Sebastiano Cicco

Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

Many researchers have speculated that the clinical progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by defects in dendritic cell (DC) function. However, evidence supporting this assumption is controversial, and no mechanism for the putative DC dysfunction has been demonstrated thus far. We studied DC subsets from the bone marrow of MM patients compared with those of MGUS patients and control subjects. We found that myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) accumulate in the bone marrow during the MGUS-to-MM progression. After engulfment of apoptotic tumor plasma cells via CD91, bone marrow mDCs and pDCs mature and are able to activate tumor-specific CD8(+) T cells. However, by interacting directly with CD28 on live (nonapoptotic) tumor plasma cells, bone marrow mDCs downregulate the expression of proteasome subunits in these cells, thus enabling their evasion from human leukocyte antigen (HLA) class I-restricted CD8(+) T-cell killing. These results suggest that DCs play a dual, but opposing, role in MM: for one, DCs activate CD8(+) T cells against tumor plasma cells and, for the other, DCs protect tumor plasma cells from CD8(+) T-cell killing. This information should be taken into account in designing immunotherapy approaches to enhance immune surveillance in MGUS and to break down immune tolerance in MM.

Wound Healing in Diabetes: Hemorheological and Microcirculatory Aspects

Diabetes is associated with many hemorheological alterations. The decrease of RBC deformability, increase of aggregability, vasoconstriction, increase of blood viscosity and decrease of oxygen supply have a significant effect on wound healing, such as in foot ulcers. Basically, there is endothelial dysfunction and alteration of permeability; these impair wound healing in diabetic patients. Microcirculation still functions and there is blood flow, even when there is a decrease in vessel diameter, without anatomical lesions in vessel walls. It is necessary to maintain a good oxygen supply. Analyzing microcirculation and hemorheology in diabetes and considering methodologies to treat diabetic foot ulcers (e.g., hyperbaric oxygen therapy, laser, and vacuum) may help in the treatment of patient pathologies.

The Influence of Oxygen Supply, Hemorheology and Microcirculation in the Heart and Vascular Systems

The microcirculation is an important system, containing resistance arterioles, capillaries and venules, whose main function is to transport oxygen and nutrients to the tissues. Endothelial cells are the main cell types of the microcirculation; their homeostasis is modulated by constant shear stress. Altered hemorheology induces a change in the production of vasodilator and vasoconstrictor agents. The most important pattern inducing endothelium dysfunction is an increase in oxidative stress, which decreases the amount of nitric oxide and favors microvascular phlogosis. In this review we will consider the main scientific reports about the cardiovascular risk factors such as smoking, hypercholesterolemia, hyperviscosity, hypertension, diabetes, stress and increased homocysteine levels, all having as common etiopathogenetic factor alterations in microcirculation and in tissue oxygenation. We also focus on their influence on endothelial cells, inducing endothelial changes and dysfunction related to altered oxygen supply and linked to increased oxidative stress. Also important are endothelial stem cells, that are able to repair vascular endothelial damage, especially in cardiovascular patients, with or without endothelial dysfunction. Under these circumstances the numbers of these stem cells are altered, which means there is a decrease in regeneration capability (post ischaemia modified albumin, etc.). This could be an important negative prognostic factor. Microcirculation and tissue oxygenation are very important factors strongly linked to hemorheology, especially in cardiovascular patients, and their alterations could cause impairment, or initiate cardiovascular pathologies.

Could dilated cardiomyopathy alter the peripheral microcirculation and blood rheology

Our aim was to perform a preliminary study of blood flow in the peripheral microcirculation in patients with heart failure. Cardiac patients were investigated to establish possible microcirculatory changes due to this pathology. We evaluated 16 patients (non-smokers, dislipidemic with hypercholesterolemia), receiving oral treatment and in NYHA class 2.3 +/- 0.5. A dilated cardiomyopathy (DCM) group was evaluated before cardiac resynchronization therapy (CRT) obtained by biventricular intra-cardiac defibrillator (ICD) implantation, and again 3 months after its implantation. We measured the ejection fraction (EF), peripheral blood flow (using laser Doppler) at the left wrist on the volar side, capillary morphology (using computerized videocapillaroscopy) on the nail bed of the 4th finger of the left hand, rheological status (using the LORCA), as well as hematocrit, hemoglobin concentration, red blood cell (RBC) surface acetylcholinesterase (AchE), and homocysteine. Our data show that in the DCM vs. control group, peripheral flow did not depend only on the heart: throughout the study, blood flow did not change significantly compared to controls and was increased after CRT. There was no decrease in aggregation time. The blood flow did not alter RBC deformability or RBC surface AchE. Due to the lower oxygenation and to a non-significant increase in the number of capillaries after CRT, DCM patients are at higher cardiovascular risk than healthy subjects.

