mTOR Activation Underlies Enhanced B Cell Proliferation and Autoimmunity in PrkcdG510S/G510S Mice.

Autosomal recessive PRKCD deficiency has previously been associated with the development of systemic lupus erythematosus in human patients, but the mechanisms underlying autoimmunity remain poorly understood. We introduced the Prkcd G510S mutation that we previously associated to a Mendelian cause of systemic lupus erythematosus in the mouse genome, using CRISPR-Cas9 gene editing. PrkcdG510S/G510S mice recapitulated the human phenotype and had reduced lifespan. We demonstrate that this phenotype is linked to a B cell-autonomous role of Prkcd. A detailed analysis of B cell activation in PrkcdG510S/G510S mice shows an upregulation of the PI3K/mTOR pathway after the engagement of the BCR in these cells, leading to lymphoproliferation. Treatment of mice with rapamycin, an mTORC1 inhibitor, significantly improves autoimmune symptoms, demonstrating in vivo the deleterious effect of mTOR pathway activation in PrkcdG510S/G510S mice. Additional defects in PrkcdG510S/G510S mice include a decrease in peripheral mature NK cells that might contribute to the known susceptibility to viral infections of patients with PRKCD mutations.

LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages.

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.

Monogenic lupus: Dissecting heterogeneity.

Systemic lupus erythematosus (SLE) is a severe lifelong multisystem autoimmune disease characterized by the presence of autoantibodies targeting nuclear autoantigens, increased production of type I interferon and B cell abnormalities. Clinical presentation of SLE is extremely heterogeneous and different groups of disease are likely to exist. Recently, childhood-onset SLE (cSLE) cases have been linked to single gene mutations, defining the concept of monogenic or Mendelian lupus. Genes associated with Mendelian lupus can be grouped in at least three functional categories. First, complement deficiencies represent the main cause of monogenic lupus and its components are involved in the clearance of dying cells, a mechanism also called efferocytosis. Mutations in extracellular DNASE have been also identified in cSLE patients and represent additional causes leading to defective clearance of nucleic acids and apoptotic bodies. Second, the study of Aicardi-Goutières syndromes has introduced the concept of type-I interferonopathies. Bona fide lupus syndromes have been associated to this genetic condition, driven by defective nucleic acids metabolism or innate sensors overactivity. Interferon signalling anomalies can be detected and monitored during therapies, such as Janus-kinase (JAK) inhibitors. Third, tolerance breakdown can occur following genetic mutations in B and/or T cell expressing key immunoregulatory molecules. Biallelic mutations in PRKCD are associated to lupus and lymphoproliferative diseases as PKC-δ displays proapoptotic activity and is crucial to eliminate self-reactive transitional B cells. Here we review the literature of the emerging field of Mendelian lupus and discuss the physiopathological learning from these inborn errors of immunity. In addition, clinical and biological features are highlighted as well as specific therapies that have been tested in these genetic contexts.