Treg cells or regulatory T cells constitute a large population of cellular infiltrate in atopic/allergic inflammation and a dysregulated immune response appears to be an important pathogenetic factor. Cardinal events during allergic inflammation can be classified as activation, organ-selective homing, survival and reactivation, and effector functions of immune system cells. T cells are activated by aeroallergens, food antigens, autoantigens, and bacterial exotoxins superantigens in allergic inflammation. They are under the influence of the skin, lung, or nose-related chemokine network and show organ-selective homing. (more…)

Allergen-specific immunotherapy is highly effective in the treatment of IgE-mediated allergy diseases such as rhinitis, conjunctivitis, asthma, and venom allergy hypersensitivity. It is the only treatment that leads to lifelong tolerance against previously disease-causing allergens due to restoration of the normal immunity. (more…)

An emerging concept is that pro-inflammatory signals lead to loss of Regulatory T Cells (Treg) function. Pasare and Medzhitov (2003) demonstrated that activation of DCs through TLRs led to the production of signals, including IL-6, which blocked the suppressive effect of CD4+CD25+ Treg. Subsequent studies support these observations. For example in a mouse model of allergic airway disease, IL-6 is proposed to act via two mechanisms to promote disease: direct enhancement of Th2 responses and by overcoming the suppressive function of CD4+CD25+ Treg. Tumor necrosis factor (TNF) as well as IL-7 and IL-15 have also been proposed to overcome regulatory activity in other human immunologic diseases. (more…)

The intracellular forkhead winged transcription factor Foxp3 (forkhead box P3) appears to be specifically expressed by naturally occurring Treg cells, particularly in mice, although in humans there is evidence of upregulation of Foxp3 in all T cells on activation. Foxp3 is required for the development and function of naturally occurring regulatory t cells (treg) and expression is sufficient to convert non-regulatory CD4+CD25T cells into cells with regulatory activity. Conversion of peripheral CD4+CD25 naive T cells to Foxp3+CD4+CD25 foxp3+ Treg cells can be induced by TGF-ß. In a murine asthma model, these TGF-ß-induced Treg prevented house-dust mite-induced allergic pathogenesis or infection pathogenesis in lungs. A single independent report has suggested that IL-4 and IL-13 also induce Foxp3+CD25+ Treg from CD4+CD25precursors. (more…)

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…)

The induction of immune tolerance and specific immune suppression are essential processes in the control of immune responses. Regulatory T cells (Treg) play a central role in immune control in the periphery. Two broad categories of Treg have been described: naturally occurring Treg that are present in all individuals and antigen-induced Treg that secrete inhibitory cytokines such as interleukin (IL)-10 and/or transforming growth factor (TGF)-ß. (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…)

Normally present at very low levels in plasma, antibodies of the immunoglobulin E (IgE) isotype were first discovered in 1967, decades after the description of IgA, IgG, and IM. IgE antibodies are produced primarily by plasma cells in mucosal-associated lymphoid tissue and their levels are uniformly elevated in patients suffering from atopic conditions like allergic rhinitis, asthma and atopic dermatitis. Production of allergen-specific IgE in atopic individuals is driven both by a genetic predisposition to the synthesis of this isotype as well as by environmental factors, including chronic allergen exposure. (more…)

Tumour Necrosis Factor is a pro-inflammatory cytokine implicated in the pathogenesis of asthmatic airway inflammation, hyper-reactivity and remodelling. The primary aim of the trial was to assess whether TNF antagonism, using a soluble Tumour Necrosis Factor receptor (TNFR:Fc etanercept, Enbrel ® ), can attenuate eosinophilic airway inflammation in patients with mild to moderate allergic asthma. (more…)

Most acute phase proteins are synthesized in the liver, although the genes for some are also expressed in cells and tissues elsewhere. Transcriptional control is the main mechanism for regulation of production hut mRNA stability contributes in some cases. A large number of cytokines, including interleukin I (IL-1), IL-6, tumours necrosis factor a and various interferons, are capable of inducing increased, or in some cases decreased, production of various acute phase proteins in vivo and in cultured hepatocytes and liver ccli Lines in vitro. Glucocorticoids and steroid sex hormones can play an important permissive role and neural and neuroendocrine influences may be significant in vivo. Results obtained in different laboratories with different acute phase proteins, different cytokines and different cell lines or experimental systems have shown much variation.

It has been difficult to reconcile all the findings and to identify the critical participation of particular mediators in control of particular reactants, especially because of the cascade effects by which some cytokines promote the production of others. Nevertheless it is striking that 11-6 knockout mice mount absolutely no acute phase response of serum amyloid A protein (SAA), serum amyloid P component (SAP) or complement component C3 following induction of sterile inflammation by casein or silver nitrate injection, whereas lipopolysaccharide (I .PS induces a definite, although subnormal, response.

Studies with transgenic mice bearing the human CRP gene, with transfected cells containing human SAA genes, and with hepatoma cell lines, have identified regulatory flanking regions of DNA which are targets for the action of nuclear Factors responsive to IL-6 and IL-I.

While the profile of acute phase plasma proteins is broadly similar across species there are nonetheless important differences. For example, SAP is a major acute phase reactant only in the mouse, and there are many other differences in normal levels and acute phase behaviour of other members of the pentraxin family of proteins to which it belongs. While these differences may be important for the usefulness of particular proteins as markers in clinical or experimental situations, they may not reflect, as has been pointed out above, the underlying metabolic regulation. On the other hand, some species differences are clearly of physiological and pathophysiological importance. Thus, although rats have a gene for a homolog of SAA, the expression of which is regulated as an acute phase protein, the product does not appear as a plasma lipoprotein and rats never get AA amyloidosis. This contrasts with the behaviour of SAA in all other mammals and birds which have been studied.