Regional european genetic ancestry predicts type I interferon level and risk of severe viral infection.

BACKGROUND: Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations. METHODS: In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels, and severe viral infection outcomes. RESULTS: In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the United States with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (AUC = 0.73, p = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including COVID-19, viral hepatitis, and HIV [Correlation coefficients: -0.79 (p = 4e-2), -0.94 (p = 6e-3), and -0.96 (p = 8e-2) respectively]. CONCLUSIONS: This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens.

Implementation of a Best Practice Advisory to Improve Infection Screening Prior to New Prescriptions of Biologics and Targeted Synthetic Drugs.

OBJECTIVE: Use of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with preexisting tuberculosis (TB), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection can have serious consequences. Although various society guidelines recommend routine screening for these infections before initiating certain b/tsDMARDs, adherence to these recommendations varies widely. This quality improvement initiative evaluated local compliance with screening and assessed whether an automated computerized decision support system in the form of a best practice advisory (BPA) in the electronic health record could improve patient screening. METHODS: Established patients with autoimmune rheumatic disease (ARD) aged 18 years or older with at least one visit to our rheumatology practice between October 1, 2017, and March 3, 2022, were included. When prescribing a new b/tsDMARD, clinicians were alerted via a BPA that showed the most recent results for TB, HBV, and HCV. Screening proportions for TB, HBV, and HCV before BPA initiation were compared with those of eligible patients after the BPA implementation. RESULTS: A total of 711 patients pre-BPA and 257 patients post-BPA implementation were included in the study. The BPA implementation was associated with statistically significant improvement in screening for TB from 66% to 82% (P ≤ 0.001), HCV from 60% to 79% (P ≤ 0.001), hepatitis B core antibody 32% to 51% (P ≤ 0.001), and hepatitis B surface antigen from 51% to 70% (P ≤ 0.001). CONCLUSION: Implementation of a BPA can improve infectious disease screening for patients with ARD who are started on b/tsDMARDs and has potential to improve patient safety.

High Systemic Type I Interferon Activity Is Associated With Active Class III/IV Lupus Nephritis.

OBJECTIVE: Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. METHODS: Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. RESULTS: Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. CONCLUSION: Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.

Single-cell expression quantitative trait loci (eQTL) analysis of SLE-risk loci in lupus patient monocytes.

BACKGROUND: We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS: Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16- CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS: The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS: We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.

Coronavirus Disease 2019 in a Patient With a Systemic Autoinflammatory Syndrome due to an NLRC4 Inflammasomopathy.

The effect of autoinflammatory diseases on severe acute respiratory syndrome coronavirus 2 infection remains unknown. We report a case of coronavirus disease 2019 (COVID-19) in a patient with autoinflammation with infantile enterocolitis with inflammatory flares due to a mutation in the inflammasome component NLRC4. This case highlights the role of immunosuppression in patients with autoinflammation with COVID-19.

Baseline characteristics and long-term outcomes of eosinophilic fasciitis in 89 patients seen at a single center over 20 years.

AIM: Eosinophilic fasciitis (EF) is a rare, fibrosing disorder of skin and subcutaneous tissue. This study was undertaken to describe its clinical and laboratory features and identify prognostic factors associated with outcome. METHODS: We conducted a retrospective review of all EF patients evaluated at our institution from 1 January1997 to 30 December 2016. Kaplan-Meier methods were used to determine treatment response rates over time. Potential associations between baseline characteristics and complete response were examined using Cox models adjusted for age and sex. Time-dependent covariates were used to examine treatment effects. RESULTS: We identified 89 EF patients, with a female-to-male ratio of 1:1. Clinical features included groove sign in 26 (29%), peau d'orange/dimpling in 22 (25%), inflammatory arthritis in 9 (10%) and muscle weakness in 9 (10%). Aldolase was elevated in 11/36 (31%). Complete response rate was 60% (95% confidence interval [CI]: 35-75) at 3 years. Diagnostic delay was inversely associated with treatment response (hazards ratio: 0.84 per 1 month increase; 95% CI: 0.73-0.98). No baseline characteristics correlated with treatment response, but a trend toward positive association of elevated aldolase, hypergammaglobulinemia and presence of hematologic disorders was noted. Methotrexate was the most commonly used immunosuppressant in 79%, hydroxychloroquine in 45%, mycophenolate mofetil in 18% and azathioprine in 8%. No single immunosuppressant agent was associated with a superior response during treatment. CONCLUSIONS: EF is characterized by relatively high response rates. Consensus diagnostic criteria, standardized management algorithms, and large prospective multi-center cohorts are needed to develop an evidence-directed approach to this challenging condition.

