Multiomics uncovers developing immunological lineages in human

The development of the human immune system during embryonic and fetal life has historically been difficult to research due to limited access to human tissue. Experimental animal models have been widely used to study development but cellular and molecular programmes may not be conserved across species. The advent of multiomic single-cell technologies and an increase in human developmental tissue biobank resources have facilitated single-cell multiomic studies focused on human immune development. A critical question in the near future is "How do we best reconcile scientific findings across multiple omic modalities, developmental time, and organismic space?" In this review, we discuss the application of single-cell multiomic technologies to unravel the major cellular lineages in the prenatal human immune system. We also identify key areas where the combined power of multiomics technologies can be leveraged to address specific immunological gaps in our current knowledge and explore new research horizons in human development.     

Immunologic mechanisms in hypersensitivity pneumonitis: I. Evidence for cell-mediated immunity and complement fixation in pigeon breeders' disease

Immunologic studies were performed on 5 patients with pigeon breeders' disease. Intradermal injection of pigeon serum produced an immediate wheal-and-flare reaction within 15 minutes and a secondary Arthus-type reaction within 4 to 8 hours. Immunofluorescent studies of the secondary reaction site showed IgG, C3, and C4 in 2 patients. Patients' sera produced multiple precipitin bands with pigeon serum when reacted by double diffusion in gel. IgG antibody isolated from each of the patients' serum formed precipitating immune complexes that fixed large amounts of complement (C4) when added to fresh human serum. Peripheral blood lymphocytes from 4 of the 5 patients produced macrophage migration inhibitory factor (MIF) when challenged with dilute pigeon serum. These studies are the first to show complement fixing antibodies and macrophage MIF production by lymphocytes from patients with hypersensitivity lung disease and suggest that both humoral and cellular immunity may be important in the pathogenesis of these disorders.     

Serial Testing of Postural Control After Acute Lateral Ankle Sprain

OBJECTIVE: To identify subjects' changes in postural control during single-leg stance in the 4 weeks after acute lateral ankle sprain. DESIGN AND SETTING: We used a 2 x 2 x 3 (side-by-plane-by-session) within-subjects design with repeated measures on all 3 factors. All tests were performed in a university laboratory. SUBJECTS: Seventeen young adults (9 men, 8 women; age, 21.8 +/- 5.9 years; mass, 74.9 +/- 10.5 kg; height, 176.9 +/- 7.1 cm) who had sustained unilateral acute mild or moderate lateral ankle sprains. MEASUREMENTS: Measures of center-of-pressure excursion length, root mean square velocity of center-of-pressure excursions (VEL), and range of center-of-pressure excursions (RANGE) were calculated separately in the frontal and sagittal planes during 5-second trials of static single-leg stance. RESULTS: We noted significant side-by-plane-by-session interactions for magnitude of center-of-pressure excursions in a given trial (PSL) (P =.004), VEL (P =.011), and RANGE (P =.009). Both PSL and VEL in the frontal plane were greater in the injured limbs compared with the uninjured limbs on day 1 and during week 2 but not during week 4, whereas sagittal-plane differences existed during all 3 testing sessions. Injured-limb, frontal-plane RANGE scores were greater than uninjured values at day 1 but not during weeks 2 or 4. No significant differences in sagittal-plane RANGE scores were seen. CONCLUSIONS: Postural control was significantly impaired in the injured limbs at day 1 and during week 2 after lateral ankle sprain but not during week 4. Consistent improvement in postural control measures on both injured and uninjured limbs was seen throughout the 4 weeks after ankle sprain.     

Concurrent de novo interstitial deletion of band 2p22 and reciprocal translocation (3;7)(p21;q22).

A child is described with a de novo interstitial deletion of band 2p22 and a reciprocal translocation (3;7)(p21;q22). The child has mild developmental delay, coloboma of the right eye, and Hirschsprung's disease. The clinical and cytogenetic findings are described.     

Putative role for interleukin-7 in the maintenance of the recirculating naive CD4+ T-cell pool

The capacity of the immune system to respond efficiently to new antigens depends upon a continuous source of naive CD4+ T cells. Such cells exit from the thymus and join the recirculated T-cell pool. Factors present at the sites of naive CD4+ T-cell circulation must be responsible for their survival, since upon removal from their host, naive CD4+ T cells die. However, such factors remain unknown. The presence of the cytokine interleukin-7 (IL-7) in secondary lymphoid organs and the continuous expression of its receptor on naive CD4+ T cells prompted us to examine the possibility that IL-7 might be a survival factor for naive CD4+ T cells. Using naive CD4+ T cells isolated from cord blood we show that IL-7, but not IL-2, can maintain naive CD4+ T-cell viability in vitro for at least 15 days. In addition, we find that IL-7 can induce modest proliferation of naive CD4+ T cells without affecting either their cell surface phenotype or their ability to respond to antigenic stimulation. We also find that after anti-CD3 stimulation, naive CD4+ T cells lose that ability to respond to IL-7. However, if cells are primed with IL-7 prior to antigenic stimulation, their proliferative responses are enhanced. Together, these data suggest a novel and important role for IL-7 in the maintenance and maturation of naive CD4+ T cells, ensuring that they can respond maximally when they first meet antigen in secondary lymphoid tissue.     

