Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1–7, 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 RNA8,9 and binds to guanosine10–12. 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'-cGMP10–12, 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.

Renal disease was a common occurrence in patients with mitochondrial disease, present in our study in 25% of patients. A regular screening of renal function parameters and the involvement of a nephrologist as part of the multidisciplinary approach to mitochondrial disease appears warranted.

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Background: Alport syndrome is a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family. It is a genetically heterogeneous disease with different mutations and forms of inheritance that presents with renal affection, hearing loss and eye defects. Several new mutations related to X-linked forms have been previously determined. Methods: We report the case of a 12 years old male and his family diagnosed with Alport syndrome after genetic analysis was performed. Result: A new mutation determining a nucleotide change c.3614G . T (p.Gly1205Val) in hemizygosis in the COL4A5 gene was found. This molecular defect has not been previously described. Conclusion: Molecular biology has helped us to comprehend the mechanisms of pathophysiology in Alport syndrome. Genetic analysis provides the only conclusive diagnosis of the disorder at the moment. Our contribution with a new mutation further supports the need of more sophisticated molecular methods to increase the mutation detection rates with lower costs and less time.

La nefropatía lúpica es una manifestación precoz en el desarrollo del lupus eritematoso sistémico que empeora la morbimortalidad de estos pacientes.Objetivo: Estudiar la forma de presentación de los pacientes con nefropatía lúpica, las características clínicas, inmunológicas y su relación con la histopatología renal.Pacientes y Método: Estudio retrospectivo en menores de 18 años, con nefropatía lúpica, seguidos en un hospital infantil de tercer nivel en Madrid entre enero 2012 y mayo 2020. Se registraron datos demográficos, clínicos, de laboratorio (hemograma, función renal, función hepática, proteínas, ionograma, glucemia, ácido úrico, lactato deshidrogenasa, coagulación y sistemático de orina), inmunológicos (inmunoglobulinas, anticuerpos antinucleares, complemento y anticoagulante lúpico), y su clasificación histológica. Se realizó análisis descriptivo y de asociaciones entre variables, con un p significativo < 0,05.Resultados: Se incluyeron 16 pacientes (11 mujeres), mediana de edad de presentación de 10,6 ± 2,3 años (5,7-15,3). La mediana de tiempo entre el inicio de los síntomas y el compromiso renal fue 6,3 meses ± 10,5 (rango 0-33,6). El 37,5% de los pacientes tuvo compromiso renal como manifestación inicial. El 50% presentó artralgias o artritis previo al diagnóstico, y el 25% fiebre y síntomas constitucionales (astenia, anorexia, y/o pérdida de peso). La forma más frecuente de compromiso renal fue microhematuria asociada a proteinuria en rango no nefrótico. En el estudio anatomo-patológico renal predominaron, según la clasificación ISN/RPS 2003, los grados III (46,6%) y IV (33,3%).Conclusiones: Seis pacientes presentaron compromiso renal al inicio siendo más frecuente el compromiso musculoesquelético. La mayoría (86,6%) presentaron nefritis lúpica avanzada en el estudio histológico al diagnóstico. El compromiso inmunológico fue el único marcador que se correlacionó con el compromiso sistémico.