Biomarkers in HCV-related mixed cryoglobulinemia patients withnon-Hodgkin lymphoma.

OBJECTIVE: Chronic Hepatitis C virus (HCV) infection can cause severe extrahepatic manifestations, such as mixed cryoglobulins (MC), up to the development of B cell nonHodgkin's lymphoma (B-NHL). Mechanisms transforming of HCV infection into lymphoproliferative and/or autoimmune disorders are still poorly understood. In course of HCV infection, the sustained virus-driven antigenic stimulation may probably induce a B-cell clonal expansion. Measurements of serum free light chains (FLCs) levels, considered as a direct marker of B cell activity, are analyzed with increasing interest in clinical practice, for diagnosis, monitoring and follow-up of plasma cell dyscrasia. Syndecan-1 (CD138) is a transmembrane heparan sulfate proteoglycan expressed and actively shed by most myeloma cells. Membrane CD138 represents the major receptor protein for HCV attachment to the hepatocyte surface and high levels of circulating sCD138 levels are detected in patients at early stage of B-cell chronic lymphocytic leukemia. This study is aimed to evaluate sCD138 and FLC levels as diagnostic biomarkers of HCV-related MC with B-NHL. PATIENTS AND METHODS: We enrolled 35 HCV-MC-NHL patients, characterized for the specific type of cryoglobulins, and 25 healthy blood donors (HBD) as negative control. Serum sCD138 levels were determined using ELISA kits specific for human sCD138. Serum FLCs were assessed by means of the turbidimetric assay. RESULTS: We found that serum levels of sCD138, as well as FLCs, were significantly higher in patients than in HBD (p<0.001). CONCLUSIONS: In agreement with the definition of HCV-driven lymphoproliferative disorders as the consequence of a multifactorial and multistep pathogenetic process, we suggest that sCD138 and FLCs could be considered putative independent markers of worsening progression of the disease.

Precision editing of the gut microbiota ameliorates cancer immunotherapy.

In this editorial the authors highlight recent findings which could help design a personalized approach for cancer immunotherapy.

Interrelationship between inflammatory cytokines (IL-1, IL-6, IL-33, IL-37) and acquired immunity.

It is now well-known that interleukins (ILs) play a pivotal role in shaping innate immunity: inflammatory ILs are responsible for all innate aspects of immune response, from the very first vascular reactions to the chronic non-specific response to inflammation; while anti-inflammatory ILs are responsible for keeping adaptive immunity at bay. The interactions between ILs and adaptive immunity have been long considered secondary to the effects on the innate immune system, but in recent years it has appeared more clearly that IL direct interactions with adaptive immunity are extremely important both in physiologic and pathologic immune response. In the present review we analyze the role of inflammatory ILs (IL-1, IL-6, IL-33 and IL-37) on adaptive immunity and briefly discuss the possible therapeutic perspectives of IL-blockade in adaptive immunity disorders.

Gut microbiota and immunity in common variable immunodeficiency: crosstalk with pro-inflammatory cytokines.

In recent years, gut microbiota (GM) has emerged as a key factor in shaping the pathogenesis of a vast array of immune-mediated diseases, as well as in the response to immune-based treatments such as anti PD-1 and anti-CTLA4 therapy or influenza vaccination. In addition, GM has a significant role in the immune system development and is fundamental in developing mucosal immunity. Recent data suggest that GM plays an important role in the immune system of immune deficient patients. GM status has a remarkable impact on the immune system and in immune deficient patients; this can lead to important consequences. Prebiotics are indeed a promising candidate in restoring GM homeostasis and improving immunity. Antibiotics are also capable of altering the microbial equilibrium.

Interleukin-1 family cytokines and mast cells: activation and inhibition.

Activated mast cells (MCs) secrete a number of compounds including pro-inflammatory and anti-inflammatory cytokines. MCs are a potential source of cytokines and chemokines which participate in allergic reactions and inflammation. MCs can be activated by IgE through its receptor FceRI, but also by Toll-like receptors and/or interleukin (IL)-1. MCs can be a target for both pro-inflammatory and anti-inflammatory cytokines. IL-1 activates MCs to release inflammatory chemical mediators, and cytokines/chemokines, an effect which can be potentially inhibited by IL-37. In addition, IL-36 is also a powerful cytokine with a pro-inflammatory activity. IL-38 binds IL-36R and inhibits the pro-inflammatory activity of IL-36, thus performing a therapeutic action. In this article we review the role of MCs in relation to pro-inflammatory and anti-inflammatory IL-1 family member cytokines and a possible therapeutic effect in inflammatory disorders.

