Behavior of soluble HLA-A, -B, -C and HLA-G molecules in patients with chronic hepatitis C virus infection undergoing pegylated interferon-α and ribavirin treatment: potential role as markers of response to antiviral therapy.

The serum levels of soluble HLA class I antigens (sHLA-A, -B, -C and sHLA-G) were determined in 40 HCV genotype 1-infected patients before (T 0), after 3, 6, and 12 months (T 3, T 6, and T 12) of pegylated-IFN-α plus ribavirin therapy and 6 months (T 18) after the end of treatment. Twenty patients were sustained virological responders (SVR), and 20 were non-responders (NR). sHLA-A, -B, -C levels at T 0 were significantly higher in both SVR (mean 10.48 µg/ml) and NR (mean 11.87 µg/ml) patients as compared to healthy controls (mean 0.34 µg/ml, p < 0.0001) and HIV-infected subjects (mean 1.22 µg/ml, p < 0.0001). sHLA-G levels at T 0 were significantly higher in SVR (mean 24.78 ng/ml) and NR (mean 24.93 ng/ml) patients as compared to healthy controls (mean 10.34 ng/ml, p = 0.015 and p = 0.014, respectively) but were lower as compared to HIV-infected subjects (mean 48.00 ng/ml, p < 0.0001). The levels of sHLA-A, -B, -C and sHLA-G significantly decreased in SVR from T 0 to T 18 (mean 1.64 and 1.43 ng/ml, respectively, p < 0.0001) and correlated with HCV-RNA, AST, ALT, γGT, and ALP levels. The determination of soluble HLA class I levels could be proposed as a surrogate marker to discriminate SVR and NR HCV-infected patients during PEG-IFN-α plus ribavirin therapy.

Free radicals and endothelial dysfunction: potential positive effects of TNF-α inhibitors.

OBJECTIVES: During the last decade many new biological immune modulators have entered the market as new therapeutic principles. Tumor necrosis factor (TNF)-α is a pro-inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune-mediated or inflammatory diseases. However, TNF-α also plays a key role in endothelial dysfunction and, thus, in the development and progression of atherosclerosis. What, then, is the potential therapeutic role of TNF-α inhibitors? METHODS: We analysed the current literature concerning the administration of TNF-α inhibitors and their potential benefits upon endothelial function. RESULTS: TNF-α inhibitors decrease the serum levels of inflammatory markers such as TNF-α itself, CRP, IL-6, and increased the tissue expression of endothelial NO synthase and the vasodilatory response to bradykinin. DISCUSSION: TNF-α inhibitors may change the progression of endothelial dysfunction and, thus, slow down the atherosclerotic process.

Endothelial dysfunction in rheumatic autoimmune diseases.

Rheumatic autoimmune diseases have been associated with accelerated atherosclerosis and various types of vasculopathies. Atherosclerosis is an inflammatory condition which starts as a "response to injury" favoring endothelial dysfunction which is associated with increased expression of adhesion molecules, pro-inflammatory cytokines, pro-thrombotic factors, oxidative stress upregulation and abnormal vascular tone modulation. Endothelial dysfunction in rheumatic autoimmune diseases involves innate immune responses, including macrophages and dendritic cells expression of scavenger and toll-like receptors for modified or native LDL as well as neutrophil and complement activation, and dysregulation of adaptive immune responses, including proliferation of autoreactive T-helper-1 lymphocytes and defective function of dendritic and regulatory T cells. Specific differences for endothelial function among different disorders include: a) increased amounts of pro-atherogenic hormones, decreased amounts of anti-atherogenic hormones and increased insulin resistance in rheumatoid arthritis; b) autoantibodies production in systemic lupus erythematosus and antiphospholipid syndrome; c) smooth muscle cells proliferation, destruction of internal elastic lamina, fibrosis and coagulation and fibrinolytic system dysfunction in systemic sclerosis. Several self-antigens (i.e. high density lipoproteins, heat shock proteins, ß2-glycoprotein1) and self-molecules modified by oxidative events (i.e. low density lipoproteins and oxidized hemoglobin) have been identified as targets of autoimmune responses. Endothelial dysfunction leads to accelerated atherosclerosis in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropaties whereas obliterative vasculopathy is associated with systemic sclerosis. In this paper, we will briefly review the most relevant information upon endothelial dysfunction and inflammatory mechanisms in atherosclerosis and we will summarize the similarities and differences in vascular disease patterns underlying different rheumatic autoimmune diseases.

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.

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.

Soluble human leukocyte antigen-G serum levels in patients with acquired immune deficiency syndrome affected by different disease-defining conditions before and after antiretroviral treatment.

