Immune Surveillance Ebook

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

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The Immunity Crisis in America

Have you ever wondered WHY you get sick from different things, sometimes seemingly for no reason? Haven't you ever wished that you could find some way to stop yourself from getting sick and stay healthy all the time? Well, that might be more possible than you thought at first! Your immune system is an odd system, that many scientists are still struggling to understand. However, there have been some amazing breakthroughs! Once you get access to this detailed and helpful book, you will be able to find REAL and Applicable ways to improve your immune system and keep yourself from getting sick all of the time. This book teaches you everything that you never learned about your immune system Start learning what you can Really do to improve your immune system's health and keep your body healthier for longer! It's not hard at all Get started today!

Immunity Crisis Overview

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An Introduction The Immune System

The Immune Innate Immune Adaptive Immune 6 Cells That Function in Innate Immune 8 Cells That Function in Adaptive Immune 11 Tissues of the Immune System General 12 Tissues of the Immune System Primary Lymphoid 12 Tissues of the Immune System Secondary Lymphoid Tissues 14 Soluble Mediators of the Immune At the conclusion to this chapter, the reader will have a firm understanding of the fundamental components of the immune system, and how they interact in achieving defense against environmental pathogens and or foreign substances (antigens). Host defense has been classically subdivided into the two categories innate immunity and adaptive immunity. The innate immune system, which functions as a first-line of defense to invading pathogens (antigens), is composed of cells and molecules that provide rapid host protection without memory or specificity for the responses in which they engage. The principal cell types in innate immunity are phagocytes (macrophages and neutrophils) and natural...

Innate Immune Responses to Pathogens

Innate Immune Responses to 32 This chapter introduces the innate immune system, along with the effector molecules and cells that participate in innate host defense. These cells and molecules function early following host challenge by pathogens. The innate system shows significant conservation in evolutionary terms. Cell-bound receptors present on cells of the innate defense system are conserved across evolution (so-called primitive pattern recognition receptors, PPRR), recognizing common (lipid and carbohydrate) motifs on the pathogen. Molecules of the complement system, along with other inflammatory cell products, including chemokines and cytokines function in innate immunity. From a cellular point of view, neutrophils and macrophages are the principal effectors of nonspecific host defense, and, when activated, trigger intracellular enzyme cascades that kill the engulfed microorganisms, particularly bacteria.

Metabolic Effects of Immune Response Mediators

When the organism is stressed by an injury, infection or illness, the daily swing of insulin- and glucagon-mediated metabolic shifts between fed and fasted states is disturbed. The organ system charged with recognising and responding to an injury is the immune system, which has the capacity to radically change body protein and energy metabolism and thus body composition 5 . The antigen-presenting cell (APC) of the immune system is typically a macrophage, tissue monocyte or skin dendritic cell. The APC contacts an antigen, phagocytoses it, processes an antigenic determinant, and brings it to its surface in an HLA-restricted manner in order to trigger an immune response. This immune response requires both the presence of a specific epitope from the antigen and the elaboration of one or more non-specific signals, chiefly via secretion of the cytokine IL-1. IL-1 secretion triggers activation of T cells and other portions of the immune response. The subsequent APC-initiated signals include...

Leptin and Immune Function

Initially described as an antiobesity hormone, lep-tin has subsequently been shown also to influence haematopoiesis, thermogenesis, reproduction, angiogenesis and immune response. Circulating levels of this adipocyte-derived hormone are proportional to fat mass, but may be lowered rapidly by fasting. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. There is enough reported evidence to suggest a role for leptin in linking nutritional status to cognate cellular immune function, and to provide a molecular mechanism to account for the immune dysfunction observed in starvation 44 . The decrease in leptin plasma concentrations during food deprivation leads to impaired immune function, whereas the restoration of leptin to normal levels by feeding after starvation is sufficient to ameliorate the immune response and is followed by a significant increase in Th1 activity, supporting further the role of lep-tin as a nutritional sensor...

Influence of Nutritional Status on Immune Response

A survey of the literature shows that most nutritional deficits lead to suppressed immune responses. This is not surprising, since anabolic and catabolic pathways in the immune system require the same sort of building blocks and energy sources as other physiological activities. Caloric restriction is another area of emerging interest, with important implications for human health. In general, moderate caloric restriction appears to have beneficial effects on longevity and disease resistance. However, these trends and generalisations must be approached with some caution 62 .

Selfantigens For Immunotherapy Of

Proteinase 3, a serine protease stored in azurophilic granules, is a differentiation antigen associated with myeloid granule formation and is overexpressed in a variety of myeloid leukemia types, including CML cells. Therefore, it has been considered a possible target antigen for specific active immunotherapy. CTLs specific for an HLA-A2.1-restricted nonpolymorphic peptide (PR1) derived from proteinase 3 have shown HLA-restricted cytotoxicity, and selectively inhibit CML progenitors over normal marrow cells.67 68 PR1-specific T cells have been identified by HLA-A2-PR1 peptide HLA tetramers in a majority of CML patients who responded to either IFN-a or allogeneic stem cell transplantation.69 PRl-specific CTLs isolated from these patients were capable of lysing fresh leukemia cells. Follow-up studies in patients with relapsed CML revealed a selective loss of the high-avidity PR1-CTL population by tetramer determination. A functional PRl-specific CTL immune response was also lost prior...

Impairment of the Immune System

Immunodepression is a key feature of patients with CACS. The severity of immunodepression is related to stage of disease and severity of cachexia. Several of our studies demonstrated that the immune system of cancer patients shows an impaired blastic response to mitogens. The reduced proliferative response to mitogens (such as PHA, anti-CD3 antibody and recombinant IL-2) of peripheral blood mononuclear cells (PBMCs) isolated from cancer patients has to be considered as an index of more complex functional alterations. In normal circumstances (PBMCs isolated from healthy individuals) the above-cited mitogens induce cell cascade events similar to those occurring after antigen activation production and release of cytokines, synthesis and release of IL-2 from CD4+ cells and surface expression of IL-2 receptor by lymphocytes. Thus, the blastic response depends on the amount of cytokines, IL-2 receptor expression and interaction between IL-2 and its receptor 55 . Patients with advanced...

Immune Responses to HPV

Most of those who develop benign HPV lesions eventually mount an effective cell-mediated immune response that results in lesion regression. Regression of anogenital warts is accompanied histologically by a CD4+ T cell-dominated Th1 response, and data from animal models suggest that the response is modulated by CD4+ T cell-dependent mechanisms. Failure to develop effective cell-mediated immunity to clear or control infection results in persistent infection and, in the case of the high-risk HPVs, an increased probability of progression to high-grade squamous intraepithelial lesions or invasive carcinoma. The increased prevalence of HPV infections and high-grade lesions in im-munosuppressed individuals as a consequence of HIV infection demonstrates the importance of CD4+ T cells in the control of HPV infection. The prolonged duration of infection associated with HPV seems to be associated with effective evasion of innate immunity as reflected in the absence of inflammation during virus...

Innate Immune Response to Ocular HSV1 Infection

After initial infection of the virus into the cornea, an innate immune response is triggered to clear the pathogen. Toll-like receptors (TLR), a family of pattern-recognition molecules, are known to respond to pathogens and serve as early warning molecules that induce the expression of proinflammatory molecules 5 . Of the twelve TLR subtypes found in the mouse, TLR2 and TLR9 are expressed by corneal epithelium 36 . HSV-1 stimulates TLR2 by unknown means resulting in the activation of nuclear factor (NF)-kB and production of interleukin (IL)-6 46 . HSV-1 which contains CpG motifs 106 is recognized by TLR9, resulting in the expression of type I interferon (IFN) 44 . In addition to the production of type I IFNs, the infected resident cells of the

Reactive Nitrogen Intermediateinduced Parp Activation In The Immune System

As this chapter focuses on the role of PARP in the reactive nitrogen intermediate (RNI)-induced cytotoxicity, a relatively detailed outline of the role of RNI in the immune system is given. The possible effect of PARP on the formation of T and B lymphocyte repertoire and some aspects of PARP as a transcriptional regulator of immune functions are also discussed. In summary, these results show that activation of the immune system is accompanied by iNOS expression and peroxynitrite formation due to cross-activation of T lymphocytes and monocytes macrophages. According to this scenario (a similar one to that is depicted in Figure 7.10), activation of T cells by anti-CD3 or superantigens such as SEB results in cytokine (INFy) production by activated T cells. INFy in turn activates monocytes macrophages dendritic cells to express iNOS and to switch on the oxidative burst, fueling peroxynitrite production from both sides (NO and superoxide). Peroxynitrite produced by activated monocytes...

The Autoimmune Response In Lung Cancer Is Similar To That In The Systemic Autoimmune Diseases

Found in the systemic autoimmune diseases are those directed against nuclear antigens 8, 23-26, 56 . Attempts to show nuclear reactivity in patients with cancer using characterized antigens known to be involved in the immune response in the systemic autoimmune diseases have been unrewarding 14, 57 . The failure of cancer sera to recognize those antigens may merely reflect the presence of different specificities related to the cancer itself. A characteristic profile of autoantibodies is found in each of the systemic autoimmune diseases. These autoantibodies are helpful in establishing a correct diagnosis and prognosis and frequently facilitate the follow-up and treatment of these patients. The value of these antibodies in the diagnosis of the systemic autoimmune diseases is related to their immunologic specificity. Similarly, our data suggest that some of the antinuclear antibodies found in lung cancer sera may be relatively tumor specific and can be predictive of outcome 54 ....

