Giuseppe Murdaca

The impaired NK cell cytolytic function in viremic HIV‐1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44)

Signals leading to NK cell triggering are primarily mediated by natural cytotoxicity receptors (NCR) upon binding to as‐yet‐undefined cell surface ligand(s) on normal hematopoietic cells, pathogen‐infected cells or tumor cells. In this study we tried to determine whether the decreased NK cell cytolytic function that is observed in HIV‐1‐infected patients may be related to a decreased expression of NCR. In HIV‐1‐infected patients, freshly drawn, purified NK cells expressed significantly decreased surface densities of NKp46 and NKp30 NCR. The low surface density of NKp46, NKp30 and NKp44 was also confirmed in in‐vitro‐activated NK cell populations and NK cell clones derived from HIV‐1 patients compared with uninfected donors. This defective NCR expression in HIV‐1 patients was associated with a parallel decrease of NCR‐mediated killing of different tumor target cells. Thus, the present study indicates that the defective expression of NCR represents at least one of the possible mechanisms leading to the impaired NK cell function in HIV‐1 infection and it can contribute to explain the relatively high frequency of opportunistic tumors reported in cohorts of untreated patients before the occurrence of profound immunosuppression (<200 CD4+ cells/mm3).

Vδ1 T lymphocytes producing IFN-γ and IL-17 are expanded in HIV-1–infected patients and respond to Candida albicans

In early HIV-1 infection, Vdelta1 T lymphocytes are increased in peripheral blood and this is related to chemokine receptor expression, chemokine response, and recirculation. Herein we show that, at variance with healthy donors, in HIV-1-infected patients ex vivo-isolated Vdelta1 T cells display cytoplasmic interferon-gamma (IFN-gamma). Interestingly, these cells coexpress cytoplasmic interleukin-17 (IL-17), and bear the CD27 surface marker of the memory T-cell subset. Vdelta1 T cells, isolated from either patients or healthy donors, can proliferate and produce IFN-gamma and IL-17 in response to Candida albicans in vitro, whereas Vdelta2 T cells respond with proliferation and IFN-gamma/IL-17 production to mycobacterial or phosphate antigens. These IFN-gamma/IL-17 double-producer gammadelta T cells express the Th17 RORC and the Th1 TXB21 transcription factors and bear the CCR7 homing receptor and the CD161 molecule that are involved in gammadelta T-cell transendothelial migration. Moreover, Vdelta1 T cells responding to C albicans express the chemokine receptors CCR4 and CCR6. This specifically equipped circulating memory gammadelta T-cell population might play an important role in the control of HIV-1 spreading and in the defense against opportunistic infections, possibly contributing to compensate for the impairment of CD4(+) T cells.

Significant NK cell activation associated with decreased cytolytic function in peripheral blood of HIV-1-infected patients

One of the hallmarks of HIV‐1 infection is represented by the finding of massive T cell activation in peripheral blood lymphocytes of infected patients. An impairment of NK cell function during HIV‐1 infection is also detected, and is associated with decreased expression of natural cytotoxicity receptors (NCR). In this study we tried to determine whether also NK cells are affected by relevant activation and whether this could be associated with decreased NK cell function. In 18 viremic HIV‐1‐infected patients, freshly drawn purified peripheral NK cells displayed significant levels of activation with an incomplete pattern (HLA‐DR+CD69+CD25–NKp44–). Activated (HLA‐DR+CD69+) peripheral NK cells expressed an NCRdull phenotype as determined by cytofluorometric analysis in all the patients, and did not derive from a homogeneous/oligoclonal expansion in vivo as analyzed by expression of HLA‐specific inhibitory NK cell receptors. As determined by cytotoxicity assays, activated NK cells showed a decreased cytolytic function in HIV‐1‐infected patients. Thus, the decrease in NK cell function observed during HIV‐1 infection is associated not only with decreased NCR expression, but also with significant and incomplete NK cell activation in vivo. These results suggest a consistent continuous involvement of the innate immune response in the failure to control viral replication.

Serum interleukin-17 levels are related to clinical severity in allergic rhinitis.

Background:  T helper (Th)‐17 cells are a subset of T helper lymphocytes that exert regulatory activities. Recently, it has been reported that serum interleukin (IL)‐17 levels are high in the most severe cases of birch allergy studied outside the pollen season.