Type I Interferon Predicts an Alternate Immune System Phenotype in Systemic Lupus Erythematosus.

OBJECTIVE: Type I interferon (IFN) is important to systemic lupus erythematosus (SLE) pathogenesis, but it is not clear how chronic elevations in IFN alter immune function. We compared cytokine responses after whole blood stimulation with Toll-like receptor (TLR) agonists in high- and low-IFN SLE patient subgroups. METHODS: SLE patients and nonautoimmune controls were recruited, and SLE patients were categorized as either high or low IFN. Whole blood was dispensed into tubes coated with lipopolysaccharide (LPS), oligonucleotides with cytosine-guanine repeats, Resiquimod, IFN-α, and IFN-α + LPS. Cytokine production in patient sera and after whole blood TLR stimulation was measured by multiplex assay, and type I IFN was assessed using a functional assay. RESULTS: Circulating plasmacytoid dendritic cell numbers were specifically reduced in high-IFN SLE patients and not in low-IFN SLE patients. In serum, we observed that the correlations between cytokines in serum differed to a much greater degree between the high- and low-IFN groups (P < 0.0001) than the absolute cytokine levels differed between these same groups. In stimulated conditions, the high-IFN patients had less cytokine production in response to TLR ligation than the low-IFN SLE patients. LPS produced the most diverse response, and a number of interactions between type I IFN and LPS were observed. CONCLUSION: We find striking differences in resting and stimulated cytokine patterns in high- vs. low-IFN SLE patients, which supports the biological importance of these patient subsets. These data could inform personalized treatment approaches and the pathogenesis of SLE flare following infection.

Gastrointestinal and Extra-Intestinal Manifestations of IgG4-Related Disease.

IgG4-related disease (IgG4-RD) is a chronic relapsing multi-organ fibro-inflammatory syndrome of presumed autoimmune etiology. It is characterized by increased serum levels of IgG4 and tissue infiltration by IgG4+ cells. Increased titers of autoantibodies against a spectrum of self-antigens and response to steroids have led to its characterization as an autoimmune disease. However, the pathognomonic antigens probably differ among manifestations, and different antigens or autoantibodies produce similar immune reactions in different organs. Little is known about the pathogenic effects, if any, of serum IgG4 or IgG4+ plasma cells in tissues. Despite several animal models of the disease, none truly recapitulates human IgG4-RD. Histologic analyses of tissues from patients with IgG4-RD reveal a dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, although these features vary among organs. Typical presentation and imaging findings include mass-forming synchronous or metachronous lesions in almost any organ, but most commonly in the pancreas, bile duct, retroperitoneum, kidneys, lungs, salivary and lacrimal glands, orbit, and lymph nodes. In all organs, inflammation can be reduced by corticosteroids and drugs that deplete B cells, such as rituximab. Patients with IgG4-RD have relapses that respond to primary therapy. Intense fibrosis accompanies the inflammatory response, leading to permanent organ damage and insufficiency. Death from IgG4-RD is rare. IgG4-RD is a multi-organ disease with predominant pancreatico-biliary involvement. Despite its relapsing-remitting course, patients have an excellent prognosis.

Single-cell gene expression patterns in lupus monocytes independently indicate disease activity, interferon and therapy.

