Rheumatoid arthritis associated with a cytotoxic cell leukemia is characterized by enhanced reactivity to citrullinated antigens

Abstract T cell large granular lymphocyte leukemia (T-LGLL) is characterized by clonal expansion of cytotoxic T cells and neutropenia. Compared to 1% of the general population, about 25% of T-LGLL patients develop rheumatoid arthritis (RA), an autoimmune disease characterized by anti-citrullinated protein antibodies (ACPAs). To investigate the autoimmune response in patients with both T-LGLL and RA (T-LGLL/RA), we analyzed their ACPA positivity and specificity using anti-CCP ELISA (n=30 for T-LGLL/RA and T-LGLL; n=150 for RA) and multiplex array (n=26 per group), respectively. We found that anti-CCP positivity was enriched in patients with T-LGLL/RA (90%) compared to those with RA alone (75%; p=0.09), or T-LGLL alone (33%; p<0.0001). This was supported by multiplex serological profiling of reactivity to 51 individual RA autoantigens, which demonstrated that T-LGLL/RA patients are more responsive to citrullinated (cit)-antigens. T-LGLL/RA patients were overrepresented (61%) in a cluster of highly reactive individuals compared to patients with RA (39%) or T-LGLL alone (0%), and recognized a higher number of cit-antigens than patients with either disease alone: 11.7 vs. 5.8 for RA alone (p=0.2135) and 2.4 for T-LGLL alone (p<0.0001). Among specific antigens, recognition of a cit-clusterin and a cit-fibrinogen alpha peptide were higher in patients with T-LGLL/RA than RA alone (p=0.0253 and 0.0507, respectively). Our results show that T-LGLL/RA patients have more robust anti-CCP responses and recognize a wider diversity of citrullinated RA autoantigens than patients with RA or T-LGLL alone. Investigating immune responses in T-LGLL/ RA, which may consist of an extreme form of RA, may provide insight into RA pathogenesis. This research was funded by NIH/NIAMS R01-AR079404.