Basic principles of the immune system and autoimmunity

The immune system is composed of two closely collaborative systems, an innate and an adaptive system. The innate immune system is a constitutive present system that can act rapidly to eradicate microbes. The primary cells of the innate immune system are macrophages, granulocytes, natural killer cells and dendritic cells. The adaptive system can be divided in a humoral and cellular response. The humoral response is characterized by activation of B-lymphocytes with subsequent maturation into plasma cells and production of antibodies, whereas a cellular immune response is characterized by transformation of T-lymphocytes into cytotoxic T-cells, capable of killing virally infected cells. Auto-reactive B- and T-lymphocytes can induce autoimmune diseases. Autoimmune blistering diseases are the result of type II hypersensitivity, e.g. autoantibodies are directed against cell or matrix components. In pemphigoid diseases antibodies are directed against hemidesmosomal components, whereas pemphigus is characterized by antibodies against desmosomal proteins.</p

Direct immunofluorescence microscopy

Direct immunofluorescence plays an important role in the diagnosis of autoimmune blistering diseases. The purpose of direct immunofluorescence microscopy is to detect in vivo antibodies in patient's skin or mucosa. Direct immunofluorescence of pemphigus shows depositions of immunoglobulins and/or complement on the epithelial cell surface of keratinocytes, whereas pemphigoid shows linear deposition of immunoglobulins along the epidermal basement membrane zone. This linear deposition can be separated in an n-serrated pattern and a u-serrated pattern. An n-serrated pattern is seen in blistering diseases with binding above the lamina densa with antibodies against hemidesmosomal components, e.g. bullous pemphigoid, while a u-serrated pattern points to a sublamina densa binding diseases caused by autoantibodies against type VII collagen, e.g. epidermolysis bullosa acquisita. Finally, dermatitis herpetiformis shows a granular IgA deposition along the epidermal basement membrane zone.</p

Indirect immunofluorescence microscopy

The purpose of indirect immunofluorescence microscopy is to detect circulating antibodies in patient's serum. For this purpose an adequate substrate is necessary to visualize these antibodies. Monkey esophagus is the most widely used substrate for detecting of circulating autoantibodies in patients with autoimmune blistering diseases. In all variants of pemphigus antibodies show an epithelial cell surface pattern, resulting from present autoantibodies against the desmosomal molecules desmoglein 1 and/or 3. This pattern is also called chicken wire or honeycomb pattern. In pemphigoid a linear deposition along the epithelial basement membrane can be observed, caused by autoantibodies against hemidesmosomes or their connecting proteins underneath. Human salt split skin is a valuable substrate in the diagnosis of subepidermal autoimmune blistering diseases. Important antigens in the roof of salt split skin are type XVII collagen (BP180) and BP230, whereas laminin 332, p200 and type IV collagen are situated in the floor of the blister. This implies that bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, and lichen planus pemphigoides show staining of IgG on the epidermal side of the blister. On the other hand anti-laminin 332 pemphigoid, anti-p200 pemphigoid, epidermolysis bullosa acquisita, and bullous SLE show staining on the dermal side. Other less used, but valuable substrates in some instances, are rat bladder and knock-out skin.</p

How to take a biopsy

The skin is an organ that is easy to access for microscopy. Sections of the skin may reveal the split level of the blister, the type and distribution of inflammatory cells, and the presence, class and distribution pattern of autoantibodies. A biopsy should be taken from a location with smallest change of sample error, and the specimen specially fixated and transported for the requested microscopic techniques. Taking biopsies is the area of expertise of the dermatologist, even taking conjunctiva biopsies for immunofluorescence (IF) is possible in cases of suspicion of an autoimmune blistering disease of the eye.</p

