Isotype specific antibody responses to Mycobacterium Avium subspecies Paratuberculosis antigens are associated with the use of biological therapy in Inflammatory Bowel Disease

BACKGROUND: The role of Mycobacterium avium subspecies paratuberculosis (MAP) in inflammatory bowel disease (IBD), especially Crohn's disease (CD) is controversial due conflicting results, lack of reproducibility and standardized tests. The current study focuses on the role of MAP in disease progression and genetic susceptibility as MAP is likely one of many factors involved in the complex pathogenesis of IBD, potentially affecting a subgroup depending on genetic susceptibility. METHODS: Serum from 812 patients was evaluated with seven immunoglobulin (Ig) isotype-specific serology tests assessing humoral response to three different MAP antigens. For each of these in total 21 tests, the intra-assay and inter-assay coefficients were used to evaluate test accuracy. Reliable assays were subsequently analyzed in relation to disease characteristics and need for biological therapy/surgery. Genome wide genotyping was available for all participants. Genetic determinants of humoral response to MAP antigens were evaluated using genome-wide association analysis and polygenic risk scores (PRS). RESULTS: High IgA or IgM response to MAP2609 was associated with increased use of biological therapy in CD and UC (odds ratio 2.69; 95% confidence interval 1.44-5.01; 2.60, 1.46-4.64, respectively). No associations were seen for risk of surgery (p-values>0.29). We could not identify genetic determinants nor polygenic risk scores for MAP response with genome-wide significance. CONCLUSIONS: Extensive assays for serological response to MAP were evaluated using stringent criteria for reliability. Increased IgA and IgM response to MAP antigens was seen in patients exposed to biological therapy, while no genetic determinants underlying this humoral response were found