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1.
J Clin Immunol ; 43(2): 512-520, 2023 02.
Article in English | MEDLINE | ID: mdl-36378426

ABSTRACT

PURPOSE: Biallelic loss-of-function variants in IKBKB cause severe combined immunodeficiency. We describe a case of autoimmunity and autoinflammation in a male infant with a heterozygous gain-of-function (GOF) IKBKB variant. METHODS: Case report and review of the literature. We performed in silico variant analysis, measurement of plasma soluble biomarkers associated with immune activation, functional stimulation of patient peripheral blood mononuclear cells, and functional validation of variants transduced in Jurkat cells. RESULTS: A patient with two heterozygous IKBKB variants (E518K and T559M) presents with previously undescribed autoimmune cytopenias and autoinflammation. He had decreased TNF-α-induced IkBα degradation in vitro, and had increased serum biomarkers associated with macrophage recruitment and activation. Jurkat cells transduced with the IKKb T559M variant showed increased basal levels of phosphorylation of IKKα/b and p65, and higher degradation of IkBα suggesting a GOF mechanism. No significant changes were observed in Jurkat cells transduced with the E518K variant. CONCLUSIONS: A GOF variant in IKBKB may associate with autoinflammation and autoimmunity highlighting a novel clinical phenotype.


Subject(s)
Autoimmunity , I-kappa B Kinase , Male , Humans , Autoimmunity/genetics , I-kappa B Kinase/genetics , Gain of Function Mutation , Leukocytes, Mononuclear , Biomarkers
2.
J Allergy Clin Immunol ; 150(6): 1556-1562, 2022 12.
Article in English | MEDLINE | ID: mdl-35987349

ABSTRACT

BACKGROUND: Newborn screening can identify neonatal T-cell lymphopenia through detection of a low number of copies of T-cell receptor excision circles in dried blood spots collected at birth. After a positive screening result, further diagnostic testing is required to determine whether the subject has severe combined immunodeficiency or other causes of T-cell lymphopenia. Even after thorough evaluation, approximately 15% of children with a positive result of newborn screening for T-cell receptor excision circles remain genetically undiagnosed. Identifying the underlying genetic etiology is necessary to guide subsequent clinical management and family planning. OBJECTIVE: We sought to elucidate the genetic basis of patients with T-cell lymphopenia without an apparent genetic diagnosis. METHODS: We used clinical genomic testing as well as functional and immunologic assays to identify and elucidate the genetic and mechanistic basis of T-cell lymphopenia. RESULTS: We report 2 unrelated individuals with nonsevere T-cell lymphopenia and abnormal T-cell receptor excision circles who harbor heterozygous loss-of-function variants in forkhead box I3 transcription factor (FOXI3). CONCLUSION: Our findings support the notion that haploinsufficiency of FOXI3 results in T-cell lymphopenia with variable expressivity and that FOXI3 may be a key modulator of thymus development.


Subject(s)
Genomics , Receptors, Antigen, T-Cell , Infant, Newborn , Child , Humans , Receptors, Antigen, T-Cell/genetics , T-Lymphocytes
3.
Clin Immunol ; 245: 109182, 2022 12.
Article in English | MEDLINE | ID: mdl-36368643

ABSTRACT

Newborn screening (NBS) for severe combined immunodeficiency (SCID) can identify infants with non-SCID T cell lymphopenia (TCL). The purpose of this study was to characterize the natural history and genetic findings of infants with non-SCID TCL identified on NBS. We analyzed data from 80 infants with non-SCID TCL in the mid-Atlantic region between 2012 and 2019. 66 patients underwent genetic testing and 41 (51%) had identified genetic variant(s). The most common genetic variants were thymic defects (33%), defects with unknown mechanisms (12%) and bone marrow production defects (5%). The genetic cohort had significantly lower median initial CD3+, CD4+, CD8+ and CD4/CD45RA+ T cell counts compared to the non-genetic cohort. Thirty-six (45%) had either viral, bacterial, or fungal infection; only one patient had an opportunistic infection (vaccine strain VZV infection). Twenty-six (31%) of patients had resolution of TCL during the study period.


