An exhausted phenotype of TH 2 cells is primed by allergen exposure, but not reinforced by allergen-specific immunotherapy.

BACKGROUND: Studies show that proallergic TH 2 cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T-cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts. METHODS: OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH 2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on TH 2 cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long-term AIT cohort. RESULTS: The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH 2 cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1 decreased after AIT, in particular on the surface of local lung TH 2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on TH 2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late-differentiated TH 2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase. CONCLUSIONS: This study shows that allergen exposure promotes CTLA-4 and PD-1 expression on TH 2 cells and that the dynamic change in frequencies of exhausted TH 2 cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.

Dynamic adoption of anergy by antigen-exhausted CD4+ T cells.

Exhausted immune responses to chronic diseases represent a major challenge to global health. We study CD4+ T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase and are then exposed to different levels of persistent antigen, they lose their T helper 1 (Th1) functions, upregulate exhaustion markers, resemble naturally anergic cells, and modulate their MAPK, mTORC1, and Ca2+/calcineurin signaling pathways with increasing dose and time. They also become unable to help B cells and, at the highest dose, undergo apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of T cell receptor (TCR) signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.

Primary Sjogren's syndrome and the risk of acute pancreatitis: a nationwide cohort study.

OBJECTIVE: Studies on the risk of acute pancreatitis in patients with primary Sjogren's syndrome (pSS) are limited. We evaluated the effects of pSS on the risk of acute pancreatitis in a nationwide, population-based cohort in Taiwan. STUDY DESIGN: Population-based retrospective cohort study. SETTING: We studied the claims data of the >97% Taiwan population from 2002 to 2012. PARTICIPANTS: We identified 9468 patients with pSS by using the catastrophic illness registry of the National Health Insurance Database in Taiwan. We also selected 37 872 controls that were randomly frequency matched by age (in 5 year bands), sex and index year from the general population. PRIMARY OUTCOME MEASURE: We analysed the risk of acute pancreatitis by using Cox proportional hazards regression models including sex, age and comorbidities. RESULTS: From 23.74 million people in the cohort, 9468 patients with pSS (87% women, mean age=55.6 years) and 37 872 controls were followed-up for 4.64 and 4.74 years, respectively. A total of 44 cases of acute pancreatitis were identified in the pSS cohort versus 105 cases in the non-pSS cohort. Multivariate Cox regression analysis indicated that the incidence rate of acute pancreatitis was significantly higher in the pSS cohort than in the non-pSS cohort (adjusted HR (aHR) 1.48, 95% CI 1.03 to 2.12). Cyclophosphamide use increased the risk of acute pancreatitis (aHR 5.27, 95% CI 1.16 to 23.86). By contrast, hydroxychloroquine reduced the risk of acute pancreatitis (aHR 0.23, 95% CI 0.09 to 0.55). CONCLUSION: This nationwide, retrospective cohort study demonstrated that the risk of acute pancreatitis was significantly higher in patients with pSS than in the general population.

Continuous single cell imaging reveals sequential steps of plasmacytoid dendritic cell development from common dendritic cell progenitors.

Functionally distinct plasmacytoid and conventional dendritic cells (pDC and cDC) shape innate and adaptive immunity. They are derived from common dendritic cell progenitors (CDPs) in the murine bone marrow, which give rise to CD11c+ MHCII- precursors with early commitment to DC subpopulations. In this study, we dissect pDC development from CDP into an ordered sequence of differentiation events by monitoring the expression of CD11c, MHC class II, Siglec H and CCR9 in CDP cultures by continuous single cell imaging and tracking. Analysis of CDP genealogies revealed a stepwise differentiation of CDPs into pDCs in a part of the CDP colonies. This developmental pathway involved an early CD11c+ SiglecH- pre-DC stage and a Siglec H+ CCR9low precursor stage, which was followed rapidly by upregulation of CCR9 indicating final pDC differentiation. In the majority of the remaining CDP pedigrees however the Siglec H+ CCR9low precursor state was maintained for several generations. Thus, although a fraction of CDPs transits through precursor stages rapidly to give rise to a first wave of pDCs, the majority of CDP progeny differentiate more slowly and give rise to longer lived precursor cells which are poised to differentiate on demand.

Increased risk of osteoporotic fractures in patients with systemic sclerosis: a nationwide population-based study.

