Alternative Ways to Treat Autoimmune Diseases

Autoimmune Paleo Cookbook

If you have an autoimmune disease, recipes can often be hard to find and you are often told the huge amounts of things like chocolate and certain foods with too high of a fat content that you can and can't eat. This eBook gives recipes that anyone can prepare without too much trouble. Even if you don't like cooking, this book makes cooking easy and breaks it down into steps. Best of all, the recipes do not taste like healthy medicine recipes. These recipes are delicious foods that anyone would want to eat, even if they didn't have to eat healthy. This book contains over 70 amazing recipes for anyone with an autoimmune disorder. The book comes with two free ebooks: 7 Steps to Living Well With an Autoimmune Disorder and The Top 10 Autoimmune Diseases Checklist. If you want to learn about your autoimmune disease and the best and worst foods for you, this is the book for you! Continue reading...

Autoimmune Paleo Cookbook Summary

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Highly Recommended

I started using this book straight away after buying it. This is a guide like no other; it is friendly, direct and full of proven practical tips to develop your skills.

When compared to other ebooks and paper publications I have read, I consider this to be the bible for this topic. Get this and you will never regret the decision.

Influence of FcyRIIa Polymorphism in Infectious or Autoimmune Disease

A few early studies have examined whether expression of the FcyRIIa-Arg His131 polymorphism influences susceptibility to infectious or autoimmune disease. In theory, the weaker binding of human IgG2 to the FcyRIIa-Arg131 variant suggests that this gene might be overrepresented among patients with recurrent infections characterized by certain microbes with polysaccharide coats (i.e., involving an IgG2 antibody response) and overrepresented in disease characterized by circulating immune complexes (because phagocytic cells bearing the FcgRIIa-His131 variant would clear these complexes more readily). Certainly, a skewed genotypic distribution favoring the FcyRIIa-Arg131 variant has been noted in patients with Haemophilus influenzae infections (Sanders et al., 1994) and meningococcal septic shock (Bredius et al., 1994b). Furthermore, there is also predominance of FcgRIIa-Arg131 in patients with elevated levels of immune complexes and glo-merulonephritis complicating systemic lupus...

Models of hapteninduced autoimmunity

Haptens have been intentionally applied to develop animal models of what are presumed to be human autoimmune diseases. Neurath et al. (20) applied small amounts of the hapten, trinitrobenzene sulfonic acid (TNBS) (a derivative of TNP), to the rectal mucosa of mice. This resulted in the development of a chronic transmural colitis accompanied by diarrhea and weight loss that mimicked human Crohn's disease. Histologic examination showed abundant CD4+ T cells that produced mRNA for gamma interferon in situ. Of great interest was the observation that the colitis persisted for at least 2 mo, obviously long after all hapten-modified cells had been shed and cleared. Therefore, the T cells, initially induced by hapten-modified mucosa, were able to recognize and react against unidentified proteins on normal mucosa.

Drug Induced Autoimmunity

A frequently studied example of drug-induced autoimmunity is drug-induced hepatitis that can be associated with the commonly used antihistamine, chlorpheniramine (23). Peripheral blood lymphocytes (PBLs), and several CD4+ clones derived from them, proliferated upon stimulation with a mixture of chlorpheniramine and a liver-derived protein, but not to the drug alone. These results suggested that the T-cell response was directed against the protein that had been modified, in a hapten-like manner, by the drug. In this system there was no detectable T-cell response to liver-derived protein alone, and the hepatitis resolved as soon as administration of the drug was stopped. There is evidence that the immune response induced by protein-drug conjugates can lead to autoimmunity against the native proteins. Drug-induced (e.g., hydralazine, qui-nidine, or isoniazid) systemic lupus erythematosus is associated with the development of auto-antibodies, particularly antinuclear antibody (24). As a...

Hsp70 Family Members Danger Signals And Autoimmunity

Abstract The 70 kiloDalton family of heat shock proteins (Hsp70) are known to stimulate immune responses and have been increasingly implicated in autoimmune conditions. Hsp70 proteins are present in pathogens as well as in healthy cells. They can be expressed constitutively or elevated in response to heat or other cellular stress. Immune responses stimulated by Hsp70 family members include triggering of innate inflammatory responses, enhancing antigen presentation to self-reactive T cells, and cross priming of chaperoned tumor and other self antigens. In this chapter, we present an overview of immunomodu-latory activities described for Hsp70 proteins and review the evidence implicating Hsp70 activity in autoimmunity. The ability of Hsp70 to stimulate anti-self tumor immunity and the prospect of using Hsp70 in vaccines or as adjuvants for cancer immunotherapy will be examined. Finally we discuss potential mechanisms by which Hsp70 proteins act as danger signals and regulatory molecules...

Using animal models to understand genetic contributions to autoimmunity

Rodent models of autoimmune disease have formed an important component of the scientific strategy to better understand the pathophysiology of these disorders ever since autoimmune diseases were originally described. Genetic tools and manipulation have in recent years allowed these rodent models to assume a new importance. Three major approaches have been used to study autoimmunity in murine models genetic linkage, genetic manipulation using transgenics and knockout models of individual genes and systematic mutagenesis strategies. Mouse strains exist which have an innate liability to develop autoimmune disease which resembles the diseases seen in man. Mouse models of autoimmunity that require antigenic induction of the disease phenotype (e.g. extrinsic allergic encephalomyelitis EAE or collagen-induced arthritis) provide an opportunity to map strain-specific susceptibility determinants. Spontaneous forms of autoimmunity are less artificial, the two most widely utilized being the...

Familial Infantile Myasthenia Gravis

Familial infantile myasthenia is rare, appears in children of mothers without myasthenia gravis, and presents in early infancy with ptosis, poor suck and cry, and secondary respiratory infections. Episodic crises of severe respiratory depression and apnea are precipitated by fever, excitement, or vomit-ing.151 180406 Other features include hypotonia, proximal muscle weakness, and easy fatigability, but the extraocular muscles are usually not involved. Inheritance of familial infantile myasthenia gravis has been reported to be autosomal recessive

Autoimmune Myasthenia Gravis

Acquired myasthenia gravis affects overall about 1 in 20,000 per year to 0.4 in 1,000,000 per year.519 Girls are affected two to six times as frequently as boys, and the incidence of the condition increases progressively through childhood until the end of the second decade of life. Afer the age of 50 years, males predominate the mean age of onset in women is 28 years and in men 42 years.519 Among the various childhood forms of myasthenia gravis, a recent series identified 25 (71 ) of 35 children as having the autoimmune disease.340

Other Interactions Between Metals And Proteinsimplications For Autoimmunity

Mercury has been shown to interact with the major autoantigen in Hg-induced experimental systemic autoimmunity, the nucleolar 34-kDa protein fibrillarin. First, by binding to sulfhydryl groups, fibrillarin is physically altered (Pollard et al., 1997). Second, nonap-optotic (necrotic) cell death caused by Hg modifies the proteolytic cleavage pattern for fibrillarin, resulting in neopeptides of fibrillarin (Pollard et al., 2000). Because exposure to Hg creates a 19-kDa immunogenic fragment of fibrillarin even without physical modification of fibrillarin, a new cleavage pattern of fibrillarin seems to be of prime importance for induction of autoim-munity development (Pollard et al., 2000). In another experiment, T-cell clones obtained from genetically Hg-susceptible mice that had been given repeated injections of Hg for 1 week reacted with Hg-carrying self-proteins, including Hg(II)-complexed fibrillarin (Kubicka-Muranyi et al., 1993 1995). After 8 weeks Hg treatment, the T-cell clones...

Metalinduced Autoimmunity

This is a seemingly paradoxical area of metal immu-notoxicology. Ample evidence from experimental studies demonstrate that certain metals, most notably Hg and Au, may cause autoimmune diseases in several species (Fournie et al., 2002 Hultman et al., 1995 Pollard et al., 2005 Schuhmann et al., 1990), but there are relatively few reports of metal-induced autoimmunity in humans. Some authors (Descotes, 1999) have, therefore, questioned whether metal-induced autoimmunity is a relevant issue for humans. Some factors must, however, be taken into consideration when trying to assess the potential of metals for inducing autoimmunity. First, induction of autoimmune diseases is heavily dependent on genetic susceptibility, and neither the susceptible genotype(s) in humans for metal-induced autoimmunity nor the number of humans that may carry such susceptibility is known. Because the genetic susceptibility to mercury-induced autoimmunity in rodents is, to a large extent, determined by MHC class II...

Acceleration of Spontaneous Autoimmune Diseases by Hg

Hg is a potent de novo inductor of a systemic autoimmune disease condition in rodents with certain MHC (H-2) class II genotypes (Fournie et al., 2002 Pollard and Hultman, 1997). Although these rodent models continue to be very useful for explaining immunological mechanisms in systemic autoim-munity, dose-response studies applied to humans make it likely that de novo induction of autoimmu-nity by these agents will require exposure levels occurring only in specific hazardous work places or during accidental exposure or voluntary ingestion. However, uncertainty prevails regarding the existence and prevalence of especially susceptible genotypes (Chapter 33). et al., 1999). However, recent studies have shown that the autoimmunity may be severely aggravated also in the MRL-lpr lpr strain, provided that a lower dose of Hg is administered (Pollard et al., 2005). By use of the AKR strain, which is H-2 congenic with the MRL strains, aggravation of the autoimmune disease was linked to non-MHC...