Current Views on Diagnostic Approach and Treatment of Lymphedema

Lymphedema is a chronic, progressive, and often debilitating condition. Primary lymphedema is a lymphatic malformation developing during the later stage of lymphangiogenesis. Secondary lymphedema is the result of obstruction or disruption of the lymphatic system, which can occur as a consequence of tumors, surgery, trauma, infection, inflammation, and radiation therapy. In this review, we report an update upon the diagnostic approach and the medical and surgical therapy for both primary and secondary lymphedema.

The role of Th17 lymphocytes in the autoimmune and chronic inflammatory diseases.

The emerging role of interleukin-17 as a hallmark proinflammatory cytokine of the adaptive immune system produced by a new T helper cell subset termed “Th17” has received considerable attention. In this review we will focus on recent information regarding IL-17 and its relevance in autoimmune and chronic inflammatory diseases.

Infection risk associated with anti-TNF-α agents: a review

Introduction: TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of chronic immune-mediated diseases. TNF-α inhibitors can be administered either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs (DMARDs) to treat chronic immune-mediated diseases. Areas covered: Patients receiving TNF-α inhibitors are at high risk of infections. Based on our experience, in this paper, we discuss the risk of infections associated with the administration of TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events. Expert opinion: Infliximab more so than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis (LTB) infection and the overall risk of opportunistic infections should be considered before beginning TNF-α inhibitor therapy. A careful medical history, Mantoux test and chest-x-ray should always be performed before prescribing TNF-α inhibitors. Particular attention should be paid to risk factors for Pneumocystis jirovecii infection. Hepatitis B and C virological follow-up should be considered during TNF-α inhibitor treatment. Finally, patients who are at high risk of herpes zoster (HZ) reactivation would benefit from a second vaccination in adulthood when receiving TNF-α inhibitors.

Traditional and non traditional risk factors in accelerated atherosclerosis in systemic lupus erythematosus: role of vascular endothelial growth factor (VEGATS Study).

OBJECTIVE To evaluate the role of vascular endothelial growth factor (VEGF) in accelerated atherosclerosis in patients with Systemic Lupus Erythematosus (SLE). METHODS We have enrolled 80 SLE female patients and 80 age-matched healthy control females who underwent a structured interview, physical examination, routine laboratory tests, VEGF plasma level determination and B-mode ultrasonography of carotid arteries to determine carotid intima media thickness (IMT). Framingham risk factors for cardiovascular events were also calculated and VEGF plasma levels were correlated with traditional and nontraditional cardiovascular risk factors. RESULTS SLE was significantly associated with higher mean IMT values (0.74+/-0.15 mm versus 0.59+/-0.12 mm in controls, p<0.001) and higher mean plasma VEGF levels (307.9+/-292.2 pg/mL versus 120.7+/-118.4 pg/mL in controls, p<0.001) independently from age, smoking habits, and Framingham risk factors. A significant correlation was also found between IMT and VEGF values (r=0.25; p<0.001). CONCLUSION We show that SLE patients have increased mean IMT and VEGF values as compared with healthy age-matched controls and that IMT and VEGF values are independently and directly associated with SLE disease.

Emerging biological drugs: a new therapeutic approach for Systemic Lupus Erythematosus. An update upon efficacy and adverse events.

B-cells abnormalities leading to autoantibody production play a central role in Systemic Lupus Erythematosus (SLE) pathogenesis. B-cell targeted therapies, including anti-B lymphocyte stimulator (BLyS) and anti-CD20 monoclonal antibodies, are at forefront of new SLE treatments. Biologic agents targeting specific pathways (i.e. T-B lymphocyte interaction, cytokines and complement) have been also proposed as new tools for SLE treatment. In this review we will focus on biological drugs whose potential efficacy has been evaluated in open-label and randomized clinical trials.

Update upon efficacy and safety of TNF-α inhibitors

The ongoing progresses in the knowledge of the pathogenic mechanisms of various immune-mediated and inflammatory diseases as well as the availability of innovative biotechnological approaches have led to the development of new drugs that add to conventional treatments. Among these, tumor necrosis factor (TNF)-α inhibitors, that is, infliximab, adalimumab, etanercept, golimumab and certolizumab pegol, are now available for clinical use. This editorial discusses the recent indications of TNF-α inhibitors, the pretreatment considerations, the reported adverse events and, finally, the recommendations for its use in pregnancy.