An Improved Model for Relativistic Solar Proton Acceleration applied to the 2005 January 20 and Earlier Events

This paper presents results on modelling the ground level response of the higher energy protons for the 2005 January 20 ground level enhancement (GLE). This event, known as GLE 69, produced the highest intensity of relativistic solar particles since the famous event on 1956 February 23. The location of recent X-ray and gamma-ray emission (N14 W61) was near to Sun-Earth connecting magnetic field lines, thus providing the opportunity to directly observe the acceleration source from Earth. We restrict our analysis to protons of energy greater than 450 MeV to avoid complications arising from transport processes that can affect the propagation of low energy protons. In light of this revised approach we have reinvestigated two previous GLEs: those of 2000 July 14 (GLE 59) and 2001 April 15 (GLE 60). Within the limitations of the spectral forms employed, we find that from the peak (06:55 UT) to the decline (07:30 UT) phases of GLE 69, neutron monitor observations from 450 MeV to 10 GeV are best fitted by the Gallegos-Cruz & Perez-Peraza stochastic acceleration model. In contrast, the Ellison & Ramaty spectra did not fit the neutron monitor observations as well. This result suggests that for GLE 69, a stochastic process cannot be discounted as a mechanism for relativistic particle acceleration, particularly during the initial stages of this solar event. For GLE 59 we find evidence that more than one acceleration mechanism was present, consistent with both shock and stochastic acceleration processes dominating at different times of the event. For GLE 60 we find that Ellison & Ramaty spectra better represent the neutron monitor observations compared to stochastic acceleration spectra. The results for GLEs 59 and 60 are in agreement with our previous work.Comment: 42 pages, 10 figures, 10 tables, published in ApJ, August 200

B cells in the formation of Tertiary Lymphoid Organs in autoimmunity, transplantation and tumorigenesis.

TLS develop in target organs of autoimmune diseases, transplantation and cancer. • TLS can function as germinal centres supporting B-cell selection/differentiation. • TLS can be destructive or have beneficial effects at the site of inflammation/disease. • Therapeutic targeting of TLS results in beneficial effects in patients, though inhibition may lead to immune suppression while stimulation may lead to autoimmunity. Tertiary lymphoid organs named also tertiary lymphoid structures (TLS) often occur at sites of autoimmune inflammation, organ transplantation and cancer. Although the mechanisms for their formation/function are not entirely understood, it is known that TLS can display features of active germinal centres supporting the proliferation and differentiation of (auto)-reactive B cells. In this Review, we discuss current knowledge on TLS-associated B cells with particular reference on how within diseased tissues these structures are linked to either deleterious or protective outcomes in patients and the potential for therapeutic targeting of TLS through novel drugs

Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs

This work was funded by research grants from Arthritis Research UK (grant 20089 to MB; grant 20858 to ECo; Arthritis Research UK Experimental Arthritis Treatment Centre - grant 20022 to CP) and the William Harvey Research Foundation (WHRF grant 2011–2013 to MB); Elisa Corsiero was recipient of short-term travel fellowships from EMBO (ASTF 318-2010 and ASTF 102-2013

Targeted delivery of anti-inflammatory therapy to rheumatoid tissue by fusion proteins containing an IL-4-linked synovial targeting peptide

We provide first-time evidence that the synovial endothelium-targeting peptide (SyETP) CKSTHDRLC successfully delivers conjugated IL-4 to human rheumatoid synovium transplanted into SCID mice. SyETP, previously isolated by in vivo phage display and shown to preferentially localize to synovial xenografts, was linked by recombinant technology to hIL-4 via an MMP-cleavable sequence. Both IL-4 and the MMP-cleavable sequence were shown to be functional. IL-4-SyETP augmented production of IL-1ra by synoviocytes stimulated with IL-1[beta] in a dose-dependent manner. In vivo imaging confirmed increased retention of SyETP-linked-IL-4 in synovial grafts which was enhanced by increasing number of copies (one to three) in the constructs. Strikingly, SyETP delivered bioactive IL-4 in vivo as demonstrated by increased pSTAT6 in synovial grafts. Thus, this study provides proof of concept for peptide-tissue-specific targeted immunotherapy in rheumatoid arthritis. This technology is potentially applicable to other biological therapies providing enhanced potency to inflammatory sites and reducing systemic toxicity

Relativistic Proton Production During the 14 July 2000 Solar Event: The Case for Multiple Source Mechanisms

Protons accelerated to relativistic energies by transient solar and interplanetary phenomena caused a ground-level cosmic ray enhancement on 14 July 2000, Bastille Day. Near-Earth spacecraft measured the proton flux directly and ground-based observatories measured the secondary responses to higher energy protons. We have modelled the arrival of these relativistic protons at Earth using a technique which deduces the spectrum, arrival direction and anisotropy of the high-energy protons that produce increased responses in neutron monitors. To investigate the acceleration processes involved we have employed theoretical shock and stochastic acceleration spectral forms in our fits to spacecraft and neutron monitor data. During the rising phase of the event (10:45 UT and 10:50 UT) we find that the spectrum between 140 MeV and 4 GeV is best fitted by a shock acceleration spectrum. In contrast, the spectrum at the peak (10:55 UT and 11:00 UT) and in the declining phase (11:40 UT) is best fitted with a stochastic acceleration spectrum. We propose that at least two acceleration processes were responsible for the production of relativistic protons during the Bastille Day solar event: (1) protons were accelerated to relativistic energies by a shock, presumably a coronal mass ejection (CME). (2) protons were also accelerated to relativistic energies by stochastic processes initiated by magnetohydrodynamic (MHD) turbulence.Comment: 38 pages, 9 figures, accepted for publication in the Astrophysical Journal, January, 200

Blocking T cell co-stimulation in primary Sjögren's syndrome:rationale, clinical efficacy and modulation of peripheral and salivary gland biomarkers

There is accumulating evidence that patients with primary Sjögren's syndrome (pSS) display aberrant CD4+ T cell responses, both in the peripheral compartment and in the inflamed salivary glands. CD4+ T cell abnormalities are also critically associated with B cell hyper activation, one of the hallmarks of disease, which is linked with disease severity and evolution to lymphoma. T cell activation and the cross-talk between T and B cells are tightly regulated by the balance between co-stimulatory pathways, such as the interactions between CD80/CD86:CD28, CD40:CD40L and ICOS:ICOSL, and co-inhibitory signals, including the immunoregulatory CTLA-4 protein. Evidence from patients with pSS as well as data from animal models of the disease suggests that these pathways play a critical role in pSS pathogenesis and their targeting could be exploited for therapeutic purposes. In this review, we first summarise the evidence implicating aberrant T cell co-stimulation and co-inhibition in driving the disease before focusing on the results of recent randomised controlled trials (RCTs) with compounds able to block T cell co-stimulation and enhance T cell co-inhibition. Despite a clear biological effect on downstream B cell activation has been observed in patients treated with CTLA-4-Ig (abatacept) and with monoclonal antibodies targeting CD40 and ICOSL, the clinical efficacy of this approach has so far yielded mixed results; while the anti-CD40 monoclonal antibody iscalimab showed significant improvement in systemic disease activity compared to placebo, two large RCTs with abatacept and a phase IIa RCT with an anti-ICOSL monoclonal antibody (prezalumab) failed to reach their primary endpoints. Although the discrepancies between biological and clinical efficacy of targeting T cell co-stimulation on pSS remain unresolved, several factors including drug bioavailability and receptor occupancy, patient stratification based on T-cell related biomarkers and the choice of study outcome are likely to play an important role and form the basis for further work towards the quest for a disease-modifying biologic therapy in pSS