Kazuyuki Meguro

Primary erythromelalgia (PEM) is a rare autosomal dominant disorder characterised by episodic erythema and burning pain of the extremities, typically triggered by exercise or fatigue. PEM usually begins in childhood and is caused by gain-of-function variants in SCN9A, which encodes the voltage-gated sodium channel Nav1.7. The disease concept of PEM, however, is largely unrecognised among rheumatologists. Here, we report a 20-year-old woman who had experienced recurrent burning pain and redness of the extremities since around age 10. She also exhibited livedo-like rash, leukopenia, and hypocomplementemia and tested positive for antinuclear antibodies. Nerve conduction studies showed abnormalities interpreted as compatible with multifocal mononeuropathy. Based on these findings, she was diagnosed with systemic lupus erythematosus and treated with 20 mg of prednisolone; however, the painful erythema of the extremities did not improve. Given a family history of similar episodic symptoms in her father, PEM was suspected. Genetic testing identified a heterozygous SCN9A p.G856D variant, supporting the diagnosis of autosomal dominant PEM. Direct immunofluorescence/lupus band testing of the biopsied lower-leg lesion was interpreted as negative. This case highlights that SCN9A-associated PEM may present with lupus-like cutaneous erythema in young patients, potentially leading to misdiagnosis and ineffective immunosuppression. PEM should be considered in patients with childhood-onset, trigger-induced painful erythema of the extremities, particularly when there is family history or poor response to steroids.

X-linked agammaglobulinemia (XLA) is an inborn error of immunity (IEI) caused by loss-of-function variants in the Bruton tyrosine kinase ( BTK ) gene, classically presenting in early childhood with recurrent bacterial infections. Here, we report an atypical case of XLA diagnosed in adulthood during evaluation of inflammatory arthritis. A 42-year-old man with no history of severe or recurrent infections initially presented with monoarticular inflammation of the right elbow joint and later developed Doppler-positive synovitis and tenosynovitis of the hands, together with a methicillin-sensitive Staphylococcus aureus lung abscess and a subsequent deep gluteal abscess. Immunological evaluation showed profound hypogammaglobulinemia with markedly reduced circulating B cells. Genetic testing revealed a BTK splice-site variant, c.1103-2A>G (NM_000061.3). Functional analyses demonstrated abnormal splicing at the exon 12–13 junction, reduced BTK mRNA expression, and reduced but detectable BTK protein expression in monocytes, supporting residual protein expression consistent with a hypomorphic or leaky phenotype. Although XLA is generally considered to show limited genotype-phenotype correlation, residual BTK expression in this case could have contributed, at least in part, to the relatively mild early infectious phenotype. In addition, the patient’s longstanding social withdrawal, with presumably limited exposure to infectious sources, may also have contributed to delayed clinical recognition until adulthood. Importantly, immunoglobulin replacement therapy was followed by sustained prevention of further deep infections and gradual improvement of synovitis, tenosynovitis, and skin manifestations. This case highlights that common rheumatologic presentations in adults, such as arthritis, may mask an underlying IEI. Early recognition of IEI can enable timely immunoglobulin replacement therapy, which may restore humoral immune protection, prevent further severe infections, and improve rheumatologic manifestations. It also underscores the importance of integrating immunological and genetic evaluation with protein- and transcript-level analyses when interpreting atypical presentations and splice-site variants.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyperinflammatory syndrome caused by excessive cytokine release from activated T cells and macrophages. Primary HLH, or familial HLH (FHL), results from genetic mutations affecting cytotoxic lymphocyte function. Case Report: We present a case of FHL Type 2 (FHL2) caused by compound heterozygous variants in the PRF1 gene, including one novel missense variant of p.Ala21Val (A21V). A 5‐month‐old boy presented with persistent fever, pancytopenia, coagulopathy, hepatosplenomegaly, and elevated ferritin, meeting the HLH‐2004 diagnostic criteria. Bone marrow revealed hemophagocytosis, and NK cell activity was markedly reduced. Genetic analysis identified compound heterozygous PRF1 variants: A21V and p.Pro16Ser (P16S). Flow cytometric analysis demonstrated markedly reduced PRF1 protein expression in the patient’s NK cells. The patient was treated with etoposide, dexamethasone palmitate, and cyclosporine, followed by cord blood transplantation. The patient has been in remission for over a year. Discussion: The PRF1 A21V variant has not been described in the public database or the literature and is therefore considered a novel pathogenic variant for FHL2 with functional validation. Although the PRF1 P16S variant has been previously reported in the heterozygous state in an adult patient with primary HLH, our findings provide functional and clinical evidence supporting a contributory role of the P16S variant in autosomal recessive early‐onset FHL2 when present in trans with the novel A21V variant. Conclusion: We identified a previously unreported PRF1 variant, A21V, and provided the first functional evidence of impaired perforin expression associated with A21V/P16S, highlighting the importance of functional validation of rare PRF1 variants in FHL2.

