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Senescent cells drive age-related tissue dysfunction partially via the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated. Mitochondria also control apoptosis, a cell fate generally perceived as distinct from cellular senescence, which is apoptosis resistant. Here, we show that mitochondrial outer membrane permeability (MOMP) occurring in a small subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), depends on the formation of BAX and BAK macropores and results in release of mitochondrial DNA (mtDNA) into the cytosol, which in turn activates the cGAS/STING pathway, a major regulator of the SASP. Importantly, we found that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan parameters in aged mice. Our results propose the novel concept that apoptosis and senescence are regulated by similar mitochondrial-dependent mechanisms, and that sub-lethal mitochondrial apoptotic stress is a major driver of the SASP. We also provide proof-of-concept that inhibition of miMOMP may be a new therapeutic avenue to improve healthspan.

Existing ways of assessing CVID patients at risk of pulmonary infections are not universally accepted. The need to identify additional prognostic factors allowed us to evaluate the anti-polysaccharide IgA and IgM responses in 125 CVID patients immunized with the 23-valent pneumococcal polysaccharide (PS) vaccine (Pneumovax(®)).We used a new anti-PS23 IgM and IgA ELISA assay, which evaluates a global response to all 23 polysaccharides contained in Pneumovax(®).Anti-PS23 IgM and/or IgA antibodies were detectable in a minority of CVID patients. Antibody responses were correlated to B cell subpopulations and serum immunoglobulin concentrations. The non responders had a higher incidence of pneumonia and bronchiectasis and responders had the lowest incidence of respiratory complications.This new ELISA assay allows for studying vaccine response in patients on Ig replacement therapy. This test also is an additional method of evaluation of specific antibody responses representing a valuable contribution to identify prognostic marker in CVID patients.

CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation. Here, we found that both apoptotic epitope-specific and hepatitis C virus (HCV)-specific CD8(+) T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA(+) cell subsets expressing a dysfunctional T-helper 1-like signature program in chronic HCV infection. However, apoptotic epitope-specific CD8(+) T cells produced tumor necrosis factor AŽÂ± and interleukin 2 at the intrahepatic level significantly more than HCV-specific CD8(+) T cells, despite both populations expressing high levels of programmed death 1 receptor. Contextually, only apoptotic epitope-specific CD8(+) T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Together, these data suggest that, compared with HCV-specific CD8(+) T cells, apoptotic epitope-specific CD8(+) T cells can better sustain chronic immune activation, owing to their capacity to produce tumor necrosis factor AŽÂ±, and exhibit greater resistance to inhibitory signals during chronic HCV infection.

Objective. To investigate the contribution of inherited and acquired thrombophilic defects to the clinical manifestations of mixed cryoglobulinaemia vasculitis. Methods. The following thrombophilic defects were investigated in 64 consecutive patients with HCV-associated mixed cryoglobulinaemia: aPLs, lupus anti-coagulant, homocysteinaemia, protein C and protein S concentrations, activated protein C resistance, plasminogen activator inhibitor-1 4G4G and 5G5G genotypes, and the presence of mutations of factor V (Leiden and H1299R), of prothrombin (G20210A) and of methyl tetrahydrofolate reductase (C677T and A1298C). Additional variables were demographic data, duration of the disease, cryocrit level and vascular risk factors (diabetes, hypertension, hypercholesterolaemia and smoking habit). The following clinical manifestations of mixed cryoglobulinaemia were analysed as dependent covariates: severity of purpura, presence of necrotic skin ulcers, presence of peripheral neuropathy and presence of kidney disease. Results. Logistic regression analysis identified hyperhomocysteinaemia as a risk factor for severe purpura (P < 0.0001) and for the presence of skin ulcers (P < 0.0001), whereas none of the other thrombophilic defects influenced the clinical presentation of mixed cryoglobulinaemia. Purpura improved in two patients after lowering homocysteine with vitamin supplementation. Conclusions. Hyperhomocysteinaemia may be a risk factor for severe cutaneous manifestations in mixed cryoglobulinaemia.