Immune Response to Genital HSV2 Infection

During initial infection of the mucosa of the vagina with HSV-2, the virus begins to replicate in the epithelium, typically restricted to the epidermis or cervicovaginal epithelium 43 . The initial host response to infection includes the induction of type I IFNs (i.e., IFN-a species) through TLR9 recognition of HSV-2 CpG motifs 52 . The IFN-responsive pathway, double-stranded RNA-dependent protein kinase but not 2',5'-oligoadenylate synthetases is essential for resistance to infection, as mice deficient in this pathway are highly susceptible to HSV-2-mediated mortality (D.J.J. Carr, L. Tomanek, R.H. Silverman, and B.R.G. Williams, manuscript in preparation). In addition to type I IFN production, IL-12,1L-15, IL-18, NK cells, and PMNs are important first lines of defense against HSV-2 replication and spread 1,31,59 . Current evidence suggests the resident populations of Langerhans cells 19 do not traffic to the inguinal iliac lymph nodes with most migrating cells consisting of B...

Adoptive Immunotherapy

Khatri et al. demonstrated the striking temporal relationship between the endogenous expansion of a TCR Vfi-restricted, CD3+CD8+ population of MHC class I-restricted CTL and the regression of a monoclonal PTLD in a HSCT recipient. Unfortunately, the delay in recovery of such immune surveillance against transformed EBV-positive B cells results in the development of potentially fatal PTLD. T-cell immunotherapy has been reported to be efficacious in the management of PTLD in this setting.39 O'Reilly et al. reported on 18 HSCT patients with EBV-PTLD who were treated with nonspecific donor lymphocyte infusions (DLI) 16 of 18 patients experienced eradication of PTLD. However, only 10 survived in sustained CR and 3 patients died of GVHD, a major side effect of DLI.50 Attempts have been made to improve the efficacy and reduce the risk of GVHD by administering EBV-spe-cific CTLs.51 Rooney et al. detailed the outcome of 39 recipients of matched unrelated donor partially mismatched related donor...

Active Specific Immunotherapy Vaccines

As a general concept a therapeutic antitumor vaccine refers to the subcutaneous administration of a tumor-specific antigen with the intent to induce an active and possibly long-lasting humoral and or cellular immune response able to eliminate tumor cells harboring the putative antigen. Many years of disappointing clinical results with antitumor vaccines against different types of advanced solid tumors has taught tumor immunologists that the best setting for effective immunotherapy is the situation of MRD (10). In CML, like in other tumors, the ideal vaccine candidate would be an antigen expressed only in tumor cells, but common to all patients. It should be highly immunogenic and should be essential for tumor cell survival, and thus not susceptible to mutation or deletion. Several CML antigens have been identified as potential targets for an anti-CML vaccine strategy (Fig. 1), and different approaches at different stages of development are now under evaluation for CML patients (Table...

An Environmental Factor Can Preferentially Costimulate Autoimmune Response and Disease in Neonatal Mice

The neonatal but not adult response to self-Ags is also uniquely modified by the environmental pinworm infection (Agersborg et al. 2001). Without pin-worm infection, neonatal injection of pZP3 in water did not elicit an immune response. However, when infected with the rodent pinworm Syphacia obve-lata, neonatal mice injected with self-pZP3 in water developed strong ZP3-specific Th2 responses and severe eosinophilic AOD, followed by a strong pathogenic Th2 memory when challenged with pZP3 in CFA. In contrast, pinworm-infected adults mounted a pathogenic Th1 response when immunized with pZP3 in CFA. Therefore, pinworm infection dramatically promotes a strong autoimmune Th2 pathogenic response however, the effect only impacts neonatal mice.

Immunotherapy Approaches

Cancer immunotherapy is part of a growing research trend in attempting to harness the cytolytic function of immune cells against cancer. Difficulties in tumor immunotherapy arise due to the evasiveness of the cancer. Tumors are able to hide from NK cell immune surveillance by downregulating or shedding ligands of activating NK receptors. In addition, activating NK receptors succumb to the control of tumor cells and their released factors. Therefore, multiple studies have focused on the biological processes of tumor evasion to create therapies to counteract the tumor's progression.

Acquired Immune Deficiency Syndrome

Primary non-Hodgkin lymphoma (NHL) of the brain has occurred consistently as an acquired immune deficiency syndrome (AIDS)-defining illness in around 0.5 of AIDS patients 39 . A population-based study in Italy during the period 1985-1994 found that 22 out of 40 (55 ) cases of brain NHL at age 15-49 years occurred in people with AIDS, giving a standardized incidence ratio of over 2,000 40 . In an analysis of cancer incidence among nearly 48,000 human immunodeficiency virus (HIV)-seropositive people from North America, Europe, and Australia, the adjusted annual incidence of cerebral NHL fell significantly from 1.7 per 1,000 during the period 1992-1996, to 0.7 per 1,000 during the years 1997-1999, indicating a

Nonspecific Immunotherapy Interferon

IFN-a has been a standard therapy for CP CML for nearly two decades. The introduction of imatinib has replaced its role as first line agent, but IFN-a could play a key role in modulating a nonspecific immune-mediated effect toward MRD persisting during imatinib therapy. Several immunologic effects of IFN-a have been documented, including increased expression of adhesion molecules, and enhanced antigen presentation and generation of highly active monocyte-derived DCs (45). Nevertheless, it is still unclear as to which effect is precisely responsible for its antileukemic activity. Recently, the presence of PR3-specific CTLs has been documented in IFN-a-treated patients, but not in imatinib-treated patients. This suggests that IFN-a may enhance the induction of natural anti-PR3 CTLs, thus modulating a direct immune-mediated antitumor effect against CML cells (27). Indirect evidence of an underlying immune control of leukemic cells mediated by IFN-a is the fact that some patients maintain...

Symeonidis A And Immune Function Parameters

Costimulation of lymphocyites the role of CD28, CTLA-4, and B7 BB1 in interleukin-2 production and immunotherapy. Cell 1992 71 1065-1068. 55. Apostolopoulos A, Symeonidis A, Zoumbos N. Prognostic significance of immune function parameters in patients with chronic lymphocytic leukaemia. Eur J Haematol 1990 44 39-44.

The Influence Of Cigarette Smoke On The Effectors Of The Immune System

Cigarette smoke has been, and is, a major risk factor for lung carcinoma, cardiovascular disease and chronic obstructive lung disease (reviewed in ref. 9 . Although, the entire spectrum of effects of cigarette smoking on the immune system are not fully realized, The immune responses triggered following immunization with TGP in animals consists also of a predominant IgE response in mice 29 , neonatal rabbits 30 and guinea pigs 31 , An IgE mediated wheal and flare response has also been demonstrated in human volunteers injected intradermally with TGP, suggesting effects of smoking on the humoral immune system.

Abnormal immune response due to activation of antigen presenting cells

The recognition of peptides MHC complexes at the cell surface of an antigen presenting cell by a specific T lymphocyte is not sufficient for triggering an immune response. Dendritic cells, that are the professional antigen presenting cells, need to be activated for initiating the immune response 1 . Signals delivered by pathogens through the toll receptors at the dendritic cell surface and signals generated in injured tissues activate dendritic cells. For example, platelets that con-stitutively express CD40L can interact with CD40 at the cell surface of dendritic cells leading to their activation in a bleeding tissue. Non immune tissue injury leads to necrotic death, release of reactive oxygen species, of heat shock proteins (HSP) and of lymphokines such as IL-1, TNFa, type I interferons, each being able to stimulate dendritic cells. Activation of dendritic cells results in upregulation of costimulatory molecules, in-tracellular formation of immunogenic MHC-class II peptide complexes...

See also Purine Degradation The Immune Response from Chapter 7 Antibody Structure from Chapter 7 Generation of Antibody

Persons with severe combined immune deficiency (SCID) are totally unable to mount an immune response to antigens. Both the B and T lymphocytes are affected. The disease arises from an inherited lack of a degradative enzyme, adenosine deaminase (ADA). The reaction shown here illustrates the pathways affected. Lack of ADA allows dATP to accumulate. High dATP levels inhibit production of the other dNTPs needed for DNA replication due to its effect on the regulation of ribonucleotide reductase. White blood cells, which must proliferate for an immune response to occur, and which have abundant salvage enzymes for making dATP, are most affected by lack of the enzyme. They are unable to proliferate, a necessary step for antibody production.

Cancer Immune Surveillance

In the early twentieth century, Ehrlich first proposed the existence of immune surveillance for eradicating nascent transformed cells before they are clinically detected (Ehrlich, 1909). Almost 50 years later, Burnet and Thomas postulated that the control of nascent transformed cells may represent the actions of an ancient immune system, which played a critical role in preventing malignant transformation (Burnet, 1957). The idea was supported by experimental results showing strong immune-mediated rejection of transplanted tumors into mice. Although there was excellent evidence in support of the belief that immune surveillance mechanisms prevent the outgrowth of tumor cells induced by horizontally transmitted, ubiquitous, potential oncogenic viruses, there was much less evidence for immune surveillance acting against chemically induced tumors in syn-geneic mice (Klein, 1976). The use of genetically identical mice, however, generated tumor-specific protection from methylcho-lantrene...

