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BackgroundBiological sex plays an integral role in the immune response to various pathogens. The underlying basis for these sex differences is still not well defined. Here, we show that Coxsackievirus B3 (CVB3) induces a viral-specific CD4+ T cell response that can protect female mice from mortality.MethodsWe inoculated C57BL/6 Ifnar-/- mice with CVB3. We investigated the T cell response in the spleen and mesenteric lymph nodes in male and female mice following infection.ResultsWe found that CVB3 can induce expansion of CD62Llo CD4+ T cells in the mesenteric lymph node and spleen of female but not male mice as early as 5 days post-inoculation, indicative of activation. Using a recombinant CVB3 virus expressing a model CD4+ T cell epitope, we found that this response is due to viral antigen and not bystander activation. Finally, the depletion of CD4+ T cells before infection increased mortality in female mice, indicating that CD4+ T cells play a protective role against CVB3 in our model.ConclusionsOverall, these data demonstrated that CVB3 can induce an early CD4 response in female but not male mice and further emphasize how sex differences in immune responses to pathogens affect disease.

Sex is a significant contributor to the outcome of human infections. Males are frequently more susceptible to viral, bacterial, and fungal infections, often attributed to weaker immune responses. In contrast, a heightened immune response in females enables better pathogen elimination but leaves females more predisposed to autoimmune diseases. Unfortunately, the underlying basis for sex-specific immune responses remains poorly understood. Here, we show a sex difference in the CD8+ T cell response to an enteric virus, Coxsackievirus B3 (CVB3). We found that CVB3 induced expansion of CD8+ T cells in female mice but not in male mice. CVB3 also increased the proportion and number of CD11ahiCD62Llo CD8+ T cells in female mice, indicative of activation. This response was independent of the inoculation route and type I interferon. Using a recombinant CVB3 virus expressing a model CD8+ T cell epitope, we found that the expansion of CD8+ T cells in females is viral-specific and not due to bystander activation. Finally, the depletion of CD8+ T cells, prior to infection, led to enhanced mortality, indicating that CD8+ T cells are protective against CVB3 in female mice. These data demonstrate that CVB3 induces a CD8+ T cell response in female mice and highlight the importance of sex-specific immune responses to viral pathogens.

Juvenile systemic lupus erythematosus (JSLE) is diagnosed in children younger than 18 years of age. Depression and anxiety are common, but not well understood in JSLE. We investigated the clinical and psychological factors associated with the psychological manifestations of JSLE. Twenty-nine JSLE patients were recruited for the study. Patients completed surveys evaluating their psychological status and perceptions about their health. Medical records were used to obtain laboratory results. The JSLE patient population was compared with adult-onset SLE (ASLE) patients and unaffected controls. Kidney involvement was associated with depression in the JSLE patients. The BUN levels, BUN/creatinine ratio, and leukocyturia were all significantly associated with depressive symptoms. Multivariate analysis found that the BUN/creatinine ratio was the most predictive value for both depression and anxiety. Depressive symptoms in JSLE were less pronounced than in ASLE, although anxiety was not different. Age and education are likely to be protective against depression in the JSLE patients. These findings may indicate that symptomatology is an important indicator of whether the patient needs psychiatric care.

ABSTRACT COVID-19 convalescent plasma (CCP) was an early and widely adopted putative therapy for severe COVID-19. Results from randomized control trials and observational studies have failed to demonstrate a clear therapeutic role for CCP for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Underlying these inconclusive findings is a broad heterogeneity in the concentrations of neutralizing antibodies (nAbs) between different CCP donors. We conducted this study to evaluate the effectiveness and safety of nAb titer-defined CCP in adults admitted to an academic referral hospital. Patients positive by a SARS-CoV-2 nucleic acid amplification test and with symptoms for 1:640 (high-titer group) or ≥1:160 to 1:640 (standard-titer group) in addition to standard of care treatments. The primary clinical outcome was time to hospital discharge, with mortality and respiratory support evaluated as secondary outcomes. Adverse events were contrasted by CCP titer. Between 28 August and 4 December 2020, 316 participants were screened, and 55 received CCP, with 14 and 41 receiving high- versus standard-titer CCP, respectively. Time to hospital discharge was shorter among participants receiving high- versus standard-titer CCP, accounting for death as a competing event (hazard ratio, 1.94; 95% confidence interval [CI], 1.05 to 3.58; Gray’s P = 0.02). Severe adverse events (SAEs) (≥grade 3) occurred in 4 (29%) and 23 (56%) of participants receiving the high versus standard titer, respectively, by day 28 (risk ratio, 0.51; 95% CI, 0.21 to 1.22; Fisher’s P = 0.12). There were no observed treatment-related AEs. (This study has been registered at ClinicalTrials.gov under registration no. NCT04524507). IMPORTANCE In this study, in a high-risk population of patients admitted for COVID-19, we found an earlier time to hospital discharge among participants receiving CCP with nAb titers of >1:640 compared with participants receiving CCP with a lower nAb titer and no CCP-related AEs. The significance of our research is in identifying a dose response of CCP and clinical outcomes based on nAb titer. Although limited by a small study size, these findings support further study of high-nAb-titer CCP defined as >1:640 in the treatment of COVID-19.