Belimumab restores Treg/Th17 balance in patients with refractory systemic lupus erythematosus

Belimumab, a specific inhibitor of the soluble B lymphocyte stimulator (BlyS), is the first biological drug approved by the United States Food and Drug Administration for the treatment of patients with active systemic lupus erythematosus (SLE) refractory to standard therapy. Given that an imbalance between regulatory T cells (Treg) and interleukin (IL)-17A-secreting T cells (Th17) has been reported in various autoimmune disorders, we assessed the frequency of both Treg and Th17 peripheral blood populations before and after belimumab administration in 20 patients with active SLE refractory to standard therapy. After six months of treatment, the mean SELENA-SLEDAI score as well as the mean anti-double-stranded DNA antibody titers were significantly decreased. In addition, we observed a significant increase in Treg percentages and a parallel, significant decrease in Th17 percentages, accompanied by significantly reduced serum levels of IL-21. In vitro studies showed that Treg purified from belimumab-treated patients were fully functional and displayed a suppressor function similar to that of Treg purified from healthy donors. Belimumab can restore Treg/Th17 balance in SLE patients with uncontrolled disease activity, and this results in decreased flare rate and reduced glucocorticoid dosage.

Suspected Pericardial Tuberculosis Revealed as an Amyloid Pericardial Mass

Primary systemic amyloidosis is not easily diagnosed. The immunoglobulin deposits are usually localized in the kidney, heart, and liver. We describe an unusual case of a patient suffering from a pericardial amyloidoma with internal calcifications and air bubbles that compressed the right ventricle and shifted the heart to the left. Since the patient was in shock, urgent pericardiotomy was performed. This site showed PET uptake. A monoclonal component was present. On these findings, differential diagnoses included multiple myeloma and atypical pericardial tuberculosis, whereas a periumbilical fat tissue biopsy demonstrated amyloidosis. A previous Salmonella species infection had most likely stimulated the production of amyloid. The patient received bortezomib/dexamethasone treatment and achieved a good response.

Vasculitis in connective tissue diseases

Vasculitis is a recurrent complication of connective tissue diseases. It is often an under-recognized manifestation that can lead to significant morbidity and mortality due to vital organ damage. Cutaneous lesions, representing small-vessel vasculitis, dominate clinical presentation, although widespread necrotizing visceral medium- and large-vessel involvement, mimicking primary vasculitic syndromes, may also occur. The pathogenesis of vascular inflammation is not completely understood, but immune complexes are believed to play a crucial role. The diagnosis is usually based on the combination of clinical findings, laboratory testing, tissue biopsy and imaging of the involved blood vessels. Timely and aggressive pulse treatment with high dose of glucocorticosteroids and immunosuppressive agents, followed by gradual tapering, can significantly improve patients’ survival.

Granulomatosis with Polyangiitis (Wegener’s)

Granulomatosis with polyangiitis (GPA) is a relatively rare necrotizing vasculitis belonging to the so-called ANCA-associated vasculitides, in that circulating anti-proteinase-3 neutrophil cytoplasmic antibodies (c-ANCA) can be detected in the large majority of patients. The major clinical manifestations include necrotizing granulomatous lesions in the upper and/or lower respiratory tract, and glomerulonephritis. Although generalized necrotizing vasculitis involving both arteries and veins is a frequent indication of its systemic character, limited forms restricted to paranasal sinuses can also be observed. In the absence of suitable therapies, the disease can lead to death in a high percentage of patients. The introduction of glucocorticoids associated to cyclophosphamide has marked a milestone in the treatment of GPA. This combination has in fact been able to remarkably improve the previously ominous prognosis of these patients, resulting in a 10-years’ survival rate of approximately 75 %. More recently, additional immunosuppressive drugs such as azathioprine, methotrexate, and rituximab have been employed, with comparable or even better results.