Immune perturbation in patients with TGFbeta pathway defects (LYM7P.729)

Abstract

Abstract Intro: Mutations in TGFbR1, TGFbR2 and SMAD3 are associated with familial thoracic aortic aneurysms and aortic dissections (TAAD). These patients offer an opportunity to study their immune development. Methods: PBMC from TAAD (n=9) and controls (CT, n=8) were analyzed by FACS. Th1 (IFNg) and Th17 (IL17A) were determined with intracellular cytokine staining. Foxp3+ Tregs were detected with anti-Foxp3. CD19+ were analyzed for naive (IgD+CD27-), unswitched (IgD+CD27+) and switched memory (IgD-CD27+). Plasmacytoid (CD303+pDC) and myeloid (CD1c+mDC) were defined within lineage-1 negative population. Results: %CD3-CD16+NK, CD3+CD16+NKT, CD4+, CD8+ and CD4+CD45RA+ in TAAD were similar to HC. Average %CD19+ (20.8vs7.3, p=0.006) and naive B cells (81.3vs66.6, p=0.004) were higher in TAADvsCT. The unswitched were similar but the switched B cells were lower (8.6vs15.5, p=0.01). While the %Tregs were similar, there was a remarkable reduction (1/2-3 folds, p<0.05) in Foxp3 concentration based on median fluorescence intensity of Foxp3 in TAAD. There was a significant reduction of %Th17 (0.14vs0.61, p=0.01), while the Th1 were similar. %pDC (9.4vs24.1, p=0.009) and %mDC (11.4vs17.9, p=0.01) were also lower in TAAD. Conclusions: These results demonstrate the involvement of TGFbeta signaling in B cells, DCs, Th17 and Treg development. Further studies and monitoring of the clinical effects of these immunological perturbations are needed to appreciate the impact of their underlying disease.