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- Lingman Framme, Jenny, 1977, et al.
(författare)
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Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs
- 2022
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Ingår i: Journal of Clinical Immunology. - : Springer. - 0271-9142 .- 1573-2592. ; 42, s. 618-633
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Tidskriftsartikel (refereegranskat)abstract
- Background: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS).Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS.Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed.Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells.Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring.Clinical Implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.
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| 2. |
- Lundberg, Vanja
(författare)
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Thymic exosomes - effects on selection and maturation of thymocytes
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- T cell tolerance is primarily shaped in the thymus, through direct and indirect presentation of self-antigens to developing T cells. Medullary thymic epithelial cells (mTECs), producing and expressing self-antigens, together with dendritic cells (DCs) are the key antigen presenting cells in the thymus. In addition to direct presentation of self-antigens by mTECs, antigens are transferred to DCs followed by presentation to developing thymocytes. The underlying mechanism of this antigen transfer is not understood. Extracellular vesicles (EVs), and more specifically exosomes, are known to carry antigens and genomic material with a biological function to target cells. This thesis report thymic exosomes as mediators of antigen transfer important for T cell maturation, negative selection and Treg development. Furthermore, we show that thymic exosomes carry co-stimulatory molecules and MHC II. In the first paper, we report that exosomes derived from primary human thymic epithelial cell cultures carry self-antigens associated with autoimmune diseases. The second paper demonstrates how exosomes from mouse thymic tissue induce the final maturation of thymocytes, independently of antigen presenting cells (APCs), before they egress the thymus as T cells, in vitro. In order to study the impact of thymic exosomes on central tolerance in vivo, we used the transgenic mouse model insHEL-3A9 TCR, which is well described in studies of central tolerance. We report that thymic exosomes from HEL-mice carry the dominant HEL-peptide in complex with MHC II on their surface. Injection of thymic exosomes from HEL-mice into 3A9 TCR mice resulted in a reduction of HEL-specific thymocytes and expansion of peripheral Tregs, suggesting that thymic exosomes are important for tolerance induction. In conclusion, this thesis reports that thymic exosomes carry self-antigens and are mediators for the induction of central and peripheral tolerance.
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