Immune System Boosters

How To Bolster Your Immune System

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The author presents a well detailed summery of the major headings. As a professional in this field, I must say that the points shared in this book are precise.

As a whole, this manual contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

Hsps Are Unique Targets Of Autoimmune Responses

Autoimmunity, generally considered unfavorable for the host, at its root means recognition of self and hence has to be viewed in an unbiased form (3,6,38). The outcome of self-recognition depends on the context Elimination of aberrant cells via recognition of self-epitopes indicating an abnormally altered state may be to the benefit of the host. When such an autoimmune reaction, however, becomes chronic or exacerbated owing to permanent stimulation by the ongoing inflammation, autoimmune disease may arise. The y 8 T cells have been proposed to play a unique role in recognizing certain antigens indicative for stress such as hsps (20-24,39). Hsp epitopes which are expressed after stress (e.g., after viral infection) become detectable for the specific immune system and thus can serve as an indicator for abnormality. The structures visible to the immune system are MHC peptide complexes and perhaps also hsps on the cell surface (6). Either kind of recognition would promote immune...

The Small Immune System Of The Newborn

A newborn mouse has only 1 of the immune system of an adult animal1. In man the information is less complete, but Brandtzaeg has shown how strikingly especially the IgA-producing B cells increase in number in the intestinal mucosa during the first several weeks - months of life2. The newborn can be compared with a gem-free, but not antigen-free, animal where one can see a 10-fold increase in the number of lymphocytes in the gut mucosa after colonization even with one single bacterial strain3,4These observations give a relatively good picture of the size of the whole immune system since about 2 3 ofthat is found in the intestinal mucosa5. Not only has the newborn an immune system oflimited size, but it is also somewhat functionally deficient at birth. Switching through the immunoglobulin isotype genes is inefficient and early antibody responses are mainly composed of IgM antibodies . Immunologic memory is reported to be sparse and several cytokines are only produced in small amounts...

Intestinal Colonization Of The Newborn And The Immune System

The strongest stimulus expanding the immune system seems to be the colonization ofthe intestinal mucosa with bacteria after birth7. It may also be one reason why the intestine grows with some 20-25 cm in the first few days, but here growth factors and cytokines in the mother's milk may well be important also.

Immune Responses to R akari

The host immune responses to infection with R. akari have been characterized partially in various studies. Athymic and thymus-intact BALB c mice treated with antibiotics survive intraperitoneal infection with 2.5 X 108 rickettsiae, and develop robust titers of antirickettsial antibodies (134). However, only euthymic mice develop postinfection immunity to subsequent challenge with R. akari. The passive transfer of anti-R. akari antibodies, or the transplantation of splenic cells from mice that had recovered from infection, will protect susceptible immuno-competent mice from fatal infection with R. akari. Macrophages from athymic or euthymic mice will destroy opsonized R. akari in vitro, even though infection in the presence of antibody does not occur in vivo. These results suggest a crucial role for T-cell-mediated activation of macrophages in recovery from infection with R. akari (134). Murine antibody responses to R. akari and other spotted fever group rickettsiae appear as early as...

Cell Mediated Immune Responses

An association between a cell-mediated immune response to the C. trachomatis 57-kDa hsp and fallopian tube infection (salpingitis) has also been demonstrated. In the presence of purified recombinant C. trachomatis 57-kDa hsp (11), peripheral blood lymphocytes (PBLs) from 9 of 18 (50 ) women with salpingitis, none of 10 women with a lower genital tract cervicitis, and 3 of 42 (7.1 ) healthy women proliferated (12). Furthermore, it appeared that among the patients with salpingitis, those women with a previous history of salpingitis or ectopic pregnancy had the highest prevalence of sensitization to hsp. This suggested that a prolonged or repeated exposure to C. trachomatis might be necessary to induce immune sensitization to hsp in most women. Additional testing utilizing the 57-kDa protein that had been freed of possible endotoxin contamination demonstrated that PBLs from 6 of 14 (42.9 ) women with salpingitis, but none of the PBLs from women without evidence of an upper genital The...

Protective Immune Response in Primary Q Fever

The control of the infection in patients with primary Q fever involves systemic cell-mediated immune response and granuloma formation. The granulomatous lesions have a central open space and a fibrin ring, and are referred to as doughnut granulomas. They consist of macrophages with epithelioid morphology and of multinucleated giant cells, and are pau-cibacillary (16-18). A systemic cell-mediated immune response, manifesting as a marked proliferative response to C. burnetii antigen, is observed in patients who have convalesced from acute Q fever and patients with acute Q fever hepatitis (19). The individuals vaccinated with formalin-inactivated C. burnetii exhibit specific lymphoproliferation and interferon (IFN)-y production in response to C. burnetii challenge (20,21). The combination of IFN-y production and granuloma formation suggest a Th1-type polarization of immune response. Nevertheless, immune control of Q fever does not lead to C. burnetii eradication as animals exhibit...

Selection For Gentle Retroviruses And The Mucosal Immune System

Translating this argument to the case of a virus of a metazoan host, the situation that corresponds to preventing a new infection of the multicellular host organism is preventing entry of the STD agent into the tissues of the host's sexual tract. It would appear that the most effective way for this circumstance to be implemented by an infecting pathogen is to stimulate the host to mount both a cellular and humoral (especially IgA) response in the mucosal surfaces against the virus. This need not have any major influence on the pathogen particles already inside other parts of the body, but some minor side effects might well ameliorate or slow down the disease process within the host. Extensive studies of mucosal immune responses have and are being made. While these studies were are largely designed to look for opportunities for future vaccine development, they serve for the present purposes of showing that IgA and T-cell responses are made in mucosal tissues (Mestecky and Russell,...

Variable Stimulation Of The Immune System Of Primates Under Different Conditions

The long-term survival of the pathogen in a vertebrate host depends on proper balance (or evasion) of the pathogen with the host's immune system. A possibly critical factor of difference among modern humans, the Stone Age man, and the modern non-human primate needs to be recognized here. Some of the possible differences would make the response greater or weaker, and could consequently support or conflict with the hypothesis proposed here. This balance could depend on the variety and extent of immune stimulation in general and is in addition to the responses of these host species to their particular retroviruses. The stimulation of the immune system, variety of stimulations, and the age dependency of individuals exposed to other antigens before they are challenged by viral antigen do vary greatly (see for example, Miedema and Klein, 1996). There must be marked differences in the antigenic stimulation of the members of primate societies in the wild, the humans in developing countries,...

Acquired Immune Deficiency Syndrome

The pathogenesis of AIDS immunosuppression begins with the binding of the human immunodeficiency virus (HIV) virions to the CD4 lymphocytes (also known as helper T cells) via an interaction between the gp120 viral envelope protein and the CD4 cell surface molecule. The viral core components, consisting of a single-stranded RNA particle and the reverse transcriptase, become internalized in the target CD4 cell. Within the cell, the single-stranded viral RNA becomes transcribed into double-stranded DNA, which incorporates into the host genome and is subsequently expressed to yield infectious viral progeny that are released with cell lysis. In progressive HIV infection, the amount of virus increases and the number of CD4 cells decreases. CD4 lymphocytes are important in the host cellular immune system. The depletion of these cells results in the impairment of cytotoxic lymphocyte and natural killer cell responses.

Proinflammatory architecture of the host immune system

Analysis of molecular interaction networks of the host immune system indicates that it is fundamentally proinflammatory 58 , and requires active control to reduce inflammatory reactions once started 59-61 . There are many positive feedback loops that escalate secretion of cytokines and promote further inflammation. Hyper-activation of a cytokine network, often called 'cytokine storm', is one of the major factors that aggravates patient health and may results in death. For example, influenza infection causes a range of cytokine release as its acute response 62, 63 . However, the infection is generally localized to epithelial cells yet extensive cytokine release often takes place systemically. This systemic release of cytokines particularly IL-1a and IFN-f aggravates inflammation leading to fever and lung inflammation, and sometimes leads to fatality. Mice infected with influenza virus in which IL-1a and IFN-f are suppressed show substantial mitigation of such risks 64, 65 . Similarly,...

Mechanisms The Immune System

While studies examining the impact of religion on the immune system are few, they are methodologically sound and offer intriguing results. One study reports an inverse relationship between frequent attendance at religious services and interleukin-6, an inflammatory cytokine and putative immune system regulator (Koenig et al., 1997a). Another study (Woods et al., 1999a) reports that subjects displaying high levels of religious behavior (e.g., attending religious services, praying) had significantly higher levels of T-helper inducer cell (CD4+) counts and higher CD4+ percentages. Schaal et al. (1998) reported that religious expression was positively correlated with natural killer (NK) cell number, T-helper cell counts, and total lymphocytes in women with metastatic breast cancer.

The Immune System And Cancer

THE INTERRELATIONSHIP OF IMMUNE RESPONSE, OLD AGE AND HIGH INCIDENCE OF CANCER Since the incidence of cancer increases rapidly in old age, ageing is another important factor associated with human cancers. Around 65 of all cancers are diagnosed in people over the age of 65 (see Chapter 2). While the increasing accumulation of mutations in genes over time is one factor contributing to the high incidence of cancers in old age, recent evidence suggests that malfunction of the immune system may also contribute (Ginaldi et al., 2001 Burns and Leventhal, 2000 Effros, 2003). It is well established that with increasing age there is deterioration of the immune response (i.e. immunosenescence), which results in increased susceptibility to infection, insufficient responses to vaccines and a high level of autoimmune disorders (Lords et al., 2001 Stacy et al., 2002 Burns, 2004). In particular, one of the common alterations in old age is a decline in T-cell mediated immune responses. The decline in...

