Deciphering imprints of impaired memory B-cell maturation in germinal centers of three patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes, and poor antigen-specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC)-derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry, and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modeling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregularly shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection, and class-switching, while in patient 3, high SHM, impaired antigen selection, and class-switching with large single clones imply increased re-cycling of cells within the irregularly shaped GCs. In the lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells are a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flow cytometry, and BCR repertoire analysis contributes to unraveling defects in the essential steps during memory formation.

Development of Nivolumab/Ipilimumab-Associated Autoimmune Nephritis during Steroid Therapy.

Immunotherapy using immune checkpoint inhibitors revolutionized therapies for a variety of malignancies. Nivolumab, an antibody blocking programmed cell death 1 protein, and ipilimumab that blocks cytotoxic T-lymphocyte-associated protein 4 effectively target tumor cells by disinhibiting the endogenous immune response. At the same time, unrestrained T-cell activation may trigger a range of immune-mediated side effects including kidney injury. Steroid therapy constitutes the mainstay of treatment of these adverse events, but dosage, route of administration, and approach to nivolumab re-exposure remain unclear. Here, we report the case of a 72-year-old male patient who developed severe nivolumab/ipilimumab-associated acute kidney injury while on oral steroid therapy for immune-mediated colitis. Acute interstitial nephritis was confirmed by renal biopsy. Administration of high-dose intravenous steroid doses was required to revert declining renal function.

Primary carnitine deficiency - diagnosis after heart transplantation: better late than never!

BACKGROUND: Primary carnitine deficiency due to mutations in the SLC22A5 gene is a rare but well-treatable metabolic disorder that puts patients at risk for metabolic decompensations, skeletal and cardiac myopathy and sudden cardiac death. RESULTS: We report on a 7-year-old boy diagnosed with primary carnitine deficiency 2 years after successful heart transplantation thanks his younger sister's having been identified via expanded newborn screening during a pilot study evaluating an extension of the German newborn screening panel. CONCLUSION: As L-carnitine supplementation can prevent and mostly reverse clinical symptoms of primary carnitine deficiency, all patients with cardiomyopathy should be investigated for primary carnitine deficiency even if newborn screening results were unremarkable.