Search

Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID. Initial studies of gene therapy for PIDs in the 1990-2000's used integrating murine gamma-retroviral vectors. While these studies showed clinical efficacy in many cases, especially with the administration of marrow cytoreductive conditioning before cell re-infusion, these vectors caused genotoxicity and development of leukoproliferative disorders in several patients. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription ("SIN" vectors). These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. Gene therapy has successfully treated several PIDs including Adenosine Deaminase Severe Combined Immunodeficiency (SCID), X-linked SCID, Artemis SCID, Wiskott-Aldrich Syndrome, X-linked Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency-I. In all, gene therapy for PIDs has progressed over the recent decades to be equal or better than allogeneic HSCT in terms of efficacy and safety. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Human inborn errors of immunity include rare disorders entailing functional and quantitative antibody deficiencies due to impaired B cells called the common variable immunodeficiency (CVID) phenotype. Patients with CVID face delayed diagnoses and treatments for 5 to 15 years after symptom onset because the disorders are rare (prevalence of ~1/25,000), and there is extensive heterogeneity in CVID phenotypes, ranging from infections to autoimmunity to inflammatory conditions, overlapping with other more common disorders. The prolonged diagnostic odyssey drives excessive system-wide costs before diagnosis. Because there is no single causal mechanism, there are no genetic tests to definitively diagnose CVID. Here, we present PheNet, a machine learning algorithm that identifies patients with CVID from their electronic health records (EHRs). PheNet learns phenotypic patterns from verified CVID cases and uses this knowledge to rank patients by likelihood of having CVID. PheNet could have diagnosed more than half of our patients with CVID 1 or more years earlier than they had been diagnosed. When applied to a large EHR dataset, followed by blinded chart review of the top 100 patients ranked by PheNet, we found that 74% were highly probable to have CVID. We externally validated PheNet using >6 million records from disparate medical systems in California and Tennessee. As artificial intelligence and machine learning make their way into health care, we show that algorithms such as PheNet can offer clinical benefits by expediting the diagnosis of rare diseases. Editor's summary: Common variable immunodeficiency (CVID) disease is an inborn error of immunity characterized by antibody deficiency and impaired B cell responses. This condition can be difficult to diagnose on account of its heterogenous presentation. Johnson et al. developed and validated a machine learning model designed to parse patient electronic health record data and rank individuals according to their likelihood of having CVID. Their retrospective analysis suggested that the method could help diagnose many individuals earlier than standard clinical methods, potentially hastening their referral for specialist treatment. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Expression of the cell-surface antigen CD10 has long been used to define the lymphoid commitment of human cells. Here we report a unique lymphoid-primed population in human bone marrow that was generated from hematopoietic stem cells (HSCs) before onset of the expression of CD10 and commitment to the B cell lineage. We identified this subset by high expression of the homing molecule L-selectin (CD62L). CD10(-)CD62L(hi) progenitors had full lymphoid and monocytic potential but lacked erythroid potential. Gene-expression profiling placed the CD10(-)CD62L(hi) population at an intermediate stage of differentiation between HSCs and lineage-negative (Lin(-)) CD34(+)CD10(+) progenitors. CD62L was expressed on immature thymocytes, and its ligands were expressed at the cortico-medullary junction of the thymus, which suggested a possible role for this molecule in homing to the thymus. Our studies identify the earliest stage of lymphoid priming in human bone marrow.

The fields of life care planning and psychology play a significant role together in assisting patients to receive the best care possible after an injury that has drastically changed their life. Neuropsychological and psychological assessments can aid the life care planner in determining the future needs of adult and pediatric patients. Testing assesses areas such as attention, cognitive decline, emotional functioning, intellectual ability, memory, and many other areas of functioning to provide a thorough picture of a person's current abilities, strengths, and weaknesses. It is important that life care planners understand psychological assessments and that psychologists provide useful information in their report that will aid others in knowing what type of care the patient will need. The objective of this article is to inform those in the life care planning field of the new developments in testing that may affect how one plans for the future care and treatment of their patient. [ABSTRACT FROM AUTHOR]