitiligo patients ( <q:math xmlns:q="http://www.w3.org/1998/Math/MathML" id="M9"><q:mi>p</q:mi><q:mo>=</q:mo><q:mn>0.05</q:mn></q:math> and <s:math xmlns:s="http://www.w3.org/1998/Math/MathML" id="M10"><s:mi>p</s:mi><s:mo>=</s:mo><s:mn>0.01</s:mn></s:math> ). We also studied the effect of microRNA-based treatment, narrow band–UVB phototherapy, and Treg-associated treatments on Tregs’ frequency, FOXP3, and IL-10 expression. Interestingly, we found increased Tregs’ frequency, FOXP3, and IL-10 expression after the treatment ( <u:math xmlns:u="http://www.w3.org/1998/Math/MathML" id="M11"><u:mi>p</u:mi><u:mo>=</u:mo><u:mn>0.007</u:mn></u:math> , <w:math xmlns:w="http://www.w3.org/1998/Math/MathML" id="M12"><w:mi>p</w:mi><w:mo><</w:mo><w:mn>0.0001</w:mn></w:math> , and <y:math xmlns:y="http://www.w3.org/1998/Math/MathML" id="M13"><y:mi>p</y:mi><y:mo>=</y:mo><y:mn>0.002</y:mn></y:math> ). Overall, our meta-analysis suggests that the Tregs play a crucial role in pathogenesis and progression of vitiligo, and hence, Treg-based therapeutic interventions could be effective in vitiligo patients.