Acceleration of Spontaneous Autoimmune Diseases by Cadmium and Lead

Recent studies using Cd and Pb have expanded the results obtained by Hg. Cd in a high dose increased the ANA in autoimmune-prone NZBWF1 mice during the first months of treatment, whereas a lower dose increased the IgG2a serum level and the proteinuria, although without affecting the IC deposition (Leffel et al., 2003). As mentioned previously, Pb enhances the autoimmune manifestations in autoimmune-prone NZBWF1 hybrid mice (Rudofsky and Lawrence, 1999). A recent study on lead in four New Zealand mixed strains revealed a complex relation between the spontaneous autoimmune disease, Pb exposure, genetics, and gender, leading to different phenotypic outcome both acceleration and inhibition of the autoimmune condition were observed (Hudson et al., 2003).

Humoral Immunity As Indirect Evidence For Autoimmunity In Ms

Molecular studies indicate that production of Abs in the CNS of MS patients is antigen-driven, making an indirect case for autoimmunity. The complementarity-determining regions (CDR) of Abs are the antigen-binding sites, and include the Ig heavy-chain variable (VH) region. Somatic hypermutations occur in the CDR when B-cells are exposed to their antigen these mutations often lead to amino acid substitutions that enhance Ig affinity for target antigen leading to affinity maturation.''

Organspecific Autoimmune Disorders

Myasthenia gravis results from a defect in neuromuscular transmission. (1) Myasthenia gravis is associated with the presence of an anti-acetylcholine receptor antibody. Binding of this antibody with the receptor at the postsynaptic membrane of the neuromuscular junction results in the loss (endocy-tosis) of the receptor.

Myasthenia Gravis

Myasthenia gravis is a common cause of ocular complaints, often diagnosed late. It may present as weakness of one muscle or one eye or any com Look at the patient's eyes and keep looking. She may blink three times with blinks of the same duration and the same interval between blinks, but she does not open as wide after each blink. Then, in the fourth blink, she keeps her eyes closed for 10-20 s. She is not sleeping and you are not that boring when she finally opens her eyes after the long blink, her ptosis is less pronounced and you can see more of her eyes. She then has three or four of her usual blinks with her ptosis increasing and then has another long blink. You are looking at a patient with myasthenia gravis. When the eye opening muscles are weak and the eye closing muscles are also weak, the diagnosis is almost always either myasthenia gravis or one of the CPEOs (see the following section). Therefore, when the patient has pto-sis (you know the eye openers are weak) test the eye...

In Vivo Immune Effects Of Senescent T Cells

The significant correlation between high proportions of CD8+CD28 T cells and poor antibody response to influenza vaccination documented in two independent clinical studies (Goronzy et al., 2001 Saurwein-Teissl et al., 2002) provides an example of putative suppressive effects of senescent CD8+ T cells on the function of other immune cells. Senescent CD8+ T cells have also been associated with suppressive effects in organ transplant patients. Donor-specific CD8+CD28 T cells are detectable in the peripheral blood of those patients with stable function of heart, liver and kidney transplants, whereas no such cells were found in patients undergoing acute rejection (Cortesini et al., 2001). Although in the context of organ transplantation, suppression may lead to a favorable outcome, in many other contexts, the CD8+CD28 T cell populations are associated with deleterious effects. For example, expanded populations of CD8+CD28 T cells are present in ankylosing spondylitis patients, and, in...

Alzheimers Disease And Atherosclerosis

Importantly, several types of infections have been hypothesized to increase the risk of CVD by causing systemic inflammation, or by triggering autoimmunity, for example, by cross-reactivity of heat shock proteins (hsp) with bacterial antigens (Mayr et al., 1999). Indeed, clinically healthy volunteers with sonographically documented carotid artery atherosclerosis have significantly increased antibody titers to hsp 65 compared to controls with no lesions, and in follow-up studies, those with highest titers showed highest mortality. The blocking of the hsp65 effect by T cell immunosuppressive agents further implicates specific immunity in the pathogenesis of atherosclerosis. Most recently, there was a report showing expanded populations of senescent CD8+ T cells in patients with coronary artery disease as compared to controls, further underscoring the potential involvement of chronic antigen-driven proliferation in atherosclerosis (Jonasson et al., 2003).

Antiphospholipid antibodies

This is an acquired condition, sometimes associated with systemic lupus erythematosus or other autoimmune diseases in its secondary form. Lupus anti-coagulant and anti-cardiolipin antibodies together form the anti-phospholipid antibody family.41 The prevalence of anti-phospholipid antibodies in patients with VTE ranges from 5 to 15 , while the prevalence in the general population is not well established.42,43 Clinically, individuals with this acquired throm-bophilic state may develop venous or arterial thrombosis and recurrent foetal loss. Placental insufficiency is thought to be the cause of the obstetric complications.42,43 It has been shown that the thrombotic risk in individuals with this abnormality is increased 9-fold, and the probability of recurrence may be higher.44

Increased Destruction Immune

Immune thrombocytopenia (ITP) Discussed at length in Chapter 11. ITP is a classic autoimmune disorder of young women. Usually it presents in an otherwise healthy person who notices the onset of increased bruising and petechiae. ITP is a diagnosis of exclusion. Treatment is evolving but initial therapy is steroids, with splenectomy for steroid failures. Severe thrombocytopenia with bleeding can be treated with immunoglobulin or anti-D (WinRho).

Active tumormediated immunosuppression mechanisms of tgfP action

TGF-P was first found to have a role in T-cell biology through its production by T cells and its role in inhibiting the interleukin-2 (IL-2) dependent proliferation of T cells (Fig. 2 16). Independent of this antiproliferative effect, TGF-P also inhibits the differentiation of T cells, and in general, prevents naive T cells from acquiring effector functions (to become cytotoxic T lymphocytes CTLs or T-helper cells under the appropriate circumstances) (17). TGF-P may mediate some of its immunosuppressive effects on T cells through secretion by and cell surface expression on CD4+CD25+ regulatory T cells (18). These in vitro effects have been validated in murine models. For example, TGF-P 1-deficient mice develop a severe autoimmune phenotype leading to death by 3 wk, resulting in part from overactive T cells (19). In addition, T-cell-specific abrogation of TGF-P signaling in mice (by expression of either the inhibitory Smad, Smad7 (20) or dominantnegative TPRII 21,22 ) results in...

Intercurrent Factors With Possible Association

Although the prevailing wisdom is that MS is an immune-mediated condition (102), it fulfills few of the criteria of an autoimmune disease (103). Rose and Bona (104) stated that'' with new knowledge gained from molecular biology and hybridoma technology, as well as the original Witebsky postulates, evidence that a human disease is autoimmune in origin includes direct evidence from transfer of pathogenic antibody or pathogenic T-cells indirect evidence based on reproduction of the autoimmune disease in experimental animals and circumstantial evidence from clinical clues.'' But MS certainly cannot fulfill Koch's postulates (direct evidence) due to the ethical problems of the necessary experiment, and satisfies their criteria only by the indirect evidence of experimental autoimmune encephalomyelitis (EAE). The problem with this is that there are important pathological as well as clinical differences between EAE and MS, as remarked by Chaudhuri and Behan (103), who have The evidence that...

Is There a Genetic Predisposition to MDS

Families with several members affected by MDS are described, but are exceptionally rare (Lucas et al. 1989). Although still very rare, familial MDS may be more likely in the family of a child with monosomy 7 (Luna-Fineman et al. 1995). An increased risk for autoimmune disease has been correlated with specific Human Leukocyte Antigen (HLA) subtypes. The response of selected MDS patients to immunosuppressive therapy catalyzed the search for an HLA restriction in MDS. Although an increased prevalence of HLA-DR2(i5) has been reported in MDS (Saunthararajah et al. 2002), this finding has not been consistent (Deeg et al. 2004 Go-wans et al. 2002).

Influence of Age Related Decline in Immune Function and Influence on Intestinal Bifidobacteria Microbiota

Immunosenescence is defined as the state of deregulated immune function that contributes to the increased susceptibility of the elderly to infection and, possibly, to autoimmune diseases and cancer (49,50). When immunosenescence appears, the functional capacity of the immune system of the host gradually declines with age. The most dramatic changes in immune function with age occur within the T cells compartment, the arm of the immune system that protects against pathogens and tumors (51-54). The fact that T lymphocytes are more severely affected than B cells or antigen-presenting cells is mainly due to the involution of the thymus, which is almost complete at the age of 60. The host is then dependent on the T cells of various specificities, which eventually leads to changes in the T cell repertoire. CD45RA + native cells are replaced by CD45RA memory cells, and a T cell receptor oligoclonality develops. At the same time, T cells with signal transduction defects accumulate. Age-related...