Acquired Adaptive Immunity

In addition to its generalized innate immunity, the human body has the ability to develop extremely powerful specific immunity against individual invading agents such as lethal bacteria, viruses, toxins, and even foreign tissues from other animals. This is called acquired or adaptive immunity. Acquired immunity is caused by a special immune system that forms antibodies and or activated lymphocytes that attack and destroy the specific invading organism or toxin. It is with this acquired immunity mechanism and some of its associated reactions especially the allergies that this chapter is concerned. Most of the preprocessing of T lymphocytes in the thymus occurs shortly before birth of a baby and for a few months after birth. Beyond this period, removal of the thymus gland diminishes (but does not eliminate) the T-lymphocytic immune system. However, removal of the thymus several months before birth can prevent development of all cell-mediated immunity. Because this cellular type of...

Spirulina In Adaptive Immune Responses

There are several studies investigating the effect of Spirulina on the antibody production by B cells in response to immunization (primary immune response) and challenge (secondary immune response) with a specific antigen. In the earliest of these studies, mice were fed diets containing 10 or 20 of S. platensis, immunized with sheep red blood cells after 7 weeks, and challenged after 9 weeks.8 Spirulina feeding significantly increased the number of IgM antibody-producing cells in the spleen during the primary immune response, but had little effect on the synthesis of IgG antibodies during the secondary immune response. As discussed previously, this study suffers from the lack of adjustment for the higher protein and essential nutrient content of the Spirulina-supplemented diets. In contrast, another group of researchers reported that Spirulina enhanced antigen-specific antibody production during the secondary, but not the primary, immune response.6 In their experiments, newly hatched...

Regulatory Activities On Immune System Of Spirulina

Spirulina And Immune System

It was reported145 that Spirulina up-regulates key cells and organs of the immune system improving their ability to function in spite of stress from environmental toxins and infectious agents. Studies on animal models documented that phycocyanin of Spirulina stimulates hematopoiesis, especially erythropoiesis by inducing erythropoietin hormone (EPO). There is also evidence that c-phcocyanin and polysaccharides of Spirulina enhance white blood cell production 146,147 The percentage of phagocytic macrophages increased when cats were administered water-soluble extract of S. platensis (Qureshi and Ali, 1996). Increased phagocytic activity was also observed in other animals such as mice and chicken 146-148 For example, Lee et al. (2003)149 studied enhancing phagocytic activity of hemo-cytes and disease resistance in the prawn Penaeus merguiensis by feeding S. platensis. Cultured prawns are prone to infectious bacterial diseases, in particular Vibrio spp. 150,151 for they are often...

The immune surveillance theory

The immune surveillance theory put forward by Thomas in 1959 and redefined by Burnet (1967) states that the immune system is constantly patrolling the body for tumour (abnormal) cells, which are recognized as foreign, and mounts an immune response that results in their elimination before they become clinically detectable (Burnet, 1967). Although this concept remains controversial, a wide range of evidence supports it. have better survival than those with few infiltrated immune cells, suggesting that such immune cells are responsible for the improved survival in these patients (Ropponen et al., 1997 Naito et al., 1998 Nakano et al., 2001 Nakayama et al., 2002 Ohno et al., 2002). Second, as described above, the incidence of cancer is higher in older people and in the neonatal period when immune responses are less efficient. Third, the incidence of cancer is much higher in immunodeficient people (e.g. AIDS patients) than in those with a normal immune system. About 40 of HIV-infected...

Lymphocyte Homing and the Structural Organisation of the Immune System

In an organised immune system cell migration needs to be directed. Tissue and microenvironment-selective lymphocyte homing is the basis for this organisation. The regulated expression of adhesion molecules and their ligands and of chemokines and their receptors underlie the structural and systemic organisations of the immune system, being essential for leukocyte development, lymphocyte recirculation, immune surveillance, and effector lymphocyte differentiation and targeting. In other words, tissue-specific homing is achieved by a sequence of overlapping steps with combinatorial diversity allowing for an address or code for leukocyte

RNAi Important to Maintain Genome Integrity A Primitive Immune System in C elegans

In plants, the RNAi pathway serves as an antiviral mechanism. Spreading of the silencing signal throughout the plant ensures that, when the plant is later exposed to same virus, it will be resistant to further infection. Although it has yet not been clearly demonstrated, the exo-RNAi pathway in worms may represent a primitive immune system for the animal. Recent studies have shown that the Argonaute RDE-1 is required for a potential antiviral silencing triggered by viral replication (Lu et al. 2005), and in vitro studies demonstrate the importance of the exo-RNAi components for antiviral defense in C. elegans (Wilkins et al. 2005).

Assessment Of Immune Response With Antigen Arrays

The feasibility of antigen microarrays was demonstrated by measuring the concentration of antibodies generated in patients against pathogen viruses and parasites as a result of a host immune defense 63-65 . Using internal calibration curves, a linear concentration-dependent response was observed with 10 coefficient of variation between the arrayed slides, and the array data were in agreement with ELISA results 63 . The arrayed antigens of herpes simplex virus types 1 and 2, cytomegalovirus, the virus of rubella and Toxoplasma gondii, were able to detect specific IgG and IgM antibodies in the sera of patients. In another study, a panel of 430 chemically synthesized peptides and recombinant proteins was prepared to detect the immune response in rhesus monkeys immunized with genetically engineered vaccinia virus derivatives carrying antigenic determinants from a chimeric simian-human immunodeficiency virus 64 . This study indicated that an immune response was generated against...

Defective Immune Response in Chronic Q Fever

Once established, chronic Q fever is characterized by defective cell-mediated immunity, thus emphasizing the major role of cell-mediated immunity in the protection against C. burnetii. Impaired cell-mediated immunity is characterized by a scarcity of granulomas, which are replaced by lymphocyte infiltration and necrosis foci in liver (32). Lymphocytes from patients with Q fever endocarditis do not proliferate in response to C. burnetii antigen, in contrast to lymphocytes from patients with acute Q fever (19). The mechanisms of this specific unresponsiveness may include alterations in T-cell subsets, but CD4+ T-cell lymphopenia was observed in patients with Q fever endocarditis and in cured patients who exhibited normal immune response (33). More likely, this specific suppression is mediated by immunoregulatory mediators such as prostaglandins E2 (34) or cytokines. Interleukin (IL)-10, an immunoregula-tory cytokine that is overproduced in chronic Q fever (35,36), may be involved in...

Humoral Immune Responses

Humoral immune responses to the C. trachomatis 57-kDa hsp have been associated with female infertility and upper genital tract infections. High-titer antibody to the chlamydial 57-kDa hsp was most prevalent in women who were infertile owing to fallopian tube occlusion (8,9) and in women with pelvic inflammatory disease who had an ectopic pregnancy (10). The relation between a humoral immune response to the chlamydial 57-kDa hsp and tubal infertility due to a C. trachomatis infection has been demonstrated (9).

Adaptive acquired specific immune response

Gambar Jangkar Sorong Pengukur

In many situations, the non-specific immune responses described above (e.g. phagocytosis, NK cell activation, inflammation), with which we are born and that occur in the first few hours of infection, may be sufficient to overcome the pathogens. If not, disease can ensue and the body may recover after the activation of adaptive immune responses against the invading pathogens (see Figure 7.1). There are two types of adaptive immune responses, namely antibody-mediated immune (AMI) responses and cell-mediated immune (CMI) responses. The most relevant cells in providing adaptive immune responses are lymphocytes, which make up between 25 and 35 of white blood cells their total number in a healthy individual is close to one billion (1012). Two major types of lymphocytes, called B cells and T cells, are present in the blood in a 1 5 ratio. B cells develop into mature immunocompetent cells in the red bone marrow and each B cell expresses an antigen receptor (i.e. antibody) of a single...

Wolbachia and the Adaptive Immune Response Serology

Anti-WSP antibody responses have been associated with disease. In rhesus monkeys experimentally infected with B. malayi, only two out of 12 monkeys exhibited IgG responses to WSP and both the WSP-positive monkeys developed lymphoedema after becoming amicrofi-laremic (67). This association between WSP reactivity and disease has also been demonstrated in humans. Human subjects with chronic disease, such as lymphoedema and hydrocele, were more likely to be seropositive for anti-WSP IgG (68,69). Also, in D. immitis infection of humans, in which the human is a dead-end host, an IgG response against WSP was only detectable in patients with pulmonary nodules and not in healthy donors from endemic areas, again suggesting that exposure of Wolbachia to the immune system is related to clinical disease (70). The death of adult worms is a significant factor involved in the development of chronic disease in filariasis (71) and this maybe associated with the release of Wolbachia and the activation...