Paraneoplastic pemphigus

Paraneoplastic pemphigus is a rare but severe potentially fatal autoimmune disease characterized by severe stomatitis and a variety of cutaneous manifestations in association with an underlying neoplasia. Pulmonary involvement may also occur. The pathogenesis involves the production of autoantibodies against desmogleins, plakins and the protease inhibitor alpha-2 macroglobuline like-1, but T-cell mediated autoimmunity is also thought to play a role. Diagnosis usually relies on the demonstration of a specific subset of circulating autoantibodies in patient serum, although in a small subset of patients these autoantibodies might be absent. Due to it's rarity, there are no guidelines for the treatment of PNP. The general approach includes a variety of immunosuppressive agents and treatment of the underlying neoplasia. Despite treatment, paraneoplastic pemphigus has high mortality rates, often due to sepsis, respiratory failure or progression of the underlying malignancy.</p

Evaluation of Nomacopan for Treatment of Bullous Pemphigoid:A Phase 2a Nonrandomized Controlled Trial

Importance: Bullous pemphigoid is a difficult-to-treat autoimmune blistering skin disease that predominantly affects older adults and is associated with an increased mortality rate. Objective: To examine the safety and therapeutic potential of nomacopan, an inhibitor of leukotriene B4and complement C5, in patients with bullous pemphigoid. Design, Setting, and Participants: This multicenter, single-group, phase 2a nonrandomized controlled trial was conducted in the dermatology departments of universities in the Netherlands and Germany. Participants were enrolled between September 2018 and April 2020. Older adult patients (aged ≥55 years) with mild to moderate, new-onset or relapsing bullous pemphigoid were recruited into the study. Interventions: Patients received nomacopan, 90 mg, subcutaneously on day 1 and 30 mg subcutaneously daily until day 42. Main Outcomes and Measures: The primary end point was the proportion of patients with grade 3 to 5 (severe) adverse events associated or possibly associated with nomacopan. Secondary end points included mean absolute and percentage changes in the Bullous Pemphigoid Disease Area Index (BPDAI) activity score, the BPDAI pruritus score, and the patient-reported outcome measures Dermatology Life Quality Index (DLQI) and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL). Results: A total of 9 patients (median [range] age, 75 [55-85] years) with bullous pemphigoid were included in the trial, of whom 5 were women (55.6%). No serious adverse events associated with nomacopan were found. The mean (90% CI) BPDAI activity score decreased from 32.0 (8.7) points on day 1 to 19.6 (9.0) points on day 42. Seven of 9 patients (77.8%) responded to nomacopan with a reduction in the BPDAI activity score of at least 8 points between days 1 and 42; in 3 responders, the reduction was 80% or greater. On day 42, the mean (90% CI) BPDAI pruritus score had decreased by 6.8 (4.6) points from 17.6 (4.0) points on day 1. The mean (90% CI) DLQI score decreased from 11.3 (4.2) points at baseline to 6.4 (3.8) points by day 42, and the mean (90% CI) TABQOL score decreased from 14.6 (5.4) points at baseline to 10.3 (5.0) points on day 42. Conclusions and Relevance: Results of this nonrandomized controlled trial suggest that nomacopan can be well tolerated in older patients with bullous pemphigoid and may have therapeutic benefits for suppressing acute flares of this disease. A larger, placebo-controlled randomized clinical trial is warranted to confirm this safety profile and to establish nomacopan as a new therapeutic option for bullous pemphigoid. Trial Registration: ClinicalTrials.gov Identifier: NCT04035733

Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector

The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements

A search for resonances decaying into a Higgs boson and a new particle X in the XH → qqbb final state with the ATLAS detector

A search for heavy resonances decaying into a Higgs boson (H) and a new particle (X) is reported, utilizing 36.1 fb−1 of proton–proton collision data at collected during 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. The particle X is assumed to decay to a pair of light quarks, and the fully hadronic final state is analysed. The search considers the regime of high XH resonance masses, where the X and H bosons are both highly Lorentz-boosted and are each reconstructed using a single jet with large radius parameter. A two-dimensional phase space of XH mass versus X mass is scanned for evidence of a signal, over a range of XH resonance mass values between 1 TeV and 4 TeV, and for X particles with masses from 50 GeV to 1000 GeV. All search results are consistent with the expectations for the background due to Standard Model processes, and 95% CL upper limits are set, as a function of XH and X masses, on the production cross-section of the resonance