CD137CD137 Ligand in the Antiviral Immune Response and in Viral Vaccination

Immunotherapy has potential for chronic and latent viral infections. Therapeutic vaccination and adoptive T-cell transfer are the strategies that are being explored for HIV and chronic viral hepatitis. Mice lacking CD137 or CD137 ligand show defects in CD8 T cell responses against viruses (DeBenedette et al., 1999 Kwon et al., 2002 Tan et al., 1999), with no defects in antibody or CD4 T cell responses to vesicular stomatitis virus (VSV), LCMV, or influenza virus (Kwon et al., 2002 Tan et al., 1999). Studies in CD137 ligand- - mice suggest that the role of this molecule is mainly focused in the long term CTL response and in the induction and maintenance of memory in the CD8+ T cell compartment (Bukczynski et al., 2004). These features make the CD137 CD137 ligand pair a very interesting target for manipulation in antiviral immunotherapy. However, very few reports have explored this possibility.

Mechanisms by which xenobiotics may induce an immune response

As summarized in Table 1, xenobiotics may induce an immune reaction by at least four mechanisms 1) by inducing an abnormal immune response due to activation of antigen presenting cells, 2) by promoting an immune response directed against an autoantigen modified by the toxin or its metabolite, 3) by activating a limited set of autoreactive T cells and 4) by inducing global immune disregulation.

Human Humoral Immune Response to Chlamydia trachomatis Infections

Infectious, extracellular elementary bodies are endowed with adhesion molecules, which permit the invasion of host cells and are reported to elicit host immune response. With the methodological approach reported above, 55 EB's antigens have been found and all the immunoreactive spots have been reported in the silver-stained 2-D gel image of C. trachomatis serovar L2 (Fig. 13.3). It is important to note that patient blots showed individually different patterns comprising a number of antigenic spots which varied from 2 to 28. In Figure 13.3 we have represented with different colors the frequencies of antigens found in the 17 patients. The high-frequency antigens (17 17-11 17) are shown in red of these it is interesting to observe that the cysteine-rich outer membrane protein 2 (OMP2) is the only one recognized by all the patient sera used. The antigens shown in blue had a medium frequency ranging from 4 to 10 out of 17 patients and those in green are all the patient-specific antigens...

Cancer And The Immune Response

The immune system is a complex multi-cellular network, which can quickly accommodate or combat novel pathogens. This network of activating and inhibitory cells and molecules result in a tight balance between immunity and autoimmunity. It is the ability of the immune system to distinguish self from non-self that results in effective clearance of pathogens and immunologic memory. The primary challenge facing the field of tumor immunology is that, unlike infections, all tumor cells contain self-antigens that vary from normal tissue, primarily by mutation or by expression level. Many of these self-antigens are critical for biologic processes, such as DNA replication, or are expressed at some level on normal tissues. Thus, effective tumor immunity carries the risk of clinically significant autoimmunity.

Immune Response And Gestational Trophoblastic Disease

Tumors are analogous to tissue graft in that they are most likely recognized by the immune system, yet through either a tolerance or evasion mechanism, do not elicit a destructive immune response. Clinical evidence shows that individuals with suppressed immune systems are most susceptible to tumor appearance. However, animal experimentation indicates that immune surveillance is directed toward viruses rather than tumors. Because tumors do appear and grow within a host, they must somehow evade an immune response. Tumors may be characteristically poor antigen-presenting cells (APCs), contributing to their nonimmunogenicity. Immune response requires In gestational trophoblastic disease (GTD) and in choriocarcinoma in particular, the malignant trophoblast, like healthy trophoblast, continues to evade the maternal immune response. However, the methods and mechanisms of avoiding this response may differ. For example, in a study by Sunderland 31 , 40-70 of the tumor cells studied expressed...

There Is No Immune Response to Prions

Cjd Pathology

People die from infectious diseases when their immune systems have not made enough B or T cells to fight off the infection. In some cases, infectious agents carry antigens for which no amount of DNA rearrangement can yield the proper receptor. In other cases, one group of people may be able to rearrange their DNA to produce the right receptors while others do not. This partly explains why some people do not become ill when exposed to an infectious disease, while others die from the same exposure. Substance amplifies immune response Substance amplifies immune response Figure 11.15 Cell-mediated immunity. T lymphocytes divide to produce different populations of cells (1) Memory cells carry the specific antigen receptor (2) cytotoxic T cells attack and kill cells and (3) helper T cells boost the immune response. Sometimes an infectious agent is effectively combated by the immune system, only to reemerge in a form that is newly pathogenic. Pathogens are under evolutionary pressure to...

Aps Associated With Immunotherapy

Immunotherapy using interleukin-2 (IL-2), ainterferon or both, for patients with melanoma may induce increased levels of antithyroid microsomal and antithyroglobulin antibodies which may persist for months 104-106 as well as the induction of other autoantibodies 107 , Becker et al. 108 reported that immunotherapy in patients with cancer may be associated with the induction of aPL. Thirty melanoma patients were studied and 2 out of 4 treated with -interferon alone (50 ) and 3 out of 8 (37.5 ) treated with IL-2 and interferon (37.5 ) developed aPL. In this group, aPL elevations were detected on -interferon alone.

The Immune System and Cancer Prevention

Inulin and fructooligosaccharides modulate the response of the immune system to illness, through the stimulation of bifidobacteria and lactobacilli, and the improvement of the general microfloral balance in the colon (Watzl et al., 2005 Yasui et al., 1992). In this role, prebiotics have been shown to promote the production of macrophages, lymphocytes, and antibodies, in particular the local production of immunoglobulin A (IgA)-positive cells in the intestines and cecal mucosa (Bornet, 2001 Hosono et al., 2003 Kadooka et al., 1991 Roberfroid, 2005 Yasui et al., 1992). In addition, thriving bifidobacteria and lactobacilli populations help to strengthen the mucosa-blood barrier in the intestine lining. They do this by outcompeting pathogens for adhesion sites on the intestinal lining, producing short-chain fatty acids that nourish cells in the mucosal layer, lowering intestinal pH to levels unfavorable to pathogens, and releasing bacteriocins against pathogens (Anon., 2006 Wang and...

AIDS is a Disease of the Immune System

The increased susceptibility to illness in these men resulted from a decline in their immune-system function. As is discussed in detail in Chapter 11, the role of the immune system is to maintain the integrity of the body. The cells of the immune system constantly patrol the tissues and organs of the body for anything that is not clearly produced by the body that is, anything that is non-self. Upon encountering non-self entities, the immune system acts to eliminate it this is known as an immune response. A non-self substance, object, or organism typically has a unique chemical signature that causes an immune response. This signature is called an antigen. Immune-system cells called lymphocytes respond to antigens. Lymphocytes carry proteins on their cell membranes, called receptors, which recognize and are attracted to particular antigens (Figure 9.1). The binding of an antigen to an antigen receptor on a lymphocyte starts the immune response. Our bodies can make 100 trillion to 1...

Keeping Control CNS Immune Surveillance

Here, a crucial question arises if the immune response is essential for tissue repair in all tissues outside the CNS, does the CNS similarly depend on immune responses for its maintenance and repair, particularly after injury Since the pioneering work of Michal Schwarz (Molaem et al. 1999), extensive studies have confirmed and described the phenomenon that autoreactive T cells, as well as activated macrophages, are capable of promoting neuroprotection and neuroregeneration in experimental models (Schwartz and Kionis 2005). In fact this is not a very new idea, since in the animal kingdom it is well known that a high degree of immune privilege is associated with a low potential of regeneration. Therefore, it is indeed possible that the inability of the CNS to recover after injury is the price it pays for being an immune-privileged site. Perhaps this is a necessary price to pay in evolutionary terms, in which avoiding risk to healthy individuals is more important than helping injured...

Dendritic Cell Immunotherapy

The successful induction of cell-mediated antitumor immunity relies on the efficient capture of antigen by antigen-presenting cells, antigen processing, and presentation to T-lymphocytes. Antigen presenting cells (APC) such as B-cells, macrophages, and dendritic cells display antigenic peptides in the context of major histocompatibility complexes (MHC) to T-cells. Although B-cells and macrophages are capable of antigen uptake, processing, and antigen presentation, these APC are ineffective activators cf na'iive T-cells. In contrast, dendritic cells (DC) are considered the most effective, efficient, and potent APC of the immune system, because they are the only subset of APC that can present antigen to naive T-cells resulting in T-cell activation (63). Cell-mediated tumor cytotoxicity is the desired outcome of tumor immunotherapy. Modalities aimed at the induction of specific anti-tumor T-cell responses by DC are extremely promising in the fight against cancer. The following sections...

The Immune System

Our ability to coexist with the vast array of microbes present in our environment is a measure of the efficacy of various defense systems to monitor insults to the internal cellular environment from the extracellular world. Arguably the most important of these defense systems is the immune system. In essence the immune system is the instrument by which the body discriminates self from nonself, and destroys nonself. Important functional elements of the immune system include several cell types, tissues, serum proteins, and small peptides such as chemokines and cytokines. While components of the immune system interact with one another, detailed discussion is simplified by classification into two categories, innate immunity and adaptive immunity. The innate immune system is made up of cells and molecules that function early in the protective response to a foreign substance (antigen), using primitive I There is no unique antigenic specificity that triggers the elements of the innate immune...

Immune Response

The other major myth of the cryopreservation era was that these homografts were essentially immunologically privileged in part because the myofibroblasts were buried within the matrix. This mythology led to commercial processing by some companies of human homo-grafts with modifications in the technique to enhance viability, ultimately not only of fibroblasts, but also of endothelium. This enhanced viability was marketed without any evidence that this retained viability actually contributed to prolonged durability. In contrast, valves processed by the techniques of at least one not-for-profit tissue processor were intentionally exposed to solutions to remove endothelium, while the remainder of the processing steps were kinder to myofibroblasts. The decreased durability of cryopreserved allografts in younger children (especially in neonates) has been consistently attributed to an immune response-mediated accelerated valve failure. Both T cell and B cell infiltration has been...

