Case report: Refractory Evans syndrome in two patients with spondyloenchondrodysplasia with immune dysregulation treated successfully with JAK1/JAK2 inhibition.

Biallelic mutations in the ACP5 gene cause spondyloenchondrodysplasia with immune dysregulation (SPENCDI). SPENCDI is characterized by the phenotypic triad of skeletal dysplasia, innate and adaptive immune dysfunction, and variable neurologic findings ranging from asymptomatic brain calcifications to severe developmental delay with spasticity. Immune dysregulation in SPENCDI is often refractory to standard immunosuppressive treatments. Here, we present the cases of two patients with SPENCDI and recalcitrant autoimmune cytopenias who demonstrated a favorable clinical response to targeted JAK inhibition over a period of more than 3 years. One of the patients exhibited steadily rising IgG levels and a bone marrow biopsy revealed smoldering multiple myeloma. A review of the literature uncovered that approximately half of the SPENCDI patients reported to date exhibited increased IgG levels. Screening for multiple myeloma in SPENCDI patients with rising IgG levels should therefore be considered.

Feasibility of Specimen Self-collection in Young Children Undergoing SARS-CoV-2 Surveillance for In-Person Learning.

Importance: There is an urgent need to assess the feasibility of COVID-19 surveillance measures in educational settings. Objective: To assess whether young children can feasibly self-collect SARS-CoV-2 samples for surveillance testing over the course of an academic year. Design, Setting, and Participants: This prospective pilot cohort study was conducted from September 10, 2020, to June 10, 2021, at a K-8 school in San Mateo County, California. The research consisted of quantitative data collection efforts: (1) demographic data collected, (2) student sample self-collection error rates, and (3) student sample self-collection time durations. Students were enrolled in a hybrid learning model, a teaching model in which students were taught in person and online, with students having the option to attend virtually as needed. Data were collected under waiver of consent from students participating in weekly SARS-CoV-2 testing. Main Outcomes and Measures: Errors over time for self-collection of nasal swabs such as contaminated swabs and inadequate or shallow swabbing; time taken for sample collection. Results: Of 296 participants, 148 (50.0%) were boys and 148 (50.0%) were girls. A total of 87 participants (29.2%) identified as Asian; 2 (0.6%), Black or African American; 13 (4.4%), Hispanic/Latinx; 103 (34.6%), non-Hispanic White; 87 (29.2%), multiracial; and 6 (2.0%), other. The median school grade was fourth grade. From September 2020 to March 2021, a total of 4203 samples were obtained from 221 students on a weekly basis, while data on error rates were collected. Errors occurred in 2.7% (n = 107; 95% CI, 2.2%-3.2%) of student encounters, with the highest rate occurring on the first day of testing (20 [10.2%]). There was an overall decrease in error rates over time. From April to June 2021, a total of 2021 samples were obtained from 296 students on a weekly basis while data on encounter lengths were collected. Between April and June 2021, 193 encounters were timed. The mean duration of each encounter was 70 seconds (95% CI, 66.4-73.7 seconds). Conclusions and Relevance: Mastery of self-collected lower nasal swabs is possible for children 5 years and older. Testing duration can be condensed once students gain proficiency in testing procedures. Scalability for larger schools is possible if consideration is given to the resource-intensive nature of the testing and the setting's weather patterns.

Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy.

BACKGROUND: Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. OBJECTIVE: We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. METHODS: The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n= 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. RESULTS: Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG(4) levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4(+)CD25(high)CD127(low)CD45RO(+) forkhead box protein 3 (Foxp3)(+) memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. CONCLUSION: The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells.

Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease.

Approximately 25% of subjects with common variable immunodeficiency (CVID) develop autoimmune disease. We analyzed T cell subsets, specifically regulatory T cells along with B cell subsets to determine whether there were changes in regulatory T cells which would correlate with the autoimmune disease clinical phenotype in CVID subjects. We hypothesized that regulatory T cell (CD4+CD25hiCD127lo) suppressive function would be impaired in CVID subjects with autoimmune disease. Using purified, sorted Treg from CVID subjects (n=14) and from healthy controls (HC, n=5) in standard suppression assays, we found the suppressive function of Treg from CVID subjects with autoimmune disease (CVID w/ AI, n=8) to be significantly attenuated compared to CVID subjects with no autoimmune disease (CVID w/o AI, n=6) and to HC (n=5). A number of proteins associated with Treg function were decreased in expression as detected through immunofluorescent antibody via flow cytometry (mean fluorescence intensity (MFI) of FoxP3, Granzyme A, XCL1, pSTAT5, and GITR in Treg was significantly lower (by up to 3 fold) in CVID w/ AI compared to CVID w/o AI and HC. Furthermore, a statistically significant correlation was found between intracellular MFI of FoxP3, Granzyme A, and pSTAT5 in Treg and the degree of Treg dysfunction. These results suggest that attenuation of Treg function is associated with autoimmune disease in CVID subjects and may contribute to autoimmune pathogenesis.

CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.

BACKGROUND: Bronchial asthma is associated with an inflammatory process that is characterized by the presence in the airways of large numbers of CD4+ T cells producing interleukin-4 and interleukin-13. However, the CD4 antigen is expressed not only by class II major histocompatibility complex (MHC)-restricted CD4+ T cells, but also by a newly identified subgroup of T cells, CD1d-restricted natural killer T cells. These cells express a conserved (invariant) T-cell receptor and have a potent immunoregulatory function. Because mouse models of allergic asthma indicate that natural killer T cells are required for the development of allergen-induced airway hyperreactivity, we hypothesized that natural killer T cells play an important role in human asthma. METHODS: We used CD1d-tetramers, antibodies specific for natural killer T cells, as well as reverse-transcriptase-polymerase-chain-reaction analysis of the invariant T-cell receptor of natural killer T cells to assess the frequency and distribution of natural killer T cells in the lungs and in the circulating blood of 14 patients with asthma. RESULTS: About 60 percent of the pulmonary CD4+CD3+ cells in patients with moderate-to-severe persistent asthma were not class II MHC-restricted CD4+ T cells but, rather, natural killer T cells. The natural killer T cells expressed an invariant T-cell receptor and produced type 2 helper cytokines. In contrast, the CD4+ T cells found in the lungs of patients with sarcoidosis were conventional CD4+CD3+ T cells, not natural killer T cells. CONCLUSIONS: Together with studies in mice indicating a requirement for natural killer T cells in the development of allergen-induced airway hyperreactivity, our results strongly suggest that CD4+ natural killer T cells play a prominent pathogenic role in human asthma.

Effectiveness of a multicomponent self-management program in at-risk, school-aged children with asthma.

BACKGROUND: Improving asthma knowledge and self-management is a common focus of asthma educational programs, but most programs have had little influence on morbidity outcomes. We developed a novel multiple-component intervention that included the use of an asthma education video game intended to promote adoption of asthma self-management behaviors and appropriate asthma care. OBJECTIVE: To determine the effectiveness of an asthma education video game in reducing morbidity among high-risk, school-aged children with asthma. METHODS: We enrolled 119 children aged 5 to 12 years from low-income, urban areas in and around San Francisco, CA, and San Jose, CA. Children with moderate-to-severe asthma and parental reports of significant asthma health care utilization were randomized to participate in the disease management intervention or to receive their usual care (control group). Patients were evaluated for clinical and quality-of-life outcomes at weeks 8, 32, and 52 of the study. RESULTS: Compared with controls, the intervention group had significant improvements in the physical domain (P = .04 and P = .01 at 32 and 52 weeks, respectively) and social activity domain (P = .02 and P = .05 at 32 and 52 weeks, respectively) of asthma quality of life on the Child Health Survey for Asthma and child (P = .02 at 8 weeks) and parent (P = .04 and .004 at 32 and 52 weeks, respectively) asthma self-management knowledge. There were no significant differences between groups on clinical outcome variables. CONCLUSIONS: A multicomponent educational, behavioral, and medical intervention targeted at high-risk, inner-city children with asthma can improve asthma knowledge and quality of life.

Clinical efficacy of microencapsulated timothy grass pollen extract in grass-allergic individuals.

BACKGROUND: Conventional allergen immunotherapy is clinically effective in reducing the symptoms of allergic rhinitis and asthma. It differs from other pharmacotherapies in that it can induce long-term clinical remission of these diseases. However, it requires years of treatment and is associated with serious allergic reactions. OBJECTIVE: To evaluate the safety, clinical efficacy, and immunologic mechanisms of immunotherapy with an oral, microencapsulated form of timothy grass allergen. METHODS: In this double-blind, placebo-controlled study, 24 patients aged 19 to 55 years with grass pollen allergy were randomized to receive either microencapsulated timothy grass pollen extract or placebo once a day for 10 weeks. The dose of study drug was doubled weekly. Safety was evaluated through weekly visits, daily symptom diaries, and routine laboratory tests. Efficacy was evaluated by comparing medication use and symptoms scores during peak grass pollen season before and after treatment. Allergen-specific T-cell responses, cytokine production, and IgG, IgE, and skin reactivity were measured to evaluate immunologic mechanisms. RESULTS: Eleven of 12 patients in the active treatment group had a decrease in the combined medication and symptom score, but only 4 of 10 patients in the placebo group had a decrease in scores. The proliferative response to timothy grass was reduced by at least 30% in 9 of the 12 grass-treated patients, but only 3 of 11 placebo patients had a proliferative response reduction. Timothy grass-induced interleukin-5 messenger RNA was reduced in the active group, but not in the placebo group. There were no significant changes in either group in IgG, IgE, and skin reactivity. CONCLUSIONS: Oral immunotherapy with microencapsulated allergen induces a form of immunologic tolerance to the allergen and is a safe, efficient, and effective method of allergen immunotherapy.