Type 1 Diabetes in STAT Protein Family Mutations: Regulating the Th17/Treg Equilibrium and Beyond
Article Figures & Tables
Figures
- Figure 1
The altered balance between Th17 and Tregs in patients with STAT3 GOF and the potential mechanisms underlying it. In the context of STAT3 GOF, an increase in IRF4 expression induction is able to drive the skewing of Th17. At the same time, TGF-β and IL-6 together with IL-21 are able to induce a similar amplification of the induction of this cell type. There are two possible ways through which STAT3 GOF could instead affect Tregs development: directly via STAT3 inhibition of FOXP3 or indirectly via SOCS3-dependent inhibition of FOXP3. R, receptor.
- Figure 2
Location of the pathogenic mutations of STAT3b. The crystal structure of STAT3b bound to double-stranded DNA (PDB code 4E68) was visualized using the software Pymol (www.pymol.org). The STAT3b chains in the homodimer are shown as light blue and cyan cartoon, the double-stranded DNA is colored orange. The location of the mutations in the structure is shown with red (Glu415Lys and Asn646Lys, affecting DNA binding), yellow (Arg152Trp, affecting the helical region), green (Lys392Arg, whose effect is at the present unclear), and pink (Thr716Met, modifying the dimerization surface).
- Figure 3
Models linking STAT1 GOF to Th17 deficiency. In the intrinsic model (A), STAT1 GOF inhibits STAT3 activity via SOCS3 and consequently impairs Th17 development. In the T-cell extrinsic model (B), inhibition of Th17 occurs in trans, via PD-L1 overexpression in neighboring cells. It is currently unknown how a reduction in Th17 cells may increase susceptibility to T1D. R, receptor.
Tables
- Table 1
Cases of T1D in patients with STAT3 GOF mutations currently described in the literature
Patient STAT3 mutation TID HLA type Age at diagnosis (weeks) Concomitant manifestations Islet cell–specific AAbs Th17/Treg alteration Reference Patient 1 p.Thr716Met DRB1*03-DQB1*02/DRB1*03-DQB1*02 (high risk) 2 Celiac disease; primary hypothyroidism Positive Not described Flanagan et al. (30) (patient 2 also presented by Haapaniemi et al. [31]) Patient 2 p.Lys392Arg DRB1*04-DQB1*0302 (high risk) 0 Celiac disease; desquamative interstitial pneumonitis; T cell large granular lymphocyte leukemia Positive Yes Patient 3 p.Asn646Lys DQA1*01-B1*05/DQA1*01 (low risk) 3 Eczema Negative Not described Patient 4 p.Asn646Lys DQA1*03-B1*03:02/A1*01-B1*06:02 (low risk) 43 Eczema; juvenile arthritis Positive Not described Patient 5 p.Arg152Trp Not described Not described Lymphoproliferation; recurrent herpes zoster; lung nodules Not described Yes Milner et al. (32) Patient 6 p.Glu415Lys Not described Not described Enteropathy; achalasia; atopic dermatitis; lymphoproliferation; lung nodules; short stature; recurrent urinary tract infections Not described Yes The four patients described by Flanagan et al. (30) presented with early-onset T1D with positive antibody detection in patients 1, 2, and 4. Patients 3 and 4 developed diabetes in a context of low-risk HLA predisposition, where patient 3 was also negative in autoantibody screening. In light of these findings, we can hypothesize a fundamental role of cellular-mediated immunity in T1D pathogenesis, at least in the context of STAT3 GOF mutations.
- Table 2
Summary showing the altered Th17/Tregs equilibrium described in STAT1 GOF and STAT3 GOF
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