Immunology of IgG4‐related disease Della‐Torre, E.; Lanzillotta, M.; Doglioni, C.
Clinical and experimental immunology,
August 2015, Letnik:
181, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Summary
Immunoglobulin G4‐related disease (IgG4‐RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4+ plasma cells in affected tissues, as well ...as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4‐RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4‐RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4‐RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.
In order to adopt the best safety procedures, man-made earthquakes should be differentiated as a function of their origin. At least four different types of settings can be recognized in which ...anthropogenic activities may generate seismicity: (I) fluid removal from a stratigraphic reservoir in the underground can trigger the compaction of the voids and the collapse of the overlying volume, i.e., graviquakes; the deeper the reservoir, the bigger the volume and the earthquake magnitude; (II) wastewater or gas reinjection provides the reduction of friction in volumes and along fault planes, allowing creep or sudden activation of tectonic discontinuities, i.e., reinjection quakes; (III) fluid injection at supra-lithostatic pressure generates hydrofracturing and micro-seismicity, i.e., hydrofracturing quakes; (IV) fluid extraction or fluid injection, filling or unfilling of artificial lakes modifies the lithostatic load, which is the maximum principal stress in extensional tectonic settings, the minimum principal stress in contractional tectonic settings, and the intermediate principal stress in strike-slip settings, i.e., load quakes; over given pressure values, the increase of the lithostatic load may favour the activation of normal faults, whereas its decrease may favour thrust faults. For example, the filling of an artificial lake may generate normal fault-related seismicity. Therefore, each setting has its peculiarities and the knowledge of the different mechanisms may contribute to the adoption of the appropriate precautions in the various industrial activities.
Display omitted
•Induced seismicity can be differentiated as a function of the geological setting.•Anthropogenic activities may modify the hydrostatic or lithostatic pressure.•At least four types of induced seismicity can be recognized.•Fluid removal or injection can determine sub- or supra-hydrostatic pressure.•Supra-lithostatic pressure and load modifications can also generate seismicity.
We investigate a large geodetic data set of interferometric synthetic aperture radar (InSAR) and GPS measurements to determine the source parameters for the three main shocks of the 2016 Central ...Italy earthquake sequence on 24 August and 26 and 30 October (Mw 6.1, 5.9, and 6.5, respectively). Our preferred model is consistent with the activation of four main coseismic asperities belonging to the SW dipping normal fault system associated with the Mount Gorzano‐Mount Vettore‐Mount Bove alignment. Additional slip, equivalent to a Mw ~ 6.1–6.2 earthquake, on a secondary (1) NE dipping antithetic fault and/or (2) on a WNW dipping low‐angle fault in the hanging wall of the main system is required to better reproduce the complex deformation pattern associated with the greatest seismic event (the Mw 6.5 earthquake). The recognition of ancillary faults involved in the sequence suggests a complex interaction in the activated crustal volume between the main normal faults and the secondary structures and a partitioning of strain release.
Key Points
Coseismic ground deformation of the 2016 Central Italy earthquake sequence measured with InSAR and GPS data
At least four main normal fault segments played an active role in the sequence
Antithetic faults and/or preexisting compressional structures may have been reactivated during the sequence with extensional kinematics
Background
Despite evidence of different malignant potentials, postoperative follow-up assessment is similar for G1 and G2 pancreatic neuroendocrine tumors (panNETs) and adjuvant treatment currently ...is not indicated. This study investigated the role of Ki67 with regard to recurrence and survival after curative resection of panNET.
Methods
Patients with resected non-functioning panNET diagnosed between 1992 and 2016 from three institutions were retrospectively analyzed. Patients who had G1 or G2 tumor without distant metastases or hereditary syndromes were included in the study. The patients were re-categorized into Ki67 0–5 and Ki67 6–20%. Cox regression analysis with log-rank testing for recurrence and survival was performed.
