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! More here...

Autoimmune Paleo Cookbook Summary

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Transition From Benign To Pernicious Autoimmunity

Fortunately, the process of transition from immune recognition of self to the full blown antiself attack is relatively uncommon autoimmune disease affects about 5 of the population. For a disease to develop, several conditions must be met. The individual must have certain predisposing genetic features, including human leukocyte antigens (HLAs). HLA molecules are a set of surface proteins expressed on immune cells that are important in forming a complex with peptides to be recognized by T cells. In addition to HLA, hormonal factors, tissue susceptibilities, and others, along with an inciting event, trigger the development of the disease. This trigger is often an infection. The infectious agent (viral or bacterial) may have antigenic epitopes that activate T cells capable of attacking the self the immune attack against a foreign invader starts an immune reaction that spills over and results in mistaken antiself attack. Alternatively, an emotional stress may result in loss of regulation...

Microbeinduced cardiac autoimmunity Rheumatic fever

The 'grand-daddy' of all microbial-induced autoimmune heart disease is rheumatic fever (RF). The concept of autoimmunity playing a role in this disease was introduced over 50 years ago by a number of investigators when antibodies to heart were noted in the sera of patients with acute rheumatic fever (ARF) and or rheumatic heart disease (RHD). The origin of these antibodies was better defined when Kaplan and colleagues noted that immunization of rabbits with group A streptococci induced antibodies that bound to human heart in a manner strikingly similar to that observed with human patient sera. Further experiments revealed that the cross-reacting In addition to the presence of immunoglobulin in these biopsies, numerous investigators have also commented on the presence of chronic lymphocytic infiltrates in these tissues, suggesting that abnormalities in cellular reactivity might also be involved in the initiation and or perpetuation of target organ damage. Santos-Buch and colleagues...

Neuromuscular Junction Autoimmunity

There are three antibody-mediated disorders of the neuromuscular junction. In myasthenia gravis (MG) antibodies cause loss of the muscle acetylcholine receptor (AChR). It meets in full Witebsky's criteria for antibody-mediated autoimmune disease 1) the presence of antibodies against a defined antigen (AChR) 2) transfer of the disorder to naive experimental animals by injection of MG immunoglobulins 3) induction of the disorder in experimental animals by specific immunization against AChR and 4) transfer of disease from immunized to naive animals by their lymphocytes. The Lambert-Eaton myasthenic syndrome (LEMS) is an antibody-mediated presynaptic disorder where the target is the nerve terminal voltage-gated calcium channel, and in which the first two of the above criteria are met. It is of additional interest as the best example currently available of an autoantibody-mediated paraneoplastic neurological disease. Acquired neuromyotonia (Isaacs' syndrome) has recently been shown to be...

Polyendocrine Autoimmunity

There are two major autoimmune polyglandular syndromes (APS), type I and type II, comprising a constellation of endocrine diseases caused by autoimmunity. The key features of each syndrome are described below. Although additional features have been described in individual patients, it is difficult to know whether these are true associations or ascertainment artifacts. Rarely, patients have features of both types of syndrome. Other polyendocrine autoimmunity disorders are considered after the two main syndromes.

Skin Autoimmune Diseases

Autoimmune diseases of the skin may be divided into several groups according to different criteria. For example, one may make a distinction between autoimmune diseases that are systemic in nature but have prominent skin involvement and those that are primarily cutaneous in nature and are only rarely associated with symptoms in other organ systems. An alternative way of distinguishing subsets of dermatological autoimmune diseases is by dividing them into groups that are certainly autoimmune, probably autoimmune, and possibly autoimmune (Table 1). In this entry, emphasis will be on auto

Autoimmunity And The Hosttumor Relationship

Although Paul Ehrlich (Ehrlich and Morgenroth, 1957) argued that the organism should never react to its own tissues, during the last century a number of diseases resulting from immune reactions within the organism to its own or self' antigens have now been described. A discussion of the development of autoimmune disease is beyond the scope of this text however, the interested student may consider the following references Schwartz, 1993 Eisenbarth and Bellgrau, 1994 Mayes, 1999 Bach, 1995. Interestingly, Prehn and Prehn (1987) have presented arguments that neoplasia, at least in part, should itself be considered an autoimmune disease. However, here are considered only an artificially induced autoimmune condition leading to neo-plastic development and its potential application as well as some examples of autoimmunity stimulated in the host by antigens present in neoplasms. An artificial autoimmune disease has been induced in rodents by the production of runt disease resulting from a...

