Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.
Membrane receptors and ion transport mechanisms probably have an important role in lymphocyte activation leading to T-lymphocyte proliferation in the immune response. Here we have applied a gigaohm-seal patch clamp technique to reveal the identity and properties of ion channels in human T lymphocytes. A voltage-dependent potassium channel bearing a resemblance to the delayed rectifier of nerve and muscle cells was found to be the predominant ion channel in these cells. In the whole cell recording conformation, the channels open with sigmoid kinetics during depolarizing voltage steps, reaching a maximum K+ conductance of 3-5 nS. The current subsequently becomes almost completely inactivated during a long-lasting depolarization. Currents through single K+ channels recorded in whole cell and outside-out patch recording conformations reveal a unitary channel conductance of about 16 pS in normal Ringer solution. Thus, the peak current corresponds to approximately 200-300 conducting K+ channels per cell. Phytohaemagglutinin (PHA), at concentrations that produce mitogenesis, alters K+ channel gating within 1 min of addition to the bathing solution, causing channels to open more rapidly and at more negative membrane potentials. 3H-thymidine incorporation by T lymphocytes following PHA stimulation is inhibited by the 'classical' K+ channel blockers tetraethylammonium and 4-aminopyridine, and also by quinine, at doses found to block the K+ channel in voltage-clamped T lymphocytes, suggesting that K+ channels may play a part in mitogenesis.
SUMMARY1. Human peripheral T lymphocytes were studied at 20-24 TC using the gigaohm seal recording technique in whole-cell or outside-out patch conformations. The predominant ion channel present under the conditions employed was a voltage-gated K+ channel closely resembling delayed rectifier K+ channels of nerve and muscle.2. The maximum K+ conductance in ninety T lymphocytes ranged from 0-7 to 8-9 nS, with a mean of 4-2 nS. The estimated number of K+ channels per cell is 400, corresponding to a density of about three channels/sm2 apparent membrane area.3. The activation of K+ currents could be fitted by Hodgkin-Huxley type n4 kinetics. The K+ conductance in Ringer solution was half-maximal at -40 mV.4. The time constant of K+ current inactivation was practically independent of voltage except near the threshold for activating the K+ conductance. Recovery from inactivation was slow and followed complex kinetics. Steady-state inactivation was half-maximal at -70 mV, and was complete at positive potentials.5. Permeability ratios, relative to K+, determined from reversal potential measurements were: K+(1-0) > Rb+(0-77) > NH4+(0-10) > Cs+(0-02) > Na+(< 0'01).6. Currents through K+ channels display deviations from the independence principle. The limiting outward current increases when external K+ is increased, and Rb+ carries less inward current than expected from its relative permeability.7. Tail current kinetics were slowed about 2-fold by raising the external K+ concentration from 4-5 to 160 mm, and were 5 times slower in Rb+ Ringer solution than in K+ Ringer solution.8. Single K+ channel currents had two amplitudes corresponding to about 9 and 16 pS in Ringer solution. Replacing Ringer solution with isotonic K+ Ringer solution increased the unitary conductance and resulted in inward rectification of the unitary current-voltage relation. Comparable effects ofexternal K+ were seen in the whole-cell conductance and instantaneous current-voltage relation.9. Several changes in the K+ conductance occurred during the first few minutes after achievement of the whole-cell conformation. Most are explainable by dissipation of a 10-20 mV junction potential between pipette solution and the cytoplasm, and by the use of a holding potential more negative than the resting potential. However, 11. Inward currents were observed in a few cells. These currents displayed voltage dependence, kinetics, unitary conductance, and pharmacological sensitivity characteristic of voltage-gated Na+ channel currents in excitable cells. Tetrodotoxin did not measurably inhibit phytohaemagglutinin-induced mitogenesis in T lymphocytes.
Aging represents a state of paradox where chronic inflammation is associated with declining immune responses. Dendritic cells (DCs) are the major APCs responsible for initiating an immune response. However, DC functions in aging have not been studied in detail. In this study, we have compared the innate immune functions of monocyte-derived myeloid DCs from elderly subjects with DCs from young individuals. We show that although phenotypically comparable, DCs from the aging are functionally different from DCs from the young. In contrast to DCs from the young, DCs from elderly individuals display 1) significantly reduced capacity to phagocytose Ags via macropinocytosis and endocytosis as determined by flow cytometry; 2) impaired capacity to migrate in vitro in response to the chemokines MIP-3β and stromal cell-derived factor-1; and 3) significantly increased LPS and ssRNA-induced secretion of TNF-α and IL-6, as determined by ELISA. Investigations of intracellular signaling revealed reduced phosphorylation of AKT in DCs from the aging, indirectly suggesting decreased activation of the PI3K pathway. Because the PI3K-signaling pathway plays a positive regulatory role in phagocytosis and migration, and also functions as a negative regulator of TLR signaling by inducing activation of p38 MAPK, this may explain the aberrant innate immune functioning of DCs from elderly subjects. Results from real-time PCR and protein expression by flow cytometry demonstrated an increased expression of phosphatase and tensin homolog, a negative regulator of the PI3K-signaling pathway, in DCs from the aging. Increased phosphatase and tensin homolog may thus be responsible for the defect in AKT phosphorylation and, therefore, the altered innate immune response of DCs from elderly humans.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.