Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy.

STAT2 is distinguished from other STAT family members by its exclusive involvement in type I and III interferon (IFN-I/III) signaling pathways, and its unique behavior as both positive and negative regulator of IFN-I signaling. The clinical relevance of these opposing STAT2 functions is exemplified by monogenic diseases of STAT2. Autosomal recessive STAT2 deficiency results in heightened susceptibility to severe and/or recurrent viral disease, whereas homozygous missense substitution of the STAT2-R148 residue is associated with severe type I interferonopathy due to loss of STAT2 negative regulation. Here we review the clinical presentation, pathogenesis, and management of these disorders of STAT2.

Persistent High Percentage of HLA-DR+CD38high CD8+ T Cells Associated With Immune Disorder and Disease Severity of COVID-19.

Background: The global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR+CD38+ CD8+ T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38+HLA-DR+ CD8+ T population was reported to play contradictory roles in SARS-CoV-2 infection. Methods: A total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3-7 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines/chemokines/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally. Results: We revealed that the HLA-DR+CD38+ CD8+ T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR+CD38dim and HLA-DR+CD38hi. We observed a persistent accumulation of HLA-DR+CD38hi CD8+ T cells in severe COVID-19 patients. These HLA-DR+CD38hi CD8+ T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR+CD38dim CD8+ T cells. Moreover, the clinical and laboratory data supported that only HLA-DR+CD38hi CD8+ T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients. Conclusions: Our findings indicated that HLA-DR+CD38hi CD8+ T cells were correlated with disease severity of COVID-19 rather than HLA-DR+CD38dim population.

Administration of COVID-19 vaccines in immunocompromised patients.

Since the beginning of vaccination programs against COVID-19 in different countries, several populations such as patients with specific immunological conditions have been considered as the priorities for immunization. In this regard, patients with autoimmune diseases or those receiving immunosuppressive agents and anti-cancer therapies, need special attention. However, no confirmed data is presently available regarding COVID-19 vaccines in these populations due to exclusion from the conducted clinical trials. Given the probable suppression or over-activation of the immune system in such patients, reaching a consensus for their vaccination is critical, besides gathering data and conducting trials, which could probably clarify this matter in the future. In this review, besides a brief on the available COVID-19 vaccines, considerations and available knowledge about administering similar vaccines in patients with cancer, hematopoietic stem cell transplantation, solid organ transplantation, multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatologic and dermatologic autoimmune disorders are summarized to help in decision making. As discussed, live-attenuated viruses, which should be avoided in these groups, are not employed in the present COVID-19 vaccines. Thus, the main concern regarding efficacy could be met using a potent COVID-19 vaccine. Moreover, the vaccination timing for maximum efficacy could be decided according to the patient's condition, indicated medications, and the guides provided here. Post-vaccination monitoring is also advised to ensure an adequate immune response. Further studies in this area are urgently warranted.

COVID-19 Vaccination in Fragile Patients: Current Evidence and an Harmonized Transdisease Trial.

Patients diagnosed with malignancy, neurological and immunological disorders, i.e., fragile patients, have been excluded from COVID-19 vaccine trials. However, this population may present immune response abnormalities, and relative reduced vaccine responsiveness. Here we review the limited current evidence on the immune responses to vaccination of patients with different underlying diseases. To address open questions we present the VAX4FRAIL study aimed at assessing immune responses to vaccination in a large transdisease cohort of patients with cancer, neurological and rheumatological diseases.

Antibody response to inactivated COVID-19 vaccine (CoronaVac) in immune-mediated diseases: a controlled study among hospital workers and elderly.

OBJECTIVE: To assess antibody response to inactivated COVID-19 vaccine in patients with immune-mediated diseases (IMD) among hospital workers and people aged 65 and older. METHODS: In this cross-sectional study, we studied 82 hospital workers with IMD (mean age: 42.2 ± 10.0 years) and 300 (mean age: 41.7 ± 9.9 years) controls. Among + 65 aged population, we studied 22 (mean age: 71.4 ± 4.5 years) patients and 47 controls (mean age: 70.9 ± 4.8 years). All study subjects had a negative history for COVID-19. Sera were obtained after at least 21 days following the second vaccination. Anti-spike IgG antibody titers were measured quantitatively using a commercially available immunoassay method. RESULTS: Patients with IMD were significantly less likely to have detectable antibodies than healthy controls both among the hospital workers (92.7% vs 99.7%, p < 0.001) and elderly population (77.3% vs 97.9%, p = 0.011). Among patients with IMD, those using immunosuppressive or immune-modulating drugs (64/75, 85.3%) were significantly less likely to have detectable antibodies compared to those off treatment (29/29, 100%) (p = 0.029). Additionally, a negative association between age and the antibody titer categories among patients (r = - 0.352; p < 0.001) and controls (r = - 0.258; p < 0.001) were demonstrated. CONCLUSIONS: Among hospital workers, the vast majority of patients with IMD and immunocompetent controls developed a significant humoral response following the administration of the second dose of inactivated COVID-19 vaccine. This was also true for the elderly population, albeit with lower antibody titers. Immunosuppressive use, particularly rituximab significantly reduced antibody titers. Antibody titers were significantly lower among those aged ≥ 60 years both in patient and control populations. Whether these individuals should get a booster dose warrants further studies.

Profiling of immune dysfunction in COVID-19 patients allows early prediction of disease progression.

With a rising incidence of COVID-19-associated morbidity and mortality worldwide, it is critical to elucidate the innate and adaptive immune responses that drive disease severity. We performed longitudinal immune profiling of peripheral blood mononuclear cells from 45 patients and healthy donors. We observed a dynamic immune landscape of innate and adaptive immune cells in disease progression and absolute changes of lymphocyte and myeloid cells in severe versus mild cases or healthy controls. Intubation and death were coupled with selected natural killer cell KIR receptor usage and IgM+ B cells and associated with profound CD4 and CD8 T-cell exhaustion. Pseudo-temporal reconstruction of the hierarchy of disease progression revealed dynamic time changes in the global population recapitulating individual patients and the development of an eight-marker classifier of disease severity. Estimating the effect of clinical progression on the immune response and early assessment of disease progression risks may allow implementation of tailored therapies.

Potential roles of micronutrient deficiency and immune system dysfunction in the coronavirus disease 2019 (COVID-19) pandemic.

Preliminary studies indicate that a robust immune response across different cell types is crucial in recovery from coronavirus disease 2019 (COVID-19). An enormous number of investigations point to the vital importance of various micronutrients in the interactions between the host immune system and viruses, including COVID-19. There are complex and multifaceted links among micronutrient status, the host immune response, and the virulence of pathogenic viruses. Micronutrients play a critical role in the coordinated recruitment of innate and adaptive immune responses to viral infections, particularly in the regulation of pro- and anti-inflammatory host responses. Furthermore, inadequate amounts of micronutrients not only weaken the immune system in combating viral infections, but also contribute to the emergence of more virulent strains via alterations of the genetic makeup of the viral genome. The aim of this study was to evaluate the evidence that suggests the contribution of micronutrients in the spread as well as the morbidity and mortality of COVID-19. Both the presence of micronutrient deficiencies among infected individuals and the effect of micronutrient supplementation on the immune responses and overall outcome of the disease could be of great interest when weighing the use of micronutrients in the prevention and treatment of COVID-19 infection. These investigations could be of great value in dealing with future viral epidemics.