Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases.

BACKGROUND: In the isoprenoid biosynthesis pathway, mevalonate is phosphorylated in 2 subsequent enzyme steps by MVK and PMVK to generate mevalonate pyrophosphate that is further metabolized to produce sterol and nonsterol isoprenoids. Biallelic pathogenic variants in MVK result in the autoinflammatory metabolic disorder MVK deficiency. So far, however, no patients with proven PMVK deficiency due to biallelic pathogenic variants in PMVK have been reported. OBJECTIVES: This study reports the first patient with functionally confirmed PMVK deficiency, including the clinical, biochemical, and immunological consequences of a homozygous missense variant in PMVK. METHODS: The investigators performed whole-exome sequencing and functional studies in cells from a patient who, on clinical and immunological evaluation, was suspected of an autoinflammatory disease. RESULTS: The investigators identified a homozygous PMVK p.Val131Ala (NM_006556.4: c.392T>C) missense variant in the index patient. Pathogenicity was supported by genetic algorithms and modeling analysis and confirmed in patient cells that revealed markedly reduced PMVK enzyme activity due to a virtually complete absence of PMVK protein. Clinically, the patient showed various similarities as well as distinct features compared to patients with MVK deficiency and responded well to therapeutic IL-1 inhibition. CONCLUSIONS: This study reported the first patient with proven PMVK deficiency due to a homozygous missense variant in PMVK, leading to an autoinflammatory disease. PMVK deficiency expands the genetic spectrum of systemic autoinflammatory diseases, characterized by recurrent fevers, arthritis, and cytopenia and thus should be included in the differential diagnosis and genetic testing for systemic autoinflammatory diseases.

Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3.

Increasing evidence suggests multilineage cytopenias (also known as Evans syndrome) may be caused by inborn errors of immunity (IEI) with immune dysregulation. We studied a patient with autoimmune haemolytic anaemia and immune thrombocytopenia and identified a germline mutation in SASH3 (c.862C>T;p.Arg288Ter), indicating a recently identified IEI. Immunohistochemistry performed after clinically indicated splenectomy revealed severe hypoplasia/absence of germinal centres. The autoimmune phenotype was associated with an increased CD21low T-bet+ CD11c+ subset along with decreased regulatory T cells, impaired T-cell proliferation and T-cell exhaustion. The younger brother carries the same SASH3 mutation and shares immunophenotypic features but is currently clinical asymptomatic, indicating heterogeneity of SASH3 deficiency.

Human repair-related Schwann cells adopt functions of antigen-presenting cells in vitro.

The plastic potential of Schwann cells (SCs) is increasingly recognized to play a role after nerve injury and in diseases of the peripheral nervous system. Reports on the interaction between immune cells and SCs indicate their involvement in inflammatory processes. However, the immunocompetence of human SCs has been primarily deduced from neuropathies, but whether after nerve injury SCs directly regulate an adaptive immune response is unknown. Here, we performed comprehensive analysis of immunomodulatory capacities of human repair-related SCs (hrSCs), which recapitulate SC response to nerve injury in vitro. We used our well-established culture model of primary hrSCs from human peripheral nerves and analyzed the transcriptome, secretome, and cell surface proteins for pathways and markers relevant in innate and adaptive immunity, performed phagocytosis assays, and monitored T-cell subset activation in allogeneic co-cultures. Our findings show that hrSCs are phagocytic, which is in line with high MHCII expression. Furthermore, hrSCs express co-regulatory proteins, such as CD40, CD80, B7H3, CD58, CD86, and HVEM, release a plethora of chemoattractants, matrix remodeling proteins and pro- as well as anti-inflammatory cytokines, and upregulate the T-cell inhibiting PD-L1 molecule upon pro-inflammatory stimulation with IFNγ. In contrast to monocytes, hrSC alone are not sufficient to trigger allogenic CD4+ and CD8+ T-cells, but limit number and activation status of exogenously activated T-cells. This study demonstrates that hrSCs possess features and functions typical for professional antigen-presenting cells in vitro, and suggest a new role of these cells as negative regulators of T-cell immunity during nerve regeneration.