Tissue-resident memory T cells in renal autoimmune diseases

The discovery of tissue-resident memory T cells (TRM cells) reinterpreted the potential of human tissue-specific immunity. Following T cell receptor (TCR) activation and clonal expansion, effector T cells migrate to peripheral tissues where they remain long-term and differentiate to TRM cells after antigen clearance. This allows for prompt immunological responses upon antigen re-encounter. In addition to their protective properties in acute infections, recent studies have revealed that TRM cells might lead to aggravation of autoimmune diseases, such as lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). These diseases present as proliferative and crescentic glomerulonephritis (cGN), which is a life-threatening condition leading to end-stage renal disease (ESRD) if left untreated. A better understanding of renal TRM cells might lead to identifying new therapeutic targets for relapsing autoimmune diseases of the kidney. In this review, we summarize the current knowledge of renal TRM cells and discuss their potential pathophysiological roles in renal autoimmune diseases

Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis

Crescentic glomerulonephritis is mediated by inappropriate humoral and cellular immune responses toward self-antigens that may result from defects in central and peripheral tolerance. Evidence now suggests that regulatory T cells (Tregs) may be of pathophysiological importance in proliferative and crescentic forms of glomerulonephritis. To analyze the role of endogenous Tregs in a T cell-dependent glomerulonephritis model of nephrotoxic nephritis, we used ‘depletion of regulatory T cell' (DEREG) mice that express the diphtheria toxin receptor under control of the FoxP3 (forkhead box P3) gene promoter. Toxin injection into these mice efficiently depleted renal and splenic FoxP3+ Treg cells as determined by fluorescent-activated cell sorting (FACS) and immunohistochemical analyses. Treg depletion exacerbated systemic and renal interferon-γ (IFNγ) expression and increased recruitment of IFNγ-producing Th1 cells into the kidney without an effect on the Th17 immune response. The enhanced Th1 response, following Treg cell depletion, was associated with an aggravated course of glomerulonephritis as measured by glomerular crescent formation. Thus, our results establish the functional importance of endogenous Tregs in the control of a significantly enhanced systemic and renal Th1 immune response in experimental glomerulonephritis

A fetal wave of human type 3 effector gamma delta cells with restricted TCR diversity persists into adulthood

Accumulating evidence suggests that the mouse embryonic thymus produces distinct waves of innate effector gamma delta T cells. However, it is unclear whether this process occurs similarly in humans and whether it comprises a dedicated subset of innate-like type 3 effector gamma delta T cells. Here, we present a protocol for high-throughput sequencing of TRG and TRD pairs that comprise the clonal gamma delta TCR. In combination with single-cell RNA sequencing, multiparameter flow cytometry, and TCR sequencing, we reveal a high heterogeneity of gamma delta T cells sorted from neonatal and adult blood that correlated with TCR usage. Immature gamma delta T cell clusters displayed mixed and diverse TCRs, but effector cell types segregated according to the expression of either highly expanded individual V delta 1(+) TCRs or moderately expanded semi-invariant V gamma 9V delta 2(+) TCRs. The V gamma 9V delta 2(+) T cells shared expression of genes that mark innate-like T cells, including ZBTB16 (encoding PLZF), KLRB1, and KLRC1, but consisted of distinct clusters with unrelated V gamma 9V delta 2(+) TCR clones characterized either by TBX21, FCGR3A, and cytotoxicity-associated gene expression (type 1) or by CCR6, RORC, IL23R, and DPP4 expression (type 3). Effector gamma delta T cells with type 1 and type 3 innate T cell signatures were detected in a public dataset of early embryonic thymus organogenesis. Together, this study suggests that functionally distinct waves of human innate-like effector gamma delta T cells with semi-invariant V gamma 9V delta 2(+) TCR develop in the early fetal thymus and persist into adulthood

Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis

Peer reviewe

Immune-mediated glomerular diseases: new basic concepts and clinical implications

