Search

Dysregulated type I interferon responses play crucial roles in the development of multiple forms of autoimmunity. Many patients with lupus, systemic sclerosis, Sjogren’s syndrome, and dermatomyositis demonstrate enhanced type I IFN signaling. Type I IFN excess is associated with disease severity, autoantibodies, and could potentially predict response to newer therapies targeting type I IFN pathways. Herein, we provide an overview of the signaling pathway and immune functions of type I IFNs in health and disease. We also review the systemic autoimmune diseases classically associated with type I IFN upregulation and current therapeutic strategies targeting the type I IFN system.

Background The prevalence of burnout and depressive symptoms is high among physician trainees. Research Question What is the burden of burnout and depressive symptoms among fellows training in pulmonary and critical care medicine (PCCM) and what are associated individual fellow, program, and institutional characteristics? Study Design and Methods We conducted a cross-sectional electronic survey of fellows enrolled in pulmonary, PCCM, and critical care medicine training programs in the United States to assess burnout and depressive symptoms. Burnout symptoms were measured using the Maslach Burnout Index two-item measure. The two-item Primary Care Evaluation of Mental Disorders Procedure was used to screen for depressive symptoms. For each of the two outcomes (burnout and depressive symptoms), we constructed three multivariate logistic regression models to assess individual fellow characteristics, program structure, and institutional polices associated with either burnout or depressive symptoms. Results Five hundred two of the 976 fellows who received the survey completed it—including both outcome measures—giving a response rate of 51%. Fifty percent of fellows showed positive results for either burnout or depressive symptoms, with 41% showing positive results for depressive symptoms, 32% showing positive results for burnout, and 23% showing positive results for both. Reporting a coverage system in the case of personal illness or emergency (adjusted OR [aOR], 0.44; 95% CI, 0.26-0.73) and access to mental health services (aOR, 0.14; 95% CI, 0.04-0.47) were associated with lower odds of burnout. Financial concern was associated with higher odds of depressive symptoms (aOR, 1.13; 95% CI, 1.05-1.22). Working more than 70 hours in an average clinical week and the burdens of electronic health record (EHR) documentation were associated with a higher odds of both burnout and depressive symptoms. Interpretation Given the high prevalence of burnout and depressive symptoms among fellows training in PCCM, an urgent need exists to identify solutions that address this public health crisis. Strategies such as providing an easily accessible coverage system, access to mental health resources, reducing EHR burden, addressing work hours, and addressing financial concerns among trainees may help to reduce burnout or depressive symptoms and should be studied further by the graduate medical education community.

Background/Purpose Interferon (IFN) gene expression signatures have been observed in whole blood and mixed immune cell populations in systemic lupus erythematosus (SLE), but the significance of this IFN signaling in immune cell subsets is not well understood. We examined gene expression in individual SLE patient monocytes to explore the impact of increased IFN-induced transcription in single cells. Methods CD14++CD16- classical monocytes and CD14dimCD16+ non classical monocytes from SLE patients were purified by magnetic separation. Single cells were isolated, and gene expression in each individual cell was examined by rtPCR. Results Monocytes from the same SLE patient blood sample demonstrated varying levels of IFN-induced gene expression. In classical monocytes, high IFN score correlated with CD32a, IL1B, and IL8 expression. In non-classical monocytes, high IFN score was correlated with a larger number of inflammatory mediators, including cytokines such as IL12, IL23, and IL15; the immune receptors CD36, CD32a, CD80, and TLR7; and inflammatory signaling genes such as RELA, STAT2, IRAK1, IRAK4, and MyD88. Conclusion We observed striking diversity in the IFN responses of individual monocytes, demonstrating that IFN signaling has distinct effects upon classical and non-classical monocytes. Single cell studies can reveal effects of IFN on single immune cells and uncommon populations such as non-classical monocytes, which would be masked in whole blood or mixed cell populations.

Identifying populations at risk of SLE who remain unaffected would provide insights for potential disease prevention. Using a unique resource of SLE patient family members, first degree relatives (FDRs) of SLE patients (n = 154) with plasma samples available from previous genetic studies and who remained unaffected at follow-up evaluation (mean time = 6.8 years) were matched to healthy individuals unrelated to SLE patients (Controls). FDRs and Controls provided clinical and demographic information, and completed screening questionairres at baseline (BL) and follow-up (FU). BL and FU plasma samples were assessed for autoantibody production and soluble mediators. FDRs had significantly higher BL and FU CSQ scores (p

Healthy relatives of lupus patients have an increased risk of developing SLE, but predictors and mechanisms of disease transition are unknown. Unaffected relatives of SLE patients (n=409) were enrolled in this follow-up study to identify factors associated with transition to SLE. Participants provided detailed demographic and clinical information, including the Connective Tissue Disease Screening Questionnaire (CSQ). Medical records were reviewed for ACR classification criteria. Plasma samples were tested for the presence of autoantibodies and soluble mediators. Forty-five relatives (11%) transitioned to classified SLE during follow-up (mean time = 6.4 years) who had more autoantibodies (p

Autoantibodies and interferon (IFN) are associated with clinical illness in systemic lupus erythematosus (SLE), but how these factors influence autoimmune disease development is unknown. This study evaluates the timing and changes in SLE-linked autoantibody specificities, serum IFN-α activity, and IFN-associated soluble mediator levels in the years preceding SLE classification. Serial sera from 55 SLE cases spanning pre- and post-SLE classification (average time = 4.3 years) and matched healthy controls (HC) were obtained from the Department of Defense Serum Repository. Cases with positive serum IFN-α activity had more SLE-linked autoantibody specificities (p4 years before SLE classification (Random Forest). These data indicate that pre-clinical immune system perturbations allow for the accumulation of autoantibodies and subsequent elevation in IFN-α activity immediately preceding clinical symptoms and SLE classification.

Processes that lead to clinical illness in SLE years before diagnosis are not well characterized. This study evaluates the temporal relationship between autoantibody production, cytokine levels and the onset of SLE. Serial sera from 60 SLE cases before diagnosis with no ACR criteria to SLE classification (average timespan=4.4 years) and matched healthy controls (HC) were obtained from the DODSR. Sera samples were tested for autoantibodies (BioPlex2200), C-reactive protein (hs-CRP), Von Willebrand’s Factor (VWF) and 32 soluble inflammatory mediators, including cytokines, chemokines, and soluble receptors. Patient samples before ACR classification had significant (p < 0.01) alterations in 16 soluble mediators of inflammation, as well as VWF and hs-CRP. TNF Receptor levels, TNFRI, TNFRII, BLyS, and APRIL, dramatically increased as lupus classification approached (p < 0.001). The increase in TNFR shedding parallels the accumulation of autoantibodies in SLE cases. Interferon (IFN)-associated mediators of inflammation, IFN-γ, IP-10, MIG, and MIP-1α (p < 0.01), were also increased leading up to classification. That these alterations are present prior to the transition to active SLE suggests that multiple perturbations in immune-mediated inflammatory processes occur long before clinical classification and suggest that high-risk, pre-clinical individuals, can be identified before their illness is clinically manifested and damage occurs.

Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signaling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single-nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines, and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon and other proinflammatory mediators, and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I interferon production and absence of anti-RNA-binding protein antibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral interferon pathway in vivo in humans, and is associated with a novel sub-phenotype in SLE.