The Importance of Complying with Vaccination Protocols in Developed Countries: "Anti-Vax" Hysteria and the Spread of Severe Preventable Diseases.

BACKGROUND: Vaccines are very effective medical tools for disease prevention and life span increase. Controversies have raised concern about their safety, from autism to polio vaccine contamination with simian virus 40 (SV-40). Hysteria surrounding vaccine-associated risks has resulted in a declining number of vaccinations in developed countries. Outbreaks of vaccine-preventable diseases (e.g. measles) have occurred in Europe and North America, causing also some causalities. OBJECTIVES: In this review, data on safety and efficacy of vaccines are discussed, showing that the benefits of vaccines far outweigh the risks and that it is important to comply with vaccination protocols, to avoid spreading of severe, preventable diseases. METHODS: Those opposed to vaccinations suggest that scientific literature supporting vaccines is influenced by pharmaceutical companies. In this review, studies on influenza produced by independent scientists and those authored by those who received some kind of benefit from the industry are discussed separately. All the chosen papers were selected through a MEDLINE research. RESULTS: Vaccination rates are decreasing, even though they are effective public health tools. Influenza, for example, is responsible for 250,000-500,000 deaths each year, according to the WHO. Yet, campaigns to extend influenza vaccine to all elderly subjects report little success, because of the vaccine scare and because not all patients develop immunity following vaccination. CONCLUSIONS: This review proves that vaccine hysteria is detrimental because: 1) it causes an increased morbidity and mortality from preventable diseases; 2) it jeopardizes research for new vaccines; 3) patients are reluctant to accept any form of immune-therapy, commonly referred to as "vaccination".

The "Real Welfare" scheme: Identification of risk and protective factors for welfare outcomes in commercial pig farms in the UK.

From 2013-2016, animal-based measures were collected as part of the "Real Welfare" protocol adopted by the Red Tractor Pigs Assurance Scheme to assess the welfare in finisher pig herds in the UK. Trained veterinarians from 89 veterinary practices assessed 112,241 pens (hospital pens excluded) from 1928 farms using a multistage sampling protocol, and collected data about pig welfare, management and farm environment. Multivariable analyses were conducted for five main welfare outcomes: lameness, pigs requiring hospitalization, severe tail lesions, severe body marks and enrichment use ratio (number of active pigs interacting with the enrichment/total number of active pigs). Additionally, a multiple correspondence analysis (MCA) was conducted to analyse systematic patterns of variations of environmental characteristics and improve understanding of the connection between welfare outcomes and environment. The prevalence of the four welfare outcomes and the mean enrichment use ratio differed between pen types (P<0.05), with a higher mean prevalence of lame pigs (0.39%) but lower mean prevalence of pigs requiring hospitalization (0.07%), severe tail lesions (0.07%) and severe body marks (0.12%) in outdoor pens. In&outdoor pens had the highest mean prevalence of the measured outcomes (P<0.05). After adjusting for the farm, date and pen type, lameness, pigs requiring hospitalization and severe tail lesions were less prevalent in large pens (P<0.01), pens with substrates (P≤0.05) and pens fed with meal (P≤0.05), while enrichment use ratio was higher with substrates (P<0.001). Moreover, pigs requiring hospitalization and severe body marks were more prevalent in pens with powered ventilation (P<0.05). On the MCA graph, higher prevalences of lameness and pigs requiring hospitalization (>1, 5 and 10%) were located in the same direction as lower enrichment use ratio, liquid feed, trough feeding, floor feeding, restricted feed and in&outdoor pens. Results suggested that higher prevalences were not specifically connected to a particular system, but that all welfare outcomes were connected to several inappropriate features in the environment. This study highlights individual risk factors which can be considered to improve animal welfare, but also indicates the need to consider the environment as a whole because of potential factor combinations and confounds. Understanding of these requires a large scale database, which can be drawn from assessments carried out as part of farm assurance and support evidence-based advice and future formulation of standards for good practice.

The 'Real Welfare' scheme: benchmarking welfare outcomes for commercially farmed pigs.