OBJECTIVES: To identify the incidence rate (IR) and risk factors of osteoporotic fractures (OFs) among systemic sclerosis (SSc) patients. METHODS: A cohort study was conducted using the Taiwan National Health Insurance database. Patients with SSc and respective age- and gender-matched controls without SSc were enrolled. The primary endpoint was the first occurrence of OF. The Cox proportional hazard model was used to investigate the risk factor of OFs in the SSc cohort. RESULTS: Among 1712 SSc patients (77.8% female, mean age 50.3 years) with a median follow-up of 5.2 years, 54 patients developed vertebral fractures, 17 patients developed hip fractures, and 7 patients developed radius fractures (IR: 6.99, 2.18 and 0.90 per 1000 person-years, respectively). Compared with the controls, the incidence rate ratios (IRRs) (95% CIs) among SSc patients were 1.78 (1.30 to 2.39, p<0.001) for vertebral fractures and 1.89 (1.05 to 3.22, p=0.026) for hip fractures. The IRRs for overall OFs were 1.74 (1.32 to 2.27, p<0.001) for women and 1.06 (0.33 to 2.66, p=0.856) for men. The SSc patients experienced hip fractures at a younger age (67.2 vs 75.2 years, p=0.005), and had a higher 1-year mortality rate (13% vs 3%, p=0.006) of vertebral fractures than did the controls. Multivariable Cox regression analyses indicated that older age, being female, using daily prednisolone equivalent to >7.5 mg, and bowel dysmotility treated with intravenous metoclopramide are associated with OF. CONCLUSIONS: SSc patients had a high IR of vertebral and hip fractures, especially those who were female, older, used a high dose of corticosteroid or experienced bowel dysmotility.

Clinical features and outcomes of posterior reversible encephalopathy syndrome in patients with systemic lupus erythematosus.

OBJECTIVE: To analyze the clinical features and outcomes of patients with posterior reversible encephalopathy syndrome(PRES), the risk factors of PRES-related intracranial hemorrhage (ICH), and all-cause mortality in patients with systemic lupus erythematosus (SLE). METHODS: Twenty-six episodes of PRES were identified in 23 SLE patients, using an electronic medical records database of 3,746 SLE patients. RESULTS: The prevalence of PRES was 0.69% among SLE patients. The scores of the SLE Disease Activity Index without neurologic descriptors (SLEDAI-N) were significantly elevated from baseline for a mean of 3.3 during PRES (P = 0.009). Rapidly deteriorating renal function, pulmonary hemorrhage, thrombotic microangiopathy, macrophage activation syndrome, or multiple organ dysfunction syndrome appeared during 65.4% of episodes. In 16 episodes, patients completely recovered from PRES-related symptoms within a median of 7 days. Visual impairment was reversed within 2 days in 8 of 15 patients, but impairment in other patients was protracted for up to 4 months, especially when ICH was present. Hypoalbuminemia (<20 gm/liter; odds ratio [OR] 30, 95% confidence interval [95% CI] 2.04­441.84) and thrombocytopenia (<30,000/mm(3); OR 21, 95% CI 1.27­346.93) were risk factors for PRES-related ICH. Patients with SLEDAI-N scores >18 during a PRES attack had significantly higher mortality rates than did patients with SLEDAI-N scores ≤18 (P = 0.009 by log rank test). CONCLUSION: PRES frequently occurs during active SLE with multiple complications. Hypoalbuminemia and thrombocytopenia may contribute to PRES-related ICH. The extra neurologic disease activity of lupus during PRES may influence the mortality rate of SLE patients.

Association of systemic lupus erythematosus with a higher risk of cervical but not trochanteric hip fracture: a nationwide population-based study.

