Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy

Abstract

Transforming growth factor (TGF)-β1 (encoded by TGFB1) is the prototypic member of the TGF-β family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis. Following its discovery , enormous interest and numerous controversies have emerged about the role of TGF-β in coordinating the balance of pro- and anti-oncogenic properties, pro- and anti-inflammatory effects , or pro- and anti-fibrinogenic characteristics . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-β1-LAP complex, which is suggestive of perturbed bioavailability of TGF-β1. Our study shows that TGF-β1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

“…Complex dysregulation of transforming growth factor beta as a result of autosomal dominant mutations in TGFBR1 and TGFBR2 (Loeys‐Dietz syndrome) cause a syndrome with a variety of phenotypes including skeletal involvement, arterial abnormalities and immunological abnormalities, IBD, and encelopathy . Recently, biallelic LOF mutations in the TGFB1 gene encoding TGF‐β1 have been described in patients with central nervous system disease including epilepsy, brain atrophy, and posterior leukoencephalopathy, and severe VEO‐IBD . The mutations in TGFB1 seemingly impaired the bioavailability of TGF‐β1.…”

Zero tolerance! A perspective on monogenic disorders with defective regulatory T cells and IBD‐like disease

“…Most recently, patients with TGF‐β1 deficiency have been described . These patients had severe IBD presenting within the first few months of life.…”

“…TGF‐β1 is a pleiotropic cytokine with functions in regulating developmental processes and immune responses . Besides IBD, the TGF‐β1 deficient patients also presented with disease of the central nervous system (CNS), most notably, brain atrophy, indicating a crucial and nonredundant role of TGF‐β1 not only in gut homeostasis but also in the CNS . TGF‐β1 plays a critical role in the differentiation and maintenance of Treg cells, especially Tregs generated in the gut .…”

“…Most recently, patients with TGF-β1 deficiency have been described. 60 These patients had severe IBD presenting within the first few months of life. TGF-β1 is a pleiotropic cytokine with functions in regulating developmental processes and immune responses.…”

“…61 Besides IBD, the TGF-β1 deficient patients also presented with disease of the central nervous system (CNS), most notably, brain atrophy, indicating a crucial and nonredundant role of TGF-β1 not only in gut homeostasis but also in the CNS. 60 TGF-β1 plays a critical role in the differentiation and maintenance of Treg cells, especially Tregs generated in the gut. [61][62][63][64] Tgf-β1 knockout mice have significantly reduced peripheral Treg cell numbers and develop a lethal lymphoproliferative autoimmune disease resembling that of Foxp3-deficient mice.…”