OBJECTIVES: Important findings can be masked in gene expression studies of mixed cell populations. We examined single-cell gene expression in SLE patient monocytes in the context of clinical and immunological features. METHODS: Monocytes were purified from patients with SLE and controls, and individually isolated for single-cell gene expression measurement. A panel of monocyte-related transcripts were measured in individual classical (CL) and non-classical (NCL) monocytes. RESULTS: Analyses of both CL and NCL monocytes demonstrated that many genes had a lower expression rate in SLE monocytes than in controls. Unsupervised hierarchical clustering of the CL and NCL data sets demonstrated independent clusters of cells from the patients with SLE that were related to disease activity, type I interferon (IFN) and medication use. Thus, each of these factors exerted a different impact on monocyte gene expression that could be identified separately, and a number of genes correlated uniquely with disease activity. We found within-cell correlations between genes directly induced by type I IFN-induced and other non-IFN-induced genes, suggesting the downstream biological effects of type I IFN in individual human SLE monocytes which differed between CLs and NCLs. CONCLUSIONS: In summary, single-cell gene expression in monocytes was associated with a wide range of clinical and biological features in SLE, providing much greater detail and insight into the cellular biology underlying the disease than previous mixed-cell population studies.

Lupus-Associated Functional Polymorphism in PNP Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells.

OBJECTIVE: Systemic lupus erythematosus (SLE) is frequently characterized by activation of the type I interferon (IFN) pathway. We previously observed that a missense single-nucleotide polymorphism (rs1049564) in the purine nucleoside phosphorylase (PNP) gene was associated with high levels of IFN in SLE. PNP is a key enzyme involved in purine metabolism. In this study, we performed functional follow-up of this polymorphism in human cells. METHODS: Type I IFN was measured in patient sera, using a reporter cell assay. Structural modeling of the PNP variant was performed using PyMOL software. PNP messenger RNA (mRNA) and protein levels and type I IFN-induced gene expression were measured in lymphoblastoid cell lines with known PNP rs1049564 genotypes. The cell cycle was assayed using flow cytometry. RESULTS: Structural modeling indicated no major disruption in folding related to rs1049564. We observed that homozygous rs1049564 TT lymphoblastoid cells had decreased PNP mRNA expression and protein levels, and that cells with the TT genotype had reduced PNP enzymatic activity even when the amount of PNP was controlled. Cells with the TT genotype had a 2-fold increase in S-phase block as compared with cells with the homozygous CC phenotype. The S-phase block could be pharmacologically reversed with hypoxanthine and adenosine, supporting the notion that relative PNP deficiency is the cause of the S-phase block. Type I IFN-induced transcripts were increased in a dose-response manner related to the rs1049564 T allele, at both baseline and after type I IFN stimulation. CONCLUSION: The PNP rs1049564 T allele is a loss-of-function variant that induces S-phase block and IFN pathway activation in lymphocytes. The S-phase block could be rescued in our in vitro experiments, suggesting the potential for personalized treatment.

Broad Concepts in Management of Systemic Lupus Erythematosus.

Systemic lupus erythematosus is a multisystem autoimmune disease with protean manifestation. Although commonly seen in young women, it can affect men as well as elderly patients. Approach to treatment is multidisciplinary, involves defining the extent of organ involvement, and distinguishing between active manifestations and damage. The mainstay of therapy is judicious use of immunosuppressive medications. Long-term follow-up to address morbidity arising from treatment complications, disease damage, and increased cardiovascular risk is essential.

Concomitant Disruption of CD4 and CD8 Genes Facilitates the Development of Double Negative αß TCR+ Peripheral T Cells That Respond Robustly to Staphylococcal Superantigen.

Mature peripheral double negative T (DNT) cells expressing αß TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated CD4 and CD8 genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3+ αß TCR+ thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3+ αß TCR+ cells and Foxp3+ T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.

Cancer risk in cutaneous lupus erythematosus: a population-based cohort study.

