Approaching a diagnostic point-of-care test for pediatric tuberculosis through evaluation of immune biomarkers across the clinical disease spectrum
SCIENTIFIC REPORTS
Authors: Jenum, Synne; Dhanasekaran, S.; Lodha, Rakesh; Mukherjee, Aparna; Saini, Deepak Kumar; Singh, Sarman; Singh, Varinder; Medigeshi, Guruprasad; Haks, Marielle C.; Ottenhoff, Tom H. M.; Doherty, Timothy Mark; Kabra, Sushil K.; Ritz, Christian; Grewal, Harleen M. S.
Abstract
The World Health Organization (WHO) calls for an accurate, rapid, and simple point-of-care (POC) test for the diagnosis of pediatric tuberculosis (TB) in order to make progress "Towards Zero Deaths". Whereas the sensitivity of a POC test based on detection of Mycobacterium tuberculosis (MTB) is likely to have poor sensitivity (70-80% of children have culture-negative disease), host biomarkers reflecting the on-going pathological processes across the spectrum of MTB infection and disease may hold greater promise for this purpose. We analyzed transcriptional immune biomarkers direct ex-vivo and translational biomarkers in MTB-antigen stimulated whole blood in 88 Indian children with intrathoracic TB aged 6 months to 15 years, and 39 asymptomatic siblings. We identified 12 biomarkers consistently associated with either clinical groups "upstream" towards culture-positive TB on the TB disease spectrum (CD14, FCGR1A, FPR1, MMP9, RAB24, SEC14L1, and TIMP2) or "downstream" towards a decreased likelihood of TB disease (BLR1, CD3E, CD8A, IL7R, and TGFBR2), suggesting a correlation with MTB-related pathology and high relevance to a future POC test for pediatric TB. A biomarker signature consisting of BPI, CD3E, CD14, FPR1, IL4, TGFBR2, TIMP2 and TNFRSF1B separated children with TB from asymptomatic siblings (AUC of 88%).
Fc gamma Receptor I-Coupled Signaling in Peripheral Nociceptors Mediates Joint Pain in a Rat Model of Rheumatoid Arthritis
ARTHRITIS & RHEUMATOLOGY
Authors: Liu, Fan; Shen, Xinhua; Su, Si; Cui, Huan; Fang, Yehong; Wang, Tao; Zhang, Lianfeng; Huang, Yuguang; Ma, Chao
Abstract
Objective. Rheumatoid arthritis (RA) is often accompanied by joint pain and inflammation. Previous studies have demonstrated that functional Fc gamma receptor I (Fc gamma RI) is expressed in dorsal root ganglion (DRG) neurons and might contribute to pain in rodent models of antigen-induced arthritis (AIA). This study was undertaken to elucidate the roles of nociceptive neuronal Fc gamma RI-coupled signaling in the development of joint pain in AIA. Methods. RNA sequencing was used to investigate the transcriptome profile changes in the DRG in a rat model of AIA. A primary sensory neuron-specific Fcgr1a conditional-knockout (CKO) rat was established by crossing rats carrying a loxP-flanked Fcgr1a with a Pirt-specific Cre line. Behavioral, morphologic, and molecular studies were conducted to evaluate the differences between wild-type (WT) and CKO rats after AIA. Results. We first showed that AIA induced a transcriptome profile change in the DRG, involving a number of key proteins downstream of the Fc gamma RI-related signaling pathway. Compared to the WT rats, both the IgG immune complex-induced acute pain and AIA-induced pain were alleviated in CKO rats. Moreover, the AIA-induced activation of Fc gamma RI-related signaling in DRGs was significantly reduced in CKO rats. In addition, CKO rats showed attenuated joint swelling after AIA. Conclusion. These results indicate that activation of Fc gamma RI-coupled signaling in DRG neurons plays an important role in the development of joint pain in AIA. Our findings may provide novel insights into the interactions between the peripheral nervous system and the immune system in pathologic conditions and might suggest potential biotargets for the treatment of pain in RA.