<jats:title>Abstract</jats:title><jats:p>Mafic volcanic activity is dominated by effusive to mildly explosive eruptions. Plinian and ignimbrite-forming mafic eruptions, while rare, are also possible; however, the conditions that promote such explosivity are still being explored. Eruption style is determined by the ability of gas to escape as magma ascends, which tends to be easier in low-viscosity, mafic magmas. If magma permeability is sufficiently high to reduce bubble overpressure during ascent, volatiles may escape from the magma, inhibiting violent explosive activity. In contrast, if the permeability is sufficiently low to retain the gas phase within the magma during ascent, bubble overpressure may drive magma fragmentation. Rapid ascent may induce disequilibrium crystallization, increasing viscosity and affecting the bubble network with consequences for permeability, and hence, explosivity. To explore the conditions that promote strongly explosive mafic volcanism, we combine microlite textural analyses with synchrotron x-ray computed microtomography of 10 pyroclasts from the 12.6 ka mafic Curacautín Ignimbrite (Llaima Volcano, Chile). We quantify microlite crystal size distributions (CSD), microlite number densities, porosity, bubble interconnectivity, bubble number density, and geometrical properties of the porous media to investigate the role of magma degassing processes at mafic explosive eruptions. We use an analytical technique to estimate permeability and tortuosity by combing the Kozeny-Carman relationship, tortuosity factor, and pyroclast vesicle textures. The groundmass of our samples is composed of up to 44% plagioclase microlites, > 85% of which are < 10 µm in length. In addition, we identify two populations of vesicles in our samples: (1) a convoluted interconnected vesicle network produced by extensive coalescence of smaller vesicles (> 99% of pore volume), and (2) a population of very small and completely isolated vesicles (< 1% of porosity). Computed permeability ranges from 3.0 × 10<jats:sup>−13</jats:sup> to 6.3 × 10<jats:sup>−12</jats:sup> m<jats:sup>2</jats:sup>, which are lower than the similarly explosive mafic eruptions of Tarawera (1886; New Zealand) and Etna (112 BC; Italy). The combination of our CSDs, microlite number densities, and 3D vesicle textures evidence rapid ascent that induced high disequilibrium conditions, promoting rapid syn-eruptive crystallization of microlites within the shallow conduit. We interpret that microlite crystallization increased viscosity while simultaneously forcing bubbles to deform as they grew together, resulting in the permeable by highly tortuous network of vesicles. Using the bubble number densities for the isolated vesicles (0.1-3<jats:sup>−3</jats:sup> × 10<jats:sup>4</jats:sup> bubbles per mm<jats:sup>3</jats:sup>), we obtain a minimum average decompression rate of 1.4 MPa/s. Despite the textural evidence that the Curacautín magma reached the percolation threshold, we propose that rapid ascent suppressed outgassing and increased bubble overpressures, leading to explosive fragmentation. Further, using the porosity and permeability of our samples, we estimated that a bubble overpressure > 5 MPa could have been sufficient to fragment the Curacautín magma. Other mafic explosive eruptions report similar disequilibrium conditions induced by rapid ascent rate, implying that syn-eruptive disequilibrium conditions may control the explosivity of mafic eruptions more generally.</jats:p&gt

T helper cell trafficking in autoimmune kidney diseases

CD4⁺ T cells are key drivers of autoimmune diseases, including crescentic GN. Many effector mechanisms employed by T cells to mediate renal damage and repair, such as local cytokine production, depend on their presence at the site of inflammation. Therefore, the mechanisms regulating the renal CD4⁺ T cell infiltrate are of central importance. From a conceptual point of view, there are four distinct factors that can regulate the abundance of T cells in the kidney: (1) T cell infiltration, (2) T cell proliferation, (3) T cell death and (4) T cell retention/egress. While a substantial amount of data on the recruitment of T cells to the kidneys in crescentic GN have accumulated over the last decade, the roles of T cell proliferation and death in the kidney in crescentic GN is less well characterized. However, the findings from the data available so far do not indicate a major role of these processes. More importantly, the molecular mechanisms underlying both egress and retention of T cells from/in peripheral tissues, such as the kidney, are unknown. Here, we review the current knowledge of mechanisms and functions of T cell migration in renal autoimmune diseases with a special focus on chemokines and their receptors

Single-cell biology to decode the immune cellular composition of kidney inflammation

Single-cell biology is transforming the ability of researchers to understand cellular signaling and identity across medical and biological disciplines. Especially for immune-mediated diseases, a single-cell look at immune cell subtypes, signaling, and activity might yield fundamental insights into the disease etiology, mechanisms, and potential therapeutic interventions. In this review, we highlight recent advances in the field of single-cell RNA profiling and their application to understand renal function in health and disease. With a focus on the immune system, in particular on T cells, we propose some key directions of understanding renal inflammation using single-cell approaches. We detail the benefits and shortcomings of the various technological approaches outlined and give advice on potential pitfalls and challenges in experimental setup and computational analysis. Finally, we conclude with a brief outlook into a promising future for single-cell technologies to elucidate kidney function

PLA₂R Antibody Levels and Clinical Outcome in Patients with Membranous Nephropathy and Non-Nephrotic Range Proteinuria under Treatment with Inhibitors of the Renin-Angiotensin System

<div><p>Patients with primary membranous nephropathy (MN) who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A₂ Receptor antibodies (PLA₂R-Ab) play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA₂R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA₂R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55%) patients. At study start (1.2±1.5 months after renal biopsy and time of diagnosis), 16 (48%) patients were positive for PLA₂R-Ab. A multivariate analysis showed that PLA₂R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HR = 3.66; 95%CI: 1.39–9.64; p = 0.009). Immunosuppressive therapy was initiated more frequently in PLA₂R-Ab positive patients (13 of 16 patients, 81%) compared to PLA₂R-Ab negative patients (2 of 17 patients, 12%). PLA₂R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management.</p></div