Immune System

Immune strength often diminishes with age. Production of antibodies falls, B and T cells react weakly to antigens, and phagocytes destroy bacteria less efficiently. These changes make many older people more vulnerable to infection. However, not all older adults show these changes - some have immune systems that function as well as those of younger adults. Differences in diet and micronutrient status are critical determinants of immune competence in old age. Nutrients often lack- Immune-system support ing in older people's diets -zinc and vitamins C, E, and B6 - are vital to proper functioning of the immune system (see Fig. 4.18).18 In a recent study, 100 healthy older adults were divided into two groups one group was given a multivitamin mineral supplement, the other group received a placebo. After 1 year the supplemented group had better immune function and fewer infections than the placebo group.19 Many of the participants had micronutrient deficiencies that were corrected by the...

Immunotherapy

Immunotherapy derives from an observation in the 19th century that cancer sometimes regressed after acute bacterial infections, i.e. in response to nonspecific immunostimulant effect. But, in general, it appears that the immune response to cancer appears to be attenuated. Attempts have been made to stimulate the host's own immune system aspiring more effectively to kill cancer cells. Exploration of immunotherapy has involved Passive immunotherapy strategies with monoclonal antibodies raised against specific tumour-associated antigens. Targeted antibodies have the advantage of high cancer specificity and low host toxicity. Examples include rituximab, an anti-CD20 monoclonal antibody licensed for the treatment of low-grade, follicular lymphomas and trastuzumab (Herceptin), which specifically binds to the her2 neu (erbB2) receptor, which is overexpressed by some breast cancers. In combination with conventional cytotoxic chemotherapy, trastuzumab significantly improves the survival of...

Adaptive Immunity

The adaptive immune response, which involves T- and B-lymphocytes, is required for immunologic memory. This response is initially slower than the innate response but leads to rapid and highly specific memory responses on subsequent challenge. Antigens may be either directly presented by tumor cells, or cross-presented by

Section I Essential Immunobiological Concepts

An Introduction The Immune System 2 The Immune Innate Immune Adaptive Immune Responses Cells That Function in Innate Immune Cells That Function in Adaptive Immune Tissues of the Immune System General Tissues of the Immune System Primary Lymphoid Organs 12 Tissues of the Immune System Secondary Lymphoid Tissues 14 Soluble Mediators of the Immune 2. Innate Immune Responses to Pathogens 31 Innate Immune Responses to 7. Cells of Adaptive Primary versus Secondary Immune Adaptive Immune Responses in Role of Innate and Adaptive Immunity in Inflammation 203 Immunotherapy of Autoimmune Disease Suppression 301 Immunotherapy of Autoimmune Disorders Cytokine Modulation 306 Evasion of Immune Novel Therapies Monoclonal Antibodies and Immunotherapy 359

Essential Immunobiological Concepts In Clinical Immunology

In the Section I chapters we have developed a broad overview of the workings of the mammalian immune system and highlighted the multiple regulatory mechanisms which exist within these interacting populations of cells. By judicious use of some clinical case discussions at the end of each chapter we have attempted to guide the reader to understand the relevance, for the practicing clinician, of the basic science we have presented in each section. In contemporary internal medicine however, the clinical immunologist deals predominantly with a number of key conditions, and these are certainly worthy of highlighting unto themselves.

Opsoninmediated Recognition

Recognition of a pathogen by phagocytes. Recognition of pathogens by phagocytes may be direct, or indirect. A. Direct recognition of pathogens occurs via primitive phagocyte receptors. For indirect recognition, phagocytes use cell surface receptors that recognize molecules (opsonins) that have bound to, or have been deposited on, the pathogen cell surface. B. complement fragment C3b), C. heat shock protein, CRP, (C-reactive protein) D. IgG produced in adaptive immunity. Fig. 2.4. Opsonin-medi-ated (IgG) recognition by FcyR on the phagocyte is followed by ingestion of the pathogen. The innate and adaptive immune systems act in concert. Antibodies produced in adaptive immunity facilitate phagocytosis because phagocytes express receptors (FcyR) that bind antibodies that are bound to the pathogen, triggering ingestion of the pathogen. Phagocytosis and activated complement are effective mechanisms for eliminating bacterial infections. Viral infections, however, require a...

Cancer Immunoediting

Although strong evidence has been presented supporting the existence of a functional cancer immune surveillance process against cancer in mice and humans, cancer continues to develop in intact immune systems and is refractory to many treatment approaches. These findings might be caused by the failure of early host tumor immunity to eradicate nascent transformed cells. Even in the presence of continued immune pressure, the failure to eradicate tumor cells results in tumor progression with reduced immunogenicity. Cancer immunoediting has been proposed in terms of the dual functions of host immunity not only for eliminating tumor cells but also for shaping malignant disease during the period of equilibrium between the tumor and host. Elimination is the hallmark of the original concept in cancer immune surveillance for the successful eradication of developing tumor cells, working in concert with the intrinsic tumor suppressor mechanisms of the nonimmunogenic surveillance processes. The...

Concluding Remarks

Owing to the abundant experimental and clinical evidence, there should no longer be any doubt for the existence of cancer immu-noediting from immune surveillance to escape. Cancer cells are gradually able to gain several mechanisms of immune evasion during tumor progression even though they are pursued by the initial and continuing phases of immune surveillance. Immuno-logical sculpting contributes to immune selection pressure, which produces tumor cell variants that are resistant to immune effector cells due to their low immunogenic-ity. In advanced cancers, the marked shifting to immunosuppressive conditions due to the constitution of the immunosuppres-sive network in tumors makes it more difficult to provoke an immune activation to eliminate cancer cells. Given that adoptive immunotherapy using the peptide vaccine and DC transfer is not sufficient to reduce tumor volume and tumor elimination by direct priming for T cells in such conditions, indirect cross-priming for T cells, which...

Soluble Mediators of Immunity III Cytokines

Cytokines are produced by cells of both the acquired immune system (lymphocytes) as well as the cells of the innate system (macrophages, mast cells etc.). Other cells (e.g., fibroblasts) not considered classically to belong to the immune system, per se, can also produce such molecules. The importance of cytokines lies in their ability to influence a number of functions in different cells cell systems. In addition to contributing to the regulation of cell cell communication and differentiation in the immune system, inflammatory cytokines are themselves activators of the inflammatory cascade.

Innate Antitumor Responses

Normal cells are endowed with intricate machinery that affords protection against genotoxic stress induced by cell intrinsic and extrinsic insults, including DNA replication errors, oxidative damage, microbial infection, and inflammation. The failure of the DNA damage response to resolve single-stranded or double-stranded DNA breaks poses a significant risk for malignant transformation. In this context, the innate immune system functions as an extrinsic surveillance mechanism for genotoxic injury. NKG2D ligands, which include the major histocompatibility complex (MHC) class I-related molecules (MHC class I chain-related A MICA and MHC class I chain-related B MICB ) and four UL16 binding proteins (ULBP1-4) in humans as well as the retinoic acid-early (RAE) indu-cible gene products and H60 in rodents, are induced by DNA damage through a pathway involving ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), Chk-1, and Chk-2 (Gasser et al., 2005). The surface...

Innate Immune Cells

Y8-T cells are a small population of T lymphocytes that integrate features of innate and adaptive immunity. While these cells undergo VDJ recombination during thymic development, their TCR diversity is relatively limited compared to conventional aP-T cells, and they function more in pattern recognition (Hayday, 2000). y -T cells constitute a significant proportion of intraepi-thelial lymphocytes (IELs) in the skin and gastrointestinal and genitourinary tract mucosa. Their importance for tumor surveillance has been revealed by the increased incidence of chemically induced fibrosarco-mas and spindle cell carcinomas in y -T cell deficient mice (Girardi et al., 2003). For example, V81-T cells are a type of y -T cell that is enriched in various tumors, and they

Adaptive Antitumor Responses

Adaptive Immunity in Immunosurveillance The importance of adaptive immunity for tumor immunosurveillance was first established through studies of mice harboring targeted mutations of the recombinase-activating gene 2 (RAG-2), which is required for immunoglobulin and T cell receptor gene rearrangement (Shankaran et al., 2001). Since the assembly of B and T lymphocyte antigen receptors requires RAG-mediated double-stranded DNA breaks to initiate V(D)J immunoglobulin gene recombination, RAG-2-deficient mice lack all B lymphocytes, ap- and yS-T cells, and NKT cells. These mice manifested an increased susceptibility to chemical carcinogen-induced tumors, and the fibrosarcomas arising in these animals were frequently rejected upon transplant to wild-type animals. Subsequent studies of mice deficient in ap- or yS-T cells alone revealed a similar enhanced susceptibility to chemical carcinogens, highlighting the key roles of T lymphocytes in tumor protection. Consistent with these findings,...

Cytokine Regulation Of Immune Tolerance To Tumors

In most cases, an effective immune response against tumors is dependent on the cellular arm of the immune system, the major players of which include CD8 + cytotoxic T lymphocytes (CTLs), CD4 + Th1 cells, y8-T cells, and NK cells. The effector functions of these cells are responsible for direct target cell killing as well as production of cytokines and other modulators that regulate the function of various cell types, including tumor cells. The cellular immune response is responsible for the host defense of intracellular pathogens however, when the cellular immune response is dysregu-lated, it can also trigger autoimmune diseases (e.g., type I diabetes). As a self-tolerance mechanism, several cytokines are involved in the suppression of cellular immune responses either under steady state or during the resolution phase of infection or trauma, which impedes the development of tumor immunity. In addition, cytokines that skew immune responses to T helper 2 (Th2) cells or to the newly...