Downregulation of the Immune Response

Interleukin-10 (IL-10) plays an antiinflammatory role in controlling the strongly activated immune response following clearance of rickettsial infection. The serum concentration of IL-10 in C3H HeN mice is elevated on day 10 after inoculation of R. typhi, but not at the peak of the bacterial load on day five or in convalescence on day 15 (34). On day 10, the rickettsial load is below the limit of detection, having been controlled by the immune response. Continued activation of antirickettsial, cell-mediated immunity after bacterial clearance could be more harmful than beneficial. The observed effects of immune regulation by high IL-10 levels include decreased IL-12 concentration and transient immunosuppression of T-cell responses between days 10 and 15. Stimulation of spleen cells collected from R. typhi-infected mice with con-canavalin A during this period yields lower production of IL-2 and IL-12 than those of na ve mice (34). Similarly, serum IL-10 concentrations are increased in...

Immunotherapy Of Tuberculosis

There have been reports of the addition of Mycobacterium vaccae immunotherapy in pulmonary tuberculosis with both drug-sensitive and drug-resistant organisms. Prior et al. administered immunotherapy with Mycobacterium vaccae to second-line antituberculous drugs and observed a dramatic cure in a patient with drug-resistant abdominal tuberculosis (64). At present the treatment of tuberculosis in this new type of tuberculin immunotherapy, particularly of multiple drug-resistant tuberculosis, requires the administration of first- and second-line antituberculous agents or combinations thereof. Because only about one-half of patients with resistance to both rifampicin and isoniazid respond to second-line drugs (65), immunotherapy has been employed. This type of antituberculous immunotherapy differs from the classical immunotherapy of Koch (66), which was designed to promote tissue destruction (67) by the injection of old tuberculin. The new therapy consists of injection of killed M. vaccae...

Role of DC Subsets in Adaptive Immunity

The human immune system has evolved to have two distinct mechanisms for protection against microbes. In response to intracellular microbes (bacteria, viruses, fungi, and intracellular parasites), DC subsets produce IL-12 or type I IFN (MDCs and pDCs, respectively), which stimulate CD4+ T helper cells to differentiate into IFN-y-producing T helper (Th) 1 cells (Lanzavecchia and Sallusto, 2001). Th1 cells activate macrophages and CD8+ cytotoxic T cells to kill intracellular microbes. On the other hand, extracellular parasites, such as helminths, trigger DCs to activate CD4+ Th cells into Th2 cells, secreting proallergic cytokines such as IL-4, IL-5, and IL-13 (Sher et al., 2003b). Th2 cytokines trigger immunoglobulin E (IgE) production, which activates mast cells and eosinophils to eradicate the extracellular microbes. The ability of MDCs and pDCs to direct Th1-versus Th2-type immune responses is determined both by their lineage origin (functional diversity) as well as the environment...

Innate natural nonspecific immune response

The innate immune response is present at birth and is mediated by a complex sequence of cellular and molecular events including phagocytosis, inflammation, complement activation and natural Table 7.1 Cells of the immune system cytokines that stimulates both antibody-mediated and cell-mediated immune response Downregulate the immune responses Table 7.2 Important cytokines of the immune system Macrophage-derived chemoattractant for immune system cells and phagocytes to site of inflammation Table 7.3 Important recognition moieties of the immune system Antigens Epitopes Substances that provoke immune responses (e.g. bacte immunization in order to stimulate the production of memory B cells and memory T cells without causing the disease. Antigenic preparation that is used in educating the immune system killer (NK) cell activation. In contrast to the adaptive immune response, which improves with each successive exposure to the same antigen, the innate immune response is non-specific so does...

Stress Proteins As Targets Of Immune Responses

Two characteristics of stress proteins greatly increase the likelihood that these proteins may become autoantigens involved either in initiating or perpetuating autoimmune diseases. First is their great phylogenetic conservation across major species barriers from prokaryotes to mammals. The second is their immuno-dominance that is, their ability to evoke strong immune responses during the course of infections with a large number of infectious agents (detailed elsewhere in this book). Thus, exposure to an infectious agent, in a genetically susceptible host, at the appropriate time during the host's development could result in an immune response to the infecting agent's stress proteins that either cross reacts with normal host stress proteins or cross reacts with organ-specific proteins, resulting in an autoimmune disease. Several laboratories tested the feasibility of this hypothesis in the human disease multiple sclerosis and in its animal model, experimental autoimmune...

Telomerase Specific Adaptive Immunotherapy 21 Rationale

Telomerase-specific adaptive immunotherapy aims to stimulate a CD8+ cytotoxic T lymphocyte (CTL) response against hTERT overexpression in cancer cells. Clinical approaches to induce CTL responses against tumor neoantigens generally make use of the professional antigen-presenting function of dendritic cells (DC) pulsed with neoantigen mRNA or, in the case of peptide vaccination approaches, with synthetic peptides capable of binding MHC class I molecules (HLA-A, HLA-B, or HLA-C). Pulsed DC prime CTL to lyse target cells displaying endogenously synthesized antigenic peptides in the context of the class I presentation pathway which is present in all nucleated cells (Rock and Goldberg 1999). Although antigen-specific CTL responses can be raised by these methods, clinical efficacy is limited, and the importance of both inhibiting CTL suppressive signals and inducing antigen-specific CD4+ T-helper cell support is now widely recognized (Emens 2006). T helper cells secrete cytokines that both...

Gene Treatment of Severe Combined Immune Deficiency

The first human gene therapy trial involves the treatment of Severe Combined Immune Deficiency (SCID) caused by adenosine deaminase (ADA) deficiency. ADA is an enzyme essential for the breakdown of de-oxyadenosine. Deficiency of this enzyme causes a build-up of the purine, which is preferentially converted to the toxic deoxyadenosine triphosphate in lymphocyte T cells, leading to damage of the immune system.

Immune Response

Antibody responses to a number of Wolbachia antigens have been observed in both human and animal filariasis, including the major surface protein (WSP), HSP60, HtrA-type serine protease, and aspartate aminotransferase (69). In patients diagnosed with pulmonary dirofilariasis, IgG responses to WSP are elevated compared to healthy individuals and blood donors from nonen-demic areas suggesting a possible serodiagnostic test for pulmonary dirofilariasis (75). Studies on WSP serology in human filariasis show an association with the presentation and the duration of chronic disease in lymphatic filariasis. A transient elevation in WSP reactivity seems associated with onset of lymphoedema suggesting that the immune response evoked by Wolbachia may trigger the development of disease (76).

Immune System

Acquired Immune Deficiency Syndrome (AIDS) attacks the body's natural defenses against other diseases, leaving it vulnerable to damage or destruction by them. AIDS is caused by the human immunodeficiency virus (HIV), a retrovirus that enters lymphocytes and merges with their DNA. The DNA is then transformed by the HIV so that it makes copies of the HIV rather than of itself the HIV copies burst out of the cell and attack new host cells. The fight against AIDS has focused attention on the immune system as never before. Although AIDS specifically attacks lymphocytes, immunity involves other parts of the body as well.


The immune response to melanoma has been extensively studied. With occasional clinical spontaneous regressions, tumor infiltrating lymphocytes capable of destroying melanoma cells, anecdotal responses of patients to immunotherapy, and the ability of cytokines to affect the growth of melanoma without any obvious direct antitumor effects there is promise in therapies that modulate the immune response to cancer. Antibodies specific for melanoma have been well characterized and are used routinely in immunohistochemistry to diagnose melanoma. The role of these antibodies in therapy has yet to be demonstrated. Interferon alfa-2b, interleukin-2, and tumor necrosis factor were discussed above as mainstays in therapy. Each of these as well as many other are included in many ongoing clinical trials. During the last decade the importance of the lymphocytic response to melanoma has been shown. In animal models the rejection of melanoma is a T-helper dependent (CD4+), cytotoxic T-lymphocyte (CD8+)...

Overview of Superantigens

Bacterial superantigens are potent T-cell stimulatory protein molecules produced by Staphylococcus aureus and Streptococcus pyogenes (1). Their function in the microbe appears primarily to debilitate the host sufficiently through their effects on cells of the immune system to permit the causation of disease (2). Their superantigenic activity can be attributed to their ability to bind to both major histocompatibility complex (MHC) class II molecules and T cell receptors by forming a trimolecular complex (1). Unlike conventional antigens they are not processed internally by antigen presenting cells (APC), and are thus not displayed as peptide antigen in the peptide-binding groove of the MHC class II molecule. Superantigens bind to APCs on the outside of MHC class II molecule and to T cells via the external face of the T-cell receptor (TCR) Vp element (see Fig. 1). Each superantigen interacts with a specific Vp region of the TCR, stimulating a large fraction of T cells (for example, up...

Injury Associated with Rickettsial Infection

Spotted fever group rickettsiae spread from cell to cell by host actin-based mobility, do not accumulate in large numbers in endothelial cells, and injure the cells by damaging their membranes. Infection of endothelial cells stimulates them to produce reactive oxygen species that cause lipid peroxidation of the cellular membranes (3-5). Water leaks into the cells with injured membranes and is sequestered in the endoplasmic reticulum. Injured endothelial cells may die and or detach and be swept away in the blood stream, allowing hemorrhage to occur, or endothelium may be activated by the immune system to kill the intracellular rickettsiae (6).

