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1. Saraiva de Matos, Carina. Immunomodulation by NOD2/CARD15 and Vitamin D3.

Degree: PhD, Medizin, 2018, Universität Regensburg

GvHD is still the most common life-threatening complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). NOD2/CARD15, an intra-cytoplasmatic pathogen-recognition receptor recognizing bacterial muramyl dipeptide (MDP), has gained substantial interest, as single nucleotide polymorphisms (SNPs) of this receptor have been identified as a risk factor for Crohn´s disease and GvHD. These data suggest that MDP sensing by hematopoietic cells is of crucial importance for the immune homeostasis in target organs of GvHD, especially in the gastrointestinal tract and/or skin. Nevertheless, the exact mechanism by which the mutation in the NOD2 receptor affects the outcome of transplantation is not entirely understood. In the present work, the impact of NOD2 polymorphisms on the immune cell composition in peripheral blood of healthy donors was evaluated. We found that donors with NOD2 mutations presented differences in their myeloid compartment, with less CD33+ cells (a common myeloid marker) and less myeloid dendritic cells (mDCs). A more detailed analysis on the monocyte population revealed that donors with SNP12 or SNP13 but not SNP8 had increased CD16 expression. CD14+CD16+ monocytes have been identified as a major proinflammatory cell population as they exhibit a distinct cytokine secretion pattern, with low IL-10 production and high levels of IL-1β, TNF and IL-12. Moreover, it has been shown that these monocytes are more efficient antigen-presenting cells than their classical counterparts. These results provide a new insight by which NOD2 polymorphisms can have a modulatory function in the course of inflammation. TGF-β is a pleiotropic cytokine with strong regulatory and inflammatory activity. Our analysis demonstrated that TGF-β is capable of inducing the expression of CD16 on monocytes, independent of the NOD2 status. However, we noticed that the highest number of CD14+CD16+ cells was found in donors with SNP12 or 13 mutations. The cytokine profile of these cells revealed a decrease in IL-8 secretion by SNP12 or 13 donors and, although not significant, a strong trend towards an increased IL-6 secretion, especially under non-stimulatory conditions. In line with these observations, we analysed the expression of iκB and found a constitutive degradation of IκB in one donor with both SNP8 and SNP13 mutation, indicating a constitutive activation of the NF-κB pathway. The imbalance found in the immune cell composition of the analysed NOD2 SNP donors could contribute to the association seen between NOD2 SNPs and HSCT outcome. The cellular imbalances reflect at molecular level through pro-inflammatory cytokine secretion, and it is believed that a dysregulation on cytokine production provide the first mechanism by which NOD2 variants can affect the outcome of HSCT. Beside NOD2 polymorphisms, vitamin D3 receptor gene polymorphisms have also been associated with GvHD. Furthermore, it has already been shown that vitamin D3 deficiency is a common phenomenon in allogeneic transplant patients and may also be… Advisors/Committee Members: Kreutz, Marina (advisor).

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APA (6th Edition):

Saraiva de Matos, C. (2018). Immunomodulation by NOD2/CARD15 and Vitamin D3. (Doctoral Dissertation). Universität Regensburg. Retrieved from http://epub.uni-regensburg.de/36710

Chicago Manual of Style (16th Edition):

Saraiva de Matos, Carina. “Immunomodulation by NOD2/CARD15 and Vitamin D3.” 2018. Doctoral Dissertation, Universität Regensburg. Accessed June 19, 2018. http://epub.uni-regensburg.de/36710.

MLA Handbook (7th Edition):

Saraiva de Matos, Carina. “Immunomodulation by NOD2/CARD15 and Vitamin D3.” 2018. Web. 19 Jun 2018.

Vancouver:

Saraiva de Matos C. Immunomodulation by NOD2/CARD15 and Vitamin D3. [Internet] [Doctoral dissertation]. Universität Regensburg; 2018. [cited 2018 Jun 19]. Available from: http://epub.uni-regensburg.de/36710.

Council of Science Editors:

Saraiva de Matos C. Immunomodulation by NOD2/CARD15 and Vitamin D3. [Doctoral Dissertation]. Universität Regensburg; 2018. Available from: http://epub.uni-regensburg.de/36710

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