Matteo Maria Tei

Impact of mast cells on the skin.

When through the skin a foreign antigen enters it provokes an immune response and inflammatory reaction. Mast cells are located around small vessels that are involved in vasaldilation. They mature under the influence of local tissue to various cytokines. Human skin mast cells play an essential role in diverse physiological and pathological processes and mediate immediate hypersensitive reaction and allergic diseases. Injection of anti-IgE in the skin or other agents that directly activate mast cells may cause the decrease in vascular tone, leakage of plasma and may lead to a fall in blood pressure with fatal anaphylactic shock. Skin mast cells are also implicated as effector cells in response to multiple parasites such as Leishmania which is primarily characterized by its tissue cutaneous tropism. Activated macrophages by IFNγ, cytotoxic T cells, activated mast cells and several cytokines are involved in the elimination of the parasites and immunoprotection. IL-33 is one of the latest cytokines involved in IgE-induced anaphylaxis and in the pathogenesis of allergic skin disorders. IL-33 has been shown in epidermis of patients with psoriasis and its skin expression causes atopic dermatitis and it is crucial for the development of this disease. Here we review the impact of mast cells on the skin.

Material and structural tensile properties of the human medial patello-femoral ligament

The medial patellofemoral ligament (MPFL) is considered the most important passive patellar stabilizer and acts 50-60% of the force of the medial soft-tissue which restrains the lateralization of the patella between 0° and 30°. In this work, 24 human knees have been tested to evaluate the material properties of MPFL and to determine the structural behavior of femur-MPFL-Patella complex (FMPC). Particular attention was given to maintain the anatomical orientation between the patella and MPFL and to the evaluation of the elongation during the mechanical tests. The ultimate stress of the isolated ligament was 16±11MPa, the ultimate strain was 24.3±6.8%, the Young׳s Modulus was 116±95MPa and the strain energy density was 2.97±1.69MPa. The ultimate load of the whole structure, FMPC, was 145±68N, the ultimate elongation was 9.5±2.9mm, the linear stiffness was 42.5±10.2N/mm and the absorbed energy was 818.8±440.7Nmm. The evaluation of material and structural properties of MPFL is fundamental to understand its contribution as stabilizer and for the selection of repair and reconstruction methods.

ASTHMA AND MAST CELL BIOLOGY

Asthma is a chronic inflammatory disease of the lung and its pathophysiology is initiated by mast cell activation in response to the antigen binding to IgE receptor as well as by TH2 cell activation. Mast cells are well established effector cells in asthma where they exacerbate the inflammatory response, playing a key role in early phase, degranulating and increasing histamine. Human mast cells possess high affinity IgE receptors and are ubiquitous but predominantly localized in mucosal and connective tissue and are distributed along blood vessels. There are two types of mast cells: connective tissue mast cells (TC) and mucosal mast cells (T mast cells). TC mast cells contain more heparin, whereas T mast cells contain more chondroitin sulfate. In asthma, mast cell activation can trigger degranulation, releasing secretory granule complex and preformed mediators, such as histamine and proteases, along with the synthesis of leukotrines and prostaglandins, and induction of cytokines and chemokines. Leukotrine inhibitors and omalizumab, which inhibits IgE, both relieve the asthma exacerbation when administered to humans and permit to reduce the use of other drugs. The release of cytokines by mast cells, such as TNF-alpha, IL-1, IL-6 and IL-33, participate in the pathogenesis of asthma. Stress worsens asthma, and this effect is also mediated by mast cell activation through the release of cytokines. Administration of IL-33 in experimental animals provokes pathological effects in the mucosal tissues and augments antibody IgE and IgA in blood vessels. Here, we report the impact of mast cell biology in asthma pathogenesis.

IgE generation and mast cell activation

IgE is an important marker for allergy and plays a central role in the induction of allergic diseases through its binding of the high affinity receptor on mast cells. Mast cells can influence B cell survival, proliferation and differentiation into CD138+cells. Among TH2 cytokines, interleukin (IL)-4 and IL-13 are responsible for class-switching in B cells which resolves in production of allergen-specific IgE antibodies that bind to specific receptor on mast cells. IgE synthesis by B cells is regulated by CD40 ligand, IL-4 and interferon-gamma, therefore inhibition of B cell antigen-specific IgE may prevent the cleavage of CD23 from B cells, having a therapeutic impact which also includes the removal of circulating free IgE, omalizumab, corticosteroids, mast cell stabilizers, leukotriene receptor antagonist, and others. B cell differentiation into IgE-producing cells requires two signals provided by TH2 cells and IL-4, however IL-4, IL-1 and IL-10 as well as several hormones are critical for the development of TH2 cells, while cytokines, such as interferon (IFN)-alpha, IFN-gamma, IL-12 and transforming growth factor (TGF)-beta play a negative role. However, the exact mechanism of this process has not yet been defined.