The Unique Role of Heat Shock Proteins in Infections

Parasitic microorganisms have played a tremendous role in the evolution of humans (1). Parasites are microbes which live at the expense of their mammalian hosts. Although some of these parasites interact with their hosts loosely, others achieve intimate contact, thus causing stable infection. As a direct or indirect consequence, the host is harmed and clinical disease evolves. Whether infection progresses in a stable or an abortive form and, as a corollary, whether disease develops or not is markedly influenced by the host immune system. This immune system has the capacity to identify small molecular entities which are characteristic of foreign invaders. Thus, the immune system is first able to distinguish its own molecular entities (termed self) from those of foreign intruders (termed nonself ), and second, it is able to differentiate specifically among the enormous diversity of microbial pathogens. The whole molecule to which the immune system responds is an antigen, and the small...

Metabolic and Thermoregulatory Functions

Animal studies with rats have suggested that during sleep deprivation, energy expenditure increases while temperature and weight drop until body systems begin to fail, beginning with the endocrine and immune systems.y This and other studies have led to the proposal that sleep conserves energy loss through thermoregulation When core body temperature decreases during sleep, heat loss to the environment is minimized. Similar studies have understandably not been performed in humans, but humans also show lowered body temperature during sleep. A different interpretation of temperature changes begins with the observation that sleep in general and deeper NREM sleep in particular are increased when the body is heated y therefore it is suggested that sleep functions to allow the shedding of excess accumulated heat.y This approach emphasizes not the decreased rate of heat loss in sleep due to decreased core temperature but the reduced rate of heat production due to slowed metabolism. Sleep may...

Systems Based Relationships

Proteomics is considered a subdiscipline of systems biology. So what is systems biology Weston and Hood define it as the analysis of the relationships between elements in a system in response to genetic or environmental perturbations, with the goal of understanding the system or the emergent properties of the system 6 . System is a broad term borrowed from other fields (e.g., engineering), but in a biological context the word usually refers to organelles, cells, organs, or organisms. Such a definition is therefore based largely on the physical location of the proteins studied, their network of interactions, and their collective role in defining a biological entity (such as a mitochondrion or a liver cell) or function (such as the immune response).

Functional Aspects of Hsps in Defense and Invasion

Hsps of the 60- and 70-kDa families participate in the folding unfolding of other proteins and hence are termed chaperones. This chaperone function aids in the synthesis of proteins, the formation of protein complexes, and in protein translocation from one cellular compartment to another by means of transporter systems in the separating membrane (28-30). During the immune response, BiP and grp (glucose-regulated protein) 94 (hsp 70 and hsp 90 in the endoplasmic reticulum ER ) participate in the assembly of Ig (31,32). Furthermore, hsps are involved in antigen processing and presentation. Hsps promote refolding of proteins which became partly denatured by heat or other stress stimuli. This capability of renaturing other proteins is beneficial for the infected host cell, because the mobilization of defense mechanisms causes a stressful environment not only for the invader but also for the host. The pathogen uses its own hsps to maintain its proteins in a functional state. Therefore,...

Immunological Aspects of Hsps in Defense and Invasion

Hsps are highly conserved among species. Generally, this is advantageous for the immune system Repeated contact with different microbes may expose the host to conserved regions of microbial hsps so that the immune system is already alerted when it encounters a pathogen. Because pathogens express elevated hsp levels during infection, hsps may serve as early targets of the immune response (33-35). The possibility to protect against microbes by immunization with hsp has been utilized for several pathogens. Hsps were not only used as target antigens but also as carrier molecules for unrelated antigens (36,37). Similarities between prokaryotic and eukaryotic hsps, however, may activate a cross-reactive immune response to self epitopes derived from cellular hsps. This cross-reactivity may promote immune surveillance and elimination of abnormally

Mechanisms of Homing of Natural Killer Cells Immune CD4 and CD8 Lymphocytes and Macrophages to Sites of Rickettsia

An important phenomenon is the interaction of Rickettsia-infected endothelium with cells of the immune system. The histopathologically visible result is perivascular infiltration of CD4 and CD8 T-lymphocytes and macrophages around the networks of contiguous infected endothelial cells of the microcirculation. It is presumed that the initial, and sometimes only, interaction of the endothelium with circulating lymphocytes and monocytes is at the luminal interface.

New targets for antiinfective drug development

As models evolve, they will integrate increasingly diverse sources of data. This could include information from structural biology and functional biochemistry that relate to the 'drugability' of targets. Pathogen-host systems biology comes with an additional component as infectious disease biology can only really be understood in an ecological and evolutionary framework pathogens compete for a potentially limited host population, while hosts in turn mount an immune response against pathogens and may even develop suitable strategies against pathogens. There are a host of beautiful examples of apparent host-pathogen co-evolutionary dynamics (for example between lizards and some species of Plasmodium) 72 . In addition we must consider the interaction between the host and the drug (see Chapter 9) host metabolism or modification of the drug will also influence the way it interacts with its target and the system as a whole. Every effect we study at the molecular or cellular levels may lead...

Representative Examples For Hsp Involvement In Hostpathogen Relationship

For numerous microbial pathogens the expression of hsps and eventual development of a specific immune response have been described (for extensive reviews see refs. 6,33,and 59-61). Although viruses do not encode their own hsps, they frequently induce hsp synthesis in host cells or at least maintain normal cellular levels of particular hsps. Table 1 summarizes representative examples of various types of pathogens together with the major hsp families. The physiological effect of an hsp cognate can be beneficial or detrimental for the host depending upon its specific function during infection.

Identification of Chemokine Receptors as G Protein Coupled Receptors

The initially identified receptors were generally ones that bound the inflammatory chemokines. In most instances, these receptors bind chemokine ligands in a very promiscuous manner. Thus, the redundant nature of these interactions coupled with broad cellular expression patterns made the task of identifying disease-associated targets more difficult. The chemokine receptor family also contains several examples of highly selective receptors. The number and diversity of chemokines and their receptors also begs the question Which of these genes represents the primordial ligand-receptor pair Chemokines have been characterized in many species and appear to extend back to early vertebrates. Phylogenetic analysis suggests that stromal cell-derived factor-1 (SDF-1) CXCL12 and CXCR4 likely represent the earliest ancestral chemokine-chemokine receptor pair and may have initially evolved within the context of the central nervous system and not, surprisingly, within the immune system (10). This...

Vascular Inflammation

The idea of inflammation held by many immunologists that includes activation of NF-kB and the presence of proinflammatory cytokines bears more truth in the pathogenesis of rick-ettsial vasculitis, but is not visible microscopically. The perivascular T-lymphocytes and macrophages are extremely likely to represent the components of the immune response that controls the infection. That the cytokines secreted by these cells may play a role in causing the fever and other symptoms and that the timing of action of cytotoxic T-lymphocytes against rickettsia-infected endothelium would be detrimental if the target was too large and dispersed are evidence that the immune system could also be pathogenic. On balance, however, the immune response to rickettsiae is beneficial.

Prospects For Gene Therapy

The extensive background of knowledge on mouse embryo-derived stem cells provides an experimental model for human ES cell research and a means of testing ideas on the biological basis of therapeutic interventions involving stem cells. Given the extensive database of genomic and developmental information and the long history of mutagenesis and ES cell experimentation, the mouse is the ideal model organism for this purpose. The differentiation pathways leading to many specific cell types have been elucidated for stem cells in vitro and are supported by studies on developmental potential as assayed through contribution in vivo (reviewed by Odorico et al., 2001). Even highly organized structures such as insulin-expressing cells with the three-dimensional structure of pancreatic islets have been differentiated from ES cells, demonstrating their potential for the assembly of functional organs (Lumelsky et al., 2001). The feasibility of using ES cells to effect cures through tissue...

Roles of Superantigens in Disease 41 Toxic Shock Syndrome

The consequences of superantigen exposure. The culminative effects of superantigen on the immune system leads to hypertension and systemic shock as a result of capillary leak. Prolonged exposure to superantigen can lead to immunosuppression and tolerance. Fig. 4. The consequences of superantigen exposure. The culminative effects of superantigen on the immune system leads to hypertension and systemic shock as a result of capillary leak. Prolonged exposure to superantigen can lead to immunosuppression and tolerance.

In The Peripheral Nervous System

It is imperative to consider how the PNS interacts with other systems of the body during development and maintenance, and in response to damage. This is particularly pertinent to the immune and endocrine systems, which can have considerable impact on the function of the PNS. A balanced interplay between the PNS and the immune system is necessary for healthy function, and again the Schwann cell plays a critical role in maintaining this delicate equilibrium with involvement in the initiation, perpetuation and termination of immune responses in the PNS (Chapters 6 and 7). In view of the fact that Schwann cells respond to and produce an extensive collection of immunomodulatory factors (including neurotrophins, cytokines and chemokines), it is increasingly apparent that they are key orchestrators of the immune response in the PNS (Maurer et al. 2002). Indeed, the expression of MHC class 1 and class 11 molecules (Armati et al. 1990 Gold et al. 1995 Lilje and Armati 1997) and T cell...

Chemokines Activation of Adhesion and Cell Polarisation

Homeostatic chemokines are important for the migration of lymphocytes into the lymph node, where immune surveillance and antigen-induced activation occur, as well as for effector T cells to access and infiltrate target tissue.13 In contrast to inflammatory chemokines, homeostatic chemokines display a more restricted receptor usage.

