Frequency of the New HLA-B*2709 Allele in Ankylosing Spondylitis Patients and Healthy Individuals

We have recently described a new HLA-B27 subtype, named HLA-B*2709 (Del Porto et al. 1994). This allele is identical to the subtype most frequently found in Caucasoids, HLA-B*2705, except for a single amino acid substitution (Asp to His) in position 116. This residue, that is part of the F pocket of the molecule, has been shown to be relevant in determining which C-terminal amino acid of HLA-class I-binding peptides can be accomodated into the groove (Elliott, 1993). In nonamer peptides, this aminoacid corresponds to a primary anchor position (P9; Madden et al., 1992). Accordingly, we have previously shown that B2709 molecule hardly accepts nonamer peptides with an Arg or Tyr in P9, while the same amino acids represent good anchors for B2705 molecules (Fiorillo et al., 1995). Special attention is focused on HLA-B27 subtypes because of the strong association of B27 with ankylosing spondylitis (AS). More than 90% of AS patients are B27-positive and, conversely, about 4% of B27-positive individuals in the population are affected. This represents a relative risk over 100, that is the highest in HLA-disease associations. However, little is known on the pathogenic mechanisms of the disease. Following the hypothesis that an antigenic B27-binding peptide is involved in the disease (the so-called arthritogenic peptide), differential association with the different B27 subtypes may give a clue on the nature of such peptide. If two subtypes of partially overlapping peptide binding specificity are found to be both AS-associated, this would restrict the search for peptides that can be bound by both allelic products. Conversely, if a B27 subtype is found to be non AS-associated, this would be even more helpful in eliminating an array of peptides as possible candidates

Evolutionary compromises in ecological adaptation: urea and ammonia tolerance in Drosophila suzukii and Drosophila melanogaster

The invasive species Drosophila suzukii has evolved morphological and behavioral adaptations to lay eggs under the skin of fresh fruits. This results in severe damage of a wide range of small fruits, making this species a serious agricultural and economical threat. Drosophila suzukii females typically lay few eggs per fruit, preferring not infested fruits. Hence, larvae are exposed to a reduced amount of nitrogenous waste. Differently, the innocuous Drosophila melanogaster lays eggs on fermented fruits already infested by conspecifics, with larvae developing in a crowded environment with accumulation of nitrogenous waste such as ammonia and urea. The observed differences in oviposition site and larval ecological niche suggest that these species might differ in behavioral and physiological mechanisms used to cope with nitrogenous waste. We investigated how different concentrations of ammonia and urea affect fecundity and larval development in both species. Females and larvae of D. suzukii showed greater sensitivity to high concentration of both compounds, with a dramatic decrease in fecundity and egg viability. To better understand the pathways underlying these differences, we evaluated the effect on ornithine aminotransferase and glutathione-S-transferase, two enzymes involved in nitrogen metabolism and stress response that are expressed during larval development. Both ammonia and urea significantly reduced the expression of these enzymes in D. suzukii compared to D. melanogaster. This manifests how the ecological shift of D. suzukii to fresh fruit resulted in less efficient detoxifying and excretory mechanisms, with important implications for evolutionary biology and applied research

Clinical and biochemical landmarks in systemic autoinflammatory diseases.

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immune system characterized by seemingly unprovoked inflammation recurring at variable intervals and involving skin, serosal membranes, joints, and gastrointestinal apparatus, with reactive amyloidosis as a possible severe long-term complication. Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, and hereditary pyogenic and granulomatous disorders: the vast majority of these conditions are related to the activation of the interleukin-1 pathway, which results in (or from?) a common unifying pathogenetic mechanism. Their diagnostic identification derives from the combination of clinical data, evaluation of acute phase reactants, clinical efficacy in response to specific drugs, and recognition of specific mutations in the relevant genes, although genetic tests may be unconstructive in some cases. This review will discuss clinical and laboratory clues useful for a diagnostic approach to systemic autoinflammatory diseases

Ajulemic acid exerts potent anti-fibrotic effect during the fibrogenic phase of bleomycin lung

Background: Ajulemic acid (AjA) is a synthetic analogue of tetrahydrocannabinol that can prevent and limit progression of skin fibrosis in experimental systemic sclerosis. In this study we investigated whether AjA also prevents and modulates lung fibrosis induced by bleomycin (BLM) when administered in mice during the inflammatory or the fibrogenic phase of the model. Methods: The anti-inflammatory and antifibrotic efficacy of AjA was evaluated in DBA/2 mice treated orally once a day starting either at day 0 (preventive treatment) or at day 8 (therapeutic treatment) after a single intratracheal instillation of BLM. AjA was given at a dose of 1 mg/kg or 5 mg/kg. Mice were sacrificed at day 8, 14 and 21 after BLM and lungs were processed for histology and morphometry, and examined for HO-proline content and for the expression of transforming growth factor beta 1 (TGF-β1), phosphorylated Smad2/3 (pSMAD2/3), connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and peroxisome proliferator-activated receptor-gamma (PPAR-γ). Results: In the 1st week after BLM challenge, an acute inflammation characterized by neutrophil and macrophage accumulation was the main change present in lung parenchyma. The "switch" between inflammation and fibrosis occurs between day 8 and 14 after BLM instillation and involves the bronchi and vasculature. In the subsequent week (at day 21 after BLM instillation) bronchiolocentric fibrosis with significant increase of tissue collagen develops. The fibrotic response evaluated by morphometry and quantified as HO-proline in lung tissue at day 21 after BLM treatment was significantly reduced in mice receiving either AjA in the inflammatory or in early fibrogenic phase. AjA induces marked change in the expression pattern of products implicated in fibrogenesis, such as TGF-β1, pSMAD2/3, CTGF and α-SMA. In addition, AjA increases significantly the number of PPAR-γ positive cells and its nuclear localization. Conclusions: AjA treatment, starting either at day 0 or at day 8 after BLM challenge, counteracts the progression of pulmonary fibrosis. The anti-fibrotic effectiveness of AjA is irrespective of timing of compound administration. Further clinical studies are necessary to establish whether AjA may represent a new therapeutic option for treating fibrotic lung diseases

Le indicazioni al trattamento con immunoglobuline endovena nelle malattie reumatiche. [Indications for intra-venous immunoglobulin treatment in rheumatic diseases]

Con l’immissione in commercio delle Immunoglobuline per uso endovenoso (IVIG), che risale ormai al 1981, è stato possibile ampliarne enormemente le utilizzazioni terapeutiche, dimostrando l’efficacia di tale trattamento in condizioni cliniche le più diverse. In particolare, sulla base della progressiva acquisizione di conoscenze circa la capacità delle IVIG ad alte dosi di interferire a vari livelli col sistema immunitario, ne è stato proposto l’impiego in moltissime patologie su base autoimmunitaria o comunque dipendenti da meccanismi di tipo flogistico-immunitario. Ci limiteremo in questa sede a riportare le indicazioni al trattamento con IVIG, di quelle situazioni cliniche, di stretta competenza reumatologica, per le quali l’evidenza di efficacia sia sufficientemente solida, sia cioè basata su sperimentazioni cliniche allargate e adeguatamente controllate. Prima di procedere alla disamina degli aspetti terapeutici è tuttavia opportuno ricordare brevemente i meccanismi invocati per spiegare la potente attività immunomodulante di cui sono dotate le IVIG. I meglio conosciuti e documentati sono i seguenti