Islet autoantibodies confer increased risk of CD-related autoimmunity
Having both type 1 diabetes (T1D) and coeliac disease (CD) autoimmunity in early childhood appears to be more common than expected, with the development of islet autoantibodies (IAs) conferring a significant risk of subsequent tissue transglutaminase autoantibodies (tTGAs), according to data from the TEDDY* study.
Of note is that the overlap cannot be fully explained by demographic factors and genetic risk loci, indicating that shared environmental or pathophysiological mechanisms may contribute to the co-occurrence of T1D and CD autoimmunity.
“Our results support the notion that children found to have IAs (for example, through family screening or population-based prediction) should be screened for tTGAs, as is the practice for T1D children,” the investigators said.
In the study, the investigators followed 5,891 infants with high-T1D–risk HLA antigen genotypes for a median duration of 66 months. They performed full autoantibody characterization, evaluating the development of persistent IAs and tTGAs, as well as each clinical disease, quarterly from 3 to 48 months of age and semiannually thereafter.
Over 32,454 person-years of observation, T1D was identified in 130 out of 457 (28.5 percent) children who tested positive for IAs compared with eight out of 5,434 (0.15 percent) of those who tested negative. Meanwhile, CD developed in 321 out of 898 (35.8 percent) of children who tested positive for tTGAs compared with two out of 4,993 (0.04 percent) of those who tested negative. IAs appeared in 367 children, tTGAs in 808 and both autoantibodies in 90. [Pediatrics 2017;doi:10.1542/peds.2017-1305]
“IAs usually, but not always, appeared earlier than tTGAs,” the investigators noted.
In an adjusted Cox proportional hazards model, IAs preceding tTGAs was associated with an elevated risk of developing tTGAs (hazard ratio [HR], 1.48; 95 percent CI, 1.15 to 1.91). On the other hand, a reverse relationship where tTGAs preceding IAs increased the risk of subsequent IAs was not observed (HR, 1.12; 0.75 to 1.67).
Factors significantly associated with greater co-occurrence of T1D and CD autoimmunity included a T1D family history (HR, 2.80), the presence of HLA-DR3/4 (HR, 1.94) and single-nucleotide polymorphism rs3184504 at SH2B3 (HR, 1.53).
“However, [the] observed co-occurrence was not fully accounted for by all analysed factors,” the investigators explained. “If pre-existing T1D autoimmunity triggers CD autoimmunity, a possible mechanism might be coexpression of antigens from both diseases in the same anatomic location… Inflammation in islets could thus lead to an anti-tTG immune response in adjacent lymph nodes, thereby promoting CD autoimmunity.”
Other prime candidates said to influence CD risk are ingested gluten and gut microbes. In TEDDY, however, age at gluten introduction was not significantly associated with tTGA. Furthermore, not all researchers agree regarding the involvement of gut bacterial microflora in both CD and T1D, and such relationships are understandably complicated. [Pediatrics 2015;135:239–245; Int Rev Immunol 2011;30:207–218; PLoS One 2011;6(10):e25792]
“Elucidation of relevant mechanisms will require additional studies of local immune responses, as well as common exposures (eg, gluten and microbial infections), within and outside of the TEDDY Study,” the investigators said.
In an accompanying editorial, Drs Christine Ferrara and Stephen Gitelman agreed. [Pediatrics 2017;doi:10.1542/peds.2017-2424]
“[While] the current TEDDY study contributes to the hypothesis that that initial autoimmunity triggered against one organ may potentiate additional autoimmune diseases, future studies directed to understand the risk factors and mechanism for the initial autoimmune hit [are warranted],” they said.
The resulting data from these additional studies are particularly important in that they “may pinpoint modifiable novel drug targets with the potential to prevent one or more autoimmune diseases,” Ferrara and Gitelman added.
*The Environmental Determinants of Diabetes in the Young