TLR7 gain-of-function genetic variation causes human lupus

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA and binds to guanosine. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP1 and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition

Data from: Pearls & Oy-sters: Adolescent-onset adrenomyeloneuropathy and arrested cerebral adrenoleukodystrophy

Pearls: Defects in peroxisomal transport interferes with β-oxidation of very long chain fatty acids (VLCFAs). Subsequent VLCFA accumulation triggers a cascade of events that eventually leads to adrenoleukodystrophy (ALD). Attention-deficit/hyperactivity disorder (ADHD) can be one of the early manifestations of childhood cerebral ALD (CCALD). Patients with adrenomyeloneuropathy (AMN) may have signs of occult self-halted CCALD on MRI, which can help point to a diagnosis of AMN. Oy-sters: AMN can present in adolescence, although it typically presents in adult men between 20 and 40 years of age, and at older age in women. MRI findings in the spinal cord could be normal or show minimal white matter involvement with significant bilateral spastic paraparesis. Blood pressure, glucose, and electrolytes can be normal in patients with adrenal insufficiency

A longitudinal analysis of early lesion growth in presymptomatic patients with cerebral adrenoleukodystrophy

BACKGROUND AND PURPOSE: Cerebral adrenoleukodystrophy is a devastating neurological disorder caused by mutations in the ABCD1 gene. Our aim was to model and compare the growth of early cerebral lesions from longitudinal MRIs obtained in presymptomatic patients with progressive and arrested cerebral adrenoleukodystrophy using quantitative MR imaging-based lesion volumetry. MATERIALS AND METHODS: We retrospectively quantified and modeled the longitudinal growth of early cerebral lesions from 174 MRIs obtained from 36 presymptomatic male patients with cerebral adrenoleukodystrophy. Lesions were manually segmented using subject-specific lesion-intensity thresholding. Volumes were calculated and plotted across time. Lesion velocity and acceleration were calculated between sequentially paired and triplet MRIs, respectively. Linear mixed-effects models were used to assess differences in growth parameters between progressive and arrested phenotypes. RESULTS: The median patient age was 7.4 years (range, 3.9-37.0 years). Early-stage cerebral disease progression was inversely correlated with age (r ¼ -0.6631, P,.001), early lesions can grow while appearing radiographically stable, lesions undergo sustained acceleration in progressive cerebral adrenoleukodystrophy (b ¼ 0.10 mL/month2 [95% CI, 0.05-0.14 mL/month2], P,.001), and growth trajectories diverge between phenotypes in the presymptomatic time period. CONCLUSIONS: Measuring the volumetric changes in newly developing cerebral lesions across time can distinguish cerebral adrenoleukodystrophy phenotypes before symptom onset. When factored into the overall clinical presentation of a patient with a new brain lesion, quantitative MR imaging-based lesion volumetry may aid in the accurate prediction of patients eligible for therapy