Innate immune responses and type 1 diabetes: A role for a long non-coding RNA?

Introduction: Pattern recognition receptors (PRRs) act as early sensors of microbial pathogens, but accumulating evidence indicates that PRRs also play an important role in autoimmunity. In particular, manipulation of toll-like receptors (TLRs) in the non-obese diabetic (NOD) mouse strain alters the onset of type 1 diabetes (T1D). We have identified a novel gene (Apics), for which sequence variation is associated with T1D incidence in NOD mice. The molecular function of Apics is currently unknown, but we have shown that its expression is upregulated by TLR activation in immune cell subsets. We therefore hypothesized that Apics plays a role in regulating TLR-mediated immune responses that affect the development of T1D pathogenesis in NOD mice.

Methods and Results: Bioinformatic and RT-PCR analyses indicate that Apics consists of 5 exons that are alternatively spliced into 2 transcripts, which do not encode any known protein domains nor display features of a microRNA, suggesting that Apics may encode a functional long non-coding RNA. To determine the molecular function of this novel gene, we established an Apics-deficient mouse strain and discovered that Apics-deficient immune cells, similar to NOD immune cells, exhibit altered cytokine production in response to TLR activation, as measured by a cytokine bead array. Hence, we have subsequently named this gene Apics for Attenuator of PRR-Induced Cytokine Secretion.

Conclusion: These results suggest that genetic variation for Apics, a long non-coding RNA, affects TLR-mediated innate immune responses that contribute to T1D pathogenesis in NOD mice.