Regulatory T cells Treg (picture above) is the existence of suppressor cells, which limit ongoing immune responses and prevent autoimmune disease, was postulated over 30 years ago. The recent phenotypic and functional characterization of these cells has led to a resurgence of interest in their therapeutic application in a number of immune-mediated diseases. Two broad subsets of CD3+CD4+ suppressive or Treg cells have been described: constitutive or naturally occurring versus adaptive or inducible Treg. (more…)

Neutrophils make up an army of more-or-less identical circulating phagocytes that are poised to respond quickly and in vast numbers wherever tissue injury has occurred. The mature cells, which are also known as segmented neutrophils (segs) or polymorphonuclear leukocytes (polys, or PMNs), can easily be identified by their characteristic multilobed nucleus and by the abundant storage granules in their cytoplasm (Figure bellow). (more…)

With the exception of complement protein C3, most soluble mediators of innate immunity are found in relatively small amounts in the serum under normal conditions. The concentrations of several of these proteins, however, can increase as much as 1000-fold during serious infections or other crises, as part of a coordinated protective reaction called the acute-phase response. In this response, the liver temporarily increases its synthesis of more than 30 different serum proteins, often called acute-phase proteins (Table bellow). Many of these, such as complement factors C3 and B, MBL, LBP, C-reactive protein, and serum amyloid protein P, participate in antimicrobial defense. (more…)

The Ras-dependent pathway can be triggered by a variety of cytokine receptors, as well as by certain adhesion molecules and by many other surface receptors when they contact appropriate ligands. Signaling in this pathway can be initiated by cytosolic proteins called Src-family kinases, so named because they bear regions of sequence homology to the oncoprotein Src. These Src-like kinases contain specialized protein domains, termed SH2 domains (for Src-homology region 2), that enable them to bind other proteins containing phosphorylated tyrosine residues. When a cytokine receptor binds ligand, subunits of the receptor become phosphorylated and can immediately be bound by a Src-family kinase. (more…)

The body’s innate resistance to many pathogens is provided by enzymes and other proteins in the blood and tissue fluids. These proteins are the effectors (ie, the active agents) of humoral innate immunity, and they have features in common with one another that are also characteristics of the innate immune system as a whole. First, these proteins are continually expressed throughout life, regardless of whether or not their protective effects are needed at a given moment. Second, although many of these proteins can be produced in higher quantities in times of need, their intrinsic properties (eg, substrate specificity and ige binding affinity) never change: The characteristics of these proteins have been shaped by evolution, are genetically determined, and are fixed at birth, so that they do not vary during an individual’s lifetime. (more…)

Hematopoietic progenitors depend on a variety of cytokines to control their growth and differentiation. These include several different types of colony-stimulating factor (CSFs) and interleukins that each act on specific cell types to promote or inhibit particular types of responses. Detailed discussions of individual cytokines are presented in Chapter 10; for the present, we focus on general principles of cytokine action as illustrated in their effects on hematopoiesis. (more…)

Although it is commonly imagined that hematopoiesis takes place in a liquid environment resembling the blood, with progenitors responding mainly to soluble hormone-like cytokines, this is in fact not the case at all. It is much more accurate to think of the bone marrow as a solid tissue in which different types of hematopoietic cells develop in physically different locations. These microenvironments are visible in histologic sections of bone marrow, which reveal a patchwork of microscopic foci, each devoted to the production of a particular cell type (Figure bellow). The bone marrow microenvironment is set up and maintained by bone marrow stromal cells. Within each microenvironment, contact of cells with one another or with proteins and other substances that make up the extracellular matrix (ECM) greatly facilitates cell division and differentiation. (more…)

Our understanding of hematopoiesis has advanced greatly in recent years with the isolation and characterization of hematopoietic stem cells (HSCs) and the identification of many of the factors that influence the production and differentiation of lineage-committed progenitors (Figure 1 bellow). HSCs are defined by their abilities to self-renew throughout life and to give rise to committed progenitors that can differentiate along all of the possible hematopoietic lineages. They were first purified from mice as a tiny sub-population of marrow cells that could completely reconstitute the hematopoietic systems of other mice, whose own marrows had been destroyed by inherited mutations or by radiation. (more…)

The new corticosteroid ciclesonide has been evaluated in various studies to assess its efficacy and adverse effect profile in asthma. However, there are no data comparing the effects of high-dose ciclesonide with those of fluticasone propionate on airway and systemic outcomes in patients with moderate persistent asthma.

The relative effects of 4 weeks of treatment with ciclesonide and fluticasone propionate on airway hyper-reactivity, exhaled nitric oxide levels, lung function, symptoms, and quality of life were compared in 14 patients with moderately persistent asthma. Both drugs significantly improved airway outcomes in terms of methacholine bronchial hyper-responsiveness and exhaled nitric oxide levels. Fluticasone propionate 2000 µg daily but not ciclesonide 1600 µg daily significantly suppressed hypothalamic pituitary adrenal (HPA) axis outcomes, overnight 10 h urinary cortisol levels being lower after fluticasone propionate administration than after ciclesonide administration.

The efficacy of a new medication depends upon comparison with an existing medication that is used in the community for the treatment of a particular condition. Inhaled corticosteroid, namely beclomethasone, budesonide and fluticasone, have been used in the treatment of asthma. The introduction of newer inhaled corticosteroid would depend on the efficacy of the medication in comparison with existing medication. Ciclesonide has been evaluated in various studies essentially looking at the adverse effect profile and its effectiveness in asthma. There are no reports of head-to-head comparisons with the standard inhaled corticosteroid asthma. This study compared the effects of ciclesonide with those of fluticasone propionate, albeit in a small population of moderately persistent asthmatics. The absence of significant differences between the group receiving fluticasone propionate and the group receiving ciclesonide in airway parameters, including spirometry, PEF, symptoms and Mini-AQLQ (Asthma Quality of Life Questionnaire) score, suggest that ciclesonide could prove to be a useful option in the management of asthma. With regard to safety, the treatment period of 4 weeks may not be adequate to cause significant suppression of the hypothalamic–pituitary–adrenal axis and long-term trials are required to evaluate the effects of ciclesonide on the HPA axis.

The findings of these studies, coupled with the results of earlier studies on the pharmacology, pharmacokinetics and efficacy of ciclesonide, indicate great promise for this new inhaled steroid in the treatment of asthma. The higher bioavailability and improved plasma binding of this steroid provide it with greater efficacy and minimal side effects. Furthermore, ciclesonide nasal spray with its minimal effect on the hypothalamic–pituitary–adrenal axis, could be useful in the treatment of children with asthma. However, data on the long-term effects on the HPA axis with ciclesonide are necessary if they are to be considered to be safe medications with no effect on the HPA axis.

Diagnosis of food hypersensitivity is a clinical challenge and the only current definitive test is the Double Blind Placebo-Controlled Food Challenges. Although the Double Blind Placebo-Controlled Food Challenges is the current gold standard, it is difficult to perform and is very time-consuming. Hence, researchers are continually evaluating new tests and assessing the value of the available serum tests. (more…)