Subject(s)
Lymphopenia , Severe Combined Immunodeficiency , Infant , Infant, Newborn , Humans , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics , Neonatal Screening , Genetic Testing , Lymphopenia/genetics , Lymphopenia/diagnosis , T-Lymphocytes
4.
J Pediatr ; 237: 125-135.e18, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34181987

ABSTRACT

OBJECTIVE: To assess demographic, clinical, and biomarker features distinguishing patients with multisystem inflammatory syndrome in children (MIS-C); compare MIS-C sub-phenotypes; identify cytokine biosignatures; and characterize viral genome sequences. STUDY DESIGN: We performed a prospective observational cohort study of 124 children hospitalized and treated under the institutional MIS-C Task Force protocol from March to September 2020 at Children's National, a quaternary freestanding children's hospital in Washington, DC. Of this cohort, 63 of the patients had the diagnosis of MIS-C (39 confirmed, 24 probable) and 61 were from the same cohort of admitted patients who subsequently had an alternative diagnosis (controls). RESULTS: Median age and sex were similar between MIS-C and controls. Black (46%) and Latino (35%) children were over-represented in the MIS-C cohort, with Black children at greatest risk (OR 4.62, 95% CI 1.151-14.10; P = .007). Cardiac complications were more frequent in critically ill patients with MIS-C (55% vs 28%; P = .04) including systolic myocardial dysfunction (39% vs 3%; P = .001) and valvular regurgitation (33% vs 7%; P = .01). Median cycle threshold was 31.8 (27.95-35.1 IQR) in MIS-C cases, significantly greater (indicating lower viral load) than in primary severe acute respiratory syndrome coronavirus 2 infection. Cytokines soluble interleukin 2 receptor, interleukin [IL]-10, and IL-6 were greater in patients with MIS-C compared with controls. Cytokine analysis revealed subphenotype differences between critically ill vs noncritically ill (IL-2, soluble interleukin 2 receptor, IL-10, IL-6); polymerase chain reaction positive vs negative (tumor necrosis factor-α, IL-10, IL-6); and presence vs absence of cardiac abnormalities (IL-17). Phylogenetic analysis of viral genome sequences revealed predominance of GH clade originating in Europe, with no differences comparing patients with MIS-C with patients with primary coronavirus disease 19. Treatment was well tolerated, and no children died. CONCLUSIONS: This study establishes a well-characterized large cohort of MIS-C evaluated and treated following a standardized protocol and identifies key clinical, biomarker, cytokine, viral load, and sequencing features. Long-term follow-up will provide opportunity for future insights into MIS-C and its sequelae.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/etiology , Systemic Inflammatory Response Syndrome/immunology , Adolescent , Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Nucleic Acid Testing , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Case-Control Studies , Child , Child, Preschool , Diagnosis, Differential , Female , Humans , Infant , Male , Pandemics , Phenotype , Phylogeny , Prospective Studies , Risk Factors , SARS-CoV-2/immunology , Severity of Illness Index , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/epidemiology
5.
Allergy ; 75(3): 588-595, 2020 03.
Article in English | MEDLINE | ID: mdl-31529494

ABSTRACT

BACKGROUND: Education and training in Allergy and Clinical Immunology (A/I) are characterized by a great variability worldwide. However, objective and worldwide data regarding this topic are lacking. METHODS: To investigate personal information, education, and involvement in scientific societies of juniors engaged in A/I field, a questionnaire was developed by representatives from the JMs' boards of the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma, and Immunology (AAAAI), and the World Allergy Organization (WAO). RESULTS: A total of 543 questionnaires were collected from 76 regions of all continents. The geographic distribution of responders was as follows: Africa-Middle East 3.0%, Asia-Pacific 21.4%, Europe 48.2%, Latin America 12.1%, and North America 15.3%. 59.0% of responders declared that A/I is recognized as a separate specialty in their country, Europe mostly accounting for that proportion. Primary interest in the field represents the main motivation for choosing A/I specialty. Concerning involvement in scientific societies, 41.1% of responders ever attended an EAACI Congress, 20.6% an AAAAI Congress, and 20.4% a WAO Congress. According to 40.3% of responders, scientific societies do not provide enough opportunities for young members, and 96.4% believes in a more intensive cooperation between the A/I Societies. CONCLUSIONS: The survey provides the first worldwide perspective about A/I specialty. It represents the first ever example of a structured collaboration between the junior members (JMs) of the three main A/I Societies. The findings suggest the need for harmonization, at least in terms of training and formation in the field of A/I worldwide.


Subject(s)
Allergy and Immunology , Asthma , Hypersensitivity , Academies and Institutes , Europe/epidemiology , Humans , Hypersensitivity/epidemiology
8.
J Nutr ; 142(2): 251-7, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22190023