INTRODUCTION: The multicenter prospective study provides information on adverse reactions to intravenous and subcutaneous immunoglobulin treatment in a cohort of 262 patients with common variable immunodeficiency. Severe adverse reactions are a rare but unpredictable event that might occur also in patients who tolerate substitutive intravenous or subcutaneous immunoglobulin therapy for months or years. RESULTS: Subcutaneous therapy has been proved to be a safe option in the 13 patients who had to stop intravenous treatment and who remained out of immunoglobulin replacement for long periods of time. However, severe reactions to subcutaneous therapy occurred at the first or after several subcutaneous immunoglobulin administrations in 2 out of 13 patients. CONCLUSION: Therefore, patients with previous severe reactions to intravenous immunoglobulin should be considered at particularly high risk for reaction to subcutaneous administration. In these cases, switching from in-hospital administration to home self-administration should be done with extreme care.

CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

A variety of physiological and pathological conditions may induce cell death. Therefore, it is reasonable that apoptotic cells send different signals promoting either tolerance or immune responses. Many factors influence the type of response, such as the quality (e.g. bearing or released factors, activation state), the timing and the site of cell death. In particular, the activation state of apoptotic lymphocytes (CD40L expression) may be crucial in determining the fate of their cross-presentation, i.e. cross-tolerance versus cross-priming. The cross-presentation of apoptotic activated CD40L+ T cells determines the cross-priming of apoptotic epitope-specific CD8+ T cells. These autoreactive CD8+ T cells are observed in diseases with a sustained component of chronic inflammation such as chronic viral infections and systemic autoimmune diseases. We have explored this phenomenon in HIV and chronic hepatitis C virus infections as well as in multiple sclerosis and rheumatoid arthritis, all conditions where these CD8+ T cells participate in the maintenance of a low-level state of inflammation.

Purpose To quantify the health related quality of life in primary immunodeficiency patients. Materials and methods We used generic health status and general psychological health questionnaires to determine the range of issues that needed to be considered in examining the burden of common variable immunodeficiency (CVID). Results The health status of patients with CVID was lower than that observed in normal subjects. Overall, Role-Physical and General Health scales correlated with a poorer clinical status. Surprisingly, the duration of disease did not influence health status. Being female, older, General Health Questionnaire-positive and alexithymic proved to be major risk factors associated with a poor health status. Patients with chronic lung disease and chronic diarrhea had the lowest values on the Medical Outcome Study, Short Form SF-36 (SF-36) scales. Disease severity perception was associated with the General Health Questionnaire and alexithymia status. Limitations in daily activities as a result of lower physical health were the major problems facing common variable immunodeficiency patients. Conclusion Our data underlined the importance of conducting a periodical health related quality of life assessment on patients with primary antibody deficiencies and, moreover, stressed the necessity of providing psychological support to at risk patients.

Background Patients with common variable immunodeficiency (CVID) suffer from respiratory infections leading over time to permanent lung damage. Increased radiosensitivity has been described, and clinicians should consider a risk-benefit assessment when ordering a CT scan, in that the exact level of "safe" radiation exposure is unknown. Methods Twenty-one patients with CVID were evaluated with chest CT scan, MRI, and pulmonary function tests on the same day. MRI protocol included a T2-weighted rotating blade-like k-space covering sequence (time repetition, 2,000; echo train=27; field of view, 400 mm; flip angle, 150; slice thickness, 5 mm) on axial and coronal planes. The bronchial and parenchymal abnormalities were compared with those identified by CT scan applying a modified Bhalla scoring system to assess bronchiectasis, bronchial wall thickening, number of bronchial generations involved, mucous plugging, consolidations, emphysema, bullae, and nodules. Results CT scan and MRI findings were comparable for moderate to severe degrees of bronchial and parenchymal alterations. A low concordance was found between MRI and CT scan for lower scores of bronchial abnormalities. CT scan allowed a better identification of peripheral airways abnormalities. Conclusions Lung alterations in patients with higher radiation sensitivity, such as patients with CVID, might be evaluated by MRI, a radiation-free technique alternative to CT scan.

