Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview

Interleukin-23 (IL-23) is a pro-inflammatory cytokine composed of two subunits, IL-23A (p19) and IL-12/23B (p40), the latter shared with Interleukin-12 (IL-12). IL-23 is mainly produced by macrophages and dendritic cells, in response to exogenous or endogenous signals, and drives the differentiation and activation of T helper 17 (Th17) cells with subsequent production of IL-17A, IL-17F, IL-6, IL-22, and tumor necrosis factor \u3b1 (TNF-\u3b1). Although IL-23 plays a pivotal role in the protective immune response to bacterial and fungal infections, its dysregulation has been shown to exacerbate chronic immune-mediated inflammation. Well-established experimental data support the concept that IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as PsA, Psoriasis, Psoriatic Arthritis; AS, Ankylosing Spondylitis; IBD, Inflammatory Bowel Disease; RA, Rheumatoid Arthritis; SS, Sjogren Syndrome; MS, Multiple Sclerosis. As a result, emerging clinical studies have focused on the blockade of this pathogenic axis as a promising therapeutic target in several autoimmune disorders; nevertheless, a greater understanding of its contribution still requires further investigation. This review aims to elucidate the most recent studies and literature data on the pathogenetic role of IL-23 and Th17 cells in inflammatory rheumatic diseases

Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinstein-Taybi syndrome

Rubinstein-Taybi syndrome is a rare autosomal dominant congenital disorder characterized by postnatal growth retardation, psychomotor developmental delay, skeletal anomalies, peculiar facial morphology, and tumorigenesis. Mutations in the gene encoding the cAMP response element-binding protein (CREB, also known as CREBBP or CBP) on chromosome 16p13.3 have been identified. In addition, some patients with low intelligence quotients and autistic features bear large deletions. Based on these observations, we used multiplex ligation-dependent probe amplification to search for large deletions affecting the CREBBP gene in a Rubinstein-Taybi syndrome patient. We identified a novel heterozygote deletion removing five exons (exons 17-21), encoding the histone acetyltransferase domain. We propose the use of multiplex ligation-dependent probe amplification as a fast, accurate and cheap test for detecting large deletions in the CREBBP gene in the sub-group of Rubinstein-Taybi syndrome patients with low intelligence quotients and autistic features

The in vitro addition of methotrexate and/or methylprednisolone determines peripheral reduction in Th17 and expansion of conventional Treg and of IL-10 producing Th17 lymphocytes in patients with early rheumatoid arthritis.

The aim of our study was to evaluate methotrexate (MTX) and methylprednisolone (MP) effect on peripheral Th17 and Treg subsets in patients with rheumatoid arthritis (RA). We enrolled 15 patients (10 early RA and 5 long-standing disease) with active RA and 10 age-matched healthy donors as controls. Frequencies of Th17 and Treg were quantified using flow cytometry before and after in vitro addition of MTX, MP or both drugs. Our results showed a reduction in the overall Th17 population followed by an increase in Th17 IL-10+ and Treg, after in vitro treatment of PBMCs with the drugs in patients with early RA. Long-standing disease patients showed a less evident increase in Treg cells and less enhancement of IL-10 Th17 cells. We suggest that the treatment with MTX and MP could ameliorate RA disease activity by normalizing the distribution/imbalance of Th17/Treg and indicate a new regulatory role of IL-17+ cells in RA patients. \ua9 2014, Springer-Verlag Berlin Heidelberg

Effect of The Gluten-Free Diet on Quality of Life, Gastrointestinal Symptoms and Immune System in Patients with Fibromyalgia and Non-Celiac Wheat Sensitivity. Fibromyalgia and Non-Celiac Wheat Sensitivity.

Fibromyalgia (FM) is a clinical syndrome characterized by chronic pain. FM patients complain hyperalgesia and allodynia and they are frequently affected by Non Celiac Wheat Sensitivity (NCWS), a condition where gastrointestinal and extraintestinal symptoms are triggered by gluten and/or wheat ingestion. The gluten-free diet (GFD) impact was evaluated on fibromyalgia-related and gastrointestinal symptoms, health-related quality of life and immune response of patients with both FM and NCWS in order to detect a possible pathogenetic role of wheat/gluten in the triggering of the inflammatory process. Peripheral blood from 8 FM patients, 10 FM and NCWS patients (FM+NCWS patients), 13 NCWS patients and 14 healthy subjects (HS) was taken before and after 8 weeks of GFD and used for cytofluorimetric analysis. In all FM+NCWS patients after GFD almost all the clinical parameters used to evaluate musculoskeletal and systemic symptoms related to FM were reduced as well as intestinal symptoms present before GFD. Moreover, pro-inflammatory cytokines production (IFN-\u3b3, TNF- \u3b1, IL-17 and IL-22) by T helper (Th) cells of FM+NCWS patients was reduced after GFD. Our findings suggest that gluten/wheat could represent one of the triggering factors of the inflammatory condition playing an important role in the etiopathogenesis of both FM and NCWS

Interleukin-9 Overexpression and Th9 Polarization Characterize the Inflamed Gut, the Synovial Tissue, and the Peripheral Blood of Patients With Psoriatic Arthritis