Immunological Responses to Microbes

The following chapter explores the mechanism(s) by which the immune system defends the host from pathogenic organisms. In addition to the dichotomy already discussed (Chapter 2) between the so-called innate (primitive) immune system and acquired immune defenses, the heterogeneity of mechanisms apparent in the acquired immune system is enormous. However, some order to this is readily apparent when we consider immunity to virus, bacteria (intra- or extracellular bacteria) and fungi. Generally efficient eradication of an organism occurs before the immune system is overwhelmed by further proliferation of the infectious agent. Thus, antiviral immunity depends upon recognition of a virally infected cell before production of further infectious virus. Both of the effector cells involved (NK cells and CD8+ killer cells CTL) recognize cell surface changes (different for each effector cell) which reflect invasion by virus. In contrast, phagocytes most effectively eradicate extracellular...

The Ly49 Receptor Family

Dependent on the interaction of the positively charged arginine residue of the transmembrane domain of the Ly49 receptor and the negatively charged aspartic acid residue of DAP12. Interestingly, the specific Ly49 repertoire and the amount of each Ly49 receptor directly depend on the H-2 expression of the host (Yokoyama and Plougastel, 2003). IL-12 and IL-18 treatment enables NK cells to mediate cytotoxicity and produce IFN-y despite expression of inhibitory receptors (Ortaldo and Young, 2003). These NK cells need two activating signals (activating Ly49 receptor and IL-12 IL-18) to overcome inhibition. These observations support the notion that temporary autore-activity could occur during acute inflammation from IL12 IL18 production by dendritic cells (DCs) that can induce IFN-y expression in NK cells, ultimately leading to expansion of the immune response. Another possible explanation for this phenomenon is that the main activating ligand for the Ly49 receptors is not H-2 but some...

Shuang Wei Alfred Chang And Weiping

The tumor microenvironment is a battlefield between the tumor and host immune system. The myriad of cellular interactions in the tumor microenvironment determines immune response versus tolerance to tumor cells. Recent advances in molecular and cellular tumor immunology have demonstrated that the tumor actively recruits and alters immune cell phenotypes and functions, promoting either immune suppression or tolerance of tumor-associated antigens. In this chapter, we provide a framework for understanding how the immune response is altered in favor of forming a suppressive network in the tumor microenvironment, integrating different immune cell types and molecules.

Imbalance Between Regulatory T Cells And Conventional T Cells

Regulatory T cells or Tregs are functionally defined as T cells that inhibit an immune response by influencing the activity of another cell type (Shevach, 2004). The most well-defined Treg cells are CD4+CD25+ T cells (Sakaguchi et al, 2001 Shevach, 2002 Von Herrath and Harrison, 2003). The antigen specificity, phenotype, mechanisms of action, and function of Treg cells have been discussed in the literature (Chen et al., 2005 Green et al., 2003 Peng et al., 2004 Wang et al, 2004 Wang and Wang, 2005) and are discussed in Chapter 15 of this book. The immunosuppressive cell surface molecule CTLA-4 is conceptually related to Treg cell function. The role of CTLA-4 and the effects of CTLA-4 blockade in mouse and human cells have been discussed (Chapters 10 and 12). In this chapter, the focus will be the distribution and trafficking of Treg cells in human tumors and the imbalance between Treg cells and conventional T cells in the tumor environment.

Immunodeficiency Disorders

Dysfunction in components of either innate or adaptive immunity causes immunodeficiency disorders. These disorders are classified as either primary or secondary, depending on whether the dysfunction is inherited or acquired (Fig. 15.1). Inherited, or primary disorders, may arise from defects in either cellular or humoral components of immunity, with some defects being more common than others (Fig. 15.2). In the absence of medical intervention (e.g., gene therapy), primary disorders are permanent. In contrast, acquired, or secondary disorders, may be transient or permanent depending on the factor inducing the immunosuppression. Secondary disorders are extrinsic and may result from the effect of drugs (alcohol), infection (human immunodeficiency virus (HIV)), or other miscellaneous (unknown) etiologies (e.g., insulin dependent diabetes mellitus (IDDM)), or from abnormal production of immune components. Host defense in response to a particular microbe does not necessarily result from...

Lipopolysaccharide Pneumococcal Polysaccharide

The immune response to an antigen can be enhanced in the presence of adjuvants. This is important for immunization when administering vaccines. Alum precipitate, a suspension of aluminum hydroxide mixed with antigen, is used in human vaccines to enhance immunogenicity. Alum is thought to slow the release of antigen, such that presentation of antigen to T cells is prolonged. A common adjuvant used in studies with laboratory animals is Freund's complete adjuvant (a water in oil emulsion with killed Mycobacterium tuberculae). Important functional elements of the immune system include several tissues, cell types, serum proteins, and small peptides, called cytokines. While components of the immune system interact with one another, detailed discussion is simplified by classification into two categories, innate immunity and adaptive immunity. In reality, innate and adaptive immune responses act in concert. The innate immune system is made up of cells and molecules that function very early in...

Phagocytosis Cure Cancer

Microbes penetrate the normally protective physical and chemical defenses. Having breached host barriers, they face the onslaught of both the innate and adaptive immune systems. Different components of the immune system are recruited during immune responses, depending on the organism and its mode of infectivity (Fig. 11.8). Viruses infect and replicate within cells. Intracellular bacteria also infect cells, often thriving within macrophages because they have evolved mechanisms to evade the proteolytic degradation that occurs in the phagocytic vacuole. Extracellular bacteria are not sequestered, and many have become pathogenic because they have a polysaccharide capsule that hinders phagocytosis. Extracellular bacteria thrive within the host environment, but are not sequestered within any cell. These microbes are vulnerable to soluble mediators of the immune system. Phagocytosis is the primary vehicle by which extracellular bacteria are eliminated. The process of phagocytosis is greatly...

Imbalance Between Stimulatory And Inhibitory B7 Family Molecules

In summary, epithelial tumor cells and associated myeloid DCs highly express B7-H1 and mediate T cell apoptosis or attenuate T cell activation. The significant influence of tumor environmental B7-H1 and PD-1 on the interaction between T cells, tumor cells, and APCs constitutes a novel target for tumor immunotherapy. ing their potential role in tumor pathogenesis (Bingle et al, 2002 Ohno et al, 2003 Zavadova et al, 1999). Thus, immune functional data are essential for understanding the roles and potential suppressive mechanisms of macrophages in human tumor microenvironment. In recent work, B7-H4 and TAM-mediated immune suppression have been linked in ovarian cancer.

Lymphocytes

Cells of the immune system. Cells of the innate immune system and the adaptive immune system are illustrated. Note that there are several types of cells in the various categories. which they reside (Table 1.2). In addition to its role in phagocytosis, the macroph-1 age serves as a link between innate and adaptive immunity by delivering antigen to distinct lymphocytes, a process termed antigen presentation (see below). Antigen presenting cells (APC) are cells that endocytose antigen, process it into fragments (peptides), and then display various fragments on the cell surface. For effective presentation antigen fragments must be expressed on the APC surface, cradled within the groove of special molecules termed, class II major histocompatibility proteins (class II MHC). These cell surface complexes of peptide class II MHC represent the form of antigen that is recognized by a subset of lymphocytes, T lymphocytes. Antigen presenting cells include dendritic cells, macrophages,...

Overview

Limited scientific collaborations have been conducted historically between immu-nologists, geneticists, and cell biologists who study cancer. This situation is beginning to change with an emerging consensus among all cancer researchers that inflammation and immune escape play key causal roles in the development and progression of malignancies. This finding is particularly true for adult solid tumors, the causes of which are complex and multifac-toral, posing a major clinical challenge. This book aims at cross-fertilizing ideas and concepts among investigators who are striving to develop combinatorial immunologi-cal or pharmacological agents as cancer therapeutics. The specific goals are (1) to highlight emerging principles of immune suppression in cancer patients and (2) to discuss how to combine immunotherapeu-tic and chemotherapeutic agents to defeat mechanisms of immune or inflammatory suppression and improve cancer treatment. Many immune-based therapies have focused on activating...

Hladp Hladq Hladr

Polymorphism is the distinguishing characteristic of class I and class II MHC molecules. Genes encoding each MHC locus are present in multiple forms (alleles) within the population. From an evolutionary perspective, this is advantageous for population survival because antigen fragments must associate with MHC molecules to be delivered to T cells, cells that are absolutely required for adaptive immunity. The likelihood that one of the MHC alleles present in individuals within a population will bind to, and present, an antigen fragment of any particular microorganism to T cells, is increased by the existence of numerous alleles. In the absence of such polymorphism one could envisage the evolution of a lethal organism that failed to associate with (a restricted set of) MHC determinants and was thus unable to induce T-cell immunity, with disastrous consequences for the species. This importance of MHC presentation and adaptive T-cell immunity is exemplified by consideration of immunity to...

Introduction

Since Ehrlich first proposed the idea in 1909 that nascent transformed cells arise continuously in human bodies and that the immune system scans for and eradicates these transformed cells before they are manifested clinically, immune surveillance has been a controversial topic in tumor immunology (Ehrlich, 1909). In the mid-twentieth century, experimental evidence that tumors could be repressed by the immune system came from the use of tumor transplantation models. The findings from these models strongly suggested the existence of tumor-associated antigens (TAAs) that formed the basis of immune surveillance, as postulated by Burnet and Thomas (Burnet, 1957). The functional role of antigen-presenting cells (APCs) in cross-priming for T cell activation was subsequently demonstrated, and the cancer immune surveillance model was developed. However, the idea of cancer immune surveillance resisted widespread acceptance until the 1990s when experimental animal models using knockout mice...

