Citations

AbstractToxic shock syndrome toxin‐1 (TSST‐1) is a potent superantigen produced by Staphylococcus aureus. In addition to menstrual and nonmenstrual toxic shock syndromes, TSST‐1 is also implicated in the immunopathogenesis of pneumonia, infective endocarditis, neonatal exanthematous disease, and atopic dermatitis among others. Superantigens first bind to major histocompatibility complex (MHC) class II molecules and then activate a large proportion of T cells by cross‐linking their T cell receptor. As binding to MHC class II molecules is a critical step in the robust activation of the immune system by TSST‐1 and other superantigens, polymorphic variations between different HLA‐DR alleles could potentially influence the magnitude of immune activation and immunopathology caused by TSST‐1. As TSST‐1 is highly toxic to humans and given that multiple variations of alleles of HLA‐DR and HLA‐DQ are expressed in each individual, it is difficult to determine how HLA‐DR polymorphisms quantitatively and qualitatively impact immune activation caused by TSST‐1 in humans. However, such investigations can be conducted on transgenic mice lacking all endogenous MHC class II molecules and expressing specific HLA class II alleles. Therefore, transgenic mice expressing different HLA‐DRB1 alleles (HLA‐DRB1*15:01, HLA‐DRB1*15:02, HLA‐DRB1*03:01, HLA‐DRB1*04:01), and sharing HLA‐A1*01:01 chain, were systemically challenged with purified TSST‐1 and multiple immune parameters were assessed. Among the HLA‐DR alleles, mice expressing HLA‐DRB1*15:01 allele elicited a significantly higher serum cytokine/chemokine response; greater splenic T cell expansion and most severe organ pathology. Our study highlights the potential utility of human leukocyte antigen (HLA) transgenic mice in understanding the impact of HLA polymorphisms on the outcomes of diseases caused by TSST‐1 and other superantigens.

ObjectiveIt 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.MethodsAll 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.ResultsThere 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.ConclusionCLE 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.

ObjectiveTo characterize the epidemiology of mixed connective tissue disease (MCTD) from 1983 to 2014.MethodsAn 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.ResultsA 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).ConclusionThis 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.

Abstract 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 (DRβ1*0301) and devoid of endogenous class II (both I-A and I-E genes, AE0) on a lupus-prone NZM2328 background (NZM2328.DR3+AE0). Both NZM2328 and NZM2328.DR3+AE0 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+AE0 mice (7.2 ± 4.3 and 8.6 ± 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3+AE0 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+AE0 mice. Interestingly, NZM2328.DR3+AE0 mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3+AE0 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.

Abstract 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 AEo 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 Vβ8. Lungs, livers, and kidneys from these mice showed infiltration with CD4+ and CD11b+ cells. These findings were absent in B6 and AEo 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.

AbstractWhile fertility is preserved in females with systemic lupus erythematosus (SLE), it is well established that pregnancy in these patients is associated with adverse maternal and fetal outcomes, including pregnancy loss, pre‐eclampsia, preterm delivery and intrauterine growth retardation, as well as neonatal mortality. Mechanisms underlying these adverse outcomes are poorly understood, and better understanding of these would allow development of targeted and personalized treatment strategies. Established risk factors for adverse pregnancy outcomes include active disease within 6 months prior to conception and during pregnancy, active nephritis, maternal hypertension, antiphospholipid antibodies and hypocomplementemia. While intensive monitoring is recommended, the comparative effectiveness of appropriate management strategies is unclear. While current strategies are able to achieve live births in 85–90% of pregnancies, certain aspects such as prevention of preterm birth, treatment of congenital heart block due to neonatal lupus and recurrent pregnancy loss despite best management, remains challenging. Pregnancy is also associated with an increased risk of flare of lupus, particularly in patients with active disease at time of conception or within 6 months prior to conception. Pregnant patients withSLEshould be followed in a high‐risk obstetric clinic, and care should be closely coordinated between the obstetrician and rheumatologist.

Objective Epidemiologic studies comparing the incidence and prevalence of systemic lupus erythematosus (SLE) and isolated cutaneous lupus erythematosus (CLE) are few. Olmsted County, Minnesota provides a unique setting for such a study owing to resources of the Rochester Epidemiology Project. We sought to describe and compare the incidence and prevalence of SLE and CLE from 1993–2005. Methods SLE cases were identified from review of medical records and fulfilled the 1982 American College of Rheumatology classification criteria. CLE cases included patients with classic discoid lupus erythematosus, subacute CLE, lupus panniculitis, and bullous lupus erythematosus. Age‐ and sex‐adjusted incidence and prevalence were standardized to the 2000 US white population. Results The age‐ and sex‐adjusted incidence of SLE (2.9 per 100,000; 95% confidence interval [95% CI] 2.0–3.7) was similar to that of CLE (4.2 per 100,000; 95% CI 3.1–5.2, P = 0.10). However, the incidence of CLE was 3 times higher than SLE in men (2.4 versus 0.8 per 100,000; P = 0.009). The age‐ and sex‐adjusted prevalence of CLE on January 1, 2006 was higher than that of SLE (70.4 versus 30.5 per 100,000; P < 0.001). The prevalences of CLE and SLE in women were similar, but the prevalence of CLE was higher in men than in women (56.9 versus 1.6 per 100,000; P < 0.001). The incidence of CLE rose steadily with age and peaked at 60–69 years. Conclusion The incidences of CLE and SLE are similar, but CLE is more common than SLE in men and in older adults. These findings may reflect differences in genetic or environmental etiology of CLE.