ANCA-Associated Vasculitis Following Pfizer-BioNTech COVID-19 Vaccine.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread around the world. As of the end of June 2021, there were approximately 181 million confirmed cases and more than 3.9 million deaths across the globe. The colossal impact of coronavirus disease 2019 (COVID-19) is driving the biggest vaccination campaign in human history. All 3 vaccines authorized for emergency use by the US Food and Drug Administration (Pfizer-BioNTech, Moderna, and Janssen/Johnson & Johnson) have been thoroughly studied and found to be safe and effective in preventing severe COVID-19 cases. While short-term side effects of COVID-19 vaccine resemble those of other vaccines, long-term side effects remain unknown. Rare side effects continue to surface as millions of people receive COVID-19 vaccines around the world, as compared with the thousands enrolled in the clinical trials. We report a case of new-onset renal-limited ANCA-associated vasculitis (AAV) in a 78-year-old woman with previously normal kidney function after receiving the Pfizer-BioNTech COVID-19 vaccine. The patient developed acute kidney injury with proteinuria and microscopic hematuria with many dysmorphic red blood cells in the urine. Anti-myeloperoxidase antibody titer was elevated. Kidney biopsy showed pauci-immune crescentic necrotizing glomerulonephritis. Kidney function improved after treatment with steroids and rituximab. Our patient had normal routine laboratory testing before the vaccination. Although this case cannot demonstrate a causal relationship between COVID-19 vaccination and AAV, ongoing surveillance for similar complications would be prudent as worldwide vaccination efforts continue.

COVID-19-induced granulomatosis with polyangiitis.

COVID-19 and granulomatosis with polyangiitis share many clinical and radiological features, making it challenging for clinicians to distinguish between the two. In this case report, we describe a patient who was diagnosed with COVID-19 in October 2020. One month later, she presented with persistent fatigue, shortness of breath and anaemia with worsening renal functions, found to have elevated antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies, and diagnosed with granulomatosis with polyangiitis.

Hyperammonemia syndrome due to Ureaplasma urealyticum in a kidney transplant recipient: A case of disseminated disease from a fluoroquinolone-resistant isolate.

Ureaplasma species (spp.) are common colonizers of the urogenital tract but may cause systemic infection in immunocompromised patients. They release significant amounts of ammonia via urea hydrolysis and have been recently implicated in the pathogenesis of hyperammonemia syndrome after organ transplantation. We describe a unique case of hyperammonemia syndrome after kidney transplant caused by U urealyticum infection, and the first, to our knowledge, case of a fluoroquinolone-resistant Ureaplasma strain causing hyperammonemia syndrome. A 17-year-old female developed intermittent fevers, rising creatinine, sterile pyuria and debilitating polyarthritis approximately 1 year after kidney transplant. Serum ammonia level was elevated, and urine PCR was positive for U urealyticum. Near the end of treatment with levofloxacin, she had rebound hyperammonemia, which preceded clinical relapse of polyarthritis and encephalopathy. Blood and urine PCR and synovial fluid culture were positive for U urealyticum. Susceptibility testing showed fluoroquinolone resistance, but she responded well to azithromycin and doxycycline. The frequency of Ureaplasma spp. infection in immunocompromised patients is probably underestimated due to diagnostic challenges. Ammonia levels were helpful biomarkers of response to antimicrobial therapy in our case. Susceptibility testing of clinical isolates should be pursued. In serious Ureaplasma spp. infections, particularly in immunocompromised patients, two empiric antibiotics may be indicated given the potential for antimicrobial resistance.

Chronic kidney disease alters vascular smooth muscle cell phenotype.

Vascular access dysfunction associated with arteriovenous grafts and fistulas contributes to the morbidity and mortality of chronic kidney disease (CKD) patients receiving hemodialysis. We hypothesized that the uremic conditions associated with CKD promote a pathophysiological vascular smooth muscle cell (VSMC) phenotype that contributes to neointimal hyperplasia. We analyzed the effect of culturing human VSMC with uremic serum. Expression of VSMC contractile marker genes was reduced 50-80% in cells exposed to uremic serum and the decreased expression was accompanied by changes in histone marks. There was an increase in proliferation in cells exposed to uremic conditions, with no change in the levels of apoptosis. Interestingly, we found that uremic serum inhibited PDGF-induced migration of VSMC. Histomorphometric analysis revealed venous neointimal hyperplasia in veins from chronic kidney disease (CKD) patients prior to any surgical manipulation as compared to veins from patients with no kidney disease. We conclude that uremia associated with CKD alters VSMC phenotype in vitro and contributes to neointimal hyperplasia formation in vivo contributing to the pathogenesis of vascular access dysfunction in CKD patients.

Expression of WSX1 in tumors sensitizes IL-27 signaling-independent natural killer cell surveillance.