Controlling Coagulation

Thrombin activity is critical not only for several stages in coagulation, but also for initiating protection and repair processes (Fig. 2.5). In addition, it activates the above-mentioned inhibitor of fibrinolysis, TAFI (Hryszko et al. 2001), which makes the cross-linked fibrin resistant to plasminogen. Through G-protein signalling pathways, thrombin promotes the release of interleukins IL-1 and IL-6 and various cellular adhesion molecules, notably ICAM-1 and VCAM-1 (Sugama et al. 1992). The interleukins are integral to the immune response the adhesion molecules are crucial for initiating tissue repair and also participate in endothelial interactions with leukocytes. In short, thrombin not only fulfils many different roles in haemostatic plug formation, it also participates in mounting an immune response and in initiating tissue repair. Therefore, zero thrombin activity in the plasma would result in zero coagulation and inadequate protection and repair following injury but high or...

Other Defense Factors In Milk Acting In The Infants

The presence of leptin in the milk43 may be of significance for the infant's host defense since leptin has the structure and several functions of a cytokine44,45.It stimulates haematopoeitic and lymphoid cells, especially TH1 cells which produce IFN-y it enhances phagocytosis and may upregulate inflammatory cytokines45 However, the role of milk leptin for the offspring has not yet been investigated, when it comes to its possible role for the immune system.

Distinct Gene Expression Patterns In Peripheral Blood After Delayed Preparation

Of a hypoxia signature, caused by the changes of oxygen homeostasis in the samples after blood withdrawal. Therefore, many stress-associated and hypoxia-induced genes showed elevated expression in delayed PBMC samples, e.g., the transcription factor HIFla and several downstream target genes like VEGF,4647 ADM,48 PFKFB3,48-50 and transferrin receptor.51 On the other hand, several genes associated with important physiological functions like cell cycle, proliferation, transcription, and metabolism showed decreased expression in delayed PBMC samples. A large number of genes associated with immune function (e.g., chemokines, cytokine receptors, and cell surface receptors) also revealed reduced expression and genes associated with apoptosis showed downregulated expression of both proapoptotic and antiapoptotic factors. These findings indicate the initiation of a complex regulatory machinery to compensate for the potentially lethal microenvironment during delayed sample handling. Overall,...

Advances in Device and Cellular Engineering

A number of new technologies have been developed and refined during the past several decades which set the stage for a significant advance in transplantation as a major means for treating human disease. These technologies include the identification and isolation of specific cells and cell products which play a major role in disease (hormones, growth factors, immune products, cellular toxins),30 cell engineering enabling the production of living cells which produce these specific bioactive compounds, and advances in bioreactor design for in vitro maintenance and propagation of these cells.31 A particular case of encapsulation involves immunoisolation of mammalian cells. Examples include the bioartificial pancreas, enzyme systems32 and enzyme replacement therapy,33 encapsulated hepatocytes for the treatment of severe liver failure,2 the bioartificial kidney,14 high-density cell growth for immunotherapy,5 controlled delivery of medicinal substances and other bioactive agents,34...

What Is the Balance of Discipline Areas in NASAs Biomedical Research Program

Studies to examine the space radiation-induced risks of cancer and central nervous system damage are being carried out by NSBRI investigators at new facilities at Loma Linda University for proton studies and at Brookhaven for heavy ions. These will provide greatly improved access to investigators for relevant studies. Flights are not yet available for the recommended study of the combined effects of radiation and stress on the immune system, and no preliminary ground studies on this issue appear to be planned.

Associated Neurological Findings

Decreased position, vibratory, temperature, and pain appreciation occurs in several neuropathies associated with hyposmia. These include diabetes, the neuropathy of renal and hepatic failures, and a large variety of toxic neuropathies. In patients with pernicious anemia, the large myelinated central fibers carrying position and vibration senses are preferentially affected. In the context of hepatitis, the acquired immune deficiency syndrome (AIDS), and other virus-related illnesses, hyposmia can occur along with an ascending polyneuropathy of the Guillain-Barre type. In seizure patients with uncal or temporal lobe foci that induce dysosmic auras, altered sensations in a hemibody distribution can occur as part of the seizure or as a postictal transient sequela.

Immunology of Infection

Viral infections are controlled by a combination of non-antigen-specific and antigen-specific immune responses. Most viruses induce these immune responses by causing lytic cell death which, in turn, causes inflammation and stimulates the production of cytokines. PV infection, in contrast, is non-lytic and, consequently little or no local inflammation is induced. This situation probably reflects the reduced ability of PVs to invoke effective immune responses that are capable of eliminating established lesions (Frazer, 1996). Nonetheless, there is evidence of involvement of the immune system in the control of PV infections. Humoural (antibody) immune responses directed against almost all PV proteins have been detected in The persistence of PV-induced lesions suggests that the development of an effective cellular immune response against PVs following infection is neither immediate nor universal. Nonetheless, several observations suggest that the host's cell-mediated immune response is...

Inference and Relational Generalization

Athough all analogy models use some form of CWSG, additional constraints on this inference mechanism are critical (Clement & Gentner, 1 991 Holyoak et al., 1994 Markman, 1997). If CWSG were unconstrained, then any unmapped source proposition would generate an inference about the target. Such a loose criterion for inference generation would lead to rampant errors whenever the source was not isomorphic to a subset of the target, and such isomorphism will virtually never hold for problems of realistic complexity. Several constraints on CWSG were demonstrated in a study by Lassaline (1996 also see Clement & Gentner, 1991 Spellman & Holyoak, 1996). Lassaline had college students read analogs describing properties of hypothetical animals and then rate various possible target inferences for the probability that the conclusion would be true given the information in the premise. Participants rated potential inferences as more probable when the source and target analogs shared more attributes,...

Preface to Third Edition

Human diseases (cholera, anthrax, whooping cough, tetanus, botulism, diptheria, clostridial gas gangrenes, severe diseases caused by superantigenic toxins, Helicobacter pylori-associated peptic ulcers and carcinomas, food poisons, etc.). In this respect, the targeting of immune system cells by various toxins led to a better evaluation of both their beneficial effects (for example as immunomodulators in the case of cholera toxin B subunit) and pathophysiolgical effects in certain diseases in connection with the immune system. Finally, the past years witnessed considerable progress on toxin applications in vaccinology, tumor therapy, and new approaches in the treatment of various diseases. Whether some wild-type toxins can be directly used as therapeutic agents, protein engineering permits us to model more specific and efficient molecules or molecules with a novel activity, or to target a restricted subset of cell population. Novel recombinant toxins are already proposed in the...

The Importance of the Hypoxic Microenvironment

Novel immunotherapy research feeding into improved patient treatments and outcomes. An example of the development of a novel and successful immunotherapy for treating patients undergoing haemopoietic stem cell transplantation and who have developed a CMV infection. This has been made possible through apartnership between Dr Mark Cobbold, Professor Paul Moss and colleagues at the CRUK Institute of Cancer Studies and Dr Dorothy McDonald's group in the NBS SCI department in Birmingham. CMV-tetramer-positive T cells (99 purity by flow cytometric analysis) purified on the CliniMACS (Fig. 2) were infused into patients who has received an allogeneic transplant and subsequently began to develop a CMV infection. The viral titre fell as the CMV-specific T cells expand, combating the viral infection. Details are provided in Ref. 2. Fig. 3. Novel immunotherapy research feeding into improved patient treatments and outcomes. An example of the development of a novel and successful...

Viinfluence Of The Local Environment On Target Antigens And Its Possible Significance For Pathology In

Hsps first attracted the attention of immunologists when these proteins were shown to be prominent targets of the immune response to several intracellular pathogens, particularly the facultatively intracellular mycobacteria. There have been several explanations as to why the immune system should recognize this category of antigen. One attractive idea is that the intracellular location imposes a physiological stress on the invader which responds by an upregulation of hsp. This has been clearly shown for salmonellae (62), and it appears that a somewhat similar process occurs for Chlamydia trachomatis (63). However, the concept that microbial response to stress can involve novel or upregulation of hsp synthesis now has a much wider significance with the evidence that mechanisms for global responses to a local environment can lead to significant alteration in bacterial polypeptide profiles. Such findings raise questions on how conditions in vitro can be manipulated to represent the in...

Text Mining To Interpret High Throughput Data

There are now standards for the deposition of high-throughput data sets, such as MAGE3 as well as meta-data standards (MIAME or Minimal Information about Microarray Experiments). The goal of these standards is to permit the capture and sharing of the raw datasets with no error inducing reformatting. These repositories enable reannotation, making it possible to use new information and new tools that become available over time. In one such reannotation exercise 60 , a set of raw microarray data 61 was identified and downloaded. The goal of the original experiment was to gain insight into virulence mechanisms and immune response by comparing mice infected with different strains of influenza virus the experiment had been performed in 2002, prior to extensive expansion of the Gene Ontology. The hypothesis of the reannotation experiment was that use of updated GO codes would provide significant new meta-data to assist in interpretation of the experimental results.

HBV and Immunoprophylaxis

The host--cell interactions that allow for the persistence of a virus, and the failure of the immune system to eliminate it in an immunocompetent individual, is a topic of considerable relevance for the DNA tumour virus field. For largely noncytopathic viruses, such as HPV, EBV, KSHV and HBV, they must either overwhelm an effective immune response or adopt mechanisms that allow for avoidance, as suggested by one or more of the hypothesized routes for progression from infection to generation of hepatocellular carcinoma (Figure 18). One approach for EBV therapy, as discussed elsewhere, assumes that the immune system may need to, and can, be stimulated specifically to recognize viral genes that might be expressed in its associated tumours, with beneficial effects. As noted, however, realistically such an approach is aimed at reducing morbidity, rather than effecting cure (Khanna et al., 1999). Such an approach may be even more valid for HBV, which can infect virtually all the hepatocytes...