Animal welfare standards have been incorporated in EU legislation and in farm assurance schemes, based on scientific information and aiming to safeguard the welfare of the species concerned. Recently, emphasis has shifted from resource-based measures of welfare to animal-based measures, which are considered to assess more accurately the welfare status. The data used in this analysis were collected from April 2013 to May 2016 through the 'Real Welfare' scheme in order to assess on-farm pig welfare, as required for those finishing pigs under the UK Red Tractor Assurance scheme. The assessment involved five main measures (percentage of pigs requiring hospitalization, percentage of lame pigs, percentage of pigs with severe tail lesions, percentage of pigs with severe body marks and enrichment use ratio) and optional secondary measures (percentage of pigs with mild tail lesions, percentage of pigs with dirty tails, percentage of pigs with mild body marks, percentage of pigs with dirty bodies), with associated information about the environment and the enrichment in the farms. For the complete database, a sample of pens was assessed from 1928 farm units. Repeated measures were taken in the same farm unit over time, giving 112 240 records at pen level. These concerned a total of 13 480 289 pigs present on the farm during the assessments, with 5 463 348 pigs directly assessed using the 'Real Welfare' protocol. The three most common enrichment types were straw, chain and plastic objects. The main substrate was straw which was present in 67.9% of the farms. Compared with 2013, a significant increase of pens with undocked-tail pigs, substrates and objects was observed over time (P0.3). The results from the first 3 years of the scheme demonstrate a reduction of the prevalence of animal-based measures of welfare problems and highlight the value of this initiative.

Risk factors associated with the different categories of piglet perinatal mortality in French farms.

We aimed to identify mortality patterns and to establish risk factors associated with different categories of piglet perinatal mortality in French farms. At farm level, the analyses were performed on data from 146 farms that experienced perinatal mortality problems. At piglet level, the analyses were performed on data from 155 farms (7761 piglets). All data were collected over a period of 10 years (2004-14) by a consulting company, using a non-probability sampling at farm level and a random sampling at sow level. Six main categories of mortality, determined by standardised necropsy procedure, represented 84.5% of all the perinatal deaths recorded. These six categories were, in order of significance: Death during farrowing, Non- viable, Early sepsis, Mummified, Crushing and Starvation. At farm level, the percentage of deaths due to starvation was positively correlated to the percentage of deaths due to crushing and the percentage of deaths during farrowing (r>0.30, P<0.05) .The percentage of deaths due to crushing was negatively correlated to the percentage of deaths due to early sepsis (r<-0.30, P<0.05) and positively correlated to the deaths due to acute disease (r>0.30, P<0.05). Patterns of perinatal mortality at farm level were identified using a principal component analysis. Based on these, the farms could be classified, using ascending hierarchical classification, into three different clusters, highlighting issues that underlie farm differences. Risk factors were compared at piglet level for the different categories of death. Compared to other categories of death, deaths during farrowing were significantly fewer during the night than during the day. Compared to other categories of death, the likelihood of non-viable piglets tended to be higher in summer than other seasons. A smaller number of deaths in the litter was also identified for the piglets classified as non-viable or mummified. For the six main categories of perinatal mortality, the piglets which died from a specific category tended to have more littermates which died from the same category. Parity and litter size also had more significant effects on certain categories of death compared to others. The study provides novel information on the risk factors associated with specific categories of piglet perinatal mortality. The classification of farms into the 3 different clusters could lead to a more targeted management of perinatal mortality on individual farms.

The involvement of IgH enhancer HS1.2 in the pathogenesis of Crohn's disease: how the immune system can influence a multifactorial disease.

OBJECTIVE: To study the 3' immunoglobulin heavy-chain regulatory region (3'RR) enhancer complex, active in class switching recombination and in B-cells, in Crohn's disease. PATIENTS AND METHODS: A total of 167 patients [79 females (47.3%) and 88 males (52.7%)] affected by Crohn's disease were enrolled in the study. As a control, we included 64 healthy subjects, age and sex matched, from the same geographical area. Blood tests were performed on all subjects to determine their antibody levels and to detect the presence of any possible infections. We conducted a selective PCR, which amplified the hs1.2-A region. The nested second PCR to amplify the polymorphic core of the enhancer was performed. RESULTS: No differences between cases and controls were observed with respect to sex distribution (43.8% females among controls and 49.5% among cases), age, tTG IgA, RF, serum or secretory IgA, IgG1, IgG2 and IgG3. No correlation was found between both seric and secretory immunoglobulins levels, with except of statistically significant differences between cases and controls with respect to IgA and IgG ASCA positivity (p<0.001), serum IgG4 (p<0.001) and IgD (p=0.001). CONCLUSIONS: We have demonstrated that in Crohn's disease, the HS1,2 immunoglobulins enhancer is not implicated in the disease pathogenesis. Moreover, we have found that IgG4 levels are lower in Crohn's disease patients than in controls; these data may be related to an impairment of number and function of Tregs, further linked to the presence of tissue inflammation. Crohn's disease is a complex multifactorial disease. The pathogenesis of Crohn's disease is incompletely understood although it is clear that the disease involves multiple interacting agents.