Complement

The complement system is a family of numerous ( 30) activation and regulatory proteins found either bound to the cell membrane or in circulation (Fig. 5.1). Complement proteins are synthesized mainly by the liver. However, some of these proteins are also synthesized by macrophages and fibroblasts. Many circulating complement proteins are proenzymes whose activation requires their proteolytic hydrolysis. These proteolytic fragments can function as effector molecules for the immune system (Fig. 5.2). These effector molecules (i) facilitate the interaction of phagocytes to induce opsonin-mediated phagocytosis (ii) induce osmotic lysis of microbes (iii) enhance vascular permeability by inducing degranulation of mast cells basophils (iv) induce chemotaxis of neutrophils and (v) facilitate immune complex elimination.

Conclusion

Investigations of endogenous antitumor responses have unveiled a previously unappreciated complexity of interaction among tumor cells, stroma, and immune elements. Innate immune activation by stress-inducible signals on tumor cells triggers a response aimed at controlling disease development effective responses may transition to adaptive immunity that manifests further specificity and memory. However, persistent immune activation may also result in an interplay of innate and adaptive elements that supports tumor cell proliferation, survival, invasion, angiogenesis, and metastasis. A central player that has emerged in coordinating these tumor-promoting inflammatory responses is the NF-kB transcription factor (Karin, 2006). A more detailed understanding of the mechanisms regulating the development of tumor-protective or tumor-promoting host responses is critical to the crafting of immunotherapeutic strategies. Chan, C. W., Crafton, E., Fan, H. N., Flook, J., Yoshimura, K., Skarica, M.,...

Immunization

Immunization represents a deliberate attempt to protect an individual from disease. In passive immunization, the patient receives antibodies generated in another individual (or animal). In active immunization the patient receives the antigen which stimulates the generation of an immune response, (antibody or cell mediated), by the patient. Passive and or active immunization can be administered simultaneously or independently.

Mica Micb

Mica Micb Gene

Lesions, resulting in cells that display NKG2D ligands that tag themselves for NK recognition. Genotoxic stress, microbial infection, and cell transformation all constitute types of cellular alterations in which induction of NKG2D ligands acts as an indicator of cell stress. Therefore, elevating the expression of NKG2D ligands is a common natural means to alert the immune system to the presence of disease. It is also important to note that NKG2D can trigger NK cytotoxicity despite MHC class I expression on the target cell, suggesting that this receptor, when activated, can override the protective signal of self MHC class I as long as the danger signal provided by the NKG2D ligand is available (Diefenbach et al, 2001). In the mouse system, NKG2D is able to bind three subfamilies of RAET1 genes, Rael, histocompatibility 60 (H60), and mouse UL-16 binding protein 1 (Multl) (Dienfenbach et al, 2001). Although these genes are structurally related and localized on chromosome 10, they share...

Autoimmunity

Immunotherapy of Autoimmune Disease Immunotherapy of Autoimmune Disorders Cytokine Modulation 306 The autoimmune disorders are readily understood from discussions on the development and induction of antigen specific immunity (both B- and T-cell immunity). As noted in earlier chapters, the developing immune system produces populations of cells with an infinite array of recognition receptors, which do not recognize self components as foreign. Where such cells do develop, a back-up system must be in place to suppress their function. This avoids any functional consequences from AUTOimmune reactivity. A failure at these stages results in disease.

Parts Of The Book

Part I of the book introduces principles of cancer immunobiology. In Chapter 2, the central concept of immunoediting is introduced. This fundamental process has three parts, termed immunosurveillance, immune equilibrium, and immune escape, which lead to control, stasis, or outgrowth of a malignancy. Immunoediting starts with the immune recognition and destruction of cells that have acquired genetic and epigenetic alterations characteristic of tumor cells, but at the same time, the selective pressure produced by immunoediting drives tumor evolution and progression. In this process, the cell-intrinsic traits of cancer (immortalization, growth deregulation, apoptotic resistance, and tumor suppressor inactivation) lead to the development of subclinical or occult lesions that are not clinically important until cell-extrinsic traits (invasion, angiogenesis, metastasis, and immune escape) have been achieved. The complex roles for inflammatory cells and altered immunity in the development of...

Clinical Concept

Antigen Presenting Cells Concept Map

Immune System Innate Immune System Adaptive Immune System In addition to the induction of cellular aspects of innate immunity, a system of serum proteins, the complement system, is intimately involved in this form of immunity. Following the deposition of a spontaneously generated fragment of a serum complement protein onto a microbial membrane, particularly bacterial cell membranes, the complement system is activated. Triggering complement activation signals a cascade of activation of complement component proteins, leading to the generation of various protein fragments with distinct biological activities that contribute to host defense. In addition, cytokines released during induction of cellular immunity, in conjunction with antigen presentation by antigen presenting cells, recruit the adaptive immune system, which enhances host defense. The innate immune system, therefore, is characterized by responses that lack memory and specificity, but display constancy with respect to magnitude...

Tumor Immunology

Evasion of Immune 349 Novel Therapies Monoclonal Antibodies and Immunotherapy 359 In this chapter we encounter a dynamic clinical field, that of tumor immunology. Few aspects of clinical immunology are as interesting, though to date the field has yet to realize its expectations. A major stumbling block seems to have been negotiated however, and we are now in a position to characterize molecules on tumors that are used by the immune system to distinguish tumor cells from normal cells. The student will become familiar with terms such as oncofetal antigens, tumor specific antigens and tumor associated antigens. All of the mechanisms studied to date are implicated in immunity to tumors. However, the growth of a tumor in a host indicates that immunity has failed. Thus active immunotherapy regimes must somehow circumvent this failure. A number of approaches aimed at improving tumor immunogenicity are under investigation. These mechanisms include alterations in (i) antigen presentation, (ii)...

Transplantation

Transplantation refers to the engraftment of cells or tissues from one individual (donor) to another (recipient host). Transfusion is a specific case of transplantation, using blood. Because a graft is foreign, the host's immune system will attempt to eliminate this intruder, a phenomenon termed graft rejection (Fig. 17.1). For vascularized and nonvascularized (e.g., skin) grafts genetic differences at the major histocompatibility complex (MHC), are mostly responsible for graft rejection processes. Minor histocompatibility proteins with allelic forms can also induce graft rejection, with varying degrees of immunological vigor. Current technology does not permit rapid determination of minor histocompat-ibility differences between donor and recipient, and the clinician is most concerned with the degree of MHC disparity involved.

Increased Genetic Instability

Increase vascular permeability and stimulate the migration and proliferation of endothelial cells, although at a significantly higher concentration than VEGF. VEGF-C is expressed during embryonal development where lymphatics sprout from venous vessels (66). It is also present in adult tissues and may play a role in lymphatic endothelial differentiation. Flt-4, the receptor for VEGF-C, is expressed in angioblasts, veins, and lymphatics during embryogenesis, but it is mostly restricted to the lymphatic endothelium in adult tissues. Because of these expression patterns, VEGF-C and Flt-4 may be involved in lymphangiogen-esis. This is the process of lymphatic generation. Lymphatic vasculature is very important because of its involvement in lymphatic drainage, immune function, inflammation, and tumor metastasis.

Robert M Smith BS and George Y Wu MD PhD

Despite fundamental differences in genome structure, hepatitis B (HBV) and C (HCV) viruses use many of the same strategies to achieve high-level replication and persistence of infection in hepatocytes. The limited genome size of these viruses necessitates an efficient use of host-cell machinery to carry out viral gene expression. This strong dependence on virus-host interactions restricts HBV- and HCV-cell tropism to the hepatocytes of higher primates and precludes their reliable and reproducible propagation in cell culture. Recent studies have begun to overcome this experimental limitation, so as to permit a more complete understanding of the molecular basis for viral replication, and the concomitant induction or evasion of the host antiviral immune response. Some of the important molecular biological properties of these viruses, as well as how they are reflected in the clinical manifestations of viral infection, are presented below. HBV commonly achieves infection in virtually 100...

Transforming Growth Factor3

Normally inhibits growth of human colonic cells, but in the process of becoming tumorigenic, these cells obtain a decreased response to the growth inhibitory actions of TGF-j3. TGF- 31 also serves as an inhibitor of immune surveillance (94). TGF- 31 indirectly suppresses the function of the immune system by inhibiting the production of TNF-a and by inhibiting the expression of class II major histocompatibility complex (MHC) molecules.

Gene Therapy Approaches

This approach employs the patient's physiological immune response cascade to amplify therapeutic effects (136). Most patients with cancer lack an effective immune response to their tumors. This could be caused by defects in antigen presentation, stimulation, or differentiation of activated T cells into functional effector cells. Antitumor immunity response requires participation of different immune cells, including helper effector T-cells (Th), cytotoxic T-lym-phocytes (CTLs) ,and natural killer (NK) cells. Activation of CD4+ and CD8+ T-cells requires at least two major signals. The first signal is triggered by binding of complexes of T-cell receptor (TCR) and specific antigenic peptide with MHC-class II or I molecules, respectively. The second signal for CD4+ T-cells is provided by engagement of CD28 on the T-cell surface by members of the B7 family of costimulatory molecules on the surface of professional antigen-presenting cells. The nature of second signal...

