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PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗
PubMed2026

Immune dysregulatory disorders: perspective from solving a diagnostic odyssey.

PURPOSE OF REVIEW: Inborn errors of immunity (IEIs), once considered rare disorders characterized primarily by recurrent infections, are now recognized as a rapidly expanding group of diseases encompassing autoimmunity, autoinflammation, allergy, malignancy, and immune dysregulation. Advances in next-generation sequencing, functional immunology, and systems biology have revealed overlap between traditionally distinct disease categories and highlighted the complexity of genotype-phenotype relationships. RECENT FINDINGS: While this evolution has led to the discovery of hundreds of previously unrecognized disorders, it has also challenged conventional diagnostic paradigms and demonstrated how patients may have care spread across multiple specialties, without a clear medical home. These discoveries have also highlighted ongoing challenges translating scientific findings to the clinic including difficulties in accessing genomic testing, interpretation of variants of uncertain significance, impacts of incomplete penetrance and somatic mosaicism, and limited availability of specialized functional assays. Emerging computational approaches, including artificial intelligence, offer opportunities to accelerate diagnosis but cannot replace comprehensive clinical evaluation or longitudinal physician-patient relationships. SUMMARY: This perspective examines how the diagnostic odyssey for immune dysregulatory disorders has evolved, side-by-side with the changing framework for diagnosing rare immune diseases. We propose an integrated approach combining clinical phenotyping, genomics, functional validation, and multidisciplinary expertise to unite ongoing discovery between clinicians and scientists, diagnostics, and patient outcomes.

diagnostic odyssey↗
PubMed2026

Clinical and biochemical footprints of inherited disorders of autophagy.

Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.

Autophagosome↗
PubMed2026

Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome.

With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant - alanine (A) to threonine (T) at residue 518 - in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.

Humans↗
PubMed2020

Human NK cell deficiency as a result of biallelic mutations in MCM10.

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.

Alleles↗
PubMed1978

A role for purine metabolism in the immune response: Adenosine-deaminase activity and deoxyadenosine catabolism.

We have investigated a new hypothesis for the association between adenosine deaminase (A.D.A.) deficiency and immunodeficiency--namely, that deoxyadenosine rather than adenosine (an equally effective A.D.A. substrate) is toxic to proliferating cells of lymphoid origin. This possibility was explored in mitogen-stimulated lymphocytes cultured with a potent A.D.A. inhibitor, E.H.N.A. (erythro-9[2-hydroxy-3-nonyl] adenine) to simulate A.D.A. deficiency. In this in-vitro system deoxyadenosine was inhibitory at much lower and more physiological concentrations (1 mumol/1), compared with adenosine (100 mumol/1).

Adenosine↗
PubMed1977

Clinical conditions associated with defective polymorphonuclear leukocyte chemotaxis.

Impressive numbers of clinical conditions are associated with defective leukocyte chemotaxis. In many, this cellular dysfunction is associated with other abnormalities of the immune response, but in others abnormal chemotactic responsiveness of leukocytes is the only abnormality of function identified in the laboratory. Patients are usually selected for study because of unusually severe, recurrent infections or poor response to antimicrobial agents, and therefore a frequent association between abnormality of chemotaxis and infection would be expected. Many patients demonstrate abnormal chemotaxis during remissions as well as during infections, and there seems little doubt that abnormality of chemotaxis is related to susceptibility to infections. Partial classification of disorders of chemotaxis was attempted. Major abnormalities are found when there is a primary cellular disorder or cell-directed inhibitors of chemotaxis are found. Less marked abnormalities are found when chemotactic factors are deficient.

Bacterial Infections↗
PubMed1977

[Clinical significance and problems of technique in the immunochemical determination of the third complement component C 3 (beta 1 C/beta 1 A protein) (author's transl)].

Immunochemical determination of the third complement (C) component C 3 as beta 1 C/beta 1 A protein has found extensive use in the clinical evaluation of immunopathological conditions. C 3 changes are associated with inborn C defects and acquired diseases. In the latter case, diminished C3 levels are of the greatest practical relevance. Reduced C 3 values are not necessarily due to "classical" antibody-mediated C activation, as in immune-complex diseases, but may be caused also by "alternative" pathway activation and decreased C 3 synthesis. In addition, important technique factors have to be considered in the evaluation of immunochemically-determined C 3 values. Since the antigenic pattern of C 3 changes during in vitro ageing, not only the state of conversion of C 3 in the sample and in the reference serum (standard), but above all, the specificity of the anti-C 3-serum plays an important role in critically influencing the total error of the method. In order to avoid this error C 3 can be determined as beta 1 C protein using a beta 1 C standard which is, however, not easily available. On the other hand, beta 1 A quantitation causes less problems since standard sera usually contain C 3 as beta 1 A portein. However, an incubation period of 7 days at + 37 degrees C is necessary for complete C 3 conversion. This undesirable time delay has not yet been satisfactorily overcome by in vitro acceleration of C 3 conversion using different substances.

Antibody Specificity↗
PubMed1979

Multiple biotin-dependent carboxylase deficiencies associated with defects in T-cell and B-cell immunity.

Three siblings presented in early childhood with central-nervous-system (CNS) dysfunction, candida dermatitis, keratoconjunctivitis, and alopecia. Two were studied immunologically and had absent delayed-hypersensitivity skin-test responses and absent in-vitro lymphocyte responses to candida antigen. One of them had selective IgA deficiency and no antibody response to pneumococcal polysaccharide immunisation, and the other had a subnormal percentage of T lymphocytes in peripheral blood. The first two siblings died with progressive CNS deterioration and overwhelming infection. The third child, who presented with a periorificial candida dermatitis, alopecia, keratoconjunctivitis, and intermittent ataxia at eighteen months of age, had intermittent lactic acidosis and raised excretion of beta-hydroxyproprionate, methylcitrate, beta-methylcrotonylglycine, and beta-hydroxyisovalerate in urine. After four days of oral biotin, 10 mg/per day, the metabolites in her urine were significantly reduced, suggesting a biotin-responsive multiple carboxylase deficiency. These findings, taken with previous reports of immune defects in patients with disorders of branched-chain aminoacid catabolism, suggest a new biochemical basis for primary immunodeficiency disease.

Alopecia↗