Results
The study enrolled 241 patients (86%) with Ki67 0–5% and 39 patients (14%) with Ki67 6–20%. Recurrence was seen in 34 patients (14%) with Ki67 0–5% after a median period of 34 months and in 16 patients (41%) with Ki67 6–20% after a median period of 16 months (
p
< 0.001). The 5-year recurrence-free and 10-year disease-specific survival periods were respectively 90 and 91% for Ki67 0–5% and respectively 55 and 26% for Ki67 6–20% (
p
< 0.001). The overall survival period after recurrence was 44.9 months, which was comparable between the two groups (
p
= 0.283). In addition to a Ki67 rate higher than 5%, tumor larger than 4 cm and lymph node metastases were independently associated with recurrence.
Conclusions
Patients at high risk for recurrence after curative resection of G1 or G2 panNET can be identified by a Ki67 rate higher than 5%. These patients should be more closely monitored postoperatively to detect recurrence early and might benefit from adjuvant treatment. A clear postoperative follow-up regimen is proposed.
Patients with borderline (BL) or locally advanced (LA) pancreatic adenocarcinoma are usually treated with primary chemotherapy (CT), followed by resection when feasible. Scanty data are available ...about the criteria to candidate patients to resection after CT.
Between 2002 and 2016 overall 223 patients diagnosed with BL or LA pancreatic adenocarcinoma were primarily treated with Gemcitabine combination (4-drugs or nab-paclitaxel-gemcitabine) for 3–6months followed by surgery and/or chemoradiation. Resection was carried out when radical resection could be predicted by imaging studies and intraoperative findings. The prognostic value of both pre-treatment factors and treatment response was retrospectively evaluated, searching for criteria that could improve the selection of patients for surgery.
Median survival (MS) for the whole population was 18.3months. Surgical resection was carried out in 61 patients; MS in resected patients was significantly longer (30.0months) as compared with 162 non-resected patients (16.5months) (P<0.00001). According to response criteria, 48% had a radiological partial response, 47% a stable disease and 5% a disease progression); CA19.9 response (reduction>50%) was obtained in 77.8% of patients. Among resected patients, neither pre-treatment factors, including BL/LA distinction, nor radiological response, were able to prognosticate survival differences. Survival of resected patients having no CA19.9 response was significantly lower as compared with responders (MS 15.0 versus 31.5months,P=0.04), and was similar to non-responders patients that did not undergo resection (MS 10.9months,P=0.25). Multivariate analysis carried out on the overall population, showed that Karnofsky performance status, T3–T4 status, resection and CA19.9 response were independent prognostic factors, while radiological response, BL/LA distinction and baseline CA19.9 had not significant influence on survival.
CA19.9 response may allow a better selection of patients who will benefit from resection after primary CT for BL or LA pancreatic adenocarcinoma.
One major critical issue in seismic hazard analysis deals with the computation of the maximum earthquake magnitude expected for a given region. Its estimation is usually based on the analysis of past ...seismicity that is incomplete by definition, or derived from the dimension of faults through empirical relationships with the intrinsic uncertainty in source characterization. Here, we propose a workflow aimed at providing a time-independent estimate for the maximum possible magnitude based on geological and geophysical evidence. Our estimate is also source unrelated as it is constrained by the seismic brittle volume of the crust that scales with the effective seismic energy. The seismic brittle volume is calculated considering fault kinematics and rock rheology (i.e., the brittle-ductile transition depth) over a grid that covers the entire study area. The maximum earthquake magnitude is calculated at each point of the grid based on a volume/magnitude empirical relationship. We apply this model to Italy for which we propose a map of the maximum possible magnitudes. Maximum predicted magnitudes are 7.3 ± 0.25 for thrust faulting, 7.6 ± 0.77 for normal faulting and 7.6 ± 0.37 for strike-slip faulting (± deviation from the mean value calculated at each node). These magnitudes are locally higher than the historical record. This could be due to an overestimation of the involved volumes; smaller volumes and lower magnitudes may occur where faults are detached at decollements shallower than the brittle ductile transition or where they behave aseismically. Alternatively, strong or major earthquakes could be possible, but they have longer recurrence time and they have never been recorded yet in Italy. Regardless these values are fully reliable or not, the recurrence of earthquakes with the predicted magnitude is related to current strain rates. We conclude that a large part of the Italian territory is prone to trigger Mw > 5 earthquakes.