Device Geometry Considerations

Microencapsulation refers to the formation of a spherical gel around each group of islets, cell cluster or tissue fragment. Microcapsules based on natural or synthetic polymers have been used for the encapsulation of both mammalian and microbial cells as well as various bioactive substances such as enzymes, proteins and drugs.55 A review of alternative semipermeable microcapsules prepared from oppositely charged water soluble polyelectrolyte pairs has been presented in recent papers.56,57 The main advantage of this approach is that cells, or bioactive agents, are isolated from the body by a microporous semipermeable membrane and the encapsulated material is thus protected against the attack of the immune system. In the case of microencapsulated pancreas islets, a suspension of microcapsules is typically introduced in the peritoneal cavity to deliver insulin to the portal circulation.

Chemokine Signaling in TLymphocyte Migration The Role of Phosphoinositide 3kinase

The biochemical events that are elicited upon chemokine engagement have been a major focus of interest in many cell types responding to a plethora of different chemokines. We now appreciate that collectively, chemokines can couple to a wide range of biochemical signals including phosphoinositide lipid metabolism, elevation of intracellular calcium levels, and activation of a wide array of protein and lipid kinases as well as small GTPases. Chemokine signaling events are particularly well studied in T lymphocytes where the ordered directional migration of T lymphocytes is a key process in development, immune surveillance, and immune responses. These cells therefore offer a splendid model system in which to understand the array of signals activated by chemokines and their functional importance. One of the most robust biochemical signals elicited by chemokines is the activation of several members of the phosphoinositide 3-kinase (PI3K) family. In many cell systems, PI3Ks are known to...

What Is an Autoimmune Disorder

Can be seen when the immune system is impaired, such as in AIDS from HIV impaired antibody production permits many of these diseases to come back. Also, an impaired immune system leaves the body vulnerable to additional opportunistic infections. Vaccines prevent the development of a particular virus, such as polio, for example. Vaccines work like this the vaccine serum contains a small amount of a particular virus in a deadened, noncontagious form an antigen. Essentially, the vaccine shows your body a sample of the virus. This stimulates your immune system to produce a specific antibody to combat the unwanted virus. Later, if you catch the virus, your body will have sufficient specific antibodies, as well as primed lymphocytes ready to make more, to destroy it before it can do any damage. That's why you don't necessarily need to get chicken pox to be protected from it you can be vaccinated against it instead. However, creating a vaccine is a painstaking, complicated process, and it...

Pregnancy and Autoimmune Disease

During pregnancy, the immune system is naturally suppressed in some ways to prevent the body from rejecting the fetus. After pregnancy, the immune system turns on again. But this may have a rebound effect in that it may result in the production of antibodies that attack normal thyroid tissue, which is what occurs in autoimmune thyroid disease. This may be one reason why women are more prone to autoimmune disorders after pregnancy. Thyroid disease in pregnancy is discussed more in Chapter 13.

Use Of Biological Ontologies

Ontologies are also used in different steps in ontology-based search. An ontology can be used as an index to the information in the information sources. A user can browse the ontology and use the terms in the ontology as query terms. For instance, TAIR Keyword Browser (Fly), GOFish (Yeast, Fly, Mouse, Worm) and MGI GO Browser (Mouse) use GO to browse databases. MeSH is used to index PubMed, an archive for biomedical and life sciences journal literature, and GOPubMed connects GO to PubMed. A module of Whatizit marks all GO terms in a document and links them to their entries in GO. An ontology may also be used for query refining and expansion by moving up and down in the hierarchy of concepts. For instance, when a user searches in a database for 'immune response' and gets

Pathogenetic Mechanisms

As indicated previously, it is generally believed that the local inflammatory and immune response in RA is antigen driven. Two main alternative explanations for this inflammatory response have been advocated. First, RA may be induced by a single antigenic epitope. Alternatively, RA may be induced by any epitope being cross-reactive with self. Between these two extremes, several intermediate alternatives may be postulated. During development of the initial immune response, the whole repertoire of memory T cells would potentially be attracted to the local inflammatory site. However, certain T-cells subsets may be selectively attracted to particular tissues (57). On the other hand, there is no indication that the homing process is antigen specific. Mycobacterial antigens are potent immunogens, and they are almost ubiquitous. If not presented by infection, most people will be sensitized by naturally occurring mycobacteria in the environment or by the extensively applied BCG vaccine. This...

Nonhomologous End Joining NHEJ Repair of DNA Doublestrand Breaks

The NHEJ mechanism repairs DNA double-strand breaks without the need for extensive sequence homology between the DNA ends to be joined, although a few complementary base pairs are needed to provide cohesive ends. NHEJ is an error-prone repair process, because it usually creates small deletions. NHEJ is responsible for the rejoining of DSB during V(D)J recombination in the processing of immunoglobulin genes. Defects in NHEJ in mice cause severe combined immune deficiency and radiation sensitivity.

Preface to the First Edition

Cytokines feature at the forefront of biomedical research. An understanding of their properties is now essential for the immunology student, researcher and teacher and for today's medical practitioner who needs to understand immunologic disease and immunological approaches to therapy. The pace with which this ever-expanding field has developed has been rapid enough to exceed the most optimistic expectations and to bewilder the most assiduous student. Cytokine research is expected to provide the key to pharmacological manipulation of the immune response and commands the attention of a massive and highly focused biotechnology industry. The chapters in this book are a good representation of the areas to which molecular biology has been most successfully applied. Biotechnology companies provide most of the pure, well-characterized cell growth regulatory and effector molecules used in academic and industrial laboratories or in clinical medicine as diagnostic tools or therapeutic agents.

Potential For Cellbased Therapies

Umbilical cord blood is commonly used in cell-based therapies today for reconstitution of the bone marrow after bone marrow ablation for cancers of the blood (36). There are some new experimental therapies using bone marrow transplant with cord blood cells being developed for other diseases. Umbilical cord blood transplantation in Wiskott Aldrich syndrome, which results in severe immune deficiency and early death if not treated, was found to result in rapid and reliable recovery of immune function, with low risk of graft-vs-host disease (81). Using umbilical cord blood stem cells taken from unrelated donors, Staba et al. (82) treated children with Hurler's syndrome, who lack of a functional enzyme, alpha-l-iduronidase. These researchers were able to treat these patients without bone marrow ablation and to have improvement in survival and less neuronal degeneration than Hurler's patients who received bone marrow transplants. The researchers speculate that stem cells from cord blood may...

Receptormediated Mechanisms Of Caspase Activation

TNF-family death receptors play important roles in immune system interactions with tumours. One of the principal weapons used by cytolytic T cells for killing tumour targets, for example, is Fas-ligand (FasL). Consequently, defects in Fas-induced apoptosis can contribute to tumour avoidance of immune surveillance mechanisms. Moreover, upon achieving a Fas-resistant state, it has been shown that some tumours can then tolerate expressing FasL on their surfaces, thus using this death ligand as a weapon to kill neighbouring normal cells as well as activated lymphocytes.

Preface to the Second Edition

What constitutes a new interleukin The assignation of a new designation depends on several clearly defined criteria, recently established by a sub-committee of the nomenclature committee of the International Union of Immunological Societies (Paul et al., 1992). The criteria laid down include molecular cloning and expression, a unique nucleotide and inferred amino acid sequence, and the availability of a neutralizing monoclonal antibody. Furthermore, the granting of a new interleukin designation requires that the candidate molecule be a natural product of cells of the immune system (defined loosely as lymphocytes, monocytes and other leukocytes). The new interleukin must also mediate a potentially important function in immune responses and exhibit an additional function(s) so that a simple, functional name might not be adequate. Finally, these characteristic features should have been described in a peer-reviewed publication.

Defective Phages and Prophages

Natural bacterial strains frequently harbor incomplete prophages (also called defective or cryptic) as well as complete ones. In the wild, bacteria are continually subject to infection, reinfection, and lysogenization. As lysogenic bacteria grow, their prophages experience deletions, mutations, or insertions within the prophage genome. There is generally no selection against such events, so they accumulate over evolutionary time and are frequently observed in laboratory lysogens as well. Defective lysogens were recognized early in the modern era of phage biology as strains that retained some properties of lysogens (such as immunity to infection by phage of the carried type) but did not liberate plaque-forming particles. Whole genome sequencing has underscored their frequency in natural populations. For example, the K-12 strain of E. coli harbors (in addition to l), four or five l-related defective prophages, and the enterohemorrhagic E. coli H7 0157 has seven (including a defective...

Remission and Antithyroid Medication

The main benefit to going on antithyroid medication is to try your luck at achieving full remission without the need for RAI or surgery. This usually results in either an indefinite period of normal thyroid activity or lifelong hypothyroidism. In general, antithyroid drugs are effective in achieving remission about 20 to 30 percent of the time, but some doctors report even lower success rates. The main effect of antithyroid drugs is to buy time until either a spontaneous remission occurs, in which the immune system stops producing thyroid stimulating antibodies (TSA), or the autoimmune effects destroy enough of the thyroid gland to ablate the gland despite persistent TSA production. This spontaneous remission is most likely to be seen in people with very mild thyrotoxicosis and small goiters. The process can take from six months to a year, if it is going to happen at all.