ABSTRACT

Though adolescents consume more fructose than any other age group, the relationship between fructose consumption and markers of cardiometabolic risk has not been established in this population. We determined associations of total fructose intake (free fructose plus one-half the intake of free sucrose) with cardiometabolic risk factors and type of adiposity in 559 adolescents aged 14-18 y. Fasting blood samples were measured for glucose, insulin, lipids, adiponectin, and C-reactive protein. Diet was assessed with 4-7 24-h recalls and physical activity (PA) was determined by accelerometry. Fat-free soft tissue (FFST) mass and fat mass were measured by DXA. The s.c. abdominal adipose tissue (SAAT) and visceral adipose tissue (VAT) were assessed using MRI. Multiple linear regression, adjusting for age, sex, race, Tanner stage, FFST mass, fat mass, PA, energy intake, fiber intake, and socioeconomic status, revealed that fructose intake was associated with VAT (ß = 0.13; P = 0.03) but not SAAT (P = 0.15). Significant linear upward trends across tertiles of fructose intake were observed for systolic blood pressure, fasting glucose, HOMA-IR, and C-reactive protein after adjusting for the same covariates (all P-trend < 0.04). Conversely, significant linear downward trends across tertiles of fructose intake were observed for plasma HDL-cholesterol and adiponectin (both P-trend < 0.03). When SAAT was added as a covariate, these trends persisted (all P-trend < 0.05). However, when VAT was included as a covariate, it attenuated these trends (all P-trend > 0.05). In adolescents, higher fructose consumption is associated with multiple markers of cardiometabolic risk, but it appears that these relationships are mediated by visceral obesity.


Subject(s)
Adiposity/drug effects , Cardiovascular Diseases/etiology , Fructose/administration & dosage , Fructose/adverse effects , Metabolic Diseases/etiology , Adolescent , Biomarkers , Diet , Female , Humans , Intra-Abdominal Fat/drug effects , Male , Risk Factors
9.
J Pediatr ; 158(2): 215-20, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20855079

ABSTRACT

OBJECTIVE: To examine the relationships of race, sex, adiposity, adipokines, and physical activity to telomere length in adolescents. STUDY DESIGN: Leukocyte telomere length (T/S ratio) was assessed cross-sectionally in 667 adolescents (aged 14-18 years; 48% African-Americans; 51% girls) using a quantitative polymerase chain reaction method. Generalized estimating equations analyses were performed. RESULTS: Telomere length was greater in the African-American adolescents than in the Caucasian adolescents (age- and sex-adjusted T/S ratio ± SE, 1.32 ± 0.01 vs 1.27 ± 0.01: P = .014) and greater in girls than in boys (age- and race-adjusted T/S ratio ± SE, 1.31 ± 0.01 vs 1.27 ± 0.01; P = .007). None of the adiposity or adipokine measures explained a significant proportion of the variance in telomere length. Vigorous physical activity was positively associated with telomere length (adjusted R(2) = 0.019; P = .009) and accounted for 1.9% of the total variance only in girls. CONCLUSIONS: This study, conducted in a biracial adolescent cohort, demonstrated that (1) race and sex differences in telomere length have already emerged during adolescence; (2) adiposity and adipokines are not associated with telomere length at this age; and (3) the antiaging effect of vigorous physical activity may begin in youth, especially in girls.


Subject(s)
Adipokines/blood , Adiposity/ethnology , Adiposity/genetics , Motor Activity/physiology , Telomere/genetics , Adolescent , Black or African American/genetics , Anthropometry , Body Mass Index , Cross-Sectional Studies , Female , Genetic Predisposition to Disease/epidemiology , Health Status , Humans , Leukocytes , Obesity/ethnology , Obesity/genetics , Polymerase Chain Reaction/methods , Risk Assessment , Sensitivity and Specificity , Sex Factors , White People/genetics
10.
J Pediatr Endocrinol Metab ; 24(3-4): 119-24, 2011.
Article in English | MEDLINE | ID: mdl-21648277

ABSTRACT

OBJECTIVES: To determine gender or race differences in associations between adiposity and leptin, and whether adiponectin moderates these relationships. METHODS: Subjects were 441 adolescents, 14-18 years old (44% black, 56% white; 50% female, 50% male). Percent body fat (%BF) was measured with dual-energy X-ray absorptiometry. Leptin and adiponectin were measured using immunoassays. RESULTS: Among the four groups (white boys, white girls, black boys and black girls), white girls had the highest adiponectin (p = 0.0017) and black girls had the highest leptin (p = 0.0164). Percent BF and leptin were positively correlated (p = 0.0164). The %BF-leptin relationship was stronger in boys than girls (p < 0.0001). Those with lower adiponectin had a stronger %BF-leptin relationship than those with high adiponectin in the entire sample (p = 0.0220). Statistical models were adjusted for age, race, gender and the interaction between race and gender. CONCLUSION: Our data suggest a protective metabolic interaction for adiponectin and lend additional support for obesity prevention strategies in adolescents.


Subject(s)
Adiponectin/physiology , Adiposity/physiology , Leptin/blood , Absorptiometry, Photon , Adipose Tissue/diagnostic imaging , Adiposity/ethnology , Adolescent , Black or African American/ethnology , Female , Georgia/epidemiology , Humans , Male , Obesity/ethnology , Obesity/prevention & control , Sex Factors , White People/ethnology
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