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ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.ResultsLD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.ConclusionsA rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

A panel discussion on the future of clinical trials addressed several issues raised in the course of the first day of the Workshop. The chair posed questions in six areas which the panel and audience addressed. This paper summarizes the panel discussion.

From a human histocompatibility leukocyte antigen (HLA)-DR/DQ hemizygous, B lymphoblastoid progenitor, we isolated a cell line, 10.24.6, with a DR alpha missense mutation (96P-->96S), which results in an N-linked carbohydrate addition at position 94 in the DR alpha 2 domain. Several features of 10.24.6 cells suggest that the mutation disrupts normal intracellular formation of peptide/DR complexes. The mutant HLA-DR dimers, though expressed at the cell surface, lack the conformation of the mature, peptide-loaded class II molecules of the progenitor cell, as assessed by their loss of binding of certain antibodies and by the lack of stability in detergent (sodium dodecyl sulfate) solution. In addition, presentation of endocytosed antigen to HLA-DR-restricted T cells is defective in the mutant, but can be restored by transfection of a wild type DRA gene. Assays with synthetic peptides indicate that the 10.24.6 phenotype is not due to an intrinsic inability of the mutant DR molecules to bind peptides. Therefore, to directly evaluate peptide occupancy of the mutant molecules, we analyzed acid-eluted, HLA-DR-associated peptides. The predominant species from the 10.24.6 mutant is a nested set of invariant chain (Ii)-derived peptides that are undetectable in the DR eluate from progenitor cells. The region of DR alpha altered in the mutant molecules is thus implicated in normal formation of peptide/DR complexes. Further, the same set of Ii peptides associated with the DR molecules is present in the eluate from an antigen presentation mutant with a defect in an major histocompatibility complex (MHC)-linked gene. These results suggest that DR molecules in 10.24.6 and in certain presentation mutants are affected at the same or related steps in class II molecule biosynthesis, raising the possibility that class II molecules interact with an MHC-encoded accessory molecule during antigen presentation.

IN antigen-presenting cells, class II molecules of the major histocompatibility complex (MHC) bind peptides derived from endo-cytosed proteins1. In certain B-lymphoblastoid cell mutants, MHC class II molecule–peptide complex formation is impaired, resulting in deficient antigen-presenting function2. MHC deletion mutants with this defect map the responsible gene(s) to the class II region of the MHC3–5. Here we report that multiple independent mutants with the class II presentation defect harbour lesions in HLA-DMB, an MHC-linked gene encoding a class II-like β-chain6,7. Expression of DMB complementary DNA in mutants lacking DMB messenger RNA restores the wild-type phenotype. These results establish HLA-DM as a critical regulatory molecule in class II-restricted antigen presentation and suggest that it functions at an intracellular site to promote class II molecule–peptide association.

Neurotransmitter amino acids were measured in post-mortem caudate nucleus, nucleus accumbens, frontal cortex, amygdala, and hypothalamus of chronic schizophrenic and normal control subjects. The concentrations of γ-aminobutyric acid (GABA), taurine, glycine-threonine, glutamate, aspartate, glutamine, tryptophan, and alanine were similar in both groups, with the exception of decreased GABA and tryptophan in the amygdala of the schizophrenic group. Strong positive correlations were obtained between the concentration of tryptophan, a putative agonal status marker of post-mortem brain tissue, and the concentration of GABA in all brain areas. When the GABA concentrations were adjusted for tryptophan concentrations in amygdala, the difference between the schizophrenic and control samples was no longer significant, suggesting that the original difference may have been due to different agonal or post-mortem changes in the tissues. There were, however, no significant correlations between GABA and post-mortem interval. The present results do not support the aminoacidergic hypotheses of chronic schizophrenia, although a GABA deficiency cannot be entirely excluded.

1. NADase activity has been determined on intact erythrocytes of several species. 2. Although a wide range in maximum velocity exists across species, Michaelis constants observed are very similar. 3. The enzyme is found on the outer surface of the erythrocyte plasma membrane. 4. It is inhibited by substrate after an apparent permanent modification. 5. This modification may be due to self ADP-ribosylation. 6. We have also demonstrated the presence of an ADP-ribosyltransferase on the outer surface of the sheep erythrocyte membrane.

• Serotonin (5-HT) and 5-hydroxyindoleacetic acid concentrations were determined in various brain areas of nonschizophrenic suicide victims, chronic schizophrenic patients with or without suicide as the cause of death, and normal control subjects without psychiatric or neurologic disorders. Serotonin concentrations in the basal ganglia were significantly elevated in suicide victims and chronic schizophrenic patients, as were 5-hydroxyindoleacetic acid concentrations in the occipital cortex. These differences were not specific to either patient group and may have been caused by neuroleptic or antidepressant treatment. A decreased 5-HT concentration was found in the hypothalamus of nonschizophrenic suicide victims. Among the chronic schizophrenic patients, there was no significant difference in the hypothalamic 5-HT content between the suicide victims and others, indicating that low 5-HT levels in the hypothalamus are not characteristic of schizophrenic patients who died of suicide.