Total Serum Plasma Proteins and Plasma Albumin as Biochemical Markers of Disease

Plasma proteins have functions in many organ and tissue systems. They are carrier molecules, receptor chemicals, immune response agents, and enzymes or catalytic proteins. Total plasma protein is a measure of nutrition, the status of many organs and tissues that are involved in protein metabolism, and the process of breakdown and excretion of protein metabolites. The measurement of plasma protein fractions provides more specific evidence for diagnosis and assessment of disorders. Because of its importance in maintaining osmotic pressure, the measure of albumin concentration is a reflection of this pressure. As a transport protein, the measurement of albumin monitors the ability of the body to transport such diverse substances as bilirubin, fatty acids, and calcium through the blood. Measurement of the transport proteins of a specific substance provides information about the metabolism of that substance. For example, the measurement of transferrin is helps the physician understand the...

Biology and Biochemistry of Coronaviridae

The first murine coronavirus strain (mouse hepatitis virus, MHV), was isolated in 1949 12 . MHV is a pathogen ofwild mice, and natural infection is due to horizontal transmission, resulting in acute hepatitis with death in young animals and a variable course of persistent gastrointestinal tract infection in adults 79 . MHV is not an endemic mouse virus, but infects mouse colonies sporadically. It is very closely related to some human coronaviruses both at the genomic and protein levels. For example, human sera often contain antibody reactive to MHV. Therefore, characterizing the immune response to murine coronaviruses may provide important insight to mechanisms of control and elimination which may have important implications with regards to understanding the immune response to human coronaviruses such as the SARS coronavirus.

Bioinformatics in the Postgenome

The large amounts of data create a critical need for theoretical, algorithmic, and software advances in storing, retrieving, networking, processing, analyzing, navigating, and visualizing biological information. In turn, biological systems have inspired computer science advances with new concepts, including genetic algorithms, artificial neural networks, computer viruses and synthetic immune systems, DNA computing, artificial life, and hybrid VLSI-DNA gene chips. This cross-fertilization has enriched both fields and will continue to do so in the coming decades. In fact, all the boundaries between carbon-based and silicon-based information processing systems, whether conceptual or material, have begun to shrink 29 .

Immunity to MHV Infection

The protective immune response to MHV infection is characterized predominantly by cell-mediated immunity during acute infection. A number of unique aspects of CNS viral infection have been described by analysis of the interactions between MHV and the immune response. Antibody, although protective if administered prior to infection, is not present in the serum of infected mice until after the vast majority of virus has been cleared from the CNS 56, 84 . Following infection, neutrophils, macrophages, and NK cells are rapidly recruited into the CNS, followed by T cells and B cells 104 . Inflammation is accompanied by a progressive loss of blood-brain barrier (BBB) integrity that is apparent as early as 4 days post-infection. The initial influx of innate effectors is important in facilitating T cell infiltration, as well as regulating viral replication 104 . However, the ability to survive MHV infection appears to be predominantly due to an effective T cell-mediated response 103 . Recent...

Scientific Foundations

Anti-rejection drugs work by blocking the immune response from attacking the new organ. Some anti-rejection drugs limit the number of T-lymphocyte cells, so there are fewer of them to attack the organ. Others slow the production of substances in the body that are used to make T-lymphocyte cells. Steroid drugs such as predni-sone reduce the swelling that occurs with an immune response. Prednisone This drug is a steroid. The body naturally makes steroids. Steroids reduce the swelling that occurs with an immune response. This drug is often used with cyclosporine. Mycophenolate mofetil (brand name CellCept) This drug also holds back the immune system so that it does not reject the new organ. Its side effects include loose stools (diarrhea), lower numbers of white blood cells, blood infection, and other kinds of infections.

Biochemical Parameters of Nutrition in the Elderly

And metabolism should be studied more closely. Vitamins that act as antioxidants appear to have a role in preventing coronary artery disease and cancer 53 . Current work is focusing on the actions of vitamins as related to immune function, the formation of cataracts, and the development of osteoporosis, all associated with ageing 53 . The Food and Nutrition Board, the Institute of Medicine, and the National Academy of Science and Health of Canada have recently developed a standard set of nutrient recommendations, known as dietary reference intakes (DRIs), which has added, with regard to vitamin intakes, the groups for ages 51-70 years and for 70 years and older 54 . These recommendations are listed in Table 3 54 .

Identifying Gene Families

To identify gene families that are significantly larger in one species than another, Tribe-mcl can be used to build gene families using the entire protein sets from the two species. A x2 test can then be used to identify families that have a significantly greater copy number in one species than in the other. Applying this approach to multiple nematode genomes will allow us to identify families that have contracted or expanded within each lineage. For example, in the genomes of parasitic nematodes such as Brugia malayi (30) one might expect gene families necessary for a free-living lifestyle to have contracted and families related to evasion of the host immune system to have expanded.

Chemokines and Chemokine Receptors

Are exceptions to this rule in that CXC chemokines that lack the glutamic acid-leucine-arginine (ELR) motif on the amino terminus are chemotac-tic for T cells. For example, the non-ELR chemokine CXCL10 is a potent chemoattractant for activated T cells and NK cells and functions by binding to CXCR3 expressed on the surface of these cells 40, 83, 102, 106 . However, CXCL10 does not exert a chemotactic effect on neutrophils 19 . The CC chemokines are thought to attract T cells, monocytes, and macrophages, but not neutrophils 14, 60, 94 . The CC chemokine ligand 5 (CCL5) is able to attract both T cells and macrophages by binding to one of several CC chemokine receptors including CCR1 and CCR5 14, 60, 94 . Furthermore, there is increasing evidence that chemokines, such as CCL3, influence other immune system activities including TH1 TH2 development and T cell proliferation 46, 95 . Chemokines function by binding to seven-transmembrane-spanning G protein-coupled receptors. The chemokine...

Introductionadhesion And Metastasis

Cell adhesion plays a vital role in normal cell function, including embryonic development, immune function and wound healing as well as in pathological processes such as inflammation, thrombosis and tumour metastasis (1-4). Metastasis is the principal reason for death from cancer. This phenomenon is defined as the transfer of malignant tumour cells from the primary site of growth to another organ or part of the organ not directly connected with it. Since as many as 50 of patients who present with solid cancers already have metastases (5) it is hoped that an understanding of the mechanisms involved in the biology of the process may enable us to develop novel strategies for treatment.

Tr Appear to Have a Diverse TCR Repertoire That Is Different from the CD25 TCR Repertoire

This diversity may explain the apparent ability of the naturally arising regulatory T cell population to participate in regulation of immune responses to pathogens such as Leishmania. Although TR were shown to inhibit a sterilizing immune response in the Leishmania infection model, thereby allowing for the maintenance of functional memory T cells, these and other analogous results provide insufficient support for the idea that the naturally arising Tr population evolved to control infectious immunity. From a general perspective, the potential benefits of preserving a chronic low level infection to maintain functional memory T cells over a sterilizing immune response to pathogens are not immediately obvious. Furthermore, it is possible that TR involvement in responses to pathogens may be happenstance due to the diversity of the regulatory T cell receptor repertoire and the shared features of inflammation associated with both chronic infection and autoimmunity.

Vocabulary and Notation

Terms such as bioinformatics, computational biology, computational molecular biology, and biomolecular informatics are used to denote the field of interest of this book. We have chosen to be flexible and use all those terms essentially in an interchangeable way, although one should not forget that the first two terms are extremely broad and could encompass entire areas not directly related to this book, such as the application of computers to model the immune system, or the brain. More recently, the term computational molecular biology has also been used in a completely different sense, similar to DNA computing, to describe attempts to build computing devices out of biomolecules rather than silicon. The adjective artificial is also implied whenever we use the term neural network throughout the book. We deal with artificial neural networks from an algorithmic-pattern-recognition point of view only.

Causes Of Cancers In

Since SLE is associated with abnormal growth of cells of the immune system, several researches have studies the expression of various oncogenes in patients with SLE. SLE is associated with hyperactivation of B and T cells, secretion of large amount of autoantibodies and activation of cytokines network 1, 79 . All of those abnormalities in the immune system may be associated with tissue damage and malignant transformation.

Allogeneic Transplantation

Even if a suitable donor is identified, allogeneic transplant is not a panacea for treating relapsed ALL. Limitations of transplant in patients with ALL are highlighted by reviewing patterns of failure. Patients with ALL who undergo allogeneic transplantation suffer from both treatment-related mortality as well as a significant rate of relapse. This differs from patients with acute myeloid leukemia (AML), who fail allogeneic transplantation primarily because of treatment-related mortality. This appears to be due to the graft-versus-leukemia effect in which the transplanted (donor) immune system eliminates residual leukemic cells being less effective in ALL than in AML or chronic myeloid leukemia (CML). Supporting this concept is data from the International Bone Marrow Transplant Registry, which compared identical twin (syngeneic) transplants to HLA-identical sibling (allogeneic) transplants.30 As with graft-versus-host disease, the graft-versus-leukemia is more pronounced in the...

The Physiological Function Of The Translocation Partners

The function of Abl has been studied extensively, and a very complex picture has emerged (for reviews, see Refs. 62 and 63). There is evidence for an inhibitory role of Abl in cell cycle regulation, which led to the notion that it may be considered a tumor suppressor.64 A number of studies have implicated Abl tyrosine kinase in the regulation of the cellular response to DNA damage, by interaction with several proteins involved in DNA repair or response to genotoxic stress.65-70 Yet other data suggest a role in the signal transduction from and to integrin receptors on the cell surface,7172 and there is evidence for activation of Abl kinase upon ligand binding to the platelet-derived growth factor receptor.73 Mice with homologous disruption of the ABL locus suffer from high perinatal mortality and have multiple defects, including defective immune function and skeletal abnormalities, and suffer from a poorly characterized wasting syndrome.7475 However, there is no indication that the...