Dysregulated nucleic acid sensing underlies lethal viral infections and autoimmunity. Endosomal Toll-like receptor 7 (TLR7) recognizes guanosine and oligoribonucleotides (ORNs) from single-stranded RNA via two ligand-binding sites in its leucine-rich repeat (LRR) ectodomain. Recent genetic studies have demonstrated that TLR7 gain-of-function (GOF) variants cause childhood lupus or immune thrombocytopenic purpura by enhancing TLR7 responses to canonical TLR7 ligands. However, no study has demonstrated that altered ligand specificity of TLR7 contributes to autoimmunity. Here, we provide direct evidence that relaxation of ligand specificity by TLR7 genetic variants causes lupus in both humans and mice. We describe a pediatric systemic lupus erythematosus (SLE) patient carrying a private GOF TLR7 missense variant, V825M (VarM), located within the C-terminal region of the LRR (LRR-CT). Knock-in mice harboring VarM allele spontaneously develop lupus-like systemic inflammation, including duodenitis, recapitulating the patient’s clinical features. Mechanistically, the VarM variant markedly amplifies NF-κB activation by synthetic small-molecule agonists and guanosine analogs. Notably, the VarM variant broadens the spectrum of ORN sequences that can engage the receptor. Moreover, certain pathogenic TLR7 variants located at the dimerization interface display functional properties closely resembling those of VarM. Collectively, our findings establish a new paradigm in which alterations in ligand recognition specificity by TLR7 genetic variations can trigger human autoimmune disease.

Oral tolerance has been defined as the specific suppression of immune responses to an antigen by prior oral administration of the antigen. It has been thought to serve to suppress food allergy. Previous studies have shown that dendritic cells (DCs) and regulatory T cells (Tregs) are involved in the induction of oral tolerance. However, the detailed mechanisms of Treg induction in oral tolerance remain largely unknown. Eosinophils have been recognized as effector cells in allergic diseases, but in recent years, the diverse functions of tissue-resident eosinophils have been reported. Eosinophils in the intestine have been reported to induce Tregs by releasing TGF-β, but the role of eosinophils in oral tolerance is still controversial. In this study, we analyzed the roles of eosinophils in oral tolerance using eosinophil-deficient ΔdblGATA mice (mice lacking a high-affinity GATA-binding site in the GATA1 promoter). ΔdblGATA mice showed impaired antigen-induced oral tolerance compared to wild-type mice. The induction of RORγt⁺ Tregs in mesenteric lymph nodes (MLNs) by oral tolerance induction was impaired in ΔdblGATA mice compared to wild-type mice. An increase in RORγt⁺ antigen-presenting cells (APCs), which are involved in RORγt⁺ Treg differentiation, in the intestine and MLNs was not seen in ΔdblGATA mice. Notably, the expansion of group 3 innate lymphoid cells (ILC3s), a subset of RORγt⁺ APCs, by oral tolerance induction was seen in wild-type mice but not ΔdblGATA mice. These results suggest that eosinophils are crucial in the induction of oral tolerance, possibly via the induction of RORγt⁺ APCs and RORγt⁺ Tregs.