OBJECTIVE: To determine the incidence rates and risk factors of cervical and trochanteric hip fractures (HFs) among patients with systemic lupus erythematosus (SLE) based on a nationwide population-based data set. METHODS: We conducted a cohort study using data from the Taiwan National Health Insurance database. Patients with SLE and their age- and sex-matched counterparts without SLE were identified. The primary end point was the first occurrence of HF. Cox proportional hazards model was used to evaluate the respective risk factors of cervical and trochanteric HFs in the lupus cohort. RESULTS: Among 14,544 patients with SLE (90% women, mean age 38.1 years) with a mean followup of 6 years, 75 developed HF (incidence rate 8.60 per 10,000 person-years). Compared to controls, the incidence rate ratios (IRRs) for developing HF among lupus patients were 3.17 (95% confidence interval [95% CI] 1.92-5.39, P < 0.001) for cervical HF and 1.11 (95% CI 0.58-2.11, P = 0.571) for trochanteric HF. The IRRs for HF were 2.38 (95% CI 1.58-3.63, P < 0.001) for women and 1.06 (95% CI 0.21-4.93, P = 0.922) for men. Lupus patients with cervical HF were younger than controls with cervical HF (mean age 56.7 versus 67.8 years; P = 0.007). Multivariable Cox regression analyses showed that age, use of intravenous cyclophosphamide, higher dose of steroid, and stroke were associated with cervical HF, whereas age was the only associated factor for trochanteric HF. CONCLUSION: SLE is associated with a higher risk for cervical but not trochanteric HF, and these 2 types of HFs have different risk factors.

Increased risk of subarachnoid hemorrhage in patients with systemic lupus erythematosus: a nationwide population-based study.

OBJECTIVE: A relatively common occurrence of spontaneous subarachnoid hemorrhage (SAH) in patients with systemic lupus erythematosus (SLE) has been noted; however, the subsequent studies were conflicting. This nationwide population-based study aimed to evaluate the risk of SAH in patients with SLE. METHODS: We identified 16,967 SLE patients from the Taiwan National Health Insurance (NHI) database between 2000 and 2006, and compared the incidence rate of SAH with 16,967 randomly selected age- and sex-matched non-SLE subjects. A Cox multivariable proportional hazards model was used to evaluate the risk factors of SAH in the SLE cohort. RESULTS: The SLE cohort had a higher risk of SAH, with an incidence rate ratio of 4.84 (P < 0.001). Despite a younger age, the mortality rate after SAH was significantly higher in the SLE cohort compared to all of the non-SLE SAH patients identified from the 1 million NHI beneficiaries (60.0% versus 38.9%; P = 0.007). Age (hazard ratio [HR] 1.03, 95% confidence interval [95% CI] 1.01-1.05), platelet transfusion (HR 2.75, 95% CI 1.46-5.17), red blood cell transfusion (HR 7.11, 95% CI 2.81-17.97), and a mean daily steroid dose >10 mg of prednisolone or equivalent (HR 4.36, 95% CI 2.19-8.68) were independent risk factors for the new onset of SAH. CONCLUSION: This study demonstrated that SAH is a rare but associated complication of SLE with a high mortality rate. Other than age, higher mean daily steroid use and a history of platelet or red blood cell transfusion were associated with the occurrence of SAH in patients with SLE.

Association of serum interleukin-17 and interleukin-23 levels with disease activity in Chinese patients with ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic arthritis with a pathogenesis which is not fully understood. A third subset of IL-17-producing T helper cells, called Th17 cells, has been discovered and characterized. We investigated whether IL-17 and IL-23, two Th17-related cytokines, play any roles in the pathogenesis of, and have any correlations with, disease activity and clinical manifestations in AS. METHODS: This cross-sectional study included 49 AS patients and 25 healthy control subjects. The serum IL-17 and IL-23 levels were measured using enzyme-linked immunosorbent assay kits. At the same time, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Patient Global Score (BAS-G) levels were measured, and physical examinations were performed on study participants to determine their extent of physical mobility. RESULTS: The serum IL-17 and IL-23 levels of the AS patients were significantly higher than those of the healthy controls. In the AS patients, the BASDAI scores had a better correlation with the serum IL-17 or IL-23 levels (IL-17, r = 0.351, p = 0.014; IL-23, r = 0.398, p = 0.005) than with ESR (r = 0.078, p = 0.600) and CRP (r = 0.012, p = 0.993). IL-17 or IL-23 correlate to the BASFI, BAS-G and parameters related to physical mobility. In the receiver operating characteristic (ROC) analysis, the serum IL-17 and IL-23 levels act better in discriminating patients with BASDAI≥4 (AUC value 0.88, p = 0.001) than ESR and CRP (AUC value 0.727, p = 0.008). CONCLUSION: Serum IL-17 and IL-23 levels were significantly higher in AS patients than in healthy controls and the levels correlate to disease activity measured by BASDAI scores, but not parameters of functional ability and spinal mobility. These results suggest the existence of a role of IL-17 and IL-23 in the pathogenesis of inflammation in AS.