Causes and symptoms

Other researchers are also looking into the possibility that narcolepsy may be caused by some kind of autoimmune disorder. This theory suggests that the person's immune system accidentally turns against the specific area of the brain that controls alertness and sleep, injuring or destroying it.

OG Reconnect to chapter 3 Active Transport page

Myasthenia Gravis In an autoimmune disorder, the immune system attacks part of the body. In myasthenia gravis (MG), that part is the nervous system, particularly receptors for acetylcholine on muscle cells at neuro-muscular junctions, where neuron meets muscle cell. People with MG have one-third the normal number of acetylcholine receptors at these junctions. On a whole-body level, this causes weak and easily fatigued muscles.

Contraindications And Precautions

Commission E warns against using echinacea in cases of autoimmune disorders, such as multiple sclerosis, SLE and RA, as well as tuberculosis or leukocytosis (Blumenthal et al 2000). This is based on theoretical considerations and has not been tested in controlled trials. In practice, echinacea has been successfully used by herbalists in autoimmune disease without mishap (Mills & Bone 2005). Duration of use Based on evidence that parenterally administered echinacea reversibly depresses immune parameters, Commission E has recommended that echinacea should not be used for more than 8 weeks. However, in a study in which it was taken orally for up to 6 months, no changes in immune parameters were detected (Vonau et al 2001). As such, no conclusive evidence demonstrates that long-term use is detrimental.

Granulocyte Colony Stimulating Factor

Induction of autoimmunity to murine MuG-CSF required the use of immunostimu-latory MuG-CSF conjugates (39). Immunized mice developed neutropenia coincident with an IgG autoantibody response, without effect on other peripheral blood parameters or on the number of marrow progenitor cells. The neutropenia was sustained for > 9 mo. Hematologically, these mice phenocopied mice with absolute G-CSF deficiency owing to disruption of either the G-CSF ligand (40) or receptor (41) genes.

Adrian P Kelly and John Trowsdale

The MHC, the region of the genome widely believed to be associated with disease resistance, is in fact linked with more disease susceptibility than any other region of the human genome (Price et al., 1999). One explanation for this paradox is that there is a net cost in providing resistance to infection. In other words, improved resistance to infection, manifest as a more effective immune response, results in a greater propensity to autoimmune disease. In this article we will explore this proposal by examining the main features of the MHC, the functions of the genes it contains and its role in disease (Lechler and Warrens, 2000 Marsh et al., 2000).

Environmental effects

The environment plays a major role in determining the onset and course of most autoimmune diseases. These effects contribute up to 40 of the susceptibility (Janeway et al., 2001). Most environmental factors remain to be determined although there has been no shortage of candidates. One reason why they may be so difficult to identify is that the disease symptoms may develop many years after the triggering events in the environment. Top of the list of candidates for the environmental triggers are infections. Intestinal bacteria are obvious candidates for the HLA-B27-associated conditions. Although many different organisms have been proposed as triggers, identification of precise microbial species has proved elusive so far. It may turn out that the triggers include a variety of non-specific infections. An interesting alternative possibility is that infections act to prevent disease by shaping the T cell repertoire and it is the lack of such infections in modern western cultures that may...

Mechanisms for MHC associations

Several plausible mechanisms have been proposed to explain the MHC association with autoimmunity but in no case has the precise mechanism been identified. Identification of the mechanism involved in autoimmunity is confounded by the problem that the symptoms of disease tend to occur long after the initiating events. By the time the condition has been diagnosed the inflammation around the target tissue has stimulated recruitment of T cells to a wide range of antigens. One popular idea is the molecular mimicry hypothesis. It is proposed that T cells activated by presentation of a microbial antigen cross-react with peptides present in a self antigen. The associations of particular MHC alleles arise because these would be the allotypes that present the microbial peptide or the cross-reactive self peptide. In summary, the current view of autoimmune disease involves a predisposition resulting from a combination of genetic and environmental effects. HLA provides the major genetic...

Plasmids With Genes for Fusion Proteins

Another approach to multifunctional DNA vaccines is based on covalent linking of two or more proteins (Fig. 2C). A number of DNA vaccines containing genes encoding fusion proteins have been generated. The array of possible applications of such vaccines ranges from inhibition of allergic reactions (87), through suppression of autoimmunity (88,89), to boosting vaccine-induced immunity (90). Here we present only a few out of many promising applications of this technology.

Safety concerns and ethical issues

Genomic integration of plasmid DNA is among several concerns connected to the application of DNA vaccines. Although a justifiable concern if considering mass use of gene replacement technology in the population, it may be less important when considering the limited use in terminally ill cancer patients. In essence, cancer patients already carry deregulated genes and the possibility of integrating an additional piece of DNA carrying potential treatment may be less objectionable. Moreover, the probability of plasmid integration to genomic DNA is very low (151,152), and considering the small percentage of coding and regulatory sequences in the human genome (153), the probability of plasmid integration into these functionally important regions is practically negligible. Other concerns, such as the potential for induction of immunologic tolerance or autoimmunity, and possible induction of anti-DNA antibodies, also have very little scientific confirmation at this time (154).

Clinical Presentation

Hypofunction usually manifests as xerostomia although some of those who complain of a dry mouth will have perceived rather than real salivary dysfunction. Common causes of xerostomia include drug effects, post-radiotherapy changes and autoimmune disease and, less often, endocrine disturbances.

Nonneoplastic Conditions

Graves' disease the commonest cause of hyperthyroidism and is characterised by thyrotoxicosis, a diffuse goitre, ocular signs and pretibial myxoedema. It affects females much more often than males and usually presents between the ages of 20 and 40 years. It is an autoimmune disease the thyrotoxicosis is due to activation of the TSH receptor when the autoantibodies bind to it. Typically, the gland is symmetrically and diffusely enlarged, weighing between 50 and 150 g. Histologically the lobular architecture is preserved. There is reduced colloid in the small irregular follicles, which are lined by tall active-looking columnar cells. Simple non-branching papillary infoldings are often present. Hashimoto's thyroiditis a common cause of hypothyroidism and is characterised by hypothy-roidism and firm diffuse goitre. It affects females much more often than males and usually presents between the ages of 30 and 50 years. It is an autoimmune disease the hypothyroidism is probably due to a...

Response To Immunosuppressive Therapies Suggests An Autoimmune Etiology

Glucocorticoids have a multitude of inhibitory effects on the immune system. They decrease expression of pro-inflammatory cytokines such as TNFa, IL-2, and IFN-y (117,118). In most studies, they have been shown to increase expression of anti-inflammatory cytokines such as IL-10 and TGFp-1 (119,120). Glucocorticoids also decrease MHC I and MHC II expression (121), induce T-cell apoptosis (122), inhibit nitric oxide synthesis (123), decrease expression of the adhesion molecules E selectin and ICAM-1 (124), decrease CSF matrix metalloproteinase 9 levels (125), decrease CSF IgG (126), and inhibit macrophage phagocytosis (127). Likewise, IFN-p induces a shift toward Th2 T-cell responses (128), inhibits T-cell activation (129), inhibits metalloproteinase-9 production (130), decreases Thl cytokine levels (131), modulates adhesion molecule activity (130,132), and has other anti-inflammatory effects that are still being elucidated (133). Glatiramer acetate alters the Th1 Th2 balance toward Th2...

Applications for Transient Gene Therapy

The technical innovations described above are at best laboratory proofs that will require extensive animal studies before clinical testing. However, the clinical data to date suggests that success with currently available Ad vectors is possible in applications where transient expression might be sufficient. For example, studies of therapeutic angiogenesis for coronary artery disease described above are a prototype of this type of application. Medical indications such as cancer, infectious disease, tissue remodeling (angiogenesis, recovery from surgery, stroke, or injury) are areas where development might be most appropriate. In contrast, metabolic and genetic disease, autoimmune disease, and other chronic conditions would seem to need substantial advances in adenoviral vector design or more likely some kind of hybrid vector before they become treatable on a persistent basis. Importantly, the knowledge of the cellular and host response to Ad infection in humans is still quite...

Development of Delayed Type Hypersensitivity Responses 861 Method for DTH Testing

Following vaccine treatment, five patients (2 ) exhibited a small (5-6 mm) DTH response to autologous, unmodified PBLs after treatment. This could have represented a T-cell response against normal-tissue antigens, but is more likely to be artifactual, since no other manifestations of autoimmunity were observed. As expected, 52 of patients developed DTH to DNP-modified PBLs, but in no case was the response cross-reactive with 7WP-modified PBLs.

Proinflammatory Function For Grp94

Relating to the observations noted above, the Kaufman laboratory has reported an unexpected link between danger signals (i.e. adjuvants), inflammation, and activation of the unfolded protein response signaling pathway (Zhang et al., 2006). It is well established that the accumulation of unfolded proteins in the ER triggers the unfolded protein response (UPR), which leads to the activation of a transcriptional program yielding a pronounced up-regulation of ER chaperone synthesis. Kaufman's group has found that pro-inflammatory cytokines (IL-ip and IL-6), and more significantly LPS, also activate the UPR signaling pathway both in vivo and in vitro. The exact mechanism leading to UPR signaling after detection of LPS or pro-inflammatory cytokines is not yet known these findings nonetheless provide a glimpse into the signaling pathways operating in response to adjuvant administration in the animal. This research points to new avenues of research that can be pursued in an effort to...

