[Renal manifestations in connective tissue diseases]. / Nierenbeteiligung bei Kollagenosen.

Connective tissue diseases (CTD) comprise a group of inflammatory systemic diseases that can affect various organs. Kidney involvement is frequently associated with significant irreversible damage and often before patients become symptomatic. Screening tests of blood and urine as well as clinical vigilance are therefore essential for all CTDs with possible renal involvement. A kidney biopsy is the gold standard for the diagnosis, prognosis and treatment decisions. A common and severe organ involvement in systemic lupus erythematosus (SLE) is glomerulonephritis (GN), also collectively referred to as lupus nephritis (LN). If left untreated LN often leads to end-stage renal failure. The treatment depends on the clinical parameters and histopathology of the renal involvement. Mycophenolate mofetil and cyclophosphamide are potent but nonspecific immunosuppressants which have been available for many years. Recently, new substances specific for LN have also been approved for the first time. Kidney involvement in Sjogren's syndrome has been far less studied. In studies the frequency of renal involvement is still unclear and ranges from 5% to 33%. Tubulointerstitial nephritis (IN) is the typical form of renal involvement which clearly differs from GN in its clinical presentation. Recommendations for treatment are based exclusively on retrospective studies. A renal crisis in systemic scleroderma (SSc) is a rare but feared complication with a high mortality. An antiphospholipid syndrome (APS) nephropathy (APSN) can occur during CTD. These entities are vasculopathies and often thrombotic microangiopathies, which clearly differ from GN and IN in terms of pathophysiology, clinical features and treatment. This article provides an overview of the diversity of the most important renal manifestations of CTDs.

[Sarcoidosis as prime example of a granulomatous disease]. / Sarkoidose als Paradebeispiel einer granulomatösen Erkrankung.

Sarcoidosis is the most frequent immunologically related granulomatous disease and can serve as a model for understanding diseases within this category. The evidence on the diagnostics and treatment is so far limited. It is therefore all the more important that two new and significant guidelines on diagnosis and treatment of sarcoidosis were published during the last 2 years. Additionally, there were more new publications, which were considered for this review article. In this context, this review article provides a current update and overview of sarcoidosis. Pathophysiologically, there is an increasing understanding of the complex processes and interactions involved in the inflammatory processes and granuloma formation. The probability of a diagnosis of sarcoidosis is determined by compatible histology, the exclusion of differential diagnoses and if possible evidence of a multiorgan manifestation. The clinical course is variable and ranges from an asymptomatic manifestation to severe life-threatening organ failure. The most frequently affected organ are the lungs. Pulmonary fibrosis is the most severe form and is also decisive for mortality. An increasing focus is on the extrapulmonary organ manifestations, in particular, cardiac, hepatosplenic, gastrointestinal, renal, ocular and neurological involvement. Treatment, which consists primarily of immunosuppression, should be initiated in cases of organ-threatening or quality of life-impairing activity of the disease. Additional organ-specific management must also be evaluated. In cases of organ failure transplantation should be considered. Due to the limited evidence especially for the treatment of multiorgan sarcoidosis, when possible, patients with this disease should be included in clinical trials.

Antigen Cross-Presentation by Murine Proximal Tubular Epithelial Cells Induces Cytotoxic and Inflammatory CD8+ T Cells.

Immune-mediated glomerular diseases are characterized by infiltration of T cells, which accumulate in the periglomerular space and tubulointerstitium in close contact to proximal and distal tubuli. Recent studies described proximal tubular epithelial cells (PTECs) as renal non-professional antigen-presenting cells that stimulate CD4+ T-cell activation. Whether PTECs have the potential to induce activation of CD8+ T cells is less clear. In this study, we aimed to investigate the capacity of PTECs for antigen cross-presentation thereby modulating CD8+ T-cell responses. We showed that PTECs expressed proteins associated with cross-presentation, internalized soluble antigen via mannose receptor-mediated endocytosis, and generated antigenic peptides by proteasomal degradation. PTECs induced an antigen-dependent CD8+ T-cell activation in the presence of soluble antigen in vitro. PTEC-activated CD8+ T cells expressed granzyme B, and exerted a cytotoxic function by killing target cells. In murine lupus nephritis, CD8+ T cells localized in close contact to proximal tubuli. We determined enhanced apoptosis in tubular cells and particularly PTECs up-regulated expression of cleaved caspase-3. Interestingly, induction of apoptosis in the inflamed kidney was reduced in the absence of CD8+ T cells. Thus, PTECs have the capacity for antigen cross-presentation thereby inducing cytotoxic CD8+ T cells in vitro, which may contribute to the pathology of immune-mediated glomerulonephritis.

The Amphiregulin/EGFR axis protects from lupus nephritis via downregulation of pathogenic CD4+ T helper cell responses.

Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immuno-pathogenesis. Lupus nephritis (LN) is a frequent and difficult to treat complication, which causes high morbidity and mortality. The multifunctional cytokine amphiregulin (AREG) has been implicated in SLE pathogenesis, but its function in LN currently remains unknown. We thus studied the model of pristane-induced LN and found increasing renal and systemic AREG expression during the course of disease. Importantly, renal injury was significantly aggravated in the absence of AREG, revealing a net anti-inflammatory role. Analyses of immune responses showed dual effects. On the one hand, AREG enhanced activation of pro-inflammatory myeloid cells, which however did not play a major role for the course of LN. More importantly, on the other hand, AREG strongly suppressed pathogenic cytokine production by T helper effector cells. This effect was more general in nature and could be reproduced in response to antigen immunization. Since AREG has been postulated to downregulate T cell responses via enhancing Treg suppressive capacity, we followed up on this aspect. Interestingly, however, in vitro studies revealed potential direct and Treg independent effects of AREG on T helper effector cells. In favor of this notion, we found significantly enhanced T cell responses and consecutive aggravation of LN, only if epidermal growth factor receptor (EGFR) signaling was abrogated in total T cells, but not if the EGFR was absent on Tregs alone. Finally, we also found enhanced AREG expression in plasma and renal biopsies of patients with LN, supporting the relevance of our findings for human disease. In summary, our data identify AREG as an anti-inflammatory mediator of LN via broad downregulation of pathogenic T cell immunity. These findings further highlight the AREG/EGFR axis as a potential therapeutic target.

Amphiregulin Aggravates Glomerulonephritis via Recruitment and Activation of Myeloid Cells.

BACKGROUND: Recent studies have identified the EGF receptor (EGFR) ligand amphiregulin (AREG) as an important mediator of inflammatory diseases. Both pro- and anti-inflammatory functions have been described, but the role of AREG in GN remains unknown. METHODS: The nephrotoxic nephritis model of GN was studied in AREG-/- mice after bone marrow transplantation, and in mice with myeloid cell-specific EGFR deficiency. Therapeutic utility of AREG neutralization was assessed. Furthermore, AREG's effects on renal cells and monocytes/macrophages (M/M) were analyzed. Finally, we evaluated AREG expression in human renal biopsies. RESULTS: Renal AREG mRNA was strongly upregulated in murine GN. Renal resident cells were the most functionally relevant source of AREG. Importantly, the observation that knockout mice showed significant amelioration of disease indicates that AREG is pathogenic in GN. AREG enhanced myeloid cell responses via inducing chemokine and colony stimulating factor 2 (CSF2) expression in kidney resident cells. Furthermore, AREG directly skewed M/M to a proinflammatory M1 phenotype and protected them from apoptosis. Consequently, anti-AREG antibody treatment dose-dependently ameliorated GN. Notably, selective abrogation of EGFR signaling in myeloid cells was sufficient to protect against nephritis. Finally, strong upregulation of AREG expression was also detected in kidneys of patients with two forms of crescentic GN. CONCLUSIONS: AREG is a proinflammatory mediator of GN via (1) enhancing renal pathogenic myeloid cell infiltration and (2) direct effects on M/M polarization, proliferation, and cytokine secretion. The AREG/EGFR axis is a potential therapeutic target for acute GN.

Overspecialized and undertrained? Patient diversity encountered by medical students during their internal medicine clerkship at a university hospital.

BACKGROUND: During the four-month internal medicine clerkship in their final year, undergraduate medical students are closely involved in patient care. Little is known about what constitutes their typical learning experiences with respect to patient diversity within the different subspecialties of internal medicine and during on call hours. METHODS: 25 final year medical students (16 female, 9 male) on their internal medicine clerkship participated in this observational single-center study. To detail the patient diversity encountered by medical students at a university hospital during their 16-week internal medicine clerkship, all participants self-reported their patient contacts in the different subspecialties and during on call hours on patient encounter cards. Patients' chief complaint, suspected main diagnosis, planned diagnostic investigations, and therapy in seven different internal medicine subspecialties and the on call medicine service were documented. RESULTS: 496 PECs were analysed in total. The greatest diversity of chief complaints (CC) and suspected main diagnoses (SMD) was observed in patients encountered on call, with the combined frequencies of the three most common CCs or SMDs accounting for only 23% and 25%, respectively. Combined, the three most commonly encountered CC/SMD accounted for high percentages (82%/63%), i.e. less diversity, in oncology and low percentages (37%/32%), i.e. high diversity, in nephrology. The percentage of all diagnostic investigations and therapies that were classified as "basic" differed between the subspecialties from 82%/94% (on call) to 37%/50% (pulmonology/oncology). The only subspecialty with no significant difference compared with on call was nephrology for diagnostic investigations. With respect to therapy, nephrology and infectious diseases showed no significant differences compared with on call. CONCLUSIONS: Internal medicine clerkships at a university hospital provide students with a very limited patient diversity in most internal medicine subspecialties. Shadowing the on call resident or shorter rotations could provide a more extended patient diversity.