Stability and heterogeneity in the antimicrobiota reactivity of human milk-derived immunoglobulin A.

Immunoglobulin A (IgA) is secreted into breast milk and is critical for both protecting against enteric pathogens and shaping the infant intestinal microbiota. The efficacy of breast milk-derived maternal IgA (BrmIgA) is dependent upon its specificity; however, heterogeneity in BrmIgA binding ability to the infant microbiota is not known. Using a flow cytometric array, we analyzed the reactivity of BrmIgA against bacteria common to the infant microbiota and discovered substantial heterogeneity between all donors, independent of preterm or term delivery. Surprisingly, we also observed intradonor variability in the BrmIgA response to closely related bacterial isolates. Conversely, longitudinal analysis showed that the antibacterial BrmIgA reactivity was relatively stable through time, even between sequential infants, indicating that mammary gland IgA responses are durable. Together, our study demonstrates that the antibacterial BrmIgA reactivity displays interindividual heterogeneity but intraindividual stability. These findings have important implications for how breast milk shapes the development of the preterm infant microbiota and protects against necrotizing enterocolitis.

Stability and heterogeneity in the anti-microbiota reactivity of human milk-derived Immunoglobulin A.

Immunoglobulin A (IgA) is secreted into breast milk and is critical to both protecting against enteric pathogens and shaping the infant intestinal microbiota. The efficacy of breast milk-derived maternal IgA (BrmIgA) is dependent upon its specificity, however heterogeneity in BrmIgA binding ability to the infant microbiota is not known. Using a flow cytometric array, we analyzed the reactivity of BrmIgA against bacteria common to the infant microbiota and discovered substantial heterogeneity between all donors, independent of preterm or term delivery. We also observed intra-donor variability in the BrmIgA response to closely related bacterial isolates. Conversely, longitudinal analysis showed that the anti-bacterial BrmIgA reactivity was relatively stable through time, even between sequential infants, indicating that mammary gland IgA responses are durable. Together, our study demonstrates that the anti-bacterial BrmIgA reactivity displays inter-individual heterogeneity but intra-individual stability. These findings have important implications for how breast milk shapes the development of the infant microbiota and protects against Necrotizing Enterocolitis. Summary: We analyze the ability of breast milk-derived Immunoglobulin A (IgA) antibodies to bind the infant intestinal microbiota. We discover that each mother secretes into their breast milk a distinct set of IgA antibodies that are stably maintained over time.

Functional Confirmation of DNA Repair Defect in Ataxia Telangiectasia (AT) Infants Identified by Newborn Screening for Severe Combined Immunodeficiency (NBS SCID).

BACKGROUND: The introduction of newborn screening for severe combined immunodeficiencies (NBS SCID) in 2010 was a significant public health milestone. Although SCID was the primary target, several other conditions associated with severe T-cell lymphopenia have subsequently been identified as secondary targets. The differential diagnosis in infants with an abnormal T-cell receptor excision circle result on NBS SCID who do not meet criteria for typical SCID is often broad, and often the evaluation of these conditions requires immunological and functional testing, in conjunction with genetic analysis, to obtain an accurate diagnosis and develop an appropriate management and treatment plan. OBJECTIVE: We describe here 3 infants identified by NBS SCID, who required additional workup as they did not have a typical SCID phenotype and meet the relevant diagnostic criteria. Genetic testing identified pathogenic variants in ATM in all 3 patients, and the pathogenicity of the variants was confirmed by a functional flow cytometry assay. METHODS: The patients underwent immunological and genetic workup to identify an underlying cause of their abnormal NBS SCID. Ataxia telangiectasia (AT) was suspected based on clinical and family history, and immunological analyses. The diagnosis was confirmed in all patients with a rapid functional flow cytometric assay and genetic testing. RESULTS: A rapid functional flow cytometry assay was used as a diagnostic and confirmatory tool, in conjunction with genetic testing, to make a diagnosis of AT. Experimental validation of the causal relationship between genotype and phenotype allowed for expeditious diagnosis, which facilitated early discussions with families regarding prognosis, treatment, and management. CONCLUSIONS: Even with increased rapidity and access to genetic results, functional testing is required for clinical diagnosis in infants identified by NBS SCID who do not fit into the classic categories or have novel genetic variants to confirm the diagnosis. Consideration should be given to the use of functional assays as an essential component of an integrated evaluation to characterize the genetics and mechanisms of inborn errors of immunity.

An assessment of trends in the frequency and duration of Karenia brevis red tide blooms on the South Texas coast (western Gulf of Mexico).

Limited data coverage on harmful algal blooms (HABs) in some regions makes assessment of long-term trends difficult, and also impedes understanding of bloom ecology. Here, observations reported in a local newspaper were combined with cell count and environmental data from resource management agencies to assess trends in Karenia brevis "red tide" frequency and duration in the Nueces Estuary (Texas) and adjacent coastal waters, and to determine relationships with environmental factors. Based on these analyses, the Coastal Bend region of the Texas coast has experienced a significant increase in the frequency of red tide blooms since the mid-1990s. Salinity was positively correlated with red tide occurrence in the Nueces Estuary, and a documented long-term increase in salinity of the Nueces Estuary may be a major factor in the long-term increase in bloom frequency. This suggests that freshwater inflow management efforts in Texas should consider impacts on red tide habitat suitability (i.e., salinity regime) in downstream estuaries. Natural climate variability such as the El Niño-Southern Oscillation, which is strongly related to rainfall and salinity in Central and South Texas, was also an influential predictor of red tide presence/absence. Though no significant change in the duration of blooms was detected, there was a negative correlation between duration and temperature. Specifically, summer-like temperatures were not favorable to K. brevis bloom development. The relationships found here between red tide frequency/duration and environmental drivers present a new avenue of research that will aid in refining monitoring and forecasting efforts for red tides on the Texas coast and elsewhere. Findings also highlight the importance of factors (i.e., salinity, temperature) that are likely to be altered in the future due to both population growth in coastal watersheds and anthropogenic climate change.

A Prospective Observational Study of Hypogammaglobulinemia in the First Year After Lung Transplantation.

BACKGROUND: Immunosuppressive therapies have led to improved survival for lung transplant (LT) recipients but these therapies can lead to hypogammaglobulinemia (HGG) and potentially an increased risk of infection. Large prospective studies have not been performed to evaluate the impact of HGG on outcomes for LT recipients. METHODS: This is a single-center prospective observational study of LT recipients. Pretransplant and posttransplant IgG levels were measured and related to infection, rejection, antibiotic use, and immunosuppression use. RESULTS: One hundred thirty-three LT recipients were prospectively evaluated. Pretransplant IgG values were higher than IgG values at the time of transplant or any time thereafter (all P < 0.0001). Severe HGG (IgG < 400 mg/dL) was highest at the time of transplant (32.4%) while at 3, 6, 9, and 12 months posttransplant the prevalence of severe HGG was 7.4%, 7.5%, 8.9%, and 6.3%, respectively. Severe HGG was associated with 2 or more pneumonias (P = 0.0006) and increased number of antibiotic courses (P = 0.003) compared with the subjects without severe HGG. Pretransplant IgG level and less than 30% of pretransplant protective pneumococcal antibody levels were identified as pretransplant risk factors for severe HGG. In multivariate analysis, chronic obstructive pulmonary disease as the underlying disease and the use of basiliximab as the induction agent in conjunction with higher prednisone and mycophenolate dosing were most predictive of severe HGG (P = 0.005), whereas the combination of age, severe HGG and number of acute steroid courses were most predictive of total days of pneumonia (P = 0.0001). CONCLUSIONS: Our large prospective study identifies risk factors for severe HGG after LT and demonstrates that LT recipients with severe HGG are at increased risk for recurrent pneumonias and more antibiotic courses.