Deficiency of interleukin (IL)-36 receptor antagonist (DITRA) syndrome is a rare autosomal recessive disease caused by mutations in IL36RN. IL-36R is a cell surface receptor and a member of the IL1R family that is involved in inflammatory responses triggered in skin and other epithelial tissues. Accumulating evidence suggests that IL-36R signaling may play a role in the pathogenesis of psoriasis. Therapeutic intervention of IL-36R signaling offers an innovative treatment paradigm for targeting epithelial cell-mediated inflammatory diseases such as the life-threatening psoriasis variant called generalized pustular psoriasis (GPP). We report the discovery and characterization of MAB92, a potent, high affinity anti-human IL-36 receptor antagonistic antibody that blocks human IL-36 ligand (α, β and γ)-mediated signaling. In vitro treatment with MAB92 directly inhibits human IL-36R-mediated signaling and inflammatory cytokine production in primary human keratinocytes and dermal fibroblasts. MAB92 shows exquisite species specificity toward human IL-36R and does not cross react to murine IL-36R. To enable in vivo pharmacology studies, we developed a mouse cross-reactive antibody, MAB04, which exhibits overlapping binding and pharmacological activity as MAB92. Epitope mapping indicates that MAB92 and MAB04 bind primarily to domain-2 of the human and mouse IL-36R proteins, respectively. Treatment with MAB04 abrogates imiquimod and IL-36-mediated skin inflammation in the mouse, further supporting an important role for IL-36R signaling in epithelial cell-mediated inflammation.

Background -It has been hypothesised that cryptogenic fibrosing alveolitis has an immunological pathogenesis mediated by T lymphocytes. It is, however, recognised that patients may show dysregulation of the humoral immune system and that the presence of large numbers of B lymphocytes in open lung biopsies may be associated with a poor prognosis. Evidence of a role for the humoral immune system in the pathogenesis of cryptogenic fibrosing alveolitis has been suggested, but attempts to demonstrate circulating immunoglobulin to antigen within the lung have been inconclusive. Methods -Plasma samples from 22 patients with cryptogenic fibrosing alveolitis, 22 patients with sarcoidosis, and 17 healthy controls were screened by SDS-PAGE and Western blotting for the presence of autoantibodies to lung proteins derived from cryptogenic fibrosing alveolitis, sarcoid and control lung tissue, as well as four normal non-pulmonary tissues. Possible site(s) of target protein(s) within the lung tissue were identified by immunohistochemical examination using IgG purified from the plasma of six patients and two controls. Results -Eighteen of the plasma samples from patients with cryptogenic fibrosing alveolitis had reactive IgG to lung protein(s) (Thorax 1994;49:218-224) Cryptogenic fibrosing alveolitis is the commonest form of interstitial lung disease and is characterised by progressive pulmonary fibrosis, often leading to death within five years from the time of diagnosis.' Histological examination of biopsy material from patients with cryptogenic fibrosing alveolitis has shown a mixed inflammatory cell infiltrate2 with an alveolitis affecting the more distal part of the acinar unit.3 Data from bronchoalveolar lavage have shown increased numbers of neutrophils, eosinophils, and CD4 positive lymphocytes,4 as well as raised levels of immunoglobulin5 in patients with cryptogenic fibrosing alveolitis. Both suggest an immunological pathogenesis for the disease but have not indicated any definite aetiological factors.In addition there is evidence of a more general immune dysregulation with hypergammaglobulinaemia,4 circulating immune complexes,67 and the production of recognised non-organ specific autoantibodies such as antinuclear factor and rheumatoid factor8 in some patients. Clinical studies have also shown that the collagen vascular diseases, which have a known immunological pathogenesis involving the production of non-organ specific autoantibodies, may be associated with an identical pattern of alveolitis.9The current consensus is that, whatever the aetiological agent(s), cryptogenic fibrosing alveolitis represents a persistent immunological reaction in the lung with resultant scar formation.'0 The predominance of T lymphocytes in the tissues and in the bronchoalveolar lavage fluid has suggested that the reaction may be mediated by the cellular arm of the immune system. Despite this, markers of T lymphocyte activation have not been found to correlate with disease activity or prognosis." It has also been reported th...

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Neuromuscular scoliosis (NMS) is the second most prevalent spinal deformity (after idiopathic scoliosis) and is usually first identified during early childhood. Cerebral palsy (CP) is the most common cause of NMS, followed by Duchenne muscular dystrophy (DMD). Progressive spinal deformity causes difficulty with daily care, walking and sitting, and can lead to back and rib pain, cardiac and pulmonary complications, altered seizure thresholds, and skin compromise. Early referral to specialist spinal services and early diagnosis of NMS is essential to ensure appropriate multidisciplinary patient management. The most important goals for patients are preservation of function, facilitation of daily care, and alleviation of pain. Non-operative management includes observation or bracing for less severe and flexible deformity in young patients as a temporising measure to provide postural support. Surgical correction and stabilisation of NMS is considered for patients with a deformity >40-50°, but may be performed for less severe deformity in patients with DMD. Post-operative intensive care, early mobilisation and nutritional supplementation aim to minimise the rate of post-surgical complications, which are relatively common in this patient group. However, surgical management of NMS is associated with good long-term outcomes and high satisfaction rates for patients, their relatives and carers.