OBJECTIVE: Immune dysregulation associated with chronic autoimmune diseases, such as SLE, has been associated with increased cancer risk. It is unclear whether isolated cutaneous lupus erythematosus (CLE) modifies cancer risk. We estimated the cumulative incidence of cancer in a population-based CLE cohort and compared the risk with a matched non-CLE cohort. METHODS: All incident cases of CLE in Olmsted County, MN, USA between 1965 and 2005 were identified and followed to December 2013. Estimates for the cumulative incidence of any cancer and skin cancer in patients with CLE were derived and compared with an age-, sex- and calendar-year-matched non-CLE cohort using Cox models. RESULTS: There were a total of 155 patients with CLE [age at diagnosis, 48 (sd 16) years; 65% females; BMI, 26.3 (sd 7.1) kg/m2; 40% smokers, 9% with diabetes]. During a median follow-up of 14.6 years, we observed 35 cases of incident cancer (including 10 cases of skin cancer). The cumulative 1-, 5- and 10-year incidence of any cancer after diagnosis of CLE was 1.4, 7.5 and 11.6%, respectively. Compared with matched non-CLE controls, the overall risk of malignancies was not increased in patients with CLE (smoking-adjusted hazard ratio = 1.29; 95% CI: 0.78, 2.13; P = 0.31). There was also no significant increase in risk of any skin cancer in patients with CLE (hazard ratio = 2.51; 95% CI: 0.91, 6.96; P = 0.16). CONCLUSION: CLE is not associated with an increased risk of any cancers, including skin cancers, compared with the general population. However, the number of events was small, limiting the power of the study.

Epidemiology of Mixed Connective Tissue Disease, 1985-2014: A Population-Based Study.

OBJECTIVE: To characterize the epidemiology of mixed connective tissue disease (MCTD) from 1983 to 2014. METHODS: An inception cohort of patients with incident MCTD in 1985-2014 in Olmsted County, Minnesota was identified based on comprehensive individual medical record review. Diagnosis of MCTD required fulfillment of at least 1 of the 4 widely accepted diagnostic criteria without fulfillment of classification criteria for other connective tissue diseases. Data were collected on demographic characteristics, clinical presentation, laboratory investigations, and mortality. RESULTS: A total of 50 incident cases of MCTD were identified (mean age 48.1 years and 84% were female). The annual incidence of MCTD was 1.9 per 100,000 population. Raynaud's phenomenon was the most common initial symptoms (50%), followed by arthralgia (30%) and swollen hands (16%). The diagnosis was frequently delayed with the median time from first symptom to fulfillment of criteria of 3.6 years. At fulfillment of criteria, arthralgia was the most prevalent manifestation (86%), followed by Raynaud's phenomenon (80%), swollen hands (64%), leukopenia/lymphopenia (44%), and heartburn (38%). Evolution to other connective tissue occurred infrequently with a 10-year rate of evolution of 8.5% and 6.3% for systemic lupus erythematosus and systemic sclerosis, respectively. The overall mortality was not different from the general population with a standardized mortality ratio of 1.1 (95% confidence interval 0.4-2.6). CONCLUSION: This study was the first population-based study of MCTD to provide a complete picture of epidemiology and clinical characteristics of MCTD. MCTD occurred in about 2 persons per 100,000 per year. Evolution to other connective diseases occurred infrequently and the mortality was not affected.

Risk of Cerebrovascular Accidents and Ischemic Heart Disease in Cutaneous Lupus Erythematosus: A Population-Based Cohort Study.

OBJECTIVE: It is unclear whether isolated cutaneous lupus erythematosus (CLE) affects cardiovascular risk. We estimated the cumulative incidence and mortality of cardiovascular diseases in a population-based CLE cohort and compared the risk with a matched non-CLE cohort. METHODS: All incident cases of CLE in Olmsted County, Minnesota, between 1965 and 2005 were followed until December 2013. The cumulative incidence of cerebrovascular accidents (CVAs [including stroke and transient ischemic attack]), ischemic heart disease (IHD [including coronary artery disease, myocardial infarction, and angina pectoris]), heart failure, and peripheral arterial disease (PAD) was derived and compared to an age-, sex-, and calendar year-matched non-CLE cohort using Cox models. RESULTS: There were 155 patients with CLE (mean ± SD age at diagnosis 48 ± 16 years, 65% female, mean ± SD BMI 26.3 ± 7.1 kg/m2 , 40% smokers, 9% with diabetes mellitus). During a median followup of 14.6 years, 41 CLE patients had cardiovascular events (15 patients with CVAs, 32 patients with IHD), with a 20-year cumulative incidence of 31.6%. As compared to non-CLE subjects, the risk of CVAs (smoking-adjusted hazard ratio [HR] 2.97 [95% confidence interval (95% CI) 1.13-7.78]) and PAD (HR 2.06 [95% CI 0.99-4.32]) was increased in patients with CLE, but the risk of IHD was not increased (HR 0.94 [95% CI 0.57-1.54]). There was no increase in cardiovascular mortality (HR 1.68 [95% CI 0.76-3.75]). The magnitude of risk for any cardiovascular outcome was not significantly influenced by the extent of cutaneous involvement. CONCLUSION: CLE may be associated with an increased risk of CVAs and PAD, but not IHD. Factors contributing to increased CVA risk in patients with CLE merit evaluation.