Objective. To investigate the expression and tis- sue distribution of Th9-related cytokines in patients with psoriatic arthritis (PsA). Methods. Quantitative gene expression analysis of Th1, Th17, and Th9 cytokines was performed in intestinal biopsy samples obtained from patients with PsA, HLA2B272positive patients with ankylosing spondylitis (AS), patients with Crohn’s disease (CD), and healthy controls. Expression and tissue distribu- tion of interleukin-23 (IL-23), IL-17, IL-22, IL-9, and IL-9 receptor (IL-9R) were evaluated by immunohisto- chemistry and confocal microscopy. Flow cytometry was used to study the frequency of Th9 cells among periph- eral blood, lamina propria, and synovial fluid mononuclear cells. The functional relevance of IL-9R expression on epithelial cells was assessed in functional in vitro studies. Th9 cells in synovial tissue from patients with PsA were also studied. Results. Subclinical gut inflammation in PsA patients was characterized by a clear Th17 and Th22, but not Th1, polarized immune response. Unlike AS and CD, a strong and significant up-regulation of IL-9 was observed in PsA gut, especially among infiltrating mononuclear cells, high endothelial venules, and Pan- eth cells. IL-92positive mononuclear cells were demon- strated to be in large part Th9 cells. IL-9 overexpression was accompanied by significant Paneth cell hyperplasia. Paneth cells strongly overexpressed IL-9R, and stimula- tion of epithelial cells, isolated from PsA patients, with IL-9 resulted in overexpression of a-defensin 5 and IL-23p19. Peripheral and synovial expansion of a4b71 Th9 cells was also observed in patients with PsA. Increased expression of IL-9 and IL-9R was also found in synovial tissue. Conclusion. Strong IL-9/Th9 polarization seems to be the predominant immunologic signature in patients in PsA

Abnormal F-18 Fluorodeoxyglucose Uptake of the Lung in Immunocompromised Lymphoma Patients in Complete Remission: Report of Two Cases and Revision of Literature

Limited data suggest that F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) may have a role in diagnosing infection. Here we present two cases of lymphoma patients in complete response (CR) who presented during follow-up dry cough and fever. Physical examination and serum evaluations were negative for lymphoma while whole body FDG-PET showed lung uptake which posed a differential diagnosis between relapse of lymphoma and an atypical pneumonia due to persistent lymphopenia. In both cases, cytology examination of sputum suggested Pneumocystis Jiroveci pneumonia (PJP). After appropriate antibiotic treatment, the follow-up examination showed complete resolution of the lung changes revealed by FDG-PET. False-positive results on FDG-PET were supposed to be due to the high uptake of FDG in non-neoplastic inflammatory cellular elements such as macrophages and lymphocytes. Our findings suggest that in cases of FDG-PET positive images in immunocompromised patients with previous hematologic disease, caution must be used, and differential diagnosis might include infections such as PJP in addition to relapse of disease

Analisi MLPA del gene CREB-binding protein (CREBBP) in un paziente con la sindrome di Rubinstein Taybi

La sindrome di Rubinstein-Taybi \ue8 una rara malattia congenita autosomica dominante caratterizzata da ritardo della crescita postnatale, ritardo dello sviluppo psicomotorio, anomalie scheletriche, peculiare morfologia facciale ed un aumento del rischio oncogeno. La prevalenza alla nascita \ue8 1 su 125.000 nati vivi. La malattia pu\uf2 essere associata a mutazioni nel gene che codifica per la proteina CREB-binding localizzato nella regione cromosomica 16p13.3. Recenti studi hanno dimostrato che pazienti con quoziente intellettivo basso e tratti autistici possono avere grandi delezioni. Sulla base di queste osservazioni, abbiamo usato la Multiplex Ligation-dependent Probe Amplification (MLPA) per ricercare delezioni che interessano il gene CREB-binding in un paziente con sindrome di Rubinstein-Taybi e abbiamo identificato una delezione in eterozigosi che causa la rimozione di cinque esoni (esoni 17-21) codificanti per il dominio istone acetiltransferasi. Noi proponiamo, come primo approccio diagnostico, l'uso del metodo MLPA nel sottogruppo di pazienti con la sindrtome di Rubinstein-Taybi con quoziente di intelligenza basso e fenotipo autistico

Aortic root dilation in associated with the reduction in capillary density observed at nailfold capillaroscopy in SSc patients

Systemic sclerosis (SSc) is an autoimmune disease characterized by endothelial dysfunction and fibroblasts activation. Microvascular disease may be easily observed by means of nailfold capillaroscopy. Recent evidences emphasized also the involvement of large-medium arteries in SSc, mainly in terms of increased stiffness of the vessel wall. The study aims to measure aortic root diameter in a cohort of SSc patients and to correlate echocardiographic findings with the capillaroscopic pictures. We analyzed the clinical records of 125 consecutive SSc patients (M/F 14/111, mean age 55 ± 12.7 years, median disease duration 11 years) referring in 3 second-level rheumatology centers. All subjects underwent to heart ultrasound evaluation and videocapillaroscopic evaluation. At capillaroscopy, the patients with early SSc pattern belonged to the subgroup 1, while those with the active/late patterns (characterized by the reduction of capillary density) belonged to the subgroup 2. We found aortic root dilation in 8 (6.4%) SSc patients, with a mean value of 37.8 ± 1.2 mm (range 37–40 mm). Aortic root dilation was observed in only one patient in the subgroup 1 (1/62, 1.6%) and in 7 cases of the subgroup 2 (7/63, 11.1%; p = 0.03). Our study found a significant association between aortic root dilation and impairment of capillary density at nailfold videocapillaroscopy in SSc patients. We hypothesize that SSc-related microangiopathy revealed by nailfold videocapillaroscopy could mimic that of aortic vasa vasorum, contributing to deteriorate the aortic wall structure and favoring aortic root dilation and stiffening