Display omitted
•A map of the maximum earthquake magnitude for Italy is compiled based on potential brittle volume.•Expected magnitudes correlate with the calculated brittle volumes.•Areas of relative low geodetic strain rate are more prone to nucleate earthquakes with respect to the surroundings.•Maximum magnitudes calculated on volumetric constraints are time independent.
The fault activation （fault on） interrupts the enduring fault locking （fault off） and marks the end of a seismic cycle in which the brittle-ductile transition （BDT） acts as a sort of switch. We ...suggest that the fluid flow rates differ during the different periods of the seismic cycle （interseismic, pre-seismic, coseismic and post-seismic） and in particular as a function of the tectonic style. Regional examples indicate that tectonic-related fluids anomalies depend on the stage of the tectonic cycle and the tectonic style. Although it is difficult to model an increasing permeability with depth and several BDT transitions plus independent acquicludes may occur in the crust, we devised the simplest numerical model of a fault constantly shearing in the ductile deeper crust while being locked in the brittle shallow layer, with variable homogeneous permeabilities. The results indicate different behaviors in the three main tectonic settings. In tensional tectonics, a stretched band antithetic to the normal fault forms above the BDT during the interseismic period. Fractures close and fluids are expellecl during the coseismic stage. The mechanism reverses in compressional tectonics. During the interseismic stage, an over-compressed band forms above the BDT. The band dilates while rebounding in the coseismic stage and attracts fluids locally. At the tip lines along strike-slip faults, two couples of subvertical bancls show different behavior, one in dilationJcompression and one in compressionJdilation. This deformation pattern inverts during the coseismic stage. Sometimes a pre-seismic stage in which fluids start moving may be observed and could potentially become a precursor.
Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM ...staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms.
The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided.
Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio HR of death = 16.23, 95% confidence interval CI = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability.
Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.
It is generally accepted that subduction is driven by downgoing-plate negative buoyancy. Yet plate age -the main control on buoyancy- exhibits little correlation with most of the present-day ...subduction velocities and slab dips. "West"-directed subduction zones are on average steeper (~65°) than "East"-directed (~27°). Also, a "westerly"-directed net rotation of the lithosphere relative to the mantle has been detected in the hotspot reference frame. Thus, the existence of an "easterly"-directed horizontal mantle wind could explain this subduction asymmetry, favouring steepening or lifting of slab dip angles. Here we test this hypothesis using high-resolution two-dimensional numerical thermomechanical models of oceanic plate subduction interacting with a mantle flow. Results show that when subduction polarity is opposite to that of the mantle flow, the descending slab dips subvertically and the hinge retreats, thus leading to the development of a back-arc basin. In contrast, concordance between mantle flow and subduction polarity results in shallow dipping subduction, hinge advance and pronounced topography of the overriding plate, regardless of their age-dependent negative buoyancy. Our results are consistent with seismicity data and tomographic images of subduction zones. Thus, our models may explain why subduction asymmetry is a common feature of convergent margins on Earth.
Earthquakes are dissipation of energy throughout elastic waves. Canonically is the elastic energy accumulated during the interseismic period. However, in crustal extensional settings, gravity is the ...main energy source for hangingwall fault collapsing. Gravitational potential is about 100 times larger than the observed magnitude, far more than enough to explain the earthquake. Therefore, normal faults have a different mechanism of energy accumulation and dissipation (graviquakes) with respect to other tectonic settings (strike-slip and contractional), where elastic energy allows motion even against gravity. The bigger the involved volume, the larger is their magnitude. The steeper the normal fault, the larger is the vertical displacement and the larger is the seismic energy released. Normal faults activate preferentially at about 60° but they can be shallower in low friction rocks. In low static friction rocks, the fault may partly creep dissipating gravitational energy without releasing great amount of seismic energy. The maximum volume involved by graviquakes is smaller than the other tectonic settings, being the activated fault at most about three times the hypocentre depth, explaining their higher b-value and the lower magnitude of the largest recorded events. Having different phenomenology, graviquakes show peculiar precursors.
PDF