Conclusion and Future Directions

Agents that target the tumor microenvironment represent an important strategy in cancer therapy. Just as the normal brain exists in dynamic equilibrium to maintain normal tissue function, likewise, the tumor adopts many mechanisms to maintain its functional disorder and to evade anticancer therapies. By expressing NG2, the tumor can interact with growth factors to modulate proliferation and angiogenesis can interact with integrin receptors and ECM components to mediate cellular motility, as well as stimulate signal transduction pathways to avoid apoptosis. Several questions remain to be answered. Can the therapeutic effects of anti-NG2 HMP mAb-mediated immunotherapy be enhanced to overcome the hurdles to efficient delivery and penetrance Can the administration of small molecule inhibitors of the NG2 HMP or the different signal transduction pathways mediated by the NG2 HMP be targeted With the use of RNAi in whole animals increasing, its growing implementation in experimental therapy...

Neuroendocrine Responses to Stress

Although glucocorticoid secretion is the ultimate hormonal endpoint of the HPA axis, this is just the beginning of the most important physiological effects of HPA activation. Being highly lipophilic, glucocorticoids travel through the blood and passively diffuse across plasma membranes where they bind to cytosolic receptors (Drouin et al., 1992). When activated, the glucocorticoid-receptor complex translocates to the nucleus of the cell and has the ability to alter gene transcription. This in turn leads to glucose mobilization for the organism, alterations in immune function, and changes in CNS functioning see Munck et al. (1984) for a classic review of glucocorticoid function . Furthermore, glucocorticoids can bind to receptors in the hippocampus, hypothalamus, and the anterior pituitary and subsequently decrease the release of CRH and ACTH. This serves as a negative feedback mechanism that limits the amount of glucocorticoid secreted in response to subsequent stressors (e.g.,...

Host Factors Immune Clearance and Immunity

Even after the discoveries of chloramphenicol and tetracycline in the mid-1940s, astute clinicians recognized that antibiotic therapy for RMSF, although remarkable in its impact, needed to work in tandem with the host immune response. In 1949, Harrell (66), a physician from North Carolina with considerable experience in caring for patients with RMSF, wrote, In the long run, the patient must still cure himself. No supportive therapy will be helpful unless the patient's immune response can conquer the organism. Immune clearance of rick-ettsial infections in humans is largely dependent on cellular immune functions involving T-lymphocytes the CD8+ T-lymphocytes are crucial to controlling infection and enhancing survivorship (81). In experiments primarily involving R. conorii, infected endothelial cells and macrophages were targeted by cytotoxic CD8+ lymphocytes (CTL), which provide MHC-I-restricted CTL activity, indicating this function was more important than IFN-y production. Expression...

Interferon Signalling Pathway

Interferons (IFNs) play a key role in mediating antiviral and antigrowth responses and in modulating the immune response (Seder, 1994 Trinchieri and Scott, 1995 Young and Hardy, 1995). Their signalling pathways provided the first evidence of, and have been used as the model for, the JAK-STAT pathway, which is utilized by many cytokines (Darnell et al., 1994). IFNs can be subdivided into two functional classes, and constitute the largest and most divergent subfamily of cytokines. There are more than 20 members in the type IIFN class (e.g. IFNas, - 3, and -r) and one member in the type II IFN class, i.e. IFN7. Type I and II IFNs function via related but distinct signal transduction pathways. In both classes of IFNs, signalling is initiated by the binding of the IFNs to their specific membrane receptors, that are expressed in many different cell types.

Similarities and Differences Between DC and Ageing

As mentioned above, DC patients have a median life span of 16 years, while some can survive up to 50 years old and milder cases even longer. The shorter life span in DC patients could be inferred to be the result of dysfunctional telomerase. The death of DC patients is usually caused by complications of bone marrow failure (immune deficiency or bleeding), pulmonary fibrosis, or malignancies. These are extreme examples of some of the organ or tissue dysfunction that takes place in normal ageing. Perhaps a key feature of the disease process in DC is that it involves the failure of some tissues, principally highly proliferative tissues that are dependent on renewal by stem cell activity. Ageing, however, can affect the entire organism. Nevertheless, in the first generation of mice carrying a deletion of mTR, when no hematopoietic disorders were apparent, the longevity was reduced in comparison to wild-type mice (Geserick and Blasco 2006). This observation supports a role of telomerase in...

Surfactant dysfunction

Inflammation leads to surfactant dysfunction in ARDS.75 Surfactant is secreted mainly by alveolar type II cells and consists of phospholipids (predominantly phosphatidylcholine) and surfactant specific proteins, SP-A, SP-B, SP-C and SP-D.76 The ability of surfactant to lower surface tension is critically dependent on both the phospholipid and the protein components, especially the hydrophobic proteins SP-B and SP-C. The phospholipids are stored in the lamellar bodies of type II cells and interact with surfactant proteins upon release from the cells, forming large aggregates called tubular myelin. During the normal cycle of breathing these functional large surfactant aggregates become dissipated, reducing to smaller aggregates which do not have the same surface tension lowering properties. Type II cells take up these small aggregates and recycle them into new surfactant. The hydrophilic surfactant protein SP-A, quantitatively the major surfactant protein, plays a key role in this...

Lymphocyte T cell Complex

For defence against invading organisms, such as bacteria and viruses. The T cell has evolved a very sophisticated mechanism for recognizing invader cells, involving recognition of specific proteins unique to the invaders. However, rather than recognizing the intact protein, specialized cells of the immune system degrade the foreign proteins to peptides, which can then be 'presented' for recognition at their cell surfaces. This antigen presentation is performed by a cell-surface protein complex called the major histocompatibility complex (MHC). It is the recognition of the foreign peptide on the MHC molecule by a receptor on the T cell (T cell receptor) that triggers T cell activation. The recognition and activation processes are finely tuned to provide a graded response to the foreign material.

Why Some Current Therapies For Cns Disorders May Not Be Enough

This is due to the yeoman work that the blood-brain barrier (BBB) performs in restricting entry of nonneural cells or novel molecules into the brain from the vasculature, even if such molecules have therapeutic value. (Umbilical cord stem cells may ultimately prove to be an exception to this rule, but understanding of their biology is still in its infancy.) Typically, BMT also involves irradiation and massive immuno-suppression as a preconditioning regimen, with unfortunate deleterious effects on the developing CNS.

Experiential Psychotherapy

When a person regularly and reliably relates to experiencing so as to get these felt shifts, he or she is said to have a high level of experiencing. There is evidence that a high-experiencing way of working with one's feeling about a traumatic experience has a positive effect on physical health, in the form of improved immune function. Many studies have found psychological benefits associated with high levels of experiencing.

Tumour Progression Stimulated By Effects Of Tgf8 On The Tumour Environment

TGF-ft1 also inhibits other immune functions of relevance to tumour development. Increased TGF-ft1 expression by tumour cells decreased natural killer cell activity and promoted tumour formation in nude mice that lack T cells. In addition, anti-TGF-ft antibodies suppressed tumour formation and metastasis of a breast carcinoma cell line in nude mice, while enhancing natural killer cell function. This suppression was not seen in beige mice, which lack natural killer cells, thus implicating TGF-01-induced suppression of natural killer cells in cancer progression (Arteaga et al., 1993). TGF-0-mediated suppression of neutrophil function may also be involved in tumour progression. Indeed, Fas-ligand expressing carcinoma cells underwent neutrophil-mediated rejection, but this rejection did not occur at a site with high TGF-0 levels or when TGF-01 was injected at the tumour site (Chen et al., 1998). Finally, TGF-0 down-regulates the expression of the major histocompatibility complex (MHC)...

Effects of cytotoxic chemotherapy

Cytotoxic drugs target dividing cells this means that cytotoxics have both anti-cancer effects and the potential to harm normal tissue, in particular cells that are continuously renewed, e.g. the epithelial lining of the stomach or hair follicles. There are many drugs available to treat the many different types of cancer. In this text and Table 4.2 we concentrate on categories of chemotherapeutic agents that are cytotoxic, i.e. drugs that act against cancer by killing the cancer cells themselves. There are other types of drugs to be aware of that do not fall into the 'cytotoxic' category, e.g. Herceptin, a drug developed from substances found in the immune system, is more likely to be referred to as immunotherapy.

Alternative Tissue Sources

The optimal source of xenogeneic islets remains controversial. Islets have been isolated from primates and xenografted into immunosuppressed, diabetic rodents, with short-term reversal of diabetes.98 However, there are ethical issues surrounding the use of primates for these studies. Other promising islet sources are porcine, bovine and rabbit islets, all of which function remarkably well in diabetic rodents.99 Long-term human, bovine and porcine islet xe-nograft survival has been documented in nude mice and rats, suggesting that, in the absence of an immune response, sufficient islet-specific growth factors are present in xenogeneic recipients.100

Subclinical Mastitis As A Risk Factor For Motherinfant Hiv Transmission

A recent study from South Africa found that exclusive breast feeding was associated with a lower risk of mother-to-infant transmission before 3 months than was mixed feeding.2 There are biologically plausible mechanisms whereby mixed feeding may carry the highest risk of HIV transmission. Breast milk, in addition to virus, contains antibodies and glycosaminoglycans which may inhibit virus binding to cells in the infant gut3, 4 various factors which can actively promote the infant's own immune function,5 and factors which promote development of gut integrity.6 Therefore, with exclusive breast feeding, the net result may be a low level of postnatal transmission. Feeding of other foods can damage the infant's gut and increase permeability. In breast feeding mixed with other foods, this increased permeability, together with decreased total amounts ofbreast milk immune factors, may tip the balance between virus and protective factors in milk and permit virus to enter infant cells more...