Loss of unresponsiveness role in autoimmunity

Induction of class II MHC antigens on cells which normally do not express these determinants, can lead to T cell recognition (since they may never have been rendered tolerant to tissue-specific antigens if they are not expressed on class II-positive APCs). This inappropriate activation may lead to tissue-specific autoimmunity, but it is not clear whether class II expression in these diseases is the result rather than the cause of autoimmunity. Indeed, experiments in transgenic mice with class II expression under the control of the insulin promoter, so that I-E is expressed on pancreatic p cells, showed that these (3 cells were tolerogenic rather than immunogenic, arguing against aberrant expression of MHC class II as a trigger of autoimmunity. See also Affinity Apoptosis Autoimmunity B lymphocytes CD40 and its ligand Clonal deletion Fas (CD95) and fas ligand Superantigens Suppressor T lymphocytes Thymus T lymphocyte differentiation Tolerance, peripheral Tolerance, models Transgenic...

Autoimmunity and autoimmune disease

Autoimmune reactions to autologous molecules occur in health and may well be ubiquitous. Autoimmune disease is defined when such reactions become uncontrolled and result in structural or functional pathology. Normally there exists a physiological (natural) immunological tolerance to self constituents previously, this was thought to be absolute, such that any immunological reactivity with autologous molecules would be abnormal. However, currently, tolerance can be expressed either as an absolute absence, or a controlled level, of autologous reactivity. Pathogenic autoimmunity might thus represent either an amplification of naturally occurring autologous reactivity, or be in some way qualitatively different. Natural autoimmunity could serve physiological purposes 1) early defense against infection with microorganisms that share cross-reactive epitopes with autologous molecules 2) disposal of products of injury or tissue catabolism or 3) facilitation of expansion in early life of...

Thyroid Autoimmunity Animal Models

That autoimmunity is a major cause of thyroid disease has been evident for over 35 years, but many critical questions about the immunopathogenesis remain unanswered. This entry focuses on the proto-typic autoimmune thyroid disease, chronic thyroiditis or Hashimoto disease, and aims to answer these questions by reference to experimental models. The questions pertain primarily to the molecular and genetic basis of autosensitization, to the principal thyroid antigens and the immunological characteristics of pathogenetic autoimmunity. antigen and beginning at a defined point in time and, therefore, lends itself to precise genetic and molecular investigations. Spontaneous models of thyroiditis can be found in the OS chickens, the BUF and BB strains of rats, NOD mice and the Argonne Laboratory colony of beagle dogs. Thyroiditis and a number of other organ-specific autoimmune diseases can be produced by carefully timed neonatal thymectomy of certain strains of mice, or by adult thymectomy...

Insights gained from animal models of ocular autoimmunity

The questions outlined above are being studied in animal models of ocular autoimmunity (Table 1). The best studied is experimental autoimmune uveo-retinitis (EAU), which serves as a model for human posterior uveitic disease that is most likely to result in impairment of vision. EAU can be induced in various species of rodents and in primates by any of several defined retinal antigens injected in emulsion with complete Ereund's adjuvant (CFA). A number of uveitogenic proteins derived from the photoreceptor cell layer have been identified (Table 2). EAU is characterized by destruction of the photoreceptor cells of the retina, where the eliciting antigen(s) are located (Figure 1), and is usually accompanied by autoimmune inflammation of the pineal gland ('third eye'), which shares ocular-specific antigens with the retina. A dictum which clearly emerges from studies in animal models is that mere exposure to an ocular antigen is insufficient to elicit ocular autoimmunity. Use of adjuvants...

Benign Autoimmunity

Successful, while the self-tissues are not damaged by autoimmune disease. This is achieved by a process of education in the thymus, in which most of the self-reacting T cells are purged from the mature immune cell repertoire. The thymus is an organ high in the thorax that serves as a factory for the generation of new T cells. This process of negative selection (killing of self-reactive T cells by contact with self-antigens) in the thymus is thought to be important for the prevention of autoimmunity. However, one can easily detect self-reacting antibodies and T cells in both humans and experimental animals. Analysis ofnormal human serum reveals a multitude of antibodies that bind normal tissue components. Immunization of experimental animals with self-antigens (proteins or peptides) results in the generation of self-reacting T cells that can induce autoimmune disease. Thus, the process of purging the immune repertoire from self-reactivity is far from complete, and there exist effective...