Stem Cell Transplatation

The expected results with this procedure can be exemplified by a recent series from Seattle.12 This study used targeted busulfan plus cyclophosphamide as the conditioning regimen for 131 patients in early chronic phase with a median age of 43 years (range, 14-66 years). At 3 years, the projected nonrelapse mortality rate was 14 , and 78 were projected to be alive and free of disease. Among survivors, 60 had extensive chronic graft-versus-host disease (GVHD) 1 year after transplantation, but only 10 had a Karnofsky score less than 80 . Interestingly, 11 of patients had minimal residual disease documented by PCR, but had not relapsed at the time of the report, suggesting that a mechanism such as immune surveillance could prevent relapse of the disease.12 This phenomenon would be similar to the functional cure described with IFN-a. Occasionally, patients may relapse many years after SCT. Few series have analyzed the very long-term results of SCT, and thus the magnitude of this problem is...

Hiv Coinfection Accelerates Natural History Of Hcv Disease

Greater than half of immunocompetent, HCV-infected patients develop chronic hepatitis, and about 20 develop cirrhosis after 10-20 yr of infection. Approximately 15 ofpatients with HCV-related cirrhosis will develop hepatocellular carcinoma. Immunosuppression caused by HIV significantly alters the natural history of HCV infection. Hepatic damage resulting from HCV infection is believed to be predominantly caused by direct viral cytotoxicity, with contributions from the host immune response. Cell-mediated immunity, T-helper 1 (TH1) clones that recognize multiple core epitopes of HCV, are important in immune clearance of HCV, through elimination of virally infected hepatocytes (8-10). The decline in CD4 cells associated with progressive HIV infection appears to permit greater HCV replication, with more hepatic spread of HCV, and therefore vast hepatocyte injury. Co-infection with HIV also probably

Right Ventricular Outflow Reconstructions with Cryopreserved Allografts

Series of 405 homografts inserted between 1971 and 1993 for pulmonary outflow reconstruction.49 While their longest surviving homograft conduit lasted 23 years, their series documented an overall homograft durability of over 80 at 5 years, falling to 50 at 10 years and 30 at 15 years. Best results were obtained with the first conduit and decreasing durability achieved with subsequent reoperative conduits in the same patient, suggesting perhaps immune factors might intensify in subsequent reopera-tions. They also found that older patients did less well than younger patients in terms of conduit durability in contradistinction to the findings by others as exemplified by the report of Clarke and Bishop.50 Interestingly, they also noted that conduits implanted earlier in their series seemed to have longer durability, suggesting that prolonged wet storage (fresh) might produce a homograft with better durability that cryopreserved. However, multifacto-rial analysis seemed to indicate that...

Monoclonal Antibodies

The pioneering work of Milstein (31) initiated the development of monoclonal antibodies as a therapeutic entity. Normal immune responses of B lymphocytes are polyclonal in nature and yield a heterogeneous mixture of antibodies. In order to produce monoclonal antibodies, murine antibody-producing cells were immortalized by fusion with plasma cell tumors incapable of producing immunoglobulin but capable of supporting antibody synthesis and secretion. Subsequent cloning of the hybridomas yielded clones that are capable of producing large amounts of homogeneous murine antibody that react with a single epitope. However, the use of murine antibodies in humans is restricted because of the immunogenic nature of the immunoglobulins. Repeated use of murine antibodies elicits an anti-immunoglobulin response known as the human antimouse antibody (HAMA) response. In addition, other limitations to the use of antibodies have been observed and have been overcome in part through the use of genetic...

Mapping the Systemic Lupus Erythematosus Susceptibility Genes

Systemic lupus erythematosus (SLE) is a complex disease in which immune responses are directed against a multitude of self-antigens. SLE in humans manifests with a diverse array of clinical symptoms that potentially involve multiple organ systems. At least a portion of the pathophysiology is attributed to deposition of immune complexes, which are continuously formed by autoantigens and autoantibodies, in various tissues. Thus, pathogenesis is related to dysregulation of self-reactive B cells. In addition, immune dysfunction of the T lymphocytes involved in the adaptive immune system and elements of the innate immune system, such as complement protein deficiencies, are also involved in disease expression. Association studies are used to localize genetic effects and identify differences in the distribution of allele frequencies according to the phenotypic status within a population. To date, there have been numerous candidate genes studied with SLE. Efforts have focused on genes...

Role Of Allogeneic Transplantation

Despite the current controversy surrounding the most appropriate time to proceed with allogeneic stem cell transplantation in CML, the experience with this modality has proven valuable as proof of concept regarding the clinical efficacy of immunotherapy. The model of the graft-versus-leukemia (GvL) effect has been further refined and, in turn, has given rise to immunology-based therapeutic strategies, such as donor leukocyte infusions (DLI) and reduced intensity, nonmyeloblative transplantation (mini-transplants). Such approaches have been pioneered in CML and applied, with varying degrees of success, in other forms of human leukemia.

Viral Replication In Hbv And Hcv Coinfection

Mutual suppression of viral replication occurs in hepatitis B and HCV co-infection, with HCV exerting a negative effect on HBV replication. Likewise, HBV exerts a negative effect on HCV replication. Studies investigating the relationship of viral replication markers in co-infected patients have demonstrated that HBV DNA and hepatitis B surface antigen (HBsAg) titers are lower in those individuals with concurrent HCV infection, compared to those with HBV infection alone, implying an interference of HCV on HBV replication. Lower HCV RNA titers have also been noted in patients with concurrent HBV infection, compared to those with HCV infection alone, implying HBV interference with HCV replication (8,53). This phenomena of viral interference involves a complex interplay between the host's immune system and virus-specific replication properties, but the exact mechanism remains unknown.

Ighv And Bcl6 Mutational Analysis In

SHM of the IGHV gene segments is an essential component in the generation of high affinity antibodies during the immune response. This process introduces targeted mutations primarily into the complementarity determining regions (CDRs) of productively rearranged IGHV segments at extremely high rates. IGHV mutational analysis should reflect the history of a B cell mutations indicate encounter with antigen in the germinal center, while unmutated IGHV sequences indicate antigen na ve B cells. SHM is potentially a dangerous, mutagenic process, and errors in SHM have been implicated in the pathogenesis of B-cell lymphomas through the generation of IG chromosomal translocations. SHM may also act on other non-IG genes in both normal and malignant B cells.

Selection of Suppressor T Cells in the Thymus

These mice exhibited almost complete intrathymic deletion of TCR-HA CD4 T cells however, a distinct population of clonotype-positive CD4 T cells in the periphery were observed. Upon isolation and stimulation, these CD4 T cells turned out to be anergic in vitro 5 . In follow-up studies using a gene transfer system where HA-antigen was expressed in skeletal muscle using adenoviral vectors, it was shown that concomitant adoptive transfer of TCR-HA CD4 T cells from TCR-HA x IgK-HA mice could prevent the immune response that normally accompanies adenoviral gene delivery 6 . Thus, these in vitro anergic T cells possess suppressive properties in vivo. When the expression of CD25 was assessed on the anergic cells from TCR-HA x IgK-HA mice, it was found that only a minor fraction was positive for this marker.

Factors That Shape the Repertoire of CD25 Suppressor T Cells in the Periphery

For several reasons, it is unlikely that the composition of the suppressor T cell pool as it exists in a normal immune system is a linear projection of the intrathymically generated pool. First, extrathymic conversion of conventional, na ve CD4 T cells into suppressor T cells may modulate the composition of the peripheral suppressor T cell pool. Although this has at present only been demonstrated in certain experimental systems (see preceding section), it appears reasonable to assume that the normal immune system in the steady state exploits similar pathways. Furthermore, there is accumulating evidence that the repertoire of suppressor T cells undergoes dynamic changes that are dictated by competition for survival factors such as access to cognate antigen or niches in the immune system. Among polyconal (non-TCR-transgenic) model systems, the most straightforward evidence in favor of interplay between an intra- and extrathymic encounter of self-antigen in the shaping of the repertoire...

Protein Function and Gene Ontologies

There are many ways to construct ontologies, including some with focus on molecular complexes or the immune system see for example the RiboWeb ontology 123 or the ImMunoGenetics ontology 213 . Another prominent example is the EcoCyc ontology 307, 308 , which is the ontology used in a database describing the genome and the biochemical machinery of E. coli. The database describes pathways, reactions, and enzymes of a variety of organisms, with a microbial focus. EcoCyc describes for example each metabolic enzyme of E. coli, including its cofactors, activators, inhibitors, and subunit structure. When known, the genes encoding the subunits of an enzyme are also listed, as well as the map position of a gene on the E. coli chromosome.

Alternating Dominance of HBV and HCV

Some authors (18,19) believe that, in co-infected patients, HCV plays the lead role in the maintenance and progression of liver damage, with elimination or suppression of HBV replication. A biphasic pattern of ALT activity was observed in patients with dual infection (20,21), which may represent the sequential alternating expression of HBV and HCV. HCV was thought to be responsible for the second peak of the serum ALT, because it occurred when HBV DNA was undetectable by polymerase chain reaction (PCR), and anti-HBs was detected. Immunoglobulin A anti-HBc is associated with active immune response against HBV-infected hepatocytes, and, therefore, indicates HBV-induced liver injury. In patients with positive HCV RNA, immunoglobulin A anti-HBc levels were found to be low, and equivalent to levels seen in asymptomatic HBV carriers, which implies that, in the presence of active HCV replication and low immunoglobulin A anti-HBc, the on-going liver damage is probably caused by HCV, and not...