Parotid Gland Lesions: Multiparametric Ultrasound and MRI Features.

High-resolution ultrasound (US), as a readily available, cost-effective and harmless imaging technique, is appropriately the initial imaging modality for salivary gland lesions. Benign tumors are reported to present with regular and well-defined margins, a homogeneous hypoechoic structure and demarcated vessel distribution, whereas malignant lesions are irregular, heterogeneous and diffusely perfused. Ultrasound and color Doppler features of benign and malignant salivary gland lesions overlap, and many benign tumors, particularly pleomorphic adenomas, may appear irregularly shaped, with a heterogeneous echo-structure indistinguishable from a malignant lesion. Often skilled US operators are not always able to differentiate benign from malignant lesions. The introduction of US contrast agents has allowed further perspectives in the possible improvement of lesion characterization, and the emergence of US elastography, an innovative tool for assessing lesion stiffness/elasticity characteristics, has been advocated for differentiating salivary gland lesions. When lesions are atypical on US, contrast-enhanced magnetic resonance (MR) imaging is usually the definitive imaging modality. We present a current review of benign and malignant parotid gland tumors with emphasis on the role of multiparametric US and MR imaging.

IMMUNOMODULATORY EFFECTS OF VITAMIN D ON SKIN INFLAMMATION.

Vitamin D has a major role in calcium absorption and maintenance of healthy bones. Vitamin D is also involved in cancer, cardiovascular system, allergic diseases, immune regulation and immune disor¬ders. Irradiation of food as well as animals produces vitamin D and more than 90% of previtamin D3 synthesis in the skin occurs in the epidermis. Vitamin D receptor has been found in many cells including T and B lymphocytes, macrophages, mast cells, NK cells and Tregs, and it selectively binds with high affinity to its ligand. Vitamin D binds its receptor VDR, resulting in transcription of a number of genes playing a role in inhibition of MAPK. Its effect may be also mediated by the direct activation of PKC. Vitamin D has the ability to suppress inflammatory cytokines such as TNF, IL-1, IFN-gamma and IL-2; while it increases the generation of anti-inflammatory cytokines IL-4 and IL-10. In B cells, vitamin D3 have also been shown to suppress IgE antibody class switch partly through the inhibition of NF-kB. Here we discuss the relationship between vitamin D, immunity and skin disorders.

CROSSTALK BETWEEN VITAMIN B AND IMMUNITY.

Vitamin B1 (thiamin) is considered to be the oldest vitamin and in 1936 R.R. Williams and colleagues determined its chemical structure and were able to synthesize this vitamin. Vitamin B1 influences pro-apoptotic proteins, mitochondrial membrane potential, cytochrome C release, protein kinases, p38-MAPK, suppresses oxidative stress-induced NF-kappaB and has anti-inflammatory properties. Deficiency of vitamin B1 may cause beriberi, dysfunction of the nervous system, neuroinflammation, T cell infiltration, chemokine CCL2 activation, over expression of proinflammatory cytokines, such as IL-1, TNF, IL-6, and arachidonic acid products, and induces expression of CD40 by the microglia and CD40L by astrocytes which provoke the death of neurons. Here we report the relationship between vitamin B complex and immunity.

Central and Mucosal Immunities are Modified by Non Adsorbable Antibiotic Treatment in Uncomplicated Diverticular Disease.

We review our experience on Rifaximin in uncomplicated diverticular disease. Our data show that a 2 week treatment induces modifications in the immune system: local mucosal lymphocytes with TLR-4 were increased. In the peripheral blood CD103 cells, which increased before treatment, returned to normal values after Rifaximin.

The Interaction among Microbiota, Immunity, and Genetic and Dietary Factors Is the Condicio Sine Qua Non Celiac Disease Can Develop.