Quasi-linear viscoelastic properties of the human medial patello-femoral ligament

The evaluation of viscoelastic properties of human medial patello-femoral ligament is fundamental to understand its physiological function and contribution as stabilizer for the selection of the methods of repair and reconstruction and for the development of scaffolds with adequate mechanical properties. In this work, 12 human specimens were tested to evaluate the time- and history-dependent non linear viscoelastic properties of human medial patello-femoral ligament using the quasi-linear viscoelastic (QLV) theory formulated by Fung et al. (1972) and modified by Abramowitch and Woo (2004). The five constant of the QLV theory, used to describe the instantaneous elastic response and the reduced relaxation function on stress relaxation experiments, were successfully evaluated. It was found that the constant A was 1.21±0.96MPa and the dimensionless constant B was 26.03±4.16. The magnitude of viscous response, the constant C, was 0.11±0.02 and the initial and late relaxation time constants τ1 and τ2 were 6.32±1.76s and 903.47±504.73s respectively. The total stress relaxation was 32.7±4.7%. To validate our results, the obtained constants were used to evaluate peak stresses from a cyclic stress relaxation test on three different specimens. The theoretically predicted values fit the experimental ones demonstrating that the QLV theory could be used to evaluate the viscoelastic properties of the human medial patello-femoral ligament.

Obesity, Inflammation and Neurological Alterations

Inflammation, neurodegeneration, imbalance of neurotransmitter systems, oxidative stress and depression are all risk factors for obesity. There is evidence regarding the cross-talk between adipose tissue and the immune system and obese patients may show an alteration of immune functions with major depression, including immune suppression with reduced T-cell and macrophage activity. Obesity is mediated by inflammatory cells such as lymphocytes, macrophages and mast cells which release pro-inflammatory cytokines and chemokines. Obesity-induced leukocyte infiltrations in adipose tissue cause cytokine/chemokine release and inflammation. Here, we report the relationship between obesity, neurological alterations and inflammation.

Postpartum Sacral Stress Fracture: An Atypical Case Report

Sacral stress fractures are common in elderly people. However, sacral stress fracture should be always screened in the differential diagnoses of low back pain during the postpartum period. We present a case of sacral fracture in a thirty-six-year-old woman with low back pain and severe right buttock pain two days after cesarean section delivery of a 3.9 Kg baby. The diagnosis was confirmed by MRI and CT scan, while X-ray was unable to detect the fracture. Contribution of mechanical factors during the cesarean section is not a reasonable cause of sacral fracture. Pregnancy and lactation could be risk factors for sacral stress fracture even in atraumatic delivery such as cesarean section. Our patient had no risk factors for osteoporosis except for pregnancy and lactation. Transient or focal osteoporosis is challenging to assess and it cannot be ruled out even if serum test and mineral density are within the normal range.

Impact of Mast Cells in Rejection of Allografts

Mast cells in the tissue are located close to nerves in and around the small vessels where they orchestrate important immune response after antigen recognition through Toll-like receptors. Mast cells can activate T and B lymphocytes and dendritic cells and have been postulated to act directly within tissue allografts and/or to induce indirect effects via inflammatory mediator release, therefore they have been shown to play an indispensable role in allograft tolerance. Major limitation in the success of transplantation is the immune response of the recipient to the donor tissue. The failure of tissue grafting is caused by an inflammatory reaction called rejection. Mast cells play a role during immune response and are elicited with transplanted allograft and also may exhibit their immune-regulatory effects directly through secretion of modulatory cytokines and activation of metabolic pathways. However, the role of mast cells in transplantation is poorly understood. The most severe rejection episodes have been found in patients with an increased number of mast cells. Mast cell mediators which can activate latent forms of TGF-β or increase angiotensin II levels are capable of inducing fibrosis through various mechanisms, activating fibroblasts and inducing collagen synthesis. Mast cells are also implicated in regulatory T-cell functions and are required to sustain peripheral tolerance via Treg, therefore there is an interaction between mast cells and Treg cells. Treg create IL-9 in enhancing mast cell growth and Chemotaxis, suggesting that Treg and mast cells form a functional unit that mediates graft tolerance. In this study we concentrate our attention on the role of mast cells in rejection of allografts and try to understand the role of mast cell-related immune mechanisms in organ transplantation.