Objectives IL-23 has been implicated in the pathogenesis of Ankylosing Spondylitis (AS). Aim of the study was to clarify the mechanisms underlying the increased IL-23 expression in the gut of AS patients. Methods Consecutive gut biopsies from 30 HLA-B27+ AS patients, 15 Crohn’s disease (CD) patients and 10 normal subjects were obtained. Evidence for HLA-B27 misfolding was studied. Unfolded protein response (UPR) and autophagy were assessed by rt-PCR and immunohistochemistry. The contribution of UPR and autophagy in the regulation of IL-23 expression was evaluated in in vitro experiments on isolated lamina propria mononuclear cells (LPMCs). Results Intracellular co-localization of SYVN1 and FHCs but not a significant over-expression of UPR genes was observed in the gut of AS patients. Conversely, up-regulation of the genes involved in the autophagy pathway was observed in the gut of AS and CD patients. Immunohistochemistry showed an increased expression of LC3II, ATG5 and ATG12 but not of SQSTM1 in the ileum of AS and CD patients. LC3II was expressed among infiltrating mononuclear cells and epithelial cells resembling Paneth cells and co-localized with ATG5 in AS and CD. Autophagy but not UPR was required to modulate the expression of IL-23 in isolated LPMCs of AS patients with chronic gut inflammation, CD patients and controls. Conclusions Our data suggest that HLA-B27 misfolding occurs in the gut of AS patients and is accompanied by activation of autophagy rather than an unfolded protein response. Autophagy appears to be associated with intestinal modulation of IL-23 in AS.

Objective. To compare the 2 most efficacious therapeutic regimens, intravenous immunoglobulin (IVIG) and anticoagulation with low molecular weight (LMW) heparin plus low-dose aspirin, in women with recurrent pregnancy loss associated with antiphospholipid antibodies (aPL).Methods. We examined 40 women with recurrent abortion (at least 3 occurrences) and repeatedly positive test results for anticardiolipin or lupus anticoagulant. The subjects were randomly assigned to treatment with IVIG or LMW heparin plus low-dose aspirin. Both therapies were started when the women were pregnant as documented by a positive urine test. IVIG was stopped at the thirty-first week of gestation, aspirin at the thirty-fourth week, and heparin at the thirty-seventh week. The primary outcome of interest was the rate of live births with the 2 treatments.Results. The characteristics of the 2 groups were similar at the time of randomization. The women treated with LMW heparin plus low-dose aspirin had a higher rate of live births (84%) than those treated with IVIG (57%).Conclusion. Treatment with LMW heparin plus low-dose aspirin should be considered as the standard therapy for recurrent pregnancy loss due to aPL.

Objective. The intestinal inflammation observed in patients with ankylosing spondylitis (AS) is characterized by an overexpression of interleukin-23 (IL-23). IL-23 is Conclusion. Our findings indicate that overexpression of IL-22, together with an increased number of IL-22-producing NKp44؉ NK cells, occurs in the gut of AS patients, where it appears to play a tissue-protective role.The asymptomatic ileal inflammation observed in patients with ankylosing spondylitis (AS) is immunologically characterized by the overexpression of interleukin-23 (IL-23). This overexpression, however, does not appear to be sufficient to induce Th17 polarization (1). Protective immunologic mechanisms, such as the expansion of IL-10-producing Treg cells, could, at least in part, explain the absence of a clear Th17 response despite the high levels of IL-23 observed in AS patients (2).Although the primary focus of investigations of IL-23 function has been its effect on the adaptive immune system through the regulation of the Th17 pathway, recent studies of the gut suggest an important role for IL-23 in regulating innate immune responses (3-8). These studies have in fact identified a subset of IL-23-responsive human lamina propria natural killer (NK) cells that contribute to intestinal mucosa immunity. Lamina propria NK cells comprise 2 main populations, interferon-␥ (IFN␥)-producing NKp46ϩ NK cells and IL-22-producing NKp44ϩ NK cells, which are balanced in normal human intestinal mucosa (9). This balance is disrupted in the inflamed mucosa of patients Supported by a grant from the