What Is The Pathogenic Role Of Inflammation In Ms

Lesion, including interleukin-1,2,4,6,10,12, gamma-interferon (y-IFN), tumor necrosis factor alpha (TNF-a), and transforming growth factor beta (TGF-p) (16,17). Activated endothelial cells in active lesions express adhesion molecules, fibronectin, urokinase plasmin activator receptor, major histocompatibility complex (MHC) molecules, chemokines and their receptors, and stress proteins (18). In some MS patients, immunodominant peptides of MBP become complexed with DR2 molecules at sites of demyelination (19), and T-cell clones with receptors specific for MBP have been found in MS lesions (20). These observations, coupled with the pathologic similarities between MS and experimental autoimmune encephalomyelitis (EAE), suggest that MS is an autoimmune disease, initiated by MHC-class II-restricted CD4+ Th1 lymphocytes that produce pro-inflammatory Th1 cytokines. This leads to the recruitment and activation of hematogenous macrophages, which destroy myelin sheaths, either via toxic...

Source Preparation and Antigen Loading Strategy

Several systems have been employed to load DCs with TAA. Loading MHC class I molecules with peptides derived from defined antigens is most commonly used, and is also applied to recently identified MHC class II helper epitopes. Although important for proof of concept studies, the use of peptides is limited because of their restriction to a given HLA type, the limited number of defined TAA, and the induction of a restricted repertoire of T-cell clones. Furthermore, quantity and longevity of peptide loading is difficult to control. Alternative strategies that provide both MHC class I and class II epitopes and lead to a diverse immune response involving many clones of CD4+ T cells and CTLs are needed. These include recombinant proteins, exosomes (vesicles rich in MHC-peptide complexes and heat shock proteins) (77), viral vectors, plasmid DNA, RNA transfection (78), dying tumor cells, opsonized tumors (38), immune complexes, or fusion of tumor cells and DCs (79). Few comparative data...

Nephrotic Syndrome and Other Renal Disease

Pathogenesis of the hypercoagulable state in nephrotic syndrome is urinary loss of natural anticoagulants. Low levels of both antithrombin and protein S are commonly seen. The presence of concurrent autoimmune diseases such as lupus may add associated antiphospholipid antibodies to the mix. The hypercoagulable state seen in other renal disease is less well defined. Plasma homocysteine levels are markedly elevated in renal failure and this may play a causative role in the thrombosis. Renal transplantation is also accompanied by a higher risk of thrombosis (Table 18.1). Patients with pre-existing hypercoagulable states, especially those with antiphospholipid antibodies, are at higher risk for graft thrombosis. Infusion of OKT3 has been also associated with thrombosis. Patients with a history of thrombosis should be evaluated for hypercoagulable states prior to undergoing transplantation. Patients with underlying autoimmune disease should also be evaluated for antiphospholipid...

Systemic Associations

Similar to dorsal midbrain syndrome, INO is an anatomic rather than etiological diagnosis. A host of structural, metabolic, immunological, inflammatory, degenerative, and other processes can interfere with the function of the MLF and nearby structures. In young adults, multiple sclerosis is by far the most common cause of INO.342 Multiple sclerosis also underlies most cases of bilateral INO. Although patients with bilateral INO generally remain orthotropic in primary position, they sometimes exhibit an exotropia in the wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome.311 Additional causes of INO include Arnold-Chiari malformation,23,99,118,533 hydrocephalus,352 meningoencephalitis,64,226 brainstem or fourth ventricular tumors,99,439,482,496 head trauma,49,84,254 metabolic disorders, drug intoxications, paraneoplastic effect, carcinomatous meningitis, and others. Peripheral processes, particularly myasthenia gravis and Miller Fisher syndrome, may closely mimic INO and...

HAART Influence on skin and mucocutaneous diseases

Immunosuppressive therapies, such as ultraviolet light and cyclosporin, should be limited to a few conditions such as severe autoimmune diseases, and used only with careful clinical and laboratory monitoring. Photo(chemo)therapy is able to provoke viral infections such as herpes zoster and herpes simplex, epithelial tumors, and to

Hsp60 A Pleiotropic Immune Signal

The HSP60 molecule, as it performs its chaperone function in stressed cells, also functions as a regulatory signal molecule to the wandering cells of the immune system on the look out for trouble (Figure 2). HSP60 is present in the blood during inflammation, and has been found to be a target of autoantibodies and autoimmune T cells. Moreover, HSP60 induces pro-inflammatory responses in innate immune cells. However, the administration of HSP60 was found to arrest the destructive inflammation responsible for various models of autoimmune diseases. Some explanation for this fact may be found in our recent discovery that HSP60 can directly regulate T and B-cell responses, via TLR2 and TLR4 respectively, leading also to the resolution of inflammation. The full clarification of dynamics of the crosstalk between the two arms of responses induced by HSP60 need to be worked out the results will give us a new perspective in understanding of the role of HSP60 in inflammatory response and how we...

Specific Defenses Immunity page 661

Immune complex allergic reactions involve autoimmunity, which is an immune reaction against self antigens. 10. Autoimmunity a. In autoimmune disorders, the immune system manufactures autoantibodies that attack one's own body tissues. b. Autoimmune disorders may result from a previous viral infection, faulty T cell development, or reaction to a nonself antigen that resembles a self antigen. c. Retained fetal cells can cause a condition that resembles an autoimmune disorder.

The Evolution Of Immunity

For example, four Defensin families are found in eukaryotes Alpha-Defensins and Beta-Defensins in mammals, insect Defensins, and plant Defensins (Hoffmann, Kafatos et al. 1999). This general mechanism arose long ago and clearly has remained useful up to the present. The production of nitric oxide by plants for use by the hypersensitive response, in inducing apoptosis and the expression of genes that induce the production of antimicrobials, is enzymatically similar to nitric oxide production in animals (Clarke et al. 2000), which is also used as an antibacterial toxin and against tumor cells (an appropriate type of autoimmunity) (Roitt, Brostoff et al. 1998). The associated cell death that occurs in the HR reaction in plants is functionally analogous between plants and mammals it is even found in bacteria. Cytotoxic T cells can signal a targeted cell to undergo apoptosis (Roitt, Brostoff et al. 1998). We have seen many ways, including apoptosis, by which normal development is based on...

Transient Neonatal Myasthenia

Transient neonatal myasthenia is seen in approximately one of seven infants born to mothers with myasthenia gravis. All these babies develop a weak cry and difficulty sucking in the first several days of life, and about half become generally hypotonic. This condition, caused by antiacetylcholine receptor antibody (anti-AChR antibody) received by the baby from the mother's circulation,292 responds promptly to anticholinesterase agents but will resolve in 1 to 12 weeks if untreated.344,530 There is no relapse or long-term sequela.

Congenital Myasthenic Syndromes

The frequency of congenital myasthenic syndromes varies from 8 to 21 in reported series of childhood myasthenia gravis, reportedly higher where consanguineous marriages are frequent.18,340 In the fetal period, decreased fetal movements have been reported, resulting in arthrogryposis multiplex congenital, congenital flexures, and contractures of multiple joints.498 Affected patients are born to mothers without myasthenia and may demonstrate ptosis and ophthalmoparesis during infancy. Severe generalized weakness may also present in the postnatal period with frequent apneic episodes, recurrent aspiration, failure to thrive, and poor sucking. Other patients may present during the first or second year of life with ocular signs and only mild systemic signs. Although ptosis was reported to be present in all of seven patients in one series,340 it was generally mild and not incapacitating. These disorders persist throughout life and can be distinguished from acquired myasthenia gravis and from...

Immune Function Assessment

Phenotypes of genetically altered mice can be validated and enhanced by conducting basic immune function assays. These assays provide information to distinguish whether phenotypic characteristics are associated with secondary changes and ill health, or are the direct or indirect result of genetic manipulation. Basic immune analyses provide further evidence of the validity of these observations. In addition, novel phenotypes can be identified for understanding molecules and pathways involved in immunocyte development and immune function, including immunodeficiency, cancer, autoimmunity, biology of aging, and resistance to infectious diseases. The identification of lineage-specific developmental defects in mutant mice is also possible.

Development of the Concept Metal Immunotoxicology

The potential of metals, or more accurately metallic elements, their ions and their compounds (Duffus, 2003), to cause widely divergent effects on the body because of an interaction with the immune system is a recently discovered path in the history of metal tox-icity. Disease conditions like occupational asthma and dermatitis were associated with exposure to metals such as platinum, chromium, nickel, beryllium, and mercury during the first part of the 20th century or earlier. However, a clear recognition of these conditions as immune mediated had to await the rapidly expanding knowledge in immunology during the 1960s and 1970s. At the same time, animal studies linked metal exposure with immunosuppression, as well as nonspecific immune stimulation (Koller, 1973 Vos, 1977). Metals as a mean of inducing autoimmunity began to be explored in the late 1970s. The state of the art was summarized at the International Symposium on the Immunotoxic-ity of Metals and Immunotoxicology held in...

