Emergent early markers of renal progression in autosomal-dominant polycystic kidney disease patients: implications for prevention and treatment

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common single cause of end-stage renal disease after diabetes, hypertension and glomerulonephritis. The clinical course of ADPKD is highly variable. Even with optimal care and therapy monitoring, currently the progression of ADPKD is slowed but not stopped. Newer treatments will no doubt become available in the future, but their side effect profiles will always need to be considered. Therefore, markers to distinguish ADPKD patients with a poor versus a good prognosis will be helpful. Several risk factors influencing kidney disease progression in ADPKD have been identified in the current era. The present review will discuss the spectrum of early markers of ADPKD renal disease progression. Specifically, the volume of total kidney, hypertension, glomerular hyperfiltration, renal blood flow, microalbuminuria, uric acid, and urinary molecular markers will be discussed. On this background, implications for the prevention and treatment of kidney disease progression in ADPKD are also discussed.     

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94

Peptide selectivity is a feature of inhibitory receptors for MHC class I expressed by natural killer (NK) cells. CD94–NKG2A operates in tandem with the polymorphic killer cell Ig-like receptors (KIR) and Ly49 systems to inhibit NK cells. However, the benefits of having two distinct inhibitory receptor–ligand systems are not clear. We show that noninhibitory peptides presented by HLA-E can augment the inhibition of NKG2A⁺ NK cells mediated by MHC class I signal peptides through the engagement of CD94 without a signaling partner. Thus, CD94 is a peptide-selective NK cell receptor, and NK cells can be regulated by nonsignaling interactions. We also show that KIR⁺ and NKG2A⁺ NK cells respond with differing stoichiometries to MHC class I down-regulation. MHC-I–bound peptide functions as a molecular rheostat controlling NK cell function. Selected peptides which in isolation do not inhibit NK cells can have different effects on KIR and NKG2A receptors. Thus, these two inhibitory systems may complement each other by having distinct responses to bound peptide and surface levels of MHC class I.Natural killer (NK) cells play an important role in the immune response to viral infections and cancer. Their responses are determined by signals integrated from activating and inhibitory receptor–ligand interactions (1). In many situations inhibitory signals dominate activating signals. Therefore, releasing NK cells from inhibition is an important mechanism of enhancing their response to target cells. Inhibitory interactions are mediated by receptors for self-MHC class I. Most species have at least two discrete gene families of inhibitory receptors for MHC class I: the CD94–NKG2A C-type lectin-like receptor system and either the related Ly49 family of receptors or the unrelated killer cell Ig-like receptors (KIR) (2). The KIR family is important in humans and other primates, having undergone extensive diversification under positive selection. In contrast, the CD94–NKG2A system has remained relatively well conserved across the species with orthologous genes in primates and a closely related functional homolog in rodents (3, 4). Consistent with the coevolution of these families and their MHC class I ligands, KIR bind polymorphic MHC class I, HLA-A, -B, and -C molecules, whereas CD94–NKG2A binds the conserved oligomorphic HLA-E molecule or the rodent homolog Qa-1 (5, 6).Both receptor families are important in the immune response to viral infections. KIR are genetic determinants in the outcome of both HIV and hepatitis C virus (HCV) infection (7–10). Expression of CD94–NKG2A is up-regulated on NK cells in HIV and HCV infection and in the latter has been associated with a poor response to treatment (11, 12). Furthermore NKG2A⁺ NK cell clones lyse vaccinia-infected targets (13), and CD94 is important in clearing mouse pox infection (14). Both KIR and CD94–NKG2A respond to MHC class I down-regulation. One hypothesis is that the KIR have evolved to recognize MHC class I-specific down-regulation (15). However, because the majority of MHC class I leader peptides bind HLA-E and are inhibitory for NKG2A, the CD94–NKG2A system also is able to recognize down-regulation of most MHC class I alleles. It has been shown that KIR⁺ NK cells can be modulated by changes in the peptide bound by MHC class I, which confers additional functionality on the KIR system (16–18). In particular peptide antagonism is a potent mechanism for activating KIR⁺ NK cells (19, 20). The CD94–NKG2A receptor also is peptide selective, with receptor binding being particularly influenced by residues 5, 6, and 8 of the peptide bound by HLA-E (21–23). These residues interact primarily with the nonsignaling CD94 moiety, which occupies the majority of the HLA-E–binding interface. CD94–NKG2A seems to be a target for viral escape, with peptides derived from CMV, HCV, HIV, and EBV binding HLA-E and subsequently inhibiting NK cells (24–27). Viral peptides that inhibit at KIR also are identifiable (28), but their relevance likely is limited to the subset of individuals who have the relevant peptide-binding MHC class I allele. Understanding differences in how the KIR and NKG2 systems respond to peptide may be important for interpreting their roles in the immune response to viral infections and tumors. Therefore we explored how HLA-E–bound peptide can influence NK cell reactivity.     

Lymphocytes which differentiate in an allogeneic thymus

Nude mice which have been grafted with an allogeneic H-2-incompatible thymus are frequently specifically tolerant to skin grafts from the thymus donor strain. The evidence presented here indicates that both clonal deletion and peripheral suppressor cells play a part in maintaining this tolerance.