Abstract Autoimmune diseases are driven largely by a pathogenic cytokine milieu produced by aberrantly activated lymphocytes. Many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS1) is an inducible, intracellular protein that regulates IFN-γ signaling by dampening JAK/STAT signaling. Using Fas deficient, MRL/MpJ-Faslpr/J (MRL/lpr) mice, which develop lupus-like disease spontaneously, we tested the hypothesis that a peptide mimic of the SOCS1 kinase inhibitory region (SOCS1-KIR) would inhibit lymphocyte activation and modulate lupus-associated pathologies. Consistent with in vitro studies, SOCS1-KIR intraperitoneal administration reduced the frequency, activation, and cytokine production of memory CD8+ and CD4+ T lymphocytes within the peripheral blood, spleen, and lymph nodes. In addition, SOCS1-KIR administration reduced lymphadenopathy, severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of GL7+ germinal center enriched B cells. Together, these data show that SOCS1-KIR treatment reduced auto-reactive lymphocyte effector functions and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.

HLA typing provides essential results for stem cell and solid organ transplants, as well as providing diagnostic benefits for various rheumatology, gastroenterology, neurology, and infectious diseases. It is becoming increasingly clear that understanding the expression of patient HLA transcripts can provide additional benefits for many of these same patient groups. Our study cohort was evaluated using a long-read RNA sequencing methodology to provide rapid HLA genotyping results and normalized HLA transcript expression. Our assay used NGSEngine to determine the HLA genotyping result and normalized mRNA transcript expression using Athlon2. The assay demonstrated an excellent concordance rate of 99.7%. Similar to previous studies, for the class I loci, patients demonstrated significantly lower expression of HLA-C than HLA-A and -B (Mann–Whitney U, p value = 0.0065 and p value = 0.0154, respectively). In general, the expression of class II transcripts was lower than that of class I transcripts. This study demonstrates a rapid high-resolution HLA typing assay using RNA-Seq that can provide accurate HLA genotyping and HLA allele-specific transcript expression in 7–8 h, a timeline short enough to perform the assay for deceased donors.

In this study, we found that neutralizing antibody responses in COVID-19-convalescent individuals vary in magnitude but are durable and correlate well with receptor binding domain (RBD) Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex.

ABSTRACT Characterizing the asymptomatic spread of SARS-CoV-2 is important for understanding the COVID-19 pandemic. This study was aimed at determining asymptomatic spread of SARS-CoV-2 in a suburban, Southern U.S. population during a period of state restrictions and physical distancing mandates. This is one of the first published seroprevalence studies from North Carolina and included multicenter, primary care, and emergency care facilities serving a low-density, suburban and rural population since description of the North Carolina state index case introducing the SARS-CoV-2 respiratory pathogen to this population. To estimate point seroprevalence of SARS-CoV-2 among asymptomatic individuals over time, two cohort studies were examined. The first cohort study, named ScreenNC, was comprised of outpatient clinics, and the second cohort study, named ScreenNC2, was comprised of inpatients unrelated to COVID-19. Asymptomatic infection by SARS-CoV-2 (with no clinical symptoms) was examined using an Emergency Use Authorization (EUA)-approved antibody test (Abbott) for the presence of SARS-CoV-2 IgG. This assay as performed under CLIA had a reported specificity/sensitivity of 100%/99.6%. ScreenNC identified 24 out of 2,973 (0.8%) positive individuals among asymptomatic participants accessing health care during 28 April to 19 June 2020, which was increasing over time. A separate cohort, ScreenNC2, sampled from 3 March to 4 June 2020, identified 10 out of 1,449 (0.7%) positive participants. IMPORTANCE This study suggests limited but accelerating asymptomatic spread of SARS-CoV-2. Asymptomatic infections, like symptomatic infections, disproportionately affected vulnerable communities in this population, and seroprevalence was higher in African American participants than in White participants. The low, overall prevalence may reflect the success of shelter-in-place mandates at the time this study was performed and of maintaining effective physical distancing practices among suburban populations. Under these public health measures and aggressive case finding, outbreak clusters did not spread into the general population.

