Abstract
Background Protein-losing enteropathy (PLE) is a severe complication of the Fontan circulation.
There is increasing discussion about whether lymphatic dysregulation is involved as
pathomechanism of PLE. This investigation focuses on the interplay between alteration
of lymphatic cells and immunologic pathway alterations.
Methods Micro-ribonucleic acid (miRNA) expression profiling was performed in 49 patients
(n = 10 Fontan patients with PLE, n = 30 Fontan patients without PLE, and n = 9 patients with dextro-transposition of the great arteries (dTGA). miRNA pathway
analysis was performed to identify significantly enriched pathways. To determine lymphocyte
populations and subtypes multiparameter flow cytometry was used.
Results miRNAs pathway analysis of Fontan patients with PLE revealed 20 significantly changed
networks of which four of the ten largest were associated with immunologic processes.
This finding is supported by significant T cell deficiency with decreased CD4+ count
(p = 0.0002), altered CD4 +/CD8+ ratio, and significantly modified CD4+ (p < 0.0001) and CD8+ (p = 0.0002) T cell differentiation toward effector and terminal differentiated T cells
in Fontan patients with PLE. Analyses of CD4+ T cell subsets demonstrated significantly
increased frequencies of CD4+ CD25+ CD127– regulatory T cells (Treg) in Fontan patients
with PLE (p = 0.0011).
Conclusion PLE in Fontan patients is associated with severe lymphopenia, T cell deficiency,
significant alterations of T cell differentiation, and increased Treg frequency reflecting
an immune status of chronic inflammation and shortened protection against pathogens
and autoimmunity. These cellular alterations seemed to be dysregulated by several
miRNA controlled immunological pathways.
Keywords
congenital heart disease (CHD) - inflammation - systemic - genetics - genomics