Overview of Mechanisms in Immunotoxicology

Like all xenobiotics, metals (and their metabolites) may have a direct or indirect action on the immune system. This might take the form of morphological damage to immunologically active tissues such as the thymus, lymph nodes, spleen, and myelopoiesis (bone marrow and peripheral blood), which might be grossly or microscopically evident. Further studies may show these morphological alterations to be due to abnormalities in cell proliferation, necrotic and or apoptotic cell death, causing, for example, alterations in populations of immunocompetent cells such as T and B cells and dendritic cells. Subpopulations such as T-helper type 1 and type 2 cells may also be altered by metals, disturbing the balance in finely tuned immune reactions. The functional effect of these morphological alterations may be assessed by measuring a number of endpoints related to innate, humoral, or cell-mediated immunity in vitro and in vivo using experimental animals or in humans. This forms the basis for...

Testing Dietary Interventions in Autoimmune Prone Mice to Delay Aging and Age Associated Diseases

Research because CR is the only known experimental regimen to increase life span in all experimental models tested including yeast, nematodes, flies, and rodents (Jolly, 2004). The models examined are not malnourished because the CR diets have enriched vitamin and mineral content to compensate for the decreased food intake. CR is also potent at delaying the onset of diseases like autoimmune disease and certain types of cancer. Therefore, it appears that CR may be a dietary regimen that not only increases life span by altering the biological process of aging, but also improves the quality of life by decreasing the severity of age-related diseases. proinflammatory transcription factor nuclear factor kappa B (NF-kB) activation (Jolly, 2004). In peripheral blood, CR blunted the disease-induced increases in IL-2 and IFN-y production by both CD4 and CD8 T cell subsets as well as IL-5 production in CD4 T cells (Jolly, 2004). In contrast, CR reduced the disease-associated increase in IFN-y...

Autoimmune Prone Mice as a Model of Chronic Inflammation and Heart Disease

Omega-3 fatty acids can be derived from many food sources. Flaxseed oil, enriched in linolenic acid, and fish oil, enriched in eicosapentaenoic acid and docosahex-aenoic acid, are the two sources of omega-3 fatty acids that have been commonly used to examine the anti-inflammatory properties of omega-3 fatty acids. However, direct comparisons of the two oils are limiting in the literature. Recent evidence suggests that both flaxseed and fish oil could decrease T-lymphocyte proliferation ex vivo in rats, but fish oil was the most potent. Whether this translates into fish oil being the most effective at delaying the onset of heart disease and or autoimmune disease needs to be directly addressed.

Clinical Assessment

To make a decisive observation, it is important, both before and after giving these drugs, to quantitate as accurately as possible the function of the affected muscle(s) through measurement of pertinent indicators such as lid height in primary position, levator function, saccadic velocities, ocular movement, ocular alignment, and orbicularis strength. After administering Tensilon, the examiner observes for tearing and lid fascicula-tions as evidence of cholinergic effect, and draws no conclusion if a paradoxic decrease in muscle function occurs, because this may happen in the presence or absence of myasthenia. Positive responses after either drug are fairly reliable evidence for myas-thenia but can, on rare occasions, occur in nonmyasthenic patients. False-negative responses, however, are common and therefore do not exclude myasthenia gravis. or fewer of ocular myasthenics.149,463,519 According to other reports, specifically on juvenile myasthenia gravis patients, the frequency of...

Resection Specimens

Thymectomy performed for benign or malignant thymic tumours, treatment of myasthenia gravis or may be incidental during thoracic surgery such as open-heart surgery. If the thymus is not very large, thymectomy may be carried out through a transcervical route. The usual surgical approach is through either partial or complete sternotomy. Median sternotomy involves the use of an incision in the midline from the suprasternal notch to just below the xiphoid process with division of the sternum longitudinally. Ideally there should be complete removal of the thymus with surrounding margins of normal tissue. Alternatively, tumour debulking may be undertaken. The clinical ease of excision, and the tumour circumscription or degree of spread into adjacent tissues, are strong indicators of potential for future local recurrence and invasion.

Complex Mediated Reactions

Combination of antigens and antibodies in the circulation with subsequent deposition of the immune complexes in the tissues leads to complement activation and inflammation. Alternately, the formation of the immune complexes may develop in situ in the tissues when either the antigen or the antibody is planted in the tissues separately. Type III reactions are important in all spontaneous, systemic autoimmune diseases (Jancar and Sanchez Crespo, 2005). In connection with metals, type III reactions have mostly been associated with Au (Gunnarsson et al., 2001) and Hg (Oliveira et al., 1987 Tubbs et al., 1982).

The Pro And Antiinflammatory Properties Of The Stress Protein Gp96

Abstract Although the stress protein gp96 is commonly perceived as being a universal activator of antigen presenting cells and an inducer of tumour-specific immunity, at high doses it can inhibit the induction of tumour-specific immunity and experimental autoimmune disease by a mechanism which appears to involve immunoregulatory CD4+ T cells. Studies have shown that gp96 can also delay the rejection of allogeneic skin and cardiac transplants. This chapter summarises the work which has attributed pro- and anti-inflammatory properties to gp96 and highlights the potential mechanisms that might mediate the dual functionality of this molecule

Clinical Aspects

A major cause of thymic enlargement can be neoplasms of the immune system. Thus, in childhood, acute lymphoblastic leukemias or malignant non-Hodgkin's lymphomas can be found. Myasthenia gravis can also be the consequence of a thymus neoplasm. Some immunodeficiency diseases are listed in Table 17-2.

Biochemistry And Pathology Of Macular Degeneration

Furthermore, the codistribution of IgG and terminal complement complexes in drusen implicates an immune response directed against retinal antigens, and the immune complex formation might be taking place at the site of drusen formation. This hypothesis is supported by the presence of putative anti-retinal autoantibodies in the sera of patients with ARMD. Anti-retinal autoantibodies previously have been reported in a number of ocular disorders, including retinitis pigmentosa, paraneoplastic retinopathies, and retinal vasculitis (Anderson et al., 2002). In addition, patients with membranoproliferative glomerulonephritis, in which complement activation and immune complex deposition cause glomerular injury, develop drusen deposits resembling those in ARMD in ultrastructure and composition including C5 and IgG. However, the role of antiretinal autoantibodies in the pathogenesis of ARMD has not been examined in detail. It remains unknown whether the initiation of chronic inflammation and...

General Considerations

Environmental and other agents may induce various phenotypic expressions of autoimmune diseases because of interaction with different genotypes. This includes the possibility of not only de novo autoimmune disease but also an acceleration and aggravation of autoimmune conditions with other primary genetic or nongenetic etiologies. For example, in experimental models, the polyclonal B-cell activating agent lipopoly-saccharide-lipid A portion (Hang et al., 1983), UV radiation (Ansel et al., 1985), halothane (Lewis et al., 1982), and polyinosinic polycytidylic acid (Carpenter et al., 1970) accelerate spontaneous autoimmune disease manifestations. For metals, important observations on this subject have recently emerged from studies in rodents.

Vitamin B12 Deficiency Causes Pernicious Anemia

Pernicious anemia arises when vitamin B12 deficiency blocks the metabolism of folic acid, leading to functional folate deficiency. This impairs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia). The commonest cause of pernicious anemia is failure of the absorption of vitamin B12 rather than dietary deficiency. This can be due to failure of intrinsic factor secretion caused by autoimmune disease of parietal cells or to generation of anti-intrinsic factor antibodies.

Comments on the Autoimmune Effects of Metals

The ability of metals to accelerate and aggravate genetically, as well as nongenetically, determined autoimmune disease processes in rodents is an important new observation in the immunotoxicology of metals. Although a few of these studies included some dose-response data, the potential importance of these findings for human conditions and the variation in phenotypic expression of the effect of metals warrant further dose-response studies in all autoimmune models. In addition, the mechanism(s) by which the metals are able to accelerate the autoimmune process should be examined, which will also improve the understanding of the general mechanisms in autoimmune diseases. Therefore, new findings in rodents such as major genetic factors regulating susceptibility to induction of autoimmunity by mercury, silver, and gold the existence of genetic factors determining uptake and retention of metals, as well as the threshold of metals for elicitation of autoimmunity and the accelerating...

Hdac Inhibitors As Therapeutics Against Human Diseases Other Than Cancer

Identification and characterization of novel T-cell-inhibitory compounds are generally important for developing new strategies to suppress autoimmune diseases. Skov et al. (126) recently revealed that TSA inhibited proliferation and CD154 expression in CD4 T cells by a mechanism distinct from that of well-known drugs against autoimmune diseases such as cyclosporine and FK506. In addition, the cyclic tetrapeptide FR235222, a potent HDAC inhibitor, exhibited marked immunosuppressive effects (127,128). These reports suggest the clinical use of HDAC inhibitors as novel therapeutic agents in the field of autoimmune diseases.