Mini-Osmotic Pump Infusion Model to Investigate the Systemic Effects of Chronic Continuous Exposure to Staphylococcal Superantigen in Mice.

Staphylococcus aureus can exist as a colonizer or can cause a spectrum of diseases. S. aureus elaborates several exotoxins and the superantigens are one among them. Staphylococcal superantigens (SSAg) cause robust activation of the immune system and acute exposure to significant amounts of SSAg can be potentially lethal. However, chronic exposure to SSAg is also possible. Administering SSAg using mini-osmotic pumps may mimic chronic recurrent exposure to SSAg. This is a relatively simple and safe way to administer purified SSAg or any other toxin/agent. In this chapter, we describe the mini-osmotic pump-mediated delivery of SSAg.

A Central Role for HLA-DR3 in Anti-Smith Antibody Responses and Glomerulonephritis in a Transgenic Mouse Model of Spontaneous Lupus.

MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRß1*0301) and devoid of endogenous class II (both I-A and I-E genes, AE(0)) on a lupus-prone NZM2328 background (NZM2328.DR3(+)AE(0)). Both NZM2328 and NZM2328.DR3(+)AE(0) mice developed anti-dsDNA and glomerulonephritis, but anti-dsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328.DR3(+)AE(0) mice (7.2 ± 4.3 and 8.6 ± 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3(+)AE(0) mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p < 0.001). Periarterial lymphoid aggregates, classic wire loop lesions, and occasional crescents were seen only in kidneys from NZM2328.DR3(+)AE(0) mice. Interestingly, NZM2328.DR3(+)AE(0) mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3(+)AE(0) mice that were completely devoid of endogenous class II (AE(-/) (-)) but not in mice homozygous (AE(+/+)) or heterozygous (AE(+/-)) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4(+) T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background.

Superantigens produced by catheter-associated Staphylococcus aureus elicit systemic inflammatory disease in the absence of bacteremia.

SAgs, produced by Staphylococcus aureus, play a major role in the pathogenesis of invasive staphylococcal diseases by inducing potent activation of the immune system. However, the role of SAgs, produced by S. aureus, associated with indwelling devices or tissues, are not known. Given the prevalence of device-associated infection with toxigenic S. aureus in clinical settings and the potency of SAgs, we hypothesized that continuous exposure to SAgs produced by catheter-associated S. aureus could have systemic consequences. To investigate these effects, we established a murine in vivo catheter colonization model. One centimeter long intravenous catheters were colonized with a clinical S. aureus isolate producing SAgs or isogenic S. aureus strains, capable or incapable of producing SAg. Catheters were subcutaneously implanted in age-matched HLA-DR3, B6, and AE(o) mice lacking MHC class II molecules and euthanized 7 d later. There was no evidence of systemic infection. However, in HLA-DR3 transgenic mice, which respond robustly to SSAgs, the SSAg-producing, but not the nonproducing strains, caused a transient increase in serum cytokine levels and a protracted expansion of splenic CD4(+) T cells expressing SSAg-reactive TCR Vß8. Lungs, livers, and kidneys from these mice showed infiltration with CD4(+) and CD11b(+) cells. These findings were absent in B6 and AE(o) mice, which are known to respond poorly to SSAgs. Overall, our novel findings suggest that systemic immune activation elicited by SAgs, produced by S. aureus colonizing foreign bodies, could have clinical consequences in humans.