Mo1797 Cigarette Smoke is an Environmental Factor That Reduces Innate Immune Functions Especially in Individuals With the CD-Associated Risk Variant ATG16L1-T300A

Abstract

Chronic granulomatous disease (CGD) is an X-linked or autosomal recessive genetic defect resulting in defective microbial killing and recurrent bacterial and fungal infections or inflammation, mainly in the respiratory and gastrointestinal tracts. Symptoms and findings of CGD overlap with inflammatory bowel diseases (IBD), and anti-microbial serologic responses were reported. However, in Crohn's disease (CD), serologic responses reflect loss of tolerance towards microorganisms and glycans. Anti-glycan antibodies (AGA) directed against the glycans laminaribioside, chitobioside, mannobioside and mannan further characterize CD patients. Aim: To assess the titers and prevalence of AGA in CGD patients. Methods: Serum samples were collected from well characterized CGD patients, patients with other innate immune defects (hyper IgE/ Hermanski-Pudlak syndrome, HIE/HPS), CD and healthy controls. AGA were assessed using ELISA (IBDx, Glycominds Ltd, Israel) and compared to previously determined serologic responses against the microbial antigens OmpC, I2, and CBir1 performed on the same serum samples. Results: Sixty one CGD patients (48 males, age at sample collection 24.4±1.4 years, 69% x-linked 91 phox mutation, 36% with colitis), 7 patients with HIE/HPS , 397 CD patients and 12 healthy controls were recruited. gASCA titers and prevalence were significantly higher in CGD, compared to HIE/HPS (129±5 EU, 95% vs. 35±12EU, 43%, p<0.001) and CD patients (p<0.001). Interestingly, AGA prevalence in CGD was roughly half (34-41%) and titer increase above cut-off was lower, compared to the prevalence reported for OmpC, I2 and CBir1 (69-75%) and their respective titer increases in the same samples. Two or more positive AGA were detected in 67% CGD, 22% CD, 6% HIE/HPS patients, and 7% healthy controls, respectively. gASCA was significantly lower, while ANCA higher, in CGD patients younger, compared to older than 18 years (p= 0.02, p=0.056, respectively). No differences in the prevalence of AGA were observed whether CGD patients had IBD (n=22) or not. Conclusions: CGD patients have a significantly higher serologic response against microorganisms and glycans compared to CD and other innate immune defects controls. Serologic responses against ASCA increase with age suggesting that the mechanism may be recurrent exposure. The discordant prevalence and titers of the antibody response towards microbial vs. glycan antigens in CGD may suggest lower immunogenicity of the glycans. The finding of AGA characteristic of CD in CGD, supports the notion that an innate immune defect underlies CD pathogenesis.