Case Report: A Novel IL2RG Frame-Restoring Rescue Mutation Mimics Early T Cell Engraftment Following Haploidentical Hematopoietic Stem Cell Transplantation in a Patient With X-SCID.

Mutations of the interleukin 2 receptor γ chain (IL2RG) result in the most common form of severe combined immunodeficiency (SCID), which is characterized by severe and persistent infections starting in early life with an absence of T cells and natural killer cells, normal or elevated B cell counts and hypogammaglobulinemia. SCID is commonly fatal within the first year of life, unless the immune system is reconstituted by hematopoietic stem cell transplantation (HSCT) or gene therapy. We herein describe a male infant with X-linked severe combined immunodeficiency (X-SCID) diagnosed at 5 months of age. Genetic testing revealed a novel C to G missense mutation in exon 1 resulting in a 3' splice site disruption with premature stop codon and aberrant IL2 receptor signaling. Following the diagnosis of X-SCID, the patient subsequently underwent a TCRαß/CD19-depleted haploidentical HSCT. Post transplantation the patient presented with early CD8+ T cell recovery with the majority of T cells (>99%) being non-donor T cells. Genetic analysis of CD4+ and CD8+ T cells revealed a spontaneous 14 nucleotide insertion at the mutation site resulting in a novel splice site and restoring the reading frame although defective IL2RG function was still demonstrated. In conclusion, our findings describe a spontaneous second-site mutation in IL2RG as a novel cause of somatic mosaicism and early T cell recovery following haploidentical HSCT.

Anti-Neuronal IgG4 Autoimmune Diseases and IgG4-Related Diseases May Not Be Part of the Same Spectrum: A Comparative Study.

Background: IgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features. Methods: We collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD. Results: A significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD. Conclusion: Our observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.

[Successful therapy of sacroiliitis in SAPHO syndrome by etanercept]. / Sacroileitis im Rahmen eines SAPHO Syndroms - promptes Ansprechen auf Etanercept.

Painful, aseptic osteitis remains the major problem in the treatment of patients with SAPHO syndrome. We present a child suffering of both sacroiliitis and acne conglobata in the context of SAPHO syndrome. While acne lesions responded well to systemic isotretinoin, sacroiliitis associated pain could be controlled neither by NSAR nor by intralesional or systemic steroid injection. Worse pain limited substantially patient's mobility. This changed immediately after starting etanercept. Within a few days, pain resolved and the patient regained his mobility. This favourable response lasted for 8 months when we tried to stop etanercept under protection with the DMARD sulfazalazin. Unfortunately, within a few days, pain and immobility re-occurred requiring reinstitution of etanercept. This case demonstrates that, similar to other reports, TNF blockade is able to induce prompt and long-lasting response of SAPHO syndrome associated osteoarthritis to TNF blockade.