Title: Patients with Rheumatoid Arthritis have Impaired Candida albicans Specific Th17 Responses but Preserved Oral Candida albicans Protective Immunity
Shrinivas Bishu1, EE Wern Su1, Erich Wilkerson1, Daniel Goudeau1, Kelly Reckley1, Sarah Gaffen1 and Marc C. Levesque1
Background/Purpose: Rheumatoid arthritis (RA) patients are susceptible to infections, even after controlling for the effects of medications. Recent data suggest an important role for the IL-17 producing CD4+ Th17 cell subset in the pathogenesis of RA. Development of Th17 cells is dependent on TNFa, IL-6 and T cell co-stimulation, targets for current biologic therapies for RA. In humans, Th17 cells and IL-17 are necessary for immunity to the commensal fungus Candida albicans, and response to biologics in RA is associated with reductions in Th17 cells. There is little published data on Candida albicans specific responses in RA. Therefore, our aim was to assess Candida albicans specific Th17 responses in RA and to determine the effect of biologic therapies on Candida albicans specific Th17 responses.
Methods: Subjects for this study were recruited from the University of Pittsburgh Rheumatoid Arthritis Comparative Effectiveness Registry (RACER). We used flow cytometry to compare the fraction of peripheral blood Th17 and Th1 cells between healthy controls (n= 23) and RA subjects (n=48). To assess C. albicans specific peripheral blood Th17 responses and capacity for Th17 differentiation, we used ELISA to determine IL-17A production from peripheral blood mononuclear cells (PBMCs) cultured for 5 days from healthy controls (n=10) and RA subjects (n=37). PBMC were co-cultured with either heat-killed C. albicans (HKC) or Th17 polarizing cytokines. Th17 effector responses were determined by measuring oral C. albicans colonization and candidacidal killing using saliva collected from healthy control and RA subjects. Healthy control and RA subject data were compared using Mann-Whitney U tests.
Results: Patients with RA had significantly elevated production of IL-17A during PBMC culture without HKC or cytokines as compared to healthy control PBMC (p=0.02). However, IL-17A production by RA PBMC during co-culture with HKC was significantly diminished compared to healthy control PBMC (p=0.006) despite equal production of IL-17A during PBMC co-culture with Th17 differentiating cytokines (p=0.91). The C. albicans specific peripheral blood Th17 defect was associated with a higher propensity towards oral colonization with C. albicans of RA subjects compared to healthy controls (p=0.04), although RA subjects had preserved salivary candidacidal killing capacity compared to controls (p=0.82). Furthermore, the C. albicans specific defects were not associated with differences between RA and control subjects in either circulating Th17 cell numbers (p=0.07) or the distribution of Th17 cells in the CD161+ (p=0.82) and CD45RO+ (memory) (p=0.37) compartments. There were no differences in C. albicans specific responses in subgroups of RA subjects on oral DMARDs vs. biologics.
Conclusions: We found that despite increased basal IL-17A production by RA PBMC and a preserved ability to respond to Th17 inducing cytokines, RA patients have demonstrable impairments in C. albicans specific T cell responses and increased oral colonization with C. albicans. Fortunately, biologic therapy (as compared to oral DMARD therapy) did not appear to impact C. albicans specific responses.