We have previously reported that the serum levels of soluble human leukocyte antigen (HLA)-A, -B, -C, and -G antigens are elevated in human immunodeficiency virus (HIV)-infected subjects and decrease after antiretroviral therapy. In this study, we measured soluble HLA-G serum levels in patients with acquired immune deficiency syndrome (AIDS) affected by different AIDS-defining conditions before and during antiretroviral therapy and correlated them with virologic and immunologic parameters of response to treatment. Soluble HLA-G levels were significantly higher in AIDS patients before treatment as compared with healthy controls and significantly decreased after 36 months of therapy. The decrease of soluble HLA-G correlated with the decrease of plasma HIV-RNA level and CD8(+) T-lymphocytes number and with the increase of CD4(+) T-lymphocytes number. Soluble HLA-G levels were significantly higher in patients with opportunistic infections and Kaposi's sarcoma compared with patients with the wasting syndrome. These data suggest that infections and neoplasms may trigger the shedding of soluble HLA-G molecules, and confirm that the level of soluble HLA-G in serum might represent a surrogate marker to monitor virologic response and immune reconstitution in HIV-positive individuals.

Anti-tumor necrosis factor-α treatment with infliximab for disseminated granuloma annulare.

Granuloma annulare (GA) is a chronic inflammatory disease of unknown etiology characterized by the development of plaques preferentially localized to the distal extremities. Spontaneous remission and relapses are quite common and the course of GA is not easy to predict. Moreover, most therapeutic regimens have been used anecdotally and with variable success. We report the case of a 62-year-old White female patient affected by disseminated GA unsuccessfully treated with psoralen plus UVA photochemotherapy, prednisone, and cyclosporine (ciclosporin) who responded to the anti-tumor necrosis factor-α monoclonal antibody infliximab administered intravenously at a dosage of 5 mg/kg at weeks 0, 2, and 6 and thereafter at monthly intervals for 10 additional months. Most of the GA lesions improved within 8 weeks and then slowly resolved within 10 months of treatment. We suggest that infliximab may be proposed as an additional therapeutic option in the treatment of recalcitrant forms of disseminated GA.

Behavior of non-classical soluble HLA class G antigens in human immunodeficiency virus 1-infected patients before and after HAART: comparison with classical soluble HLA-A, -B, -C antigens and potential role in immune-reconstitution.

We have reported that serum level of soluble HLA-A, -B, -C (sHLA-A,-B,-C) antigens is elevated in HIV-infected subjects and decreases after antiretroviral therapy (HAART). In this study, we measured the levels of soluble HLA-G (sHLA-G) antigens in a cohort of HIV-infected patients before and during HAART. sHLA-G and sHLA-A, -B, -C levels were significantly elevated in HIV-infected subjects as compared with controls before antiretroviral treatment and significantly decreased after 36 months of HAART. sHLA-G levels were correlated with sHLA-A, -B, -C levels, the decrease of plasma HIV-RNA level, the increase of CD4+ T-lymphocyte number and the decrease of CD8+ T-lymphocyte number. These results suggest that the measurement of sHLA-G and sHLA-A, -B, -C antigen serum levels might represent a useful surrogate marker to monitor virological response and immune reconstitution in HIV-positive subjects undergoing HAART treatment.

Behavior of serum human major histocompatibility complex class I antigen levels in human immunodeficiency virus-infected patients during antiretroviral therapy: correlation with clinical outcome.

Human major histocompatibility complex class I antigens (HLA-A, -B, and -C) are heterodimeric molecules composed of a alpha heavy chain noncovalently associated with an invariant protein known as beta(2)-microglobulin. Beside being expressed on the membrane of the large majority of nucleated cells, HLA class I antigens are evident in serum (sHLA-I). We have previously detected a significant increase in the serum level of beta(2)-microglobulin-associated HLA-I antigens in human immunodeficiency virus (HIV)-infected patients compared with HIV-negative controls. The introduction of highly active antiretroviral therapy (HAART) modified the clinical course of the disease and decreased the acquired immunodeficiency syndrome-related morbidity and mortality. Therefore, we measured the levels of sHLA-I antigens in 64 HIV-infected patients before and during HAART treatment and correlated them with the immunological and virological response to antiretroviral treatment. Serum sHLA-I antigen level was elevated in all HIV-infected patients before and significantly decreased after 36 months of HAART treatment, correlating with the decrease of plasma HIV-RNA level and with the increase of CD4+ T-lymphocyte number. These results suggest that the measurement of sHLA-I antigens serum level might represent a useful surrogate marker to monitor HIV-positive patients undergoing HAART treatment.