It is well known that the interleukin (IL)-27 receptor WSX1 is expressed in immune cells and induces an IL-27-dependent immune response. Opposing this conventional dogma, this study reveals a much higher level of WSX1 expression in multiple types of epithelial tumor cells when compared with normal epithelial cells. Expression of exogenous WSX1 in epithelial tumor cells suppresses tumorigenicity in vitro and inhibits tumor growth in vivo. Different from the role of WSX1 in immune cells, the antitumor activity of WSX1 in epithelial tumor cells is independent of IL-27 signaling but is mainly dependent on natural killer (NK) cell surveillance. Deficiency of either the IL-27 subunit EBV-induced gene 3 or the IL-27 receptor WSX1 in the host animals had no effect on tumor growth inhibition induced by WSX1 expression in tumor cells. Expression of WSX1 in epithelial tumor cells enhances NK cell cytolytic activity against tumor cells, whereas the absence of functional NK cells impairs the WSX1-mediated inhibition of epithelial tumor growth. The underlying mechanism by which WSX1 expression in tumor cells enhances NK cytolytic activity is dependent on up-regulation of NKG2D ligand expression. Our results reveal an IL-27-independent function of WSX1: sensitizing NK cell-mediated antitumor surveillance via a NKG2D-dependent mechanism.

Colocalization of MCM8 and MCM7 with proteins involved in distinct aspects of DNA replication.

Minichromosome maintenance (MCM) proteins are essential for DNA replication in eukaryotes. A subcomplex of the MCM2-7 family members, initially characterized in yeast, is thought to serve as a eukaryotic DNA replicative helicase. MCM8 is a new family member, not present in yeast, which may function alone or with other family members in aspects of DNA metabolism, including replication initiation and elongation. Through the use of chromatin immunoprecipitation, we find that MCM8, like MCM7, colocalizes on a specific DNA segment of the c-MYC replication initiation zone (c-MYC replicator) with Cdc6, a protein potentially involved in loading MCM proteins onto DNA. The association between MCM8 and MCM7 peaks in mid G1, at the time of assembly of the prereplication complex. The association of both MCM proteins with Cdc6, however, continues even after DNA replication is complete. We also find that MCM8 colocalizes at the c-MYC replicator with chromatin-bound Cdk2. Our data indicate that any role MCM8 may play in elongation is likely to be discontinuous, in its association with DNA, from a potential role in initiation. Using immunogold electron microscopy we show that MCM8 and MCM7 differ in spatial relation to RPA70 during S phase. Our data strongly suggest that MCM8 functions with other known replication proteins in processes which accompany DNA replication, especially initiation, and which are specifically adapted to suit higher eukaryotes.

Expression of Epstein-Barr virus-induced gene 3 and other interleukin-12-related molecules by human intestinal epithelium.

Antigen-presenting cells, including dendritic cells, monocytes and macrophages, produce members of the interleukin-12 (IL-12) family that are important in initiating and maintaining cell-mediated immune responses. These include IL-12p35 and p19 that dimerize with IL-12p40 to form IL-12 (also termed IL-12p75) and IL-23, respectively, and Epstein-Barr virus-induced gene 3 (EBI3) protein (a protein related to IL-12p40), that forms a dimer with p28, termed IL-27. Intestinal epithelial cells, which are the initial site of contact between the host and enteric pathogens, can act as antigen-presenting cells, and are known to express mediators important in inflammatory and immune responses. In the current studies, we hypothesized that intestinal epithelial cells express members of the IL-12 family, which can function as an early signalling system important in mucosal immunity. Using in vitro and in vivo model systems of human intestinal epithelium, we demonstrate the regulated expression of EBI3, IL-12p35 and p19 by human intestinal epithelial cells. However, intestinal epithelial cells do not coexpress IL-12p40 or p28 that are required to generate heterodimeric IL-12p75, IL-23 and IL-27. To the extent that IL-12p35, p19 and EBI3 cannot form IL-12p75, IL-23 or IL-27 heterodimers in intestinal epithelial cells, these data suggest that those cells may express other, currently unknown, molecules that can associate with EBI3, IL-12p35 and/or p19 or, alternatively, intestinal epithelial cells may release IL-12-related molecules that by themselves, or in combination with other molecules in the mucosal microenvironment, mediate biological activities.

Vigorous innate and virus-specific cytotoxic T-lymphocyte responses to murine cytomegalovirus in the submaxillary salivary gland.

To better understand the immunological mechanisms that permit prolonged shedding of murine cytomegalovirus (MCMV) from the salivary gland, the phenotypic and functional characteristics of leukocytes infiltrating the submaxillary gland (SMG) were analyzed in infected BALB/c mice. A robust innate immune response, comprised of CD11c+ major histocompatibility complex class II+ CD11b- CD8alpha+ dendritic cells and gamma/delta T-cell receptor-bearing CD3+ T cells was prominent through at least 28 days postinfection. Concurrently, a dramatic increase in pan-NK (DX5+) CD3+ and CD8+ T cells was observed, while CD4+ T cells, known to be essential for viral clearance from this tissue, increased slightly. The expression particularly of gamma interferon but also of interleukin-10 and CC chemokines was extraordinarily high in the SMG in response to MCMV infection. The gamma interferon was produced primarily by CD4+ and CD8+ T lymphocytes and DX5+ CD3+ T cells. The SMG CD8+ T cells were highly cytolytic ex vivo, and a significant proportion of these cells were specific to an immunodominant MCMV peptide. These peptide-specific clones were not exhausted by the presence of high virus titers, which persisted in the SMG despite the strength of the cell-mediated responses. In contrast, MCMV replication was efficiently cleared from the draining cervical and periglandular lymph nodes, a tissue displaying a substantially weaker antiviral response. Our data indicated that vigorous innate and acquired immune responses are elicited, activated, and retained in response to mucosal inflammation from persistent MCMV infection of the submaxillary gland.