Preop predictors for postop ventilation after transsternal thymectomy

Myasthenic syndrome, also called Eaton-Lambert syndrome, is a paraneoplastic syndrome characterized by proximal muscle weakness, which typically affects the lower extremities. Myasthenic syndrome is usually associated with small-cell carcinoma of the lung. In contrast to myasthenia gravis, the muscle weakness improves with repeated effort and is unaffected by anticholinesterase drugs.

Heat Shock Proteins As Targets For Immune Cells

Once HSP appear on the cell surface, they are accessible to the immune surveillance system. HSP expressed on cell surfaces can elicit strong immune responses, as these molecules contain several highly conserved epitope sequences with strong immunogenic properties (Kaufmann and Schoel, 1994 Shinnick, 1991 Zugel and Kaufmann, 1999). On the other hand, an overzealous immune response to HSP can have several undesirable effects. Due to high degree of phylogenic conservation, HSP species of microbial origin and HSP molecules produced by stressed host cells have similar immunogenic properties (Zugel and Kaufmann, 1999). Moreover, abundantly expressed HSP undergo processing by antigen presenting cells, and cells expressing HSP alone or presenting them in the context of MHC molecules are recognized by immune cells as potential targets of self-reactive antibodies or lymphocytes with specificity for HSP (Kaufmann and Schoel, 1994 Zugel and Kaufmann, 1999). In a number of autoimmune disorders in...

Clinical Terms Related to the Muscular System

Sensory Receptors Skeleton

Disease or disorder. myasthenia gravis (mias-the'ne-ah grav'is) Chronic disease characterized by muscles that are weak and easily fatigued. It results from the immune system's attack on neuromuscular junctions so that stimuli are not transmitted from motor neurons to muscle fibers. myokymia (mio-ki'me-ah) Persistent quivering of a muscle. myology (mi-ol'o-je) Study of muscles. myoma (mi-o'mah) Tumor composed of muscle tissue. myopathy (mi-op'ah-the) Any muscular disease. myositis (mio-si'tis) Inflammation of skeletal muscle tissue. myotomy (mi-ot'o-me) Cutting of muscle tissue. myotonia (mio-to'ne-ah) Prolonged muscular spasm. paralysis (pah-ral'i-sis) Loss of ability to move a body part. paresis (pah-re'sis) Partial or slight paralysis of the muscles. shin splints (shin' splints) Soreness on the front of the leg due to straining the anterior leg muscles, often as a result of walking up and down hills. torticollis (torti-kol'is) Condition in which the neck muscles, such as the...

The choice between Thl and Th2 responses animal models

The type, dose and route of antigen can influence subsequent T cell responses. Mycobacterial antigens such as purified protein derivative of tuberculin (PPD) induce a Th1 response, whereas parasite antigens such as Toxocara excretory substance induce a Th2 response. Low doses of parasites (e.g. Leishmania major or Trichiuris muris) tend to induce Th1 responses, whereas high doses induce Th2 responses (Abbas et al 1996, Constant & Bottomly 1997). Similarly, immunization of mice with 107 Mycobacterium vaccae induces a Th1 response, whereas 109 organisms induce a mixed response (Hernandez-Pando & Rook 1994). Efficient uptake and presentation by dendritic cells and macrophages, which both produce IL-12, probably contribute to the induction of Th1 responses. Low or high doses of soluble protein, on the other hand, tend to induce Th2 responses (reviewed by Constant & Bottomly 1997). In contrast to the parenteral administration of antigen, oral administration suppresses immune...

Patients With Cancer Can Be Immunized With Class II Peptide Based Vaccines

With the generation of HER-2 neu protein-specific T-cell immunity. Epitope, or determinant spreading, is a phenomenon first described in autoimmune disease (44) and represents the generation of an immune response to a particular portion of an immunogenic protein and then the natural spread of that immunity to other areas of the protein or even to other antigens present in the environment. The same phenomenon, epitope spreading, was reported recently in a vaccine trial immunizing breast and ovarian cancer patients with autologous DCs pulsed with MUC-1 or HER-2 neu peptides (45). Epitope spreading may represent the ability of the initial immune response to create a microenvironment at the site of the tumor that enhances endogenous local immunity (46). Despite the generation of detectable immunity against the self-protein HER-2 neu and the development of epitope spreading, none of the patients in the studies described above developed any evidence of autoimmunity directed against tissues...

How Does Heparin Transform Pf4 Into An Alloantigen

Heparin Binding Site Pf4

Antibodies to self-antigens, including certain autologous plasma proteins, can develop as a result of immune dysfunction, triggering autoimmune disease. Sometimes, however, formation of complexes between an autologous protein and a foreign substance leads to new antigens on the self protein, which can be described as cryptic alloantigens or neoantigens. Figure 2 shows how the PF4 tetramer can be modified by its binding to heparin, thereby exposing neoepitopes that were masked on native PF4. The immune stimulation resulting from such an altered self-epitope abates quickly once the inducing foreign substance is no longer present. Such a model explains some of the clinical events observed in HIT (see Chapter 2). In HIT, PF4 constitutes the self antigen, forming an alloantigen when complexed with heparin, particularly when both PF4 and heparin are present at the stoichiometric concentrations that allow formation of multimolecular

Oestrogen receptora and HS

Gen receptor (BCR) in mature or activated B-cells leads to inhibition of a number of cellular responses such as cell proliferation, antibody production and activation, and instead promotes apoptosis, whereas co-aggregation of FcyRIIB with FceRIIB receptor in mast cells leads to an inhibition of antigen-induced degranulation and cytokine production 45 . ZNF91 is highly expressed in T lymphocytes and acts to repress FcyRIIB expression in these cells. Deficiency of FcyRIIB in mice leads mainly to susceptibility to autoimmune disease.

Acquired inflammatory neuropathies

Acquired peripheral neuropathies are broadly classified into acute and chronic inflammatory demyelinating neuropathies (AIDP and CIDP, respectively). Clinical forms of these neuropathies are many, and all of them proceed with sensory abnormalities or motor weaknesses, or a combination of both. Pathogenetically inflammatory neuropathies belong to autoimmune diseases the actual neuropathy

Dose treatment of drug extravasation

Contraindications myasthenia gravis, complete heart block, SLE, Torsades de pointes. Adverse effects hypotension, heart block, myocardial depression, ventricular dysrhythmias, lupus, fever, agranulocytosis, GI irritation, lupus-like syndrome, positive Coombs' test, confusion. Comments use caution in asymptomatic PVCs, digitalis intoxication, CHF, renal or hepatic impairment

Neuromyelitis Optica Devic Disease

Neuromyelitis Optica

NMO is an idiopathic inflammatory CNS demyelinating disease characterized by either monophasic or relapsing attacks of optic neuritis and myelitis. Pathologically, NMO lesions demonstrate extensive demyelination across multiple spinal cord levels, associated with necrosis and cavitation, as well as acute axonal damage in both gray and white matter. There is a pronounced loss of oligodendrocytes within the lesions, and inflammatory infiltrates are comprised of large numbers of macrophages associated with large numbers of perivascular granulocytes and eosinophils, as well as rare CD3+ and CD8+ T-cells. A pronounced vasculocentric deposition of immunoglobulin and complement C9 neo antigen is associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions (Figure 13) (155). These findings implicate a potential role for specific autoantibody and local activation of complement in this disorder's pathogenesis. This hypothesis is supported by serologic and...

Pemphigus And Pemphigoid

Pemphigus and pemphigoid are autoimmune diseases that produce blistering of skin and or mucosa. In pemphigus, intraepithelial blistering is caused by destruction of desmogleins that connect epithelial cells. Its most common variant, pemphigus vulgaris, begins with ulcerating lesions in the mouth, as the outer epithelium of the blister sloughs. Later, skin is also involved. In pemphigoid, the basement membrane is attacked, resulting in subepithelial blisters. Mucosal involvement nearly always begins in the mouth and can spread as far caudal as the larynx. It does not involve the subglottis or trachea (7). Pemphigoid is a subepithelial blistering disease that affects skin and mucous membranes, including the nose and larynx (8).

TCell Anergy Tolerance

Most tumor-associated antigens are self-antigens that overexpressed in tumor cells. Mechanisms of the maintenance of immunological tolerance to self-antigens that hamper autoimmune reactions are also responsible for maintaining unresponsiveness to tumor cells. The existence of autoreactive T-cell clones, in both autoimmune diseases and cancer, however, demonstrates the abrogation of the control mechanisms that results in T-cell responses. In many cases, T cells ignore antigens if they are presented by nonspe-cialized APCs (68) in the absence of potent costimulation via CD28-B7 interaction (69). Recent studies provided evidence on the involvement of other membrane-associated costimulatory molecules in the generation of potent antitumor CTLs. One of these costimulatory molecules, 4-1BBL, interacts with its receptor, 4-1BB (CD137), which leads to the activation of CD4+ and CD8+ T cells via NF-kB, JNK SAPK, and p38 signaling pathways (70-72) and the induction of CTL responses against...

