Fetomaternal cell trafficking: a new cause of disease?

Isolation of fetal cells from maternal blood is under active investigation as a noninvasive method of prenatal diagnosis. In the context of studying cell surface antigens expressed on fetal cells we discovered that fetal cells from a prior pregnancy also could be detected. This led to the appreciation of the persistence of fetal cells in maternal blood for as long as 27 years postpartum, and the realization that following pregnancy, a woman becomes a chimera. Quantitative polymerase chain reaction analyses have shown that a term pregnancy is not required for the subsequent development of fetal cell microchimerism. As many as 500,000 fetal nucleated cells are transfused following an elective first trimester termination of pregnancy. The relationship between fetal cell microchimerism and maternal disease is currently being explored. During pregnancy, fetal cells in the maternal skin are related to polymorphic eruptions of pregnancy and increased fetomaternal trafficking is detectable in cases of preeclampsia. After delivery, more male DNA of presumed fetal origin is present in the blood and skin of women with scleroderma as compared with healthy controls. Scleroderma is of particular interest because it shows a strong female predilection and it is an autoimmune disease with clinical similarities to graft-versus-host disease. Fetomaternal cell trafficking provides a potential explanation for the increased prevalence of autoimmune disorders in adult women following their childbearing years.     

Autologous neural stem cell transplantation: A new treatment option for Parkinson’s disease?

The clinical motor dysfunction in Parkinson´s disease (PD) is primarily linked to the depletion of dopamine in the striatum consecutive to the loss of the large dopaminergic neurons in the substantia nigra. Despite intense investigations, no effective therapy is available to prevent the onset, or to halt the progression of the neuronal cell loss. Here, we hypothesize that autologous adult neural stem cells (NSCs) are an attractive source for cell therapy to treat PD. They overcome the ethical issues inherent to the use of human fetal tissue or embryonic stem cells. NSCs derived from adult tissue also open the possibility for autologous transplantation, where NSCs are taken out from the patient, expanded and differentiated in vitro and re-implanted back as dopaminergic precursor cells.     

Autoimmune disease: A role for new anti-viral therapies?

Many chronic human diseases may have an underlying autoimmune mechanism. In this review, the author presents a case of autoimmune CIU (chronic idiopathic urticaria) in stable remission after therapy with a retroviral integrase inhibitor, raltegravir (Isentress). Previous reports located using the search terms "autoimmunity" and "anti-viral" and related topics in the pubmed data-base are reviewed suggesting that novel anti-viral agents such as retroviral integrase inhibitors, gene silencing therapies and eventually vaccines may provide new options for anti-viral therapy of autoimmune diseases. Cited epidemiologic and experimental evidence suggests that increased replication of epigenomic viral pathogens such as Epstein-Barr Virus (EBV) in chronic human autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), and multiple sclerosis (MS) may activate endogenous human retroviruses (HERV) as a pathologic mechanism. Memory B cells are the reservoir of infection of EBV and also express endogenous retroviruses, thus depletion of memory b-lymphocytes by monoclonal antibodies (Rituximab) may have therapeutic anti-viral effects in addition to effects on B-lymphocyte presentation of both EBV and HERV superantigens. Other novel anti-viral therapies of chronic autoimmune diseases, such as retroviral integrase inhibitors, could be effective, although not without risk.     

Langerhans cell histiocytosis, a new clinical phenotype of x-linked lymphoproliferative disease?

Langerhans' cell histiocytosis (LCH) is a rare disease of unkown cause and is characterized by clonal proliferation of Langerhans cells. Here, we describe the case of a 22-month-old boy with LCH associated with X-linked lymphoproliferative disease (XLP). Sequence analysis of SH2D1A for mutations that cause T-cell dysfunction revealed a CT substitution at nucleotide 462. This is the first case that hints at an association between XLP and LCH.     

Prions: A model of conformational disease?

The discovery that a protein could mimic viral and bacterial pathogens around 1980 by Stanley Prusiner was unexpected. Evidence shows now that Creutzfeldt-Jakob disease and related disorders are caused by prions. Prions and, for example neurodegeneratives diseases, arise from the same general disease mechanism. In each, there is abnormal unfolding and then aggregation of proteins. The protein conformational changes associated with the pathogenesis of protein misfolding disorders produce β sheet rich oligomers that are partially resistant to proteolysis and have a high tendency to form amyloid-like aggregates. It is important to distinguish between prions and amyloids: prions need not to polymerize into amyloid fibrils and can undergo self-propagation as oligomers. The prion diseases are characterized by the conformational conversion of PrP^c to PrP^sc, the fundamental even underlying prion diseases. Despite the obvious differences between prions and conventional infectious microorganisms, prions fulfill the Koch's postulates. Meaningful treatments are likely to require cocktails of drugs that interfere with the conversion of precursor into prions and enhance the clearance of prions; such an approach may find application in the more common degenerative diseases.     

Mast cell myositis: a new feature of allergic asthma?

There is some evidence that, in asthma, mast cells infiltrate the airway smooth muscle layer and, as a consequence, alter the functional and structural properties of myocytes. This inflammation so-called mast-cell myositis, probably contributes to both bronchial hyperresponsiveness and airway remodelling. Previous observations have pointed out the presence of mast cells within airway smooth muscle of atopic patients and recent data obtained in asthmatic patients demonstrate that this infiltration is more important in asthmatic patients with atopy. Although the mechanism of such a mast cell attraction remains to be fully understood, experimental data demonstrate that, upon stimulation by tryptase or cytokines, smooth muscle cells can attract mast cells through the production of TGF-beta1 or SCF. Once at the site of inflammation, activated mast cells are responsible for an important extracellular deposition of inflammatory products that may facilitate the increase in smooth muscle mass. In addition, comparison of asthmatic patients with and without atopy suggests that mast cell myositis is closely related with atopy.     

