Clinical Reasoning: A Young Adult Man With Cognitive Changes, Gait Difficulty, and Renal Insufficiency.

A 22-year-old right-handed man with recently diagnosed gout and renal insufficiency presented with 3 months of progressive gait instability and cognitive changes. He initially presented to an outside institution and underwent a broad workup, but an etiology for his symptoms was not found. On subsequent presentation to our institution, his examination revealed multidomain cognitive dysfunction, spasticity, hyperreflexia, and clonus. A broad workup was again pursued and was notable for an MRI of the brain, revealing cortical atrophy advanced for his age, bland CSF, and a weakly positive serum acetylcholine receptor ganglionic neuronal antibody of unclear significance. The history of gout and inadequately explained renal insufficiency led to a workup for inborn errors of metabolism, including urine amino acid analysis, which revealed a homocysteine peak. This finding prompted further evaluation, revealing markedly elevated serum homocysteine and methylmalonic acid and low methionine. He ultimately developed superficial venous thromboses, a segmental pulmonary embolism, and clinical and electrographic seizures. He was initiated on appropriate treatment, and his symptoms markedly improved. The case serves as a reminder to include late-onset inborn errors of metabolism in the differential for young adult patients with onset of neurologic, psychiatric, renal, and thromboembolic symptoms.

T follicular helper cells in human efferent lymph retain lymphoid characteristics.

T follicular helper cells (Tfh), a subset of CD4+ T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.