Allogeneic hematopoietic cell transplantation is effective for p47phox chronic granulomatous disease: A Primary Immune Deficiency Treatment Consortium study.

BACKGROUND: P47phox (neutrophil cytosolic factor-1) deficiency is the most common cause of autosomal recessive chronic granulomatous disease (CGD) and is considered to be associated with a milder clinical phenotype. Allogeneic hematopoietic cell transplantation (HCT) for p47phox CGD is not well-described. OBJECTIVES: We sought to study HCT for p47phox CGD in North America. METHODS: Thirty patients with p47phox CGD who received allogeneic HCT at Primary Immune Deficiency Treatment Consortium centers since 1995 were included. RESULTS: Residual oxidative activity was present in 66.7% of patients. In the year before HCT, there were 0.38 CGD-related infections per person-years. Inflammatory diseases, predominantly of the lungs and bowel, occurred in 36.7% of the patients. The median age at HCT was 9.1 years (range 1.5-23.6 years). Most HCTs (90%) were performed after using reduced intensity/toxicity conditioning. HCT sources were HLA-matched (40%) and -mismatched (10%) related donors or HLA-matched (36.7%) and -mismatched (13.3%) unrelated donors. CGD-related infections after HCT decreased significantly to 0.06 per person-years (P = .038). The frequency of inflammatory bowel disease and the use of steroids also decreased. The cumulative incidence of graft failure and second HCT was 17.9%. The 2-year overall and event-free survival were 92.3% and 82.1%, respectively, while at 5 years they were 85.7% and 77.0%, respectively. In the surviving patients evaluated, ≥95% donor myeloid chimerism at 1 and 2 years after HCT was 93.8% and 87.5%, respectively. CONCLUSIONS: Patients with p47phox CGD suffer from a significant disease burden that can be effectively alleviated by HCT. Similar to other forms of CGD, HCT should be considered for patients with p47phox CGD.

Relevance of lymphocyte proliferation to PHA in severe combined immunodeficiency (SCID) and T cell lymphopenia.

Severe combined immunodeficiency (SCID) is characterized by a severe deficiency in T cell numbers. We analyzed data collected (n = 307) for PHA-based T cell proliferation from the PIDTC SCID protocol 6901, using either a radioactive or flow cytometry method. In comparing the two groups, a smaller number of the patients tested by flow cytometry had <10% of the lower limit of normal proliferation as compared to the radioactive method (p = 0.02). Further, in patients with CD3+ T cell counts between 51 and 300 cells/µL, there was a higher proliferative response with the PHA flow assay compared to the 3H-T assay (p < 0.0001), suggesting that the method of analysis influences the resolution and interpretation of PHA results. Importantly, we observed many SCID patients with profound T cell lymphopenia having normal T cell proliferation when assessed by flow cytometry. We recommend this test be considered only as supportive in the diagnosis of typical SCID.

COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.

BACKGROUND: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. OBJECTIVE: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. METHODS: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. RESULTS: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. CONCLUSION: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

Toward Atomistic Understanding of Iron Phosphate Glass: A First-Principles-Based Density Functional Theory Modeling and Study of Its Physical Properties.

Iron phosphate glasses (IPGs) have been proposed as futuristic materials for nuclear waste immobilization and anode materials for lithium batteries. Recently, many attempts have been made to propose atomistic models of IPGs to explain their properties from an atomistic viewpoint. In this paper, we seek to produce small scale models of IPG that can be handled within the scheme of density functional theory (DFT) to study its electronic structure. The starting models, generated using the Monte Carlo (MC) method, were subsequently annealed using ab initio molecular dynamics (AIMD) to minimize the coordination defects. The geometry of the equilibrated structure was then optimized at 0 K. This hybrid approach (MC + AIMD + DFT optimization) produced good atomistic models of IPG, which can reproduce the experimentally observed band gap, vibrational density of states, magnetic moment of Fe, and mechanical and optical properties. Computationally expensive melt-quench simulation can be avoided using the present approach, allowing the use of DFT for accurate calculations of properties.

Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis.

G protein-coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here, we report that Gpr37l1/GRP37L1 ranks among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and is selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) and paclitaxel (PTX) led to reduced GPR37L1 expression on the plasma membrane in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX- and STZ-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 is coexpressed with potassium channels, including KCNJ10 (Kir4.1) in mouse SGCs and both KCNJ3 (Kir3.1) and KCNJ10 in human SGCs. GPR37L1 regulates the surface expression and function of the potassium channels. Notably, the proresolving lipid mediator maresin 1 (MaR1) serves as a ligand of GPR37L1 and enhances KCNJ10- or KCNJ3-mediated potassium influx in SGCs through GPR37L1. Chemotherapy suppressed KCNJ10 expression and function in SGCs, which MaR1 rescued through GPR37L1. Finally, genetic analysis revealed that the GPR37L1-E296K variant increased chronic pain risk by destabilizing the protein and impairing the protein's function. Thus, GPR37L1 in SGCs offers a therapeutic target for the protection of neuropathy and chronic pain.

Satellite glial GPR37L1 regulates maresin and potassium channel signaling for pain control.

G protein coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR and its function remains largely unknown. Here we report that GPR37L1 transcript is highly expressed compared to all known GPCRs in mouse and human dorsal root ganglia (DRGs) and selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy following diabetes and chemotherapy by streptozotocin and paclitaxel resulted in downregulations of surface GPR37L1 in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptom (mechanical allodynia), whereas overexpression of Gpr37l1 in mouse DRGs can reverse neuropathic pain. Notably, GPR37L1 is co-expressed and coupled with potassium channels in SGCs. We found striking species differences in potassium channel expression in SGCs, with predominant expression of KCNJ10 and KCNJ3 in mouse and human SGCs, respectively. GPR37L1 regulates the surface expression and function of KCNJ10 and KCNJ3. We identified the pro-resolving lipid mediator maresin 1 (MaR1) as a GPR37L1 ligand. MaR1 increases KCNJ10/KCNJ3-mediated potassium influx in SGCs via GPR37L1. MaR1 protected chemotherapy-induced suppression of KCNJ13/KCNJ10 expression and function in SGCs. Finally, genetic analysis revealed that the GPR37L1-E296K variant is associated with increased chronic pain risk by destabilizing the protein. Thus, GPR37L1 in SGCs offers a new target for neuropathy protection and pain control.