Preparation of Protein Protein Complexes

Protein-protein interactions play an essential role at various levels in information flow associated with various biological processes, such as gene transcription and translation, cell growth and differentiation, neurotransmission, and immune response. The interactions frequently lead to changes in the shape or dynamics as well as the chemical or physical properties of proteins involved. Solution NMR spectroscopy provides a powerful tool to characterize these interactions at the atomic level and at near physiological conditions. With the use of isotopic labeling, the structures of many protein complexes in the 40 kDa total molecular mass regime have to be determined (Clore and Gronenborn, 1998). The development of novel NMR techniques and sample preparation has been further increasing the mass size available for the structural determination of protein complexes. Furthermore, NMR has been utilized to quickly identify the binding sites of the complexes based on the results of chemical...

Islet Viability and Function

The permeability of immunoisolation devices must balance two potentially conflicting requirements. First, cells enclosed within the device must receive all the molecules and factors necessary for viability and normal function. Secondly, the destructive components of the immune system should be prevented from entering the immunoisolation device. Lymphocytes and macrophages are easily excluded by all immunoisolation devices however, many soluble products of the immune system such as complement protein, cytokines and nitric oxide may also be cytotoxic to immunoisolated cells. Islets of Langerhans in vivo are highly vascularized by a network of capillaries that deliver nutrients and oxygen to each beta cell. However, in the immunoisolation state, vascular assess to the islet is eliminated, and solutes move to and from the islet cells by diffusion from the surrounding environment. The diffusion gradients of wastes, nutrients, and especially oxygen are important.

Bioartificial Organ Rejection

Initiates the cellular and humoral immune response. The former leads to activation of cytotoxic cells, macrophages and other cells of the immune system. These cells must be prevented from contacting grafted tissue, a requirement relatively easy to meet. More difficult is keeping out components of the humoral immune response. These include cytokines, for example, interleukin-1, which can have detrimental effects on beta cells, as well as the antibodies formed as a response to the antigens, which have leaked across the barrier. In addition, there may always be some antibodies already present in the antibody spectrum of the blood serum which correspond to cell surface antigens (e.g., major histocompatibility complexes) on allo- or xenografts. Antibodies produced during preexisting autoimmune disease, such as type I diabetes, might also bind to surface antigens on allogeneic cells. Finally, macrophages and certain other immune cells can secrete low-molecular weight reactive metabolites of...

Antithyroid Drugs Thionamides

The two thionamide drugs used today are propylthiouracil (PTU) and methimazole (Tapazole). These drugs were developed in the 1940s when they were found to cause goiters in laboratory animals. They work similarly to block the formation of thyroid hormone within the thyroid cells. It is possible that they may also have effects on suppressing the immune system, decreasing the autoimmune effects of Graves' disease.

T Cell Recognition Of Nonpeptidic Antigens

The different trafficking pathways of the various CD1 isoforms reflect the physiological roles they fulfill CD1a to the sorting endosomes, CD1c to the early and late endosomes, and CD1b and CD1d to the late endosomes and lysosomes, allowing the sampling of lipid from different cellular locations. This has been seen with various lipids from mycobacteria CD1b has been shown to present free mycolates, phosphatidylinositolmannosides, and glucose monomycolates and CD1d has been shown to present glycosylphosphatidylinositiols 121 . CD1 is also able to bind self-diacylglycerols and self-sphingolipids, indicating that the CD1 molecules may also have a role in establishing tolerance against self-lipids 123 as well as presenting exogenous lipid antigens to the immune system. Recently, endogenous glycolipid ligands of CD1 molecules have been identified 127 , thus paving the way forward for mass spectrometric interrogation of these molecules as ligands for this very interesting family of...

Human immunodeficiency virus infection HIV

These changes in sleep structure may be due to cytokines and other mediators of the immune response and changes in growth hormone secretion which initially promote NREM sleep. The later changes occur when the immune response is failing and may be partly due to neuronal death or dysfunction caused by direct effects of the HIV, or to changes in production or release of neurotransmitters.

Stress Protein Gene Transfer Into Tumor Cells

Work over the past decade has demonstrated the importance of heat shock proteins in the immune response to many infectious agents. Heat shock proteins have also been implicated in a variety of autoimmune conditions and situations where inappropriate immune responses are occurring, such as the immuno-pathologically mediated nerve damage seen in leprosy (13) and in thryoid follicles of patients with Graves' disease (14). Among the explanations for such findings was the possibility that high levels of heat shock proteins in a particular cell or tissue could be increasing or altering processing and or presentation of self-molecules such that they were much more likely to be recognized by the immune system. This hypothesis was tested by transfecting the macrophage cell line J774 with the mycobacterial hsp-65 gene J774 cells are weakly immunogenic tumor cells of BALB c origin and are also derived from antigen-present-ing cells, and hence they provide an ideal model for testing the...

Possible Applications For Hsp 65 Gene Transfer In The Treatment Of Tumors

INEFFECTIVE IMMUNE RESPONSE TUMORS Figure 6 Possible explanation of increase in immunogenicity of tumour cells expressing the hsp 65 gene. Expression of hsp 65 results in more effective presentation of tumor-associated antigens, leading to a more effective immune response. Figure 6 Possible explanation of increase in immunogenicity of tumour cells expressing the hsp 65 gene. Expression of hsp 65 results in more effective presentation of tumor-associated antigens, leading to a more effective immune response. Clearly, many questions remain to be answered before such an approach could be applied in humans. However, the results with the murine J774 cells clearly demonstrate the role of heat shock proteins in the augmentation of immune responses.

Cell Based Approaches and ED

One of the most important recent discoveries in biomedical research is that stem cells are found in many tissues of adults that can provide new cells for normal tissue turnover and can regenerate damaged and diseased tissue 12 . Marrow stromal cells (mesenchymal stem cells) are adult stem cells from bone marrow that have multilineage differentiation potential and contribute to the regeneration of mesenchymal tissues, including bone, cartilage, muscle, and fat 13 . As marrow stromal cells are relatively easy to isolate, expand ex vivo, and gene engineer, genetically modified marrow stromal cells with desired genes have recently been used for gene delivery and tissue regeneration in the treatment of various diseases, including ED, with little or no host immune response 14 .

Poor Survival Of Cells Transplanted Into Damaged Myocardium After Ex Vivo Culture

A major limitation to successful cellular therapy in animal models of myocardial damage has been the inability of the introduced donor cells to survive in their host environment, whether such transplants have been congenic (analogous to the autologous scenario in humans) or allogeneic. It has become clear that a major impediment to survival of the implanted cells is the alteration of their immunogenic character by prolonged ex vivo culture conditions. For example, whereas myocardial implantation of skeletal muscle in the absence of tissue culture does not induce any adverse immune response and results in grafts showing excellent survival for up to a year, injection of cultured isolated (congenic) myoblasts results in a massive and rapid necrosis of donor myoblasts, with more than 90 dead within the first hour after injection (Murry et al., 1996 Nelissen-Vrancken et al., 1996 McEwan et al., 1998 Menasche et al., 2001). This rapid myoblast death appears to be mediated by host natural...

Future Directions for HSC Transplantation

Additional potential therapeutic strategies utilizing HSC gene therapy might be aimed at more effective treatment of malignancy, including targeting HSC and their progeny with genes for regulated drug chemotherapy and radiotherapy resistance (such as MDR-1 and BCL-2),141 to enable temporal resistance to therapies that destroy tumors at the cost of lymphohematopoietic failure. An additional example includes HSC-derived immunotherapy for malignancy, which may enable the generation of targeted graft versus tumor effect without GVHD. In this approach, a fraction of autologous or allogeneic donor HSC or common lymphocyte progenitors would be transduced with alpha-beta T-cell receptor (TCR) specific to known tumor associated antigens (such as Her2Neu in breast cancer, WT-1 or PR-1 in many leukemias) presented in the context of their HLA Class I or II, such that large numbers of antigens specific TCR transgenic T-cells would be developed from TCR transduced HSC or progenitors, and generate a...

Antigenic Characterization Antigenic Variability

Like the bacteria from the genus Ehrlichia, Anaplasma have the ability to escape mammalian immune system. This phenomenon was first identified in A. marginale, which parasites the erythrocytes of ruminants. The bacteria possess a major surface protein of 36 kDa named MSP2. This protein is encoded by the MSP2 multigene family (45). In infected ruminants, A. marginale may persist several years (up to seven years) due to cyclic variation of the MSP2 (46). Each A. marginale bacteremia is associated with an MSP2 variant. Ticks ingest with their blood meal a heterogeneous population of A. marginale MSP2 variants and this heterogeneity seems restricted when the A. marginale multiplies within salivary gland of the tick (46). Other members of the genus Anaplasma such as A. phagocytophilum possess the same multigene family suggesting that this phenomenon may support the persistence of these pathogens in their infected host (46,47). Moreover, MSP2 is considered an adhesion protein and its...

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