Madoka Nishimura

Clinical targeted sequencing identified low-VAF KRAS variants in two of 26 children with childhood-onset systemic lupus erythematosus (SLE). Both had severe inflammatory manifestations but lacked Noonan syndrome features, and neither developed persistent lymphoproliferation suggestive of RAS-associated autoimmune lymphoproliferative disease during follow-up. These findings suggest that KRAS mosaicism may contribute to the development or severity of childhood-onset SLE.

A cluster of cases of IRAK4 deficiency has been identified in Okinawa Prefecture, Japan. All affected families carry the homozygous c.123_124insA variant, suggesting a founder effect and supporting the implementation of targeted newborn screening of IRAK4 deficiency in Okinawa.

Discovered >70 years ago by Ogden Bruton, X-linked agammaglobulinemia (XLA), characterized by recurrent bacterial infections, hypo/agammaglobulinemia, and peripheral blood B-cell deficiency, is among the best-established inborn errors of immunity (IEIs) and one of the most well-documented single types of IEIs, the incidence of which is estimated to be between 1:100,000 and 1:200,000. However, although the pathogenesis of XLA is well understood, several issues remain open for discussion. In this review, we describe several unresolved issues, including noncoding BTK variants, contiguous deletion syndrome, Helicobacter infection, noninfectious neurodegeneration, renal involvement, and malignancies. The primary treatment for XLA, immunoglobulin replacement therapy, administered either intravenously or subcutaneously, has remained unchanged since its discovery. Allogeneic hematopoietic cell transplantation has been successful in some XLA patients, but there are still few reports. However, it may be considered as a treatment option in the future. Given that XLA is one of the most common types of IEIs, resolving these issues is a priority.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre–α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.