Neuromuscular Disorders

Myasthenia gravis (MG) is characterized by the gradual progression of weakness over several weeks to months. The weakness tends to progress throughout the day and is worsened with physical exertion. MG is an autoimmune disorder in which antibodies to acetylcholine receptors bind to the receptors on the postsynaptic membrane of the neuromuscular junction, causing internalization and degradation of the receptors. Dysphagia is the presenting sign in 6 to 15 of adult patients (10). Bulbar and facial muscles are often affected and those patients with bulbar involvement typically have worse dysphagia and often aspirate. Treatment initially consists of medication with Mestinon (pyridostigmine), an acetylcholinesterase inhibitor, and possibly thymectomy. As disease progresses, some patients are offered plasmapheresis. Swallowing function varies as muscle function varies, so patients should be encouraged to eat early in the day and after medication.

Models of Immune Function in Aging

The most prevalent rodent models used in aging research are relatively healthy long-lived rats and mice and shortlived mice. The short-lived mice typically spontaneously develop a particular disease or are genetically altered. This review focuses on the most prevalent disease model, the autoimmune-prone mouse, to study the impact of diet on aging. The benefit of these mice is that their life span is half that of the long-lived strains, allowing for data to be generated faster. Specifically, evidence showing the beneficial effects of feeding calorie restriction, omega-3 fatty acids, and combining calorie restriction with omega-3 fatty acid feeding is discussed. Overall, the published data support the observation that the combination of calorie restriction and omega-3 fatty acid feeding is the most beneficial at delaying the onset of autoimmune disease in mice. In order to properly extrapolate this data to humans, the differences in TandB cell immunology between humans and rodents are...

Inflammatory Autoimmune

Pemphigus is a rare disease that affects mucosal membranes. Although the term pemphigus may be erroneously used interchangeably with the condition bullous pemphigoid, it is a separate entity warranting a separate discussion. Pemphigus is characterized by vesicular lesions and bulla. There are multiple subtypes, with pemphigus vulgaris and pemphigus foliaceus being the most common (7). Other subtypes include pemphigus vegetans, pemphigus erythematosus, pemphigus herpetiformis, paraneoplastic pemphigus, drug-induced pemphigus, and IgA pemphigus. Although it is a disease of all ages, it typically occurs between the ages of 30 and 60. Pemphigus affects males and females equally. There is no known ethnic predilection. Its pathogenesis stems from an autoimmune mechanism in which circulating antibodies target keratinocyte cell surfaces. Cell-to-cell adhesion is disrupted and antibody complexes activate the complement cascade, creating local tissue damage. The cause of this...

Aging And Longevity Of Species

The extraordinary capacity of centenarians to achieve exceptional old age is due to some extent to their ability to counter the increased cellular stress normally associated with aging. Hsp70 protein induction by heat is reduced in the cells of most aged humans but not in centenarians. This effect is likely due to potent HSF-1 activity. As a matter of fact, HSF-1 has auxiliary factors that contribute to its activation, and could be involved in the age-associated attenuation in the response to stress (Shamovsky and Gershon, 2004). Another study reported that low circulating serum levels of Hsp70 in centenarians could well correlate with the absence of a disease state, since damage to tissues or organs as observed in cardiovascular disease or autoimmune diseases would result in high serum levels of Hsp70 (Krall, 2005).

Specific Acquired Factor Deficiencies

Factor VIII deficiency due to specific factor antibodies is the most frequent acquired factor deficiency. This can be seen in hemophilia (discussed in Chapter 4), autoimmune disease, older patients and post-partum. Factor XI deficiency due to inhibitors can be seen in patients with autoimmune disease. These are rarely associated with bleeding.

Nonprimary HHV6 infection and the respiratory tract

Totani and co-workers (2001) described an HHV-6-positive interstitial pneumonitis in a 47-year-old woman with Sjoegren's syndrome and Lupus ery-thematosus. Both autoimmune diseases were previously shown to be accompanied by higher incidences of HHV-6 reactivation (Krueger et al., 1991 De Clerck et al., 1992). There are large numbers of publications reporting severe and even lethal HHV-6-associated interstitial pneumonias in immunocompromised patients. These patients were preferentially various organ transplant recipients, or they suffered from HIV infection, immune deficiency or autoimmune disorders (Carrigan et al., 1991 Cone et al., 1993, 1994, 1995, 1996 Pitala et al., 1993 Knox and Carrigan, 1994 Buchbinder et al., 2000 Nagate et al., 2001 Totani et al., 2001 Michaelides et al., 2002 Taplitz and Jordan, 2002 Yata et al., 2002 Hentrich et al., 2004 Yamamoto et al., 2005). HHV-6 was usually confirmed as an etiological agent of interstitial pneumonia by showing large amounts of viral...

Mark Tuszynski MD PhD

Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abraham Lieberman, C. Warren Olanow, Moussa B. H. Youdim, and Keith Tipton Handbook of Dementing Illnesses, edited by John C. Morris Handbook of Myasthenia Gravis and Myasthenic Syndromes, edited by Robert P. Lisak

HSP Immune Responses and Lack of Self Tolerance

Besides their immunodominance as microbial antigens, under various circumstances HSP do elicit immune responses also when (over-)expressed as self antigens by cells or tissues. And this seems to be a peculiar feature of HSP, especially because in many cases immune responses to this self antigen are not associated with pathogenic autoimmunity. Evidently, healthy individuals have a broad repertoire of T and B cells with specificity for mammalian or self HSP. Self HSP specific immunity has been seen to exist in mice, rats, humans and other species studied so far. Apparently, thymic selection ensures the selection of a repertoire of cells with cognate receptors that can recognize such proteins, despite the fact that they are omni-present in almost every cell of our body. In an earlier study a Hsp60 peptide in Qa-1b was reported to be a target for CD8+ CTL. These CTL were induced by Salmonella typhimurium infected macrophages, were found to be specific for a Hsp65 specific peptide and to...

Present Role Of Laboratory Animals

Discoveries elucidating interactions between viruses and the immune system resulted in the 1996 Nobel Prize awarded to Peter Doherty and Rolf Zinkernagel. Using both inbred and outbred strains of mice, Doherty, a veterinarian, and Zinkernagel pioneered work that explored cell-mediated lysis of virus-infected cells. Results from their experiments uncovered the central function of the major histocompat-ibility antigens in signaling self to the immune system. Discoveries associated with this work are significant for the understanding of autoimmune diseases and immunological surveillance mechanisms crucial in transplantation medicine.

Mutations Affecting Membrane Proteins Cause Diseases

Amino acids, sugars, lipids, urate, anions, cations, water, and vitamins across the plasma membrane. Mutations in genes encoding proteins in other membranes can also have harmful consequences. For example, mutations in genes encoding mitochondrial membrane proteins involved in oxidative phosphorylation can cause neurologic and other problems (eg, Leber's hereditary optic neuropathy LHON). Membrane proteins can also be affected by conditions other than mutations. Formation of autoantibodies to the acetyl-choline receptor in skeletal muscle causes myasthenia gravis. Ischemia can quickly affect the integrity of various ion channels in membranes. Abnormalities of membrane constituents other than proteins can also be harmful. With regard to lipids, excess of cholesterol (eg, in familial hypercholesterolemia), of lysophospho-lipid (eg, after bites by certain snakes, whose venom contains phospholipases), or of glycosphingolipids (eg, in a sphingolipidosis) can all affect membrane function.

Immunomodula Tion

According to in vitro data quercetin induces Th1 -derived cytokines (promoting cellular immunity) and inhibits Th2-derived cytokines, which exert negative effects on cellular immunity (Nair et al 2002). An excess of Th2 cytokines has also been implicated in allergic tendencies, which provides a theoretical basis for the use of quercetin as an anti-allergic substance. Conversely animal studies have demonstrated that quercetin is able to inhibit Th1 differentiation and signalling of IL-12 (Muthian & Bright 2004). As this occurred in the presence of a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis suggestive of Th1 excess, a possibility exists that quercetin actually exerts an immunomodulatory effect on these cells. Further trials are required to elucidate the exact effects of quercetin under different conditions.

Anticancer

In vitro experiments have demonstrated the possible benefits of andrographolide on various cancer cells. The compound has been shown to increase apoptosis of prostate cancer cells (Kim et al 2005), inhibit proliferation of human cancer cells and increase IL-2 induction in human peripheral blood lymphocytes in vitro (Kumar et al 2004, Rajagopal et al 2003). However, contradictory results have been described from a murine model. Andrographolide was found to decrease IFN-gamma and IL-2 production and therefore shown to have an immunosuppressive effect. Burgos et al (2005) concluded that andrographis may be useful for autoimmune disease, especially where high levels of IFN-gamma are present, for example, in multiple sclerosis and RA. In vitro and in vivo data has recently shown that andrographolide has the ability to interfere with T-cell proliferation, cytokine release and maturation of dendritic cells, as well as drastically decreasing the antibody response in delayed-type...

