Toll-like receptors (TLRs) act as receptors for numerous stimuli of immune cells, including bacterial cell wall constituents (lipopolysaccharide [LPS] from Gram-negative bacteria and lipopeptides from Gram-positive species), plasma proteins and extracellular matrix breakdown products. TLR2 and TLR4 bind lipopeptide and LPS respectively, mediating responses of alveolar macrophages and other immune cells to bacterial infection in the lungs. Exposure of lungs to LPS leads to pro-inflammatory responses of a number of cell types, including airway smooth muscle, which secretes a number of cytokines involved in leucocyte recruitment and the Th2 polarization of immune responses. Human airway smooth muscle cells were cultured with LPS in the absence and presence of peripheral blood mononuclear cells to determine direct and leucocyte-dependent TLR-mediated responses. (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…)

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…)

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…)

Other humoral effectors and humoral factors have the ability to lyse microorganisms directly. The best studied of these are a class of small peptide antibiotics known as defensins, which in their active forms are all roughly 30 amino acids long (3,5 kilodaltons), positively charged, and protease-resistant. Each also has three internal disulfide bonds. They are classified as either α or β defensins based on the arrangement of the disulfides, but both classes have nearly the same compact, folded structure consisting of three strands of antiparallel β-pleated sheets. (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.

The mediators released by mast cells and basophils can be grouped into two categories:
(1) preformed substances contained within granules and
(2) newly generated chemicals synthesized following cellular activation.

These mediators comprise the effector function of the mast cell. Together they are able to increase vascular permeability, dilate vessels, cause bronchospasm, contract smooth muscle, and summon inflammatory cells. Few cells in the body produce compounds with such a large and varied spectrum of activity. (more…)

Scleroderma is a disease of unknown cause characterized by abnormally increased collagen deposition in the skin. The course is usually slowly progressive and chronically disabling, but it can be rapidly progressive and fatal because of involvement of internal organs. It commonly begins in the third or fourth decade of life, but children are occasionally affected. The prevalence of the disease is one case per 100,000 in the population. Women are affected twice as often as men. There is no racial predisposition. (more…)

Bacteria cause allergic disease because of toxicity, invasiveness, immunopathology, or lends of these three mechanisms. Thus much of the interaction between a given bacterial species and the cellular immune response can be predicted by considering the immunological mechanisms available in relation to the mechanism of pathogenicity, and the structure of the bacterium. For a toxigenic bacterium, neutralizing antigen & antibody may be all that is needed. Otherwise destruction of the organism itself may be required. (more…)