Anti-cytokine vaccination: A new biotherapy of autoimmunity?

Anti-cytokine vaccination is an innovative strategy of targeted, active immunotherapy with potential application in autoimmune diseases. The principle is to design molecules capable of triggering a humoral immune response versus a cytokine with a recognized pathogenic role in a given disease. The most used vaccination approach is based on self-protein coupled to a carrier. This strategy proved particular efficacy in models of TNF-α-dependent diseases, and promising results come from recent clinical trials in rheumatoid arthritis and Crohn's disease. The benefit/risk ratio and long term safety of anti-cytokine vaccination need to be determined to further develop this therapeutic strategy.     

Mast cell activation tests by flow cytometry: A new diagnostic asset?

Since the late nineties, evidence has accumulated that flow-assisted basophil activation test (BAT) might be an accessible and reliable method to explore the mechanisms governing basophil degranulation and diagnostic allowing correct prediction of the clinical outcome following exposure to the offending allergen(s) and cross-reactive structures for different IgE-dependent allergies and particular forms of autoimmune urticaria. Although the BAT offers many advantages over mediator release tests, it is left with some weaknesses that hinder a wider application. It is preferable to perform the BAT analysis within 4 h of collection, and the technique does not advance diagnosis in patients with non-responsive cells. Besides, the BAT is difficult to standardize mainly because of the difficulty to perform large batch analyses that might span over several days. This article reviews the status of flow cytometric mast cell activation test (MAT) using passively sensitized mast cells (MCs) with patients' sera or plasma (henceforth indicated as passive MAT; pMAT) using both MC lines and cultured MCs in the diagnosis of IgE-dependent allergies. In addition, this paper provides guidance for generating human MCs from peripheral blood CD34⁺ progenitor cells (PBCMCs) and correct interpretation of flow cytometric analyses of activated and/or degranulating cells. With the recent recognition of the mas-related G protein-coupled receptor X2 (MRGPRX2) occupation as a putative mechanism of immediate drug hypersensitivity reactions (IDHRs), we also speculate how direct activation of MCs (dMAT)—that is direct activation by MRGPRX2 agonists without prior passive sensitization—could advance paradigms for this novel endotype of IDHRs.     

Myopia: A collagen disease?

Myopia is an increasingly important public health problem in the world. Even though previous studies have strongly implicated a role of certain environmental factors such as visual near-work in myopia development, the pathogenesis of this disease still remains unclear. There is evidence showing that myopia is primarily a hereditary condition, combined with or without environmental influence or individual habitual factors. Recent research suggests that collagens in the sclera play an important role in the development of myopia. Based on a literature review after a Medline search on articles on myopia, changes in scleral collagen appeared to underlie or be associated with the pathogenetic factors (including inheritance) involved in myopia development. Therefore, we hypothesized that myopia is a disorder, in which alterations of scleral collagens may be responsible for the pathological changes found in it.     

Diuretics in Meniere disease: a therapy or a potential cause of harm?

Despite the lack of clear evidence for their effectiveness in treating vertigo, tinnitus, hearing loss and aural fullness, diuretics, represent a common treatment for Meniere disease (MD), as they are supposed to decrease volume and pressure in the endolymphatic partition of the labyrinth. Our group have outlined the possibility of an adverse effect on inner ear function derived from an abrupt lowering of blood pressure: a subsequent exaggerated vasomotor response inducing local ischemia could be responsible for more or less permanent damage. The inner ear, owing both to its terminal vascular supply and to the necessity of a steady metabolism, seems a reliable target for any hemodynamic imbalance that acutely affect its perfusion. In our opinion, the complexity of the inner ear anatomy and function argues against the usefulness of diuretics to reduce endolymphatic volume, in analogy to their effect on the volemia: too many active mechanisms and “buffer” systems are involved in the labyrinth. Even considering that the finding of mean low pressure values is relatively common in subjects with MD, an attempt should be to maintain a stable blood perfusion to the labyrinth; in fact, an abrupt decrease in systemic blood pressure can trigger an adverse sympathetic reaction and transmit misleading information to the cochlear vasopressin receptors.     

Is Wiskott–Aldrich syndrome a cell trafficking disorder?

Recent evidence suggests that failure of dendritic cell migration contributes significantly to the progressive dysregulation of immunity, characteristic of the Wiskott–Aldrich syndrome. These findings may be relevant to the pathogenesis of other primary immunodeficiencies and acquired inflammatory disorders.     

New cell or new cycle?

In mammals, trophoblast giant (TG) cell differentiation is characterized by a physiological endoreduplication, resulting in genome size augmentation. A recent study by Ullah and colleagues (pp. 3024-3036), published in this issue of Genes & Development, now elucidates the role of the cyclin-dependent kinase inhibitors (CKIs), p21 and p57, in mammalian endocycle regulation.     

Trigeminal neuralgia: A new therapy?

Trigeminal neuralgia (TN) is a rare form of neuropathic pain that results in sudden, unilateral and recurrent pains in the distribution of one or more branches of the trigeminal nerve. The aetiology of TN remains unclear and several theories have been proposed. Many medical and surgical methods have been applied with only partial effectiveness and several side effects. New hypotheses and therapeutic methods are urgently needed.Using evidence presented in a literature review and in our own case report, we hypothesize that pain resulting from trigeminal neuralgia can be caused by demyelinating lesions in the trigger zone. These lesions can be repaired through the injection of fat containing Adipose-Derived Stem Cells (ADSC).