CD4+ T cells have numerous features of over-activated cellular metabolism in lupus patients and mouse models of the disease. This includes a higher glycolysis than in healthy controls. Glucose transporters play an essential role in glucose metabolism by controlling glucose import into the cell from the extracellular environment. We have previously shown that treatment of lupus-prone mice with 2-deoxy-D-glucose, which inhibits the first step of glycolysis was sufficient to prevent autoimmune activation. However, direct targeting of glucose transporters has never been tested in a mouse model of lupus. Here, we show that CG-5, a novel glucose transporter inhibitor, ameliorated autoimmune phenotypes in a spontaneous lupus-prone mouse model, B6.NZM2410.Sle1.Sle2.Sle3 (Triple-congenic, TC), and in a chronic graft- vs. host-disease (cGVHD) model of induced lupus. In vitro, CG-5 blocked glycolysis in CD4+ T cells, and limited the expansion of CD4+ T cells induced by alloreactive stimulation. CG-5 also modulated CD4+ T cell polarization by inhibiting Th1 and Th17 differentiation and promoting regulatory T (Treg) induction. Moreover, CG-5 treatment reduced lupus phenotypes including the expansion of germinal center B (GC B) cells, as well as the production of autoantibodies in both TC mice and cGVHD models. Finally, CG-5 blocked glycolysis in human T cells. Overall, our data suggest that blocking glucose uptake with a small molecule inhibitor ameliorates autoimmune activation, at least partially due to its inhibition of glycolysis in CD4+ T cells.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects a large number of people throughout the world. Anxiety, depression and fatigue are common symptoms of SLE that substantially contribute to decreased quality of life. This study investigates the interplay between physical and psychiatric manifestations of lupus. To this end, an SLE patient cohort was examined for correlations between clinical presentation, laboratory tests, and psychological indicators.Seventy-two lupus patients were evaluated for psychological status using a battery of instruments, including assessments for fatigue (CFS & FSS), depression (HADS), anxiety (HADS), overall health (SF-36 & PSQI) and intimate relationship satisfaction (RAS & CSI). Scores from these assessments were correlated with lupus clinical profiles and laboratory test values.The prevalence of depression in the SLE patient cohort was 41.7%, as measured by the hospital depression and anxiety scale. The study identified that pain (p = 0.001), body mass index (p = 0.026), Chalder's fatigue scale (p < 0.001), fatigue severity scale (p < 0.001), and anxiety (p = 0.001) are all positively correlated with depression in SLE patients. Total complement (CH50) (p = 0.032), and SF-36 physical and mental characteristic assessments are negatively correlated with depression. Longitudinal analysis indicated that the disease related complaint alopecia (p = 0.008) and relationship assessment scale scores (p = 0.004) may also be correlated to depression in SLE patients. Multivariant scrutiny of the clinical and psychosocial characteristics identified the fatigue severity scale (p = 0.026), SF-36 physical function (p = 0.040), physical role function (0.030), and mental health (p = 0.002) as the best indicators directly correlated with depression for the SLE cohort.These results reveal the influence of physical manifestations of lupus including fatigue, pain, body mass index and anxiety, as well as decreased physical and mental function, on depression. Fatigue is the strongest factor correlated with depression in SLE patients in the cohort. Both physical and social/psychological aspects likely contribute to the depression and anxiety in lupus.

Purpose. Rheumatoid arthritis (RA) is an often debilitating autoinflammatory disease. Patients with rheumatoid arthritis are often troubled by co-occurring depression or other psychological manifestations. RA patients have a variety of treatment options available, including biologicals that inhibit cytokines or immune cells. If these cytokines influence the psychological symptoms, then the use of cytokine inhibitors should modulate these symptoms. Methods. A cohort of 209 individuals was recruited. This group included 82 RA patients, 22 healthy subjects, 32 depressed control subjects, and 73 subjects with systemic lupus erythematosus. Of the RA patients, 51% were on a biological therapeutic. ELISA was used to measure cytokine levels. A variety of psychological assessments were used to evaluate depression, anxiety, sleep, fatigue, and relationship status. Clinical values were obtained from medical records. Results. IL-10 concentration was associated with depressive symptoms in the RA patients, healthy controls, and the lupus patients. In the patients with primary depression, depressive symptoms were associated with IL-6 and TNF-alpha. In RA patients, Tocilizumab use was associated with decreased depressive symptoms. 14 RA patients who were not using biologicals began using them by a one-month follow-up. In these patients, there was no significant change to any value except for fatigue. Conclusions. A variety of both biological and social factors influences depressive symptoms in RA. IL-10 and IL-6 are likely to be involved, since IL-10 concentration was associated with depression and Tocilizumab decreased depressive symptoms in the RA patients. The roles of these cytokines are different in RA and lupus, as high IL-10 in RA is associated with increased depressive symptoms, but high IL-10 in the lupus patients is associated with decreased depression. IL-6 was also associated with depressive symptoms in the patients with primary depression. These results strongly indicate that disease activity, including cytokine levels, has a strong impact on depressive symptoms.