NM_001558.4(IL10RA):c.349C>T (p.Arg117Cys)

For IL10RA c.349C>T (p.Arg117Cys), a pathogenic missense variant in the extracellular domain of the IL-10 receptor alpha chain that impairs IL-10 signaling and causes very-early-onset inflammatory bowel disease (VEO-IBD), anti-cytokine antibody therapy (infliximab/anti-TNF-alpha, ustekinumab/anti-IL-12/23) serves a critical role as bridge therapy to control intestinal inflammation before definitive curative treatment with allogeneic HSCT. While antibody therapy does not correct the underlying IL-10 signaling defect, it targets the downstream pro-inflammatory cascade (TNF-alpha, IL-12/23 axis) that drives tissue destruction when the IL-10 anti-inflammatory feedback loop is broken. Disease control with biological agents can improve nutritional status, reduce surgical complications, and optimize the patient for transplant conditioning.

Multiple case series have demonstrated that anti-TNF therapy (infliximab, adalimumab) achieves partial or complete endoscopic and clinical remission in a subset of IL10RA-deficient VEO-IBD patients (Kotlarz et al., Gastroenterology 2012; PMID:22504044; Engelhardt et al., J Allergy Clin Immunol 2013; PMID:23791516). The mechanistic rationale is that loss of IL-10 signaling removes the negative feedback on macrophage and dendritic cell pro-inflammatory cytokine production, leading to excessive TNF-alpha and IL-12/23-driven intestinal inflammation. Anti-TNF antibodies directly neutralize this excess TNF. For p.Arg117Cys, Arg117 is located in the extracellular ligand-binding domain of IL10RA and likely participates in IL-10 binding through electrostatic interactions; the cysteine substitution disrupts this contact and may also create aberrant disulfide bonds affecting receptor dimerization. ClinVar classifies this variant as Pathogenic. HSCT is the definitive curative therapy, with reported cure rates of >80% in experienced centers (Moens et al., J Clin Immunol 2023), by replacing the defective hematopoietic compartment with donor-derived immune cells capable of normal IL-10 signaling.

Anti-TNF and anti-IL-12/23 antibodies do not address the primary defect (IL-10 receptor dysfunction) and achieve only partial disease control in most IL10RA-deficient patients — complete sustained remission without HSCT is rare. Many patients become refractory to biological therapy over time, and some require colectomy for refractory colitis before transplant can be arranged. The infantile presentation (typically <2 years) means that anti-cytokine antibodies are used off-label in an extremely young patient population with limited pharmacokinetic data. Immunosuppression from anti-TNF therapy in the context of an already-dysregulated immune system (impaired IL-10-mediated immunoregulation) increases infection risk, particularly relevant in malnourished infants. The bridge-to-HSCT strategy requires timely donor identification and transplant center access, which may not be available in all settings. For p.Arg117Cys specifically, if the variant results in partially functional IL10RA with reduced (rather than absent) IL-10 signaling, the VEO-IBD phenotype may be milder and more responsive to biological therapy, potentially delaying the need for HSCT in select patients — but this requires formal functional characterization of each variant to guide management.