Other polyendocrine autoimmunity syndromes

Rarely, diabetes mellitus results from a decreased biological response to a normal amount of insulin. In type A insulin resistance, the problem lies in the insulin receptor, which is quantitatively or qualitatively abnormal, but in the type B syndrome autoantibodies to the insulin receptor produce diabetes mellitus. In vitro, using short-term culture experiments, these antibodies mimic the action of insulin, which may account for the occurrence of hypoglycemia in some patients. More typically, however, there is massive insulin resistance, so that even 15 000 units of insulin per day may not lower blood glucose, and prolonged in vitro experiments reveal the antagonistic properties of the antibodies. About one-third of these patients have other autoimmune diseases, including systemic lupus erythematosus, Sjogren's syndrome, scleroderma, primary biliary cirrhosis, See also Adrenal autoimmunity Autoimmune diseases Candida, infection and immunity insulin-dependent diabetes mellitus, human...

Autoimmunity

The experiments of Rivers, Sprunt and Berry in the early 1930s showing that injection of monkey brain antigens back into monkeys provoked encephalomyelitis provided the first experimental model of autoimmune disease. A decade later, Owen's observation that dizygotic cattle twins sharing the same blood supply during embryonic life did not destroy each other's nonidentical erythrocytes (even if these were injected in adult life) suggested that self tolerance is acquired during ontogeny. Such chimeric cattle are able to exchange skin grafts without subsequent tissue rejection. In 1953 Billingham, Brent and Med-awar demonstrated that neonatal injection of cells from CBA strain mice into A strain mice allowed the mice to later accept CBA skin grafts. Three years after these experiments, a series of classical papers on thyroid autoimmunity were to firmly establish the role of autoimmune phenomena in producing disease. Rose and Witebsky induced both autoantibodies and thyroiditis by...

Adrenal Autoimmunity

Adrenal autoimmunity is currently the most common cause of Addisons disease, a chronic disorder of the adrenal cortex characterized by atrophy of the adrenals. This results in deficient production of adrenocortical hormones together with increased secretion of anterior pituitary adrenocorticotropic hormone (ACTH). The clinical picture of Addisons disease may comprise weakness, anorexia, nausea, vomiting and weight loss. Hypotension and mucocutaneous hyperpigmentation are usually present. Levels of serum potassium and urea nitrogen are elevated, whereas serum sodium may be decreased. Significant laboratory findings are low plasma levels of Cortisol and elevations of ACTH. Stimulation with synthetic ACTH does not result in Cortisol increases. Idiopathic adrenal atrophy is probably an autoimmune disease, as suggested by the facts that the histopathology of the affected adrenals resembles that observed in tissues which are targets of other organ-specific autoimmune diseases, and that...

Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigue, seen especially with repetitive use of voluntary muscles. Acetylcholine receptor (AChR) antibodies impair the function of the AChR at the neuromuscular junction, causing variable amounts of muscle weakness. The muscle weakness is seen most often in proximal muscles, generally is relieved by rest, and requires long-term immunotherapy. Because the mechanism and optimal therapies for MG are well understood, much of the morbidity and mortality associated with the disease can be avoided. Aggressive management of respiratory complications associated with a myasthenic crisis is the most important issue for MG patients and emergency physicians.

Applications of agglutination and agglutination inhibition reactions

Because of the ease of their performance and high sensitivity, specific agglutination reactions have been employed for 1) the serological diagnosis of infectious diseases through the detection of a rising titer (concentration) of serum antibody 2) screening for specific tissue-directed antibodies in connective tissue and autoimmune diseases 3) detection of the presence of antigenic determinants on cells (mixed agglutination reaction) 4) blood typing and crossmatching procedures for blood transfusion, including the use of antiglobulin as a second antibody to directly cross-link incomplete agglutinins bound to Rh and ABO blood cell antigens 5) diagnosis of viral infection influenza, rubella and other viruses that directly agglutinate erythrocytes. The inhibition of viral hemagglutination by specific antibody to the virus is a particularly useful and sensitive test for titers of antiviral antibody.

Aging And The Immune System

In summary, considerable age-related changes in suppressor cells occur to an extent which shows individual variation different types of suppressor cells can change in opposite directions in the same individuals. Changes in helper cells are attributable to changes in the relative proportion of subpopulations and manifest themselves in age-related changