The β2 common integrin subunit CD18 is essential for leukocyte-endothelial adhesion and extravasation to inflamed or infected tissue. Damaging variants in ITGB2, which encodes CD18, cause leukocyte adhesion deficiency type I (LAD-I), an inborn error of immunity that leads to frequent life-threatening infections and a high risk of death among affected children. Allogeneic hematopoietic stem-cell transplantation (HSCT) represents a curative treatment but is limited by donor availability, a high incidence of graft-versus-host disease, and graft failure. In a phase 1-2, multinational, open-label study, we enrolled nine children who had severe LAD-I and treated them with marnetegragene-autotemcel (marne-cel), a gene therapy of autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector containing human ITGB2, and followed them for 24 months. The primary efficacy end point of the phase 2 study was survival without allogeneic HSCT (HSCT-free survival) at least 1 year after marne-cel infusion and at 2 years of age among the patients who were younger than 1 year of age at enrollment, tested against a null hypothesis of survival of 39% of the patients. We also report interim data from six patients enrolled in the long-term follow-up study. Serious adverse events related to myeloablative busulfan conditioning were observed. No adverse events attributed to gene therapy were reported. None of the patients had graft failure. HSCT-free survival was 100% (95% confidence interval [CI], 66 to 100) at 1 year after infusion (P<0.001). All the patients who were enrolled at younger than 1 year of age were alive beyond 2 years of age. Pretreatment neutrophilia and skin abnormalities related to LAD-I resolved. The annualized incidence of infection-related hospitalizations beyond 90 days after engraftment through 24 months after marne-cel infusion was 74.45% lower than the incidence before marne-cel infusion, the annualized incidence of prolonged infection-related hospitalizations was 81.95% lower, and the annualized incidence of prespecified serious infections was 84.90% lower. In this study, lentiviral vector-transduced autologous CD34+ HSCT was successful in treating severe LAD-I. (Funded by Rocket Pharmaceuticals and the California Institute for Regenerative Medicine; ClinicalTrials.gov numbers, NCT03812263 and NCT06282432.).

Background: Periodontitis is a multifactorial inflammatory disease influenced by immune and genetic factors. Certain genetic and immunological disorders, such as Down syndrome (DS), Leukocyte Adhesion Deficiency type I (LAD-I), and Papillon-Lefèvre syndrome (PLS), are associated with early-onset and severe periodontitis. Understanding their molecular and immunological mechanisms is crucial for advancing personalized therapeutic approaches. Methods: A systematic review was conducted following PRISMA 2020 guidelines to compare inflammatory gene expression profiles in patients with periodontitis associated with genetic or immune-mediated disorders and those without systemic conditions. Searches were performed in PubMed, Scopus, Web of Science, and Embase for studies published between 2010 and June 2025. Eligible studies reporting cytokine profiles or inflammatory gene expression were included and analyzed. Results: Six case-control studies met the inclusion criteria: three on DS, two on LAD-I, and one on PLS. DS patients showed increased serum levels of IL-1 beta, TNF-alpha, IL-4, IL-10, and IFN-gamma, with dysregulation of STAT1, STAT3, and SOCS3. LAD-I was characterized by overexpression of IL-17A, IL-6, IL-23, G-CSF, CXCL2, and CXCL5, indicating IL-17-driven inflammation and excessive neutrophil activation. In PLS, cathepsin C deficiency impaired activation of the antimicrobial peptide LL-37, leading to compromised host defense and accelerated tissue breakdown. Conclusions: Patients with periodontitis linked to genetic or immune-mediated disorders exhibit distinct inflammatory gene expression signatures that enhance disease susceptibility and progression. Identifying these immunoinflammatory pathways may guide precision periodontal therapies, although larger, standardized studies are required to validate these findings.

Leukocyte adhesion deficiency (LAD) is a group of inborn errors of immunity caused by mutations of integrin subunit b2 gene (ITGB2). Pyoderma gangrenosum (PG) is an uncommon neutrophilic dermatosis characterized by recurrent, sterile, and enlarging necrotic ulcers which may manifest as a single or multiple new lesions simultaneously. Here we report a 43-year-old woman from a consanguine marriage who was diagnosed with LAD-I in childhood, recurrent severe PG-like lesion, and atypical manifestations including celiac disease and low CD19 B-cell subsets. A targeted genetic panel revealed a novel homozygous missense variant c.988T>C (Tyr330His) in ITGB2 gene. While the treatment with prednisolone, cyclosporine, and antibiotics led to partial improvement, the patient unfortunately discontinued the therapy and later died from septicemia. Early hematopoietic cell transplantation (HCT) shortly after birth can be highly effective in managing patients with LAD and preventing life-threatening infections. However, evidence suggests that HCT does not prevent autoinflammatory and autoimmune disorders such as PG. Therefore, it is important to monitor LAD patients for the potential development of PG, even after HCT.

Leukocyte Adhesion Deficiency Type I (LAD I) is a rare inborn error of immunity caused by mutations in the ITGB2 gene coding for β2-integrin CD18 on the surface of leukocytes. Affected patients display severe clinical manifestations with life threatening infections and inflammatory complications due to an impaired ability of leukocytes to transmigrate from the blood vessel to the tissue. Here we describe the generation of eight induced pluripotent stem cell lines from two patients with LAD I and mutations in the ITGB2 gene. With this project we contribute patient individualized cell lines for explorative research in a rare disease.