Background/Purpose: Yao syndrome (YAOS, #OMIM 617321), formerly known as nucleotide-binding oligomerization protein containing 2 (NOD2)-associated autoinflammatory disease, is associated with specific NOD2 mutations and affects multiple organ systems. NOD2 is an intracellular immune sensor of bacterial peptidoglycan and is critical for innate responses to infections. Mechanistic study of immune dysfunction in YAOS is very limited, but the diverse clinical manifestations are hypothesized to be driven by aberrant NOD2 signaling in innate immune cells, such as monocytes. This study aimed to define immune cell subset frequency and function in blood of YAOS patients compared to healthy controls to identify targets for novel therapeutics.

Methods: Ten adult YAOS study volunteers of European ancestry were enrolled (n=10, 80% female, mean age 36±12 at diagnosis). These patients were identified to carry NOD2 mutations by an autoinflammatory disease gene panel and exhibited a clinical phenotype consistent with YAOS. Nine healthy adult volunteers were recruited as controls (n=9, 30% female, mean age 42±16). Flow cytometric analysis of peripheral blood immune cell populations were assessed at baseline and after 16 hours of stimulation with the bacterial cell wall-derived NOD2 ligand, muramyl dipeptide (MDP), Toll-like receptor ligands (TLRLs; LPS, Pam2Cys, PolyIC), and antibodies against CD3/CD28 (αCD3/CD28) for non-specific T cell stimulation.

Results: YAOS cases exhibited higher frequency of CD3⁺ cells (64% vs. 49%; p=0.034) compared to healthy controls with similar proportions of CD4⁺ and CD8⁺ T cells in both groups. In the CD3 negative compartment, monocytes were depleted in YAOS compared to healthy controls (18% vs. 29%; p=0.032). No significant differences were observed in the frequencies of B, Natural Killer (NK), γδ T, and MAIT cells. Following αCD3/CD28 stimulation in vitro, YAOS cases demonstrated increased interferon γ – expressing CD4⁺ T (5% vs. 1%; p=0.00017), MAIT (20% vs. 10%; p=0.047), and γδ T cells (8% vs. 1%; p=0.0021). Monocytes and NK cells from patients had relatively depressed responses to MDP compared to controls, though these differences did not reach statistical significance. Immune response to TLRLs  did not differ between groups.

Conclusion: Our study shows significant alterations in innate and adaptive immunity in YAOS patients evidenced by monocyte depletion and expansion of inflammatory CD4⁺ T, MAIT, and γδ T cells. These novel findings suggest that the disease immunopathology may be driven by antigen-independent bystander T cell activation in addition to innate cellular dysfunction. Future studies will elucidate the underlying mechanisms of this immune dysregulation, which could inform targeted therapeutic strategies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammatory-t-cell-expansion-in-yao-syndrome/