Summary The aim of this study was to investigate the expression of the interleukin (IL)‐36 axis in patients with primary Sjögren's syndrome (pSS). Blood and minor labial salivary glands (MSG) biopsies were obtained from 35 pSS and 20 non‐Sjögren's syndrome patients (nSS) patients. Serum IL‐36α was assayed by enzyme‐linked immunosorbent assay (ELISA). IL‐36α, IL‐36R, IL‐36RA, IL‐38, IL‐22, IL‐17, IL‐23p19 and expression in MSGs was assessed by reverse transcription–polymerase chain reaction (RT–PCR), and tissue IL‐36α and IL‐38 expression was also investigated by immunohistochemistry (IHC). αβ and γδ T cells and CD68+ cells isolated from MSGs were also studied by flow cytometry and confocal microscopy analysis. IL‐36α was over‐expressed significantly in the serum and in the salivary glands of pSS. Salivary gland IL‐36α expression was correlated with the expression levels of IL‐17, IL‐22 and IL‐23p19. IL‐38, that acts as inhibitor of IL‐36α, was also up‐regulated in pSS. αβ+ CD3+ T cells and CD68+ cells were the major source of IL‐36α in minor salivary glands of pSS. γδ T cells were not significantly expanded in the salivary glands of pSS but produced more IL‐17, as their percentage correlated with the focus score. Higher expression of IL‐36α and IL‐36R was also demonstrated in γδ T cells isolated from pSS compared to controls. In this study we demonstrate that a significant increase in circulating and tissue levels of IL‐36α occurs in pSS patients.

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Vgamma9/Vdelta2 T cells can contribute to protective immune response against Mycobacterium tuberculosis, although the extent to which and mechanisms by which they could actually protect against human tuberculosis remain unclear. We have previously reported that Vgamma9/Vdelta2 T cells from tuberculin purified protein derivative (PPD)-positive children, either healthy or affected by different clinical forms of tuberculosis, strongly proliferate to different phosphoantigens in vitro, whereas Vgamma9/Vdelta2 T cells from PPD-negative healthy subjects proliferate very poorly. We report here that Vgamma9/Vdelta2 T cells from tuberculous children have an increased proliferative activity, but decreased interferon (IFN)-gamma production and granulysin expression. After successful chemotherapy, the Vgamma9/Vdelta2 T cell proliferative response strongly decreased, whereas IFN-gamma and granulysin production consistently increased. Disease-associated changes in Vgamma9/Vdelta2 T cell effector functions in patients with tuberculosis are consistent with the possibility that these T cells may play a protective role in immune response against M. tuberculosis infection.

Objective. Subclinical gut inflammation has been demonstrated in patients with ankylosing spondylitis (AS).Intestinal inflammation is a shared feature of ankylosing spondylitis (AS) and Crohn's disease (CD). Shared immunologic and genetic similarities, in both clinical and preclinical stages, and the observation that 7% of patients with AS and initial chronic gut inflammation develop overt CD strongly support the hypothesis that AS patients with more pronounced gut inflammation could be considered to have preclinical CD (1-3).We have recently demonstrated that overexpres-

Objective. To determine whether prolongation of the inflammatory reaction in patients with Behçet's disease (BD) is related to apoptosis resistance and is associated with the up-regulation of antiapoptotic factors.Methods. The percentage of cell death was evaluated by flow cytometry in peripheral blood mononuclear cells from 35 patients with BD and 30 healthy volunteers. The expression levels of antiapoptotic factors and NF-B regulatory proteins were measured using Western blotting and immunohistochemical analyses. To down-regulate NF-B nuclear translocation, BD T lymphocytes were exposed in vitro to thalidomide and subjected to transfection with NF-B small interfering RNA.Results. Although CD95 is highly expressed in BD T cells, the absence of sensitivity to CD95-induced apoptosis observed may be attributable to the inhibitory action of antiapoptotic genes. Immunoblot analysis for major antiapoptotic proteins showed considerable upregulation of the short form of cellular FLIP ( Conclusion. Taken together, these results indicate that NF-B contributes to the regulation of the apoptosis-related factors and death receptors leading to apoptosis resistance in BD T cell subsets. Our results suggest that NF-B plays a crucial role in the pathogenesis of BD, and that its pharmacologic control could represent a key strategy in modulating specific immunemediated disease.