Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pathogenesis of such lymphomas is multifactorial but to a large extent depends on EBV’s ability to aggressively drive cellular DNA replication and B cell proliferation despite cell-intrinsic barriers to replication. One such barrier is oncogenic replication stress which hinders the progression of DNA replication forks. To understand how EBV successfully overcomes replication stress, we examined cellular replication forks in EBV-transformed B cells using iPOND (isolation of Proteins on Nascent DNA)-mass spectrometry and identified several cellular proteins that had not previously been linked to DNA replication. Of eight candidate replisome-associated proteins that we validated at forks in EBV-transformed cells and Burkitt lymphoma-derived cells, three zinc finger proteins (ZFPs) were upregulated early in B cells newly-infected with EBV in culture as well as expressed at high levels in EBV-infected B blasts in the blood of immunocompromised transplant recipients. Expressed highly in S- and G2-phase cells, knockdown of each ZFP resulted in stalling of proliferating cells in the S-phase, cleavage of caspase 3, and cell death. These proteins, newly-identified at replication forks of EBV-transformed and Burkitt lymphoma cells therefore contribute to cell survival and cell cycle progression, and represent novel targets for intervention of EBV-lymphomas while simultaneously offering a window into how the replication machinery may be similarly modified in other cancers. Cancer cells must overcome chronic replication stress, a central barrier to DNA replication. This is true also for cancers caused by Epstein-Barr virus (EBV). To understand how EBV overcomes this barrier to successfully drive cell proliferation, we isolated proteins associated with the cellular replication machinery in EBV-transformed B lymphocytes and identified several cellular proteins that had not previously been linked to DNA replication in cancer or healthy cells. Three of these were zinc finger proteins enriched at the replication machinery in EBV-transformed and EBV-positive Burkitt lymphoma-derived cells, upregulated in newly-infected B cells, and expressed at high levels in infected B cells from transplant recipients. These zinc finger proteins also contributed towards cell proliferation, survival, and cell cycle progression. While these proteins may also contribute to DNA replication in other cancers, they simultaneously represent potential targets in EBV-cancers, some of which are difficult to treat.

Background: Silent lupus nephritis (SLN) is systemic lupus erythematosus (SLE) without clinical and laboratory features of kidney involvement but with biopsy-proven nephritis. This study aims to describe and compare the baseline characteristics and outcomes of pediatric SLN with overt LN (OLN) and to identify associated risk factors and biochemical markers. Methods: In this retrospective, observational study, multivariate logistic regression and receiver operating characteristic (ROC) analyses studied age, sex, race, serum complements, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Results: In our cohort of 69 patients, 47 were OLN, and 22 were SLN. OLN (OR = 4.9, p = 0.03) and non-African Americans (AA) (OR = 13.0, p < 0.01) had higher odds, and increasing C3 and C4 were associated with lower odds of proliferative nephritis (OR 0.95 and 0.65 per one unit increase in C3 and C4, respectively, p < 0.01). They demonstrated a good discriminative ability to detect proliferative nephritis as assessed by the area under the ROC curve (C3 = 0.78, C4 = 0.78). C3 and C4 in proliferative SLN and OLN were comparable and significantly lower than their non-proliferative counterparts. No association was observed between age, sex, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Proliferative SLN and OLN patients received similar treatments. Adverse events were identified in the proliferative OLN only. Conclusions: Lower complement levels are associated with proliferative lesions in pediatric LN—both SLN and OLN. The non-AA population had higher odds of having proliferative nephritis than the AA. Prospective, randomized, long-term follow-up of proliferative SLN patients is needed to ascertain the beneficial effect of early diagnosis and treatment. Graphical

Anti-glomerular basement membrane (GBM) disease is caused by autoantibodies against the α3-chain of type IV collagen in the GBM. Common variable immunodeficiency (CVID) is a primary immunodeficiency manifested by hypogammaglobulinemia, inability to make functional antibody, and recurrent infections. This report extends the phenotype of CVID-associated autoimmune diseases to include anti-GBM disease. A 15-year-old Caucasian female with prior normal renal function presented with nephrotic proteinuria, pedal edema, oliguria, acute kidney injury, and was found to have positive serum anti-GBM antibody. She had been diagnosed with CVID at 3 years of age. Her renal biopsy showed crescentic glomerulonephritis (50%), and immunofluorescence showed linear staining for IgG along the glomerular capillary wall. There was no clinical or imaging evidence of pulmonary hemorrhage. She was treated with pulse IV steroids, cyclophosphamide, rituximab, and several sessions of plasmapheresis. Her serum anti-GBM antibody level decreased from 194 U/mL at presentation to 0 U/mL after therapy. However, she progressed to end-stage renal disease (ESRD) within weeks, despite aggressive therapy, and required chronic renal replacement therapy in the form of dialysis. Her clinical course was also complicated by hypertensive encephalopathy, CMV viremia and meningoencephalitis, status epilepticus, and she passed away a few months later from lower respiratory tract complications. Anti-GBM disease is a rare autoimmune condition that has not been reported in association with a primary immunodeficiency syndrome. ESRD secondary to anti-GBM disease in a patient with CVID is an interesting association and supports the role of immune dysregulation in systemic autoimmune disease.