Background Apoptosis seems to play a key role in autoimmune diseases (1). We have previously shown that T cell apoptosis generates a wide array of caspase-cleaved proteins, which can be cross-presented by dendritic cells to a broad repertoire of autoreactive CD8+ T cells. This process is involved in establishing chronic immune activation in HIV and HCV infections, but no data are currently available for rheumatoid arthritis (RA) (2-3). Objectives To evaluate whether self-apoptotic-specific CD8+ T cells may sustain chronic inflammation in RA and their possible modulation during treatment with etanercept. Methods Consecutive patients with RA classified according to the 1987 ACR criteria and designated to initiate treatment with biologics due to active disease were enrolled after obtaining informed consent. Healthy donors (HD) matched for sex and age with patients were also included. Before and after 1, 3, 6 months of therapy patients underwent blood draw to perform lymphocytic analysis. Self-specific CD8+ T cells were enumerated in the peripheral blood of HLA-A2+ patients or HD by using dextramers of HLA-A*0201 molecules complexed to apoptotic epitopes. IFNγ production by autoreactive CD8+ T cells in response to apoptotic peptides was tested by IFNγ-ELISPOT assay. The specific CD8+ T cell function was better defined based on cytokine production (IL17, IFNγ) within 18 h of contact with the relevant peptides by surface/intracellular cytometry. The clinical response to etanercept (none, moderate, good) was evaluated according to the EULAR criteria. Results 11 biologic-naive RA patients (F/M=10/1; mean age 50 years, range 36-68; mean disease duration 70 months, range 6-240) initiated treatment with etanercept. After 6 months 6 patients were considered responders. Increased frequencies of both circulating apoptotic T cells and self-reactive CD8+ T cells in RA patients compared with HD (n=8) at baseline (p=0.0006 and p Conclusions These data support the possibility that chronic inflammation in RA may be sustained, at least in part, by an autoimmune reaction towards apoptotic T cells. The presence of these self-reactive T cells, markedly increased in responders patients already at baseline, may be useful to predict the response to anti-TNF therapy. References Luis E. et al. Nature Reviews Rheumatology 6, 280-289, 2010 Rawson PM et al. Nat. Med. 13: 1431-9, 2007 Franceschini et al. PLos Pathog. 2012;8(6) Disclosure of Interest None Declared

Background Here, we evaluated the hypothesis that CD8+ T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology. Methods The percentage of autoreactive CD8+ T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer+ CD8+ T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo. Results We found that polyfunctional (IFN-γ and/or IL-17 producing) autoreactive CD8+ T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8+ T cells with a strong potential to produce IFN-γ or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8+ T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8+ T cells ex vivo. Conclusion Taken together, these data indicate that apoptotic epitope-specific CD8+ T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines.

Hepatitis B virus (HBV) reactivation represents an emerging cause of liver disease in patients undergoing treatment with biologic agents. In particular, the risk of HBV reactivation is heightened by the use monoclonal antibodies, such as rituximab (anti-CD20) and alemtuzumab (anti-CD52) that cause profound and long-lasting immunosuppression. Emerging data indicate that HBV reactivation could also develop following the use of other biologic agents, such as tumor necrosis factor (TNF)-α inhibitors. When HBV reactivation is diagnosed, it is mandatory to suspend biologic treatment and start antiviral agents immediately. However, pre-emptive antiviral therapy prior to monoclonal antibody administration is crucial in preventing HBV reactivation and its clinical consequences. Several lines of evidence have shown that risk of HBV reactivation is greatly reduced by the identification of high-risk patients and the use of prophylactic antiviral therapy. In this article, we discuss current trends in the management of HBV reactivation in immunosuppressed patients receiving biologic therapy, such as rituximab, alemtuzumab and TNF-α antagonists.

Objective: Bone demineralization is common in HIV-infected subjects. Reliable and low cost methods would be useful in order to identify and monitor bone alterations both in older and younger HIV+ patients. Recent data in normal population suggest that bone mineral quality (BMQ), assessed by a quantitative ultrasound (QUS) technique, could be an early marker of osteopenia/osteoporosis. Therefore, we investigated the usefulness of QUS in order to study bone health assessment in HIV-infected adults. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-P98 Cite this article as: Marocco et al.: Quantitative ultrasound (QUS) in HIVinfected patients: a reliable and low-cost technique for bone health assessment. Journal of the International AIDS Society 2010 13(Suppl 4):P98. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113106/