Low Percentage of Signal Regulatory Protein α/β+ Memory B Cells in Blood Predicts Development of Anti-drug Antibodies (ADA) in Adalimumab-Treated Rheumatoid Arthritis Patients

An important goal for personalized treatment is predicting response to a particular therapeutic. A drawback of biological treatment is immunogenicity and the development of antibodies directed against the drug [anti-drug antibodies (ADA)], which are associated with a poorer clinical outcome. Here we set out to identify a predictive biomarker that discriminates rheumatoid arthritis (RA) patients who are more likely to develop ADA in response to adalimumab, a human monoclonal antibody against tumor necrosis factor (TNF)α. By taking advantage of an immune-phenotyping platform, LEGENDScreen™, we measured the expression of 332 cell surface markers on B and T cells in a cross-sectional adalimumab-treated RA patient cohort with a defined ADA response. The analysis revealed seven differentially expressed markers (DEMs) between the ADA+ and ADA− patients. Validation of the DEMs in an independent prospective European cohort of adalimumab treated RA patients, revealed a significant and consistent reduced frequency of signal regulatory protein (SIRP)α/β-expressing memory B cells in ADA+ vs. ADA− RA patients. We also assessed the predictive value of SIRPα/β expression in a longitudinal RA cohort prior to the initiation of adalimumab treatment. We show that a frequency of < 9.4% of SIRPα/β-expressing memory B cells predicts patients that will develop ADA, and consequentially fail to respond to treatment, with a receiver operating characteristic (ROC) area under the curve (AUC) score of 0.92. Thus, measuring the frequency of SIRPα/β-expressing memory B cells in patients prior to adalimumab treatment may be clinically useful to identify a subgroup of active RA subjects who are going to develop an ADA response and not gain substantial clinical benefit from this treatment

The cellular amount of the common γ-chain influences spontaneous or induced cell proliferation

Mutations of the IL2RG encoding the common γ-chain (γc) lead to the X-linked SCID disease. Gene correction through ex vivo retroviral transduction restored the immunological impairment in the most of treated patients, although lymphoproliferative events occurred in five of them. Even though in two cases it was clearly documented an insertional mutagenesis in LMO2, it is conceivable that γc could have a role per se in malignant lymphoproliferation. The γc is a shared cytokine receptor subunit, involved also in growth hormone (GH) receptor signaling. Through short interfering RNA or using X-linked SCID B lympho-blastoid cell lines lacking γc, we demonstrate that self-sufficient growth was strongly dependent on γc expression. Furthermore, a correlation between γc amount and the extent of constitutive activation of JAK3 was found. The reduction of γc protein expression also reduced GH-induced proliferation and STAT5 nuclear translocation in B lymphoblastoid cell lines. Hence, our data demonstrate that γc plays a remarkable role in either spontaneous or GH-induced cell cycle progression depending on the amount of protein expression, suggesting a potential role as enhancing cofactor in lymphoproliferation. Copyright © 2009 by The American Association of Immunologists, Inc