Post-translationally modified T cell epitopes: immune recognition and immunotherapy

The functionality of proteins is greatly extended by a diverse array of post-translational modifications (PTMs), many of which are recognized by the immune system. Notably, a significant proportion of peptides presented to T cells by the major histocompatibility complex in vivo are post-translationally modified. Since the cellular mechanisms that introduce and control protein modifications can differ between health and disease, the associated changes in antigen presentation have the potential to alter immune responses. A number of such situations have been implicated with infection, inflammation, autoimmune disease, and cancer, and the investigation of PTMs that affect antigen recognition has provided insight in disease progression as well as raising prospects for novel approaches in immunotherapy.     

Time of injury affects urinary biomarker predictive values for acute kidney injury in critically ill,non-septic patients

Background

The predictive value of acute kidney injury (AKI) urinary biomarkers may depend on the time interval following tubular injury, thereby explaining in part the heterogeneous performance of these markers that has been reported in the literature. We studied the influence of timing on the predictive values of tubular proteins, measured before the rise of serum creatinine (SCr) in critically ill, non-septic patients.

Methods

Seven hundred adult critically ill patients were prospectively included for urine measurements at four time-points prior to the rise in serum creatinine (T?=?0, -16, -20 and -24 h). Patients with sepsis and or AKI at ICU entry were excluded. The urinary excretion of the proteins, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), which are up-regulated in the distal and proximal tubules, respectively, were measured as well as the constitutive cytoplasmatic enzymes, π- and α-glutathione-S-transferase (GST), which are released by the distal and proximal tubules, respectively.

Results

Five hundred and forty-three subjects were eligible for further analyses; however, 49 developed AKI in the first 48 h. Both NGAL (P?=?0.001 at T?=?-24 vs. non-AKI patients) and KIM-1 (P?<?0.0001 at T?=?0 vs. non-AKI patients) concentrations gradually increased until AKI diagnosis, whereas π- and α-GST peaked at T?=?-24 before AKI (P?=?0.006 and P?=?0.002, respectively vs. non-AKI patients) and showed a rapid decline afterwards. The predictive values at T?=?-24 prior to AKI were modest for π- and α-GST, whereas NGAL sufficiently predicted AKI at T?=?-24 and its predictive power improved as the time interval to AKI presentation decreased (area under the receiver operating characteristic curve; AUC?=?0.79, P?<?0.0001). KIM-1 was a good discriminator at T?=?0 only (AUC?=?0.73, P?<?0.0001).

Conclusions

NGAL, KIM-1, pi- and alpha-GST displayed unique and mutually incomparable time dependent characteristics during the development of non-sepsis related AKI. Therefore, the time-relationship between the biomarker measurements and the injurious event influences the individual test results.

     

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