Definition

AIED can be defined as a fluctuating or rapidly progressing sensorineural hearing loss that is responsive to immunosuppressive therapy. Vestibular dysfunction may or may not be present. In some cases, a concurrent systemic autoimmune disorder exists at the time of diagnosis. Therefore, AIED can exist in isolation as an organ-specific disease (primary AIED) or can occur as a nonspecific injury as part of a systemic autoimmune disease (secondary AIED). Currently, there is no diagnostic laboratory test or imaging modality available to confirm the diagnosis with certainty.

Cell Death

In humans, as in all other multicellular organisms, the rates of cell proliferation and cell death determine the net cell production. An abnormality in any of these rates can cause disorders of cell accumulation (e.g., hyperplasia, cancer, autoimmune diseases) or disorders of cell loss (atrophy, degenerative diseases, AIDS, ischemic injury). Therefore, the balance (homeostasis) between cell production and cell death must be carefully maintained (Fig. 2.68).

Immune System

Effectiveness of B cells is seen in the production of fewer antibodies and an impairment of their ability to differentiate between foreign invaders and the body's own cells. Consequently, the antibodies may attack the cells of the body itself, a so-called autoimmune disorder.

Polysialic Acid

Long polysialic acid chains (20-100 residues). Several monoclonal antibodies, including MAb 735 and NP-4, recognize these long polysialic acid chains (50) and have allowed characterization of this antigen in both normal and malignant tissue. Zhang et al. has demonstrated that of six SCLC tumor specimens, all were reactive by immunohistochem-istry using MAb 735, and five of the six tested SCLC tumor specimen were positive using MAb NP-4 (18). This confirms previous results of Komminoth (49), and suggests that polysialic acid may serve as a useful target for immune attack against SCLC. Polysialic acid is also expressed in the gray matter of the brain, bronchial epithelia and pneumocytes, epithelia of the colon, stomach, and pancreas, and capillary endothelial cells and ganglion neurons in the colon. The reactivity of these antibodies in epithelia is restricted to the luminal surfaces of glandular tissues, where access to the immune system is restricted. Two to 5 of normal donors have...

Pathophysiology

Patients with RP demonstrate both cell-mediated and humoral immunity against extracellular matrix components of cartilage, including type II, IX, and XI collagens, matrillin-1, cartilage oligomeric matrix protein, and proteoglycans. Evidence for cellmediated autoimmunity includes demonstration of T cells directed against type II collagen in patients with RP. Additionally, T cell clones have been isolated from an RP patient which were specific for an immunodominant epitope of type II collagen and were restricted to HLA-DRB1 * 0101 0401 alleles (9). T cell responses to type IX and XI collagens and matrillin-1 have also been reported in individual RP patients (10,11). Humoral autoimmunity is demonstrated by the presence of immunoglobulin and complement deposits in affected tissues (12). Additionally, circulating autoantibodies against native and denatured type II, IX, and XI collagens, as well as matrillin-1, are found in some patients with RP (13,14). The exact role that these...

Immune Dysregulation

There is growing evidence that immune dysregulation plays a role in MDS pathophysiology. The relationship between MDS and autoimmunity stimulated the investigation into the role of the immune system in MDS. The incidence of autoimmune disorders appears to be increased in patients with MDS (Saif et al. 2002). Autolo-gous cytotoxic T lymphocytes have been observed to exert inhibitory effects on MDS myelopoiesis in vitro. Fundamental questions remain unanswered about the precise mechanisms underlying autoimmunity in MDS. The hypothesis that T lymphocytes attack specific antigens on MDS clonal progenitors remains unproven. Likewise, it is unclear why some patients respond to im-munosuppression and others do not. Important future investigations will include confirmation of the efficacy of immunosuppressive and anti-TNF therapies in phase III clinical trials and in identifying subsets of patients who will most benefit from these therapies.

Anemia

Anemia is defined clinically as a decrease in the concentration of hemoglobin in the blood for the age and gender of an individual. While in certain anemias this decreased concentration of hemoglobin is due to a decrease in the amount of hemoglobin in each cell, most anemias are caused by a reduction in the number of erythrocytes. Causes of anemia include loss of blood (hemorrhage), insufficient production of erythrocytes, or accelerated destruction of erythrocytes in the circulation. Insufficient dietary iron or deficiencies of vitamins such as vitamin B12 or folic acid can lead to decreased production of erythrocytes. Gastric atrophy, as a result of autoimmune disease, with concomitant destruction of the parietal cells that secrete intrinsic factor, a molecule essential for absorption of vitamin B12 by cells in the ileum, is the cause of a form of anemia called pernicious anemia.

Evans Syndrome

Children with Evans syndrome often have complex immunodeficiencies. In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans sydrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.

Acknowledgements

Liu, B., Dai, J., Zheng, H., Stoilova, D., Sun, S. and Li, Z. (2003) Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Natl Acad Sci USA 100, 15824-9. Millar, D. G., Garza, K. M., Odermatt, B., Elford, A. R., Ono, N., Li, Z. and Ohashi, P. S. (2003) Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat. Med. 9, 1469-76.

Persistent Infection

Strominger screened a large number of peptides for degeneracy of amino acid side chains required for major histocompatibility complex (MHC) class II binding and activation of myelin basic protein (MBP)-responsive T-cells (40). A panel of 129 peptides satisfying these criteria was identified, of which herpes simplex virus, EBV, adenovirus type 12, influenza type A, and Pseudomonas aeruginosa peptides gave the greatest activation of MBP-specific T-cell clones derived from MS patients. Collectively, these studies support the concept that multiple common infectious agents have the potential for triggering MS by a molecular mimicry mechanism. An alternative possibility for tissue injury might also involve molecular mimicry between infectious agent and host protein, but instead of a myelin protein, a regulatory protein in the immune system or a critical host enzyme might be the target, resulting in altered immune function, disruption of the blood-brain barrier, or interference with myelin...

Immunopathology

Known mechanisms can involve antibody responses to cell surface or matrix components, for example in Goodpasture's syndrome, where the autoantigen is part of the basement membrane. This disease is organ-specific. In other cases, such as systemic lupus erythematosus (SLE), the disease is systemic and multiple tissues and organs may be affected. Immune complexes are thought to play a major role in the pathology of systemic autoimmune disease. A third group of diseases is characterized by T cell destruction of tissues and associated activated cells. This type includes T1D and RA. The classification of autoimmune diseases as organ specific or systemic reflects the underlying etiology. In some families with organ-specific disease several family members may be affected but with different organs involved. Similarly, systemic autoimmunity can affect multiple individuals in a family or a single individual can have more than one systemic condition, such as SLE together with Sjogren's syndrome.

Infectious diseases

There is strong evidence for association of only a few infectious diseases with the MHC (Table 9.1, Figure 9.1) although infection is believed to drive MHC variation (see Chapter 18). It has been proposed that the emphasis on autoimmunity is largely because research funding for studying these diseases, prevalent in western populations, has greatly exceeded that for infections that are more usually consigned to poorer countries. In fact, the funding emphasis has shifted considerably since the emergence of modern infectious diseases such as AIDS and SARS. the host HLA molecules. Statistically, these escape variants tend to appear most often for those HLA allotypes that are most frequent in the infected population. Over time, in response to the infection, these allotypes may become less common in that population and eventually new variants of the pathogen may emerge. This pattern of adaptations both by the pathogen and by distribution of allotypes in host populations leads to a dynamic,...

Choice of promoter

Properly targeted APCs may be much more efficient in priming immune responses without the risk of generating autoimmunity. This might be achieved by using tissue cell-specific promoters that could be found in sequences of genes whose expression is specifically upregulated in DCs. One of them is B7.1 CD80, a potent costimulatory molecule upregulated during DC maturation (54). Regulatory elements contained inside 3084 bp of the 5'-sequence of the putative B7.1 promoter have been shown to be sufficient to provide high expression of a reporter gene in APC-rich tissues (55,56). However, although such inducible promoters should be advantageous over constitutive promoters, they are difficult to handle largely because of plasmid size constraints. To maintain tissue specificity the presence of many upstream regulatory elements are required, and if truncated to fit the right size of the plasmid, such promoters often lose their strength and specificity (57,58). Nevertheless, an inducible...

Multiple sclerosis

Multiple Sclerosis (MS) is a chronic T-cell mediated demyelinating autoimmune disease of the central nervous system. Disease onset usually occurs between 20 and 40 years of age, after which progression is variable, but generally slow. The geographic distribution of the disease has led to much debate over the relative importance of racial susceptibility (presumably genetic) and environment. On the one hand, there is a strong gradient towards higher prevalence at higher latitudes, both north and south of the equator on the other, there are marked deviations from this pattern, including a high prevalence among Sardinians and Palestinians, and low prevalence among Chinese and Japanese, black Africans, Maoris and Amerindians (Rosati, 2001). Suspected environmental risk factors for MS include vitamin D insufficiency (with attendant reduction in the immune-suppressive effect of vitamin D), late- or post-childhood infection with Epstein-Barr virus (Martyn et al., 1993 Levin et al., 2003) and...

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