Celiac disease (CD) is an immune-mediated enteropathy, triggered by dietary wheat gluten and similar proteins of barley and rye in genetically susceptible individuals. This is a complex disorder involving both environmental and immune-genetic factors. The major genetic risk factor for CD is determined by HLA-DQ genes. Dysfunction of the innate and adaptive immune systems can conceivably cause impairment of mucosal barrier function and development of localized or systemic inflammatory and autoimmune processes. Exposure to gluten is the main environmental trigger responsible for the signs and symptoms of the disease, but exposure to gluten does not fully explain the manifestation of CD. Thus, both genetic determination and environmental exposure to gluten are necessary for the full manifestation of CD; neither of them is sufficient alone. Epidemiological and clinical data suggest that other environmental factors, including infections, alterations in the intestinal microbiota composition, and early feeding practices, might also play a role in disease development. Thus, this interaction is the condicio sine qua non celiac disease can develop. The breakdown of the interaction among microbiota, innate immunity, and genetic and dietary factors leads to disruption of homeostasis and inflammation; and tissue damage occurs. Focusing attention on this interaction and its breakdown may allow a better understanding of the CD pathogenesis and lead to novel translational avenues for preventing and treating this widespread disease.

Can vitamin a mediate immunity and inflammation?

Vitamins are natural components of foods and are organic compounds distinct from fat, carbohydrates and proteins. Vitamin A is the generic descriptor for compounds with the qualitative biological activity of retinol. Unlike beta-carotene, vitamin A is not an antioxidant and its benefit is related to possible boosting of immune reactions. The effect of vitamin A on immune function is wide-reaching and its deficiency appears to affect immunity in several ways. Innate and adaptive immune responses are affected in some way by lack of vitamin A. Retinoids seem to act on differentiation of lymphocytes, antibody production, phagocytosis of macrophages, NK, Treg, and T helper cell activity. In addition, in humans, signs of a vitamin A deficiency also include the dysregulation of cytokine/chemokine generation and release. However, excess of vitamin A has been demonstrated to have toxic effects in most species studied. Here we summarize some important effects of vitamin A in immunity and inflammation.

Neuropeptide NGF mediates neuro-immune response and inflammation through mast cell activation.

Human mast cells (first described in 1879 by Paul Ehrlich) develop from committed precursors in the bone marrow expressing the differentiation marker CD34+ and distinct from the three other myeloid cells. Mast cells are present in various tissues especially near blood vessels, epithelia and nerves and they are activated by cross-linking of FcεRI, but also by a number of neuropeptides. NGF mediates a number of inflammatory and autoimmune states in conjunction with an increased accumulation of mast cells which appear to be involved in neuroimmune interactions and tissue inflammation. Here we report some relationships between mast cells and nerve growth factor (NGF).

Interrelationship between IL-3 and mast cells.

It is well established that mast cells, which are found in the tissues in the proximity of small blood vessels and post-capillary venules, play a key role in the early phase of IgE-mediated allergic reactions. A greatly expanded understanding of the biology of IL-3 has emerged since the early 1980s. IL-3 is a specific factor that stimulates the growth of hematopoietic stem and progenitor cells of a variety of lineages and can promote the proliferation of certain classes of lymphocytes distinct from those that are dependent on IL-2. IL-3 has been identified among the most important cytokines for regulation of mast cell growth and differentiation, migration and effector function activities of many hematopoietic cells. IL-3 termed multi colony-stimulating-factor (multi-CSF) or mast cell growth factor (MCGF) is a haematopoietic growth factor which stimulates the formation of colonies for erythroid, megakaryocytic, granulocytic and monocytic lineages. It is predominantly produced by activated T cells, natural killer (NK) cells and mast cells and supports the growth-promoting effects of SCF on mast cell precursors. IL-3 causes severe hypersensivity reactions and plays a pivotal role in exacerbating the inflammatory response in vivo. Here we report the interrelationship between IL-3 and mast cells.

Nerve growth factor interactions with mast cells.

Neuropeptides are involved in neurogenic inflammation where there is vasodilation and plasma protein extravasion in response to this stimulus. Nerve growth factor (NGF), identified by Rita Levi Montalcini, is a neurotrophin family compound which is important for survival of nociceptive neurons during their development. Therefore, NGF is an important neuropeptide which mediates the development and functions of the central and peripheral nervous system. It also exerts its proinflammatory action, not only on mast cells but also in B and T cells, neutrophils and eosinophils. Human mast cells can be activated by neuropeptides to release potent mediators of inflammation, and they are found throughout the body, especially near blood vessels, epithelial tissue and nerves. Mast cells generate and release NGF after degranulation and they are involved in iperalgesia, neuroimmune interactions and tissue inflammation. NGF is also a potent degranulation factor for mast cells in vitro and in vivo, promoting differentiation and maturation of these cells and their precursor, acting as a co-factor with interleukin-3. In conclusion, these studies are focused on cross-talk between neuropeptide NGF and inflammatory mast cells.