Control of motor-unit tension by rate modulation during sustained contractions in reinnervated cat muscle

1. The aim of this study was to describe the control of tension by rate modulation of single motor units in reinnervated muscle. 2. Single fast-twitch motor units were isolated from medial gastrocnemius (MG) muscles in two groups of anesthetized adult cats: one in which the MG nerve was left untreated and another in which that nerve was sectioned and immediately sutured together 10-33 mo before study. Together with conventional measures of isometric contractile properties, units were tested with the use of computer-controlled feedback regulation of stimulation rate to maintain tension during continuous isometric contraction at a constant submaximal level [25% of maximal tension (Pmax)]. 3. For motor units from both groups, stimulation rate began to decline after target tension was attained and then settled at lower values for variable durations before rapidly increasing, usually within the last 5% of the contraction's duration, until reaching the experimentally selected limit of 100 pulses/s (pps). 4. Measures of the declining phase in stimulation rate occurring at the beginning of sustained contraction were not significantly different in comparison of untreated versus reinnervated muscles. These measures included 1) the magnitude of the decrease in rate, 2) the minimum rate attained, and 3) the time taken to reach minimum stimulation rate expressed as a fraction of endurance time (Et, total duration of the sustained contraction). 5. Most fast-twitch units from reinnervated muscles fell within normal limits for both endurance time and the number of stimuli applied over that period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of Phagocytosis-Associated Chemiluminescence by Superoxide Dismutase

During the process of phagocytosis, human leukocytes emit a burst of luminescence which can be measured in a liquid scintillation spectrometer. The enzyme superoxide dismutase, which removes superoxide anions (O(2.)), inhibited this chemiluminescence by 70% at a concentration of 100 mug/ml. The enzyme did not inhibit phagocytosis. These results support other studies indicating that O(2.) is elaborated by phagocytizing leukocytes. They also indicate that O(2.) plays a major role in phagocytosis-associated chemiluminescence, though not necessarily as the luminescing agent. Catalase and benzoate inhibited the chemiluminescence of phagocytosis to a slight extent, suggesting that hydrogen peroxide and hydroxyl radical, respectively, might also be involved in this phenomenon. The relationship between the mediators of chemiluminescence and those responsible for phagocytic bactericidal activity remains to be defined.     

Muscle-epidermis interactions affect exoskeleton patterning in Caenorhabditis elegans.

The C. elegans hypodermis is a single epithelial cell layer separated from the musculature by a thin basement membrane on its basal surface. The hypodermis secretes the extracellular material of the cuticle from its apical surface. The regulation of cuticle synthesis and apical secretion is not well understood. UNC-95 is a component of the muscle dense bodies and M-lines, which are integrin-based adhesion complexes required for force transduction to the cuticle. Using gene expression profiling and in vivo assays, we show that, in unc-95 mutant worms, there is an increase in expression levels of a group of hypodermal and pharyngeal genes related to cuticle structure and molting. Moreover, the cuticle structure of unc-95 mutant adult is impaired. Our findings suggest that aberrant force transduction from the structurally impaired muscle attachments across the basement membrane to the underlying hypodermis elicits intercellular signaling that plays a role in regulating cuticle synthesis and patterning.     

Candidemia in pediatric outpatients receiving home total parenteral nutrition.

This is a cohort study of pediatric outpatients receiving total parenteral nutrition (TPN) and follow-up care in a Tennessee hospital between January and June 1999. The study was conducted following an increase in the incidence of candidemia. Of 13 children receiving home TPN, five had candidemia; three were due to Candida parapsilosis. Case patients were more likely to have an underlying hematologic disease (P = 0.02) as well as previous history of fungemia (P = 0.02). Two case patients had successive candidemia episodes 3 months apart; karyotypes and RAPD profiles of each patient's successive C. parapsilosis isolates were similar. Candida spp. were frequently detected in hand cultures from cohort members (four of 10) and family member caregivers (nine of 11); C parapsilosis was isolated from five caregivers. Our findings underscore the challenges of maintaining stringent infection control practices in the home health care setting and suggest the need for more intensive follow-up and coordination of home TPN therapy among pediatric patients.     

Aberrant actin cytoskeleton leads to accelerated proliferation of corneal epithelial cells in mice deficient for destrin (actin depolymerizing factor)

Corneal disease is the most common cause of bilateral blindness in the world. Visual loss in this condition is often due to changes in morphology and function of the corneal epithelial surface. Corneal disease-1 (corn1) and corn1(2J) are spontaneous mouse mutants that develop irregular thickening of the corneal epithelium, similar to that observed in human corneal surface disease. These autosomal-recessive mutations cause an increase in the rate of proliferation of the corneal epithelial cells. Here, we report that the phenotypes in both mutants are caused by mutations within the destrin gene (also known as actin-depolymerizing factor). By positional cloning, we identified a deletion encompassing the entire coding sequence of the destrin gene in corn1 mice, and a point mutation (Pro106Ser) in the coding sequence of destrin in corn1(2J) mice. In situ analysis showed that destrin is highly expressed in the corneal epithelium. Consistent with the cellular roles for destrin, an essential regulator of actin filament turnover that acts by severing and enhancing depolymerization of actin filament, we observed that the corn1 mutations increased the content of filamentous actin in corneal epithelial cells. Our results suggest an in vivo connection between remodeling of the actin cytoskeleton and the control of cell proliferation, and a new pathway through which an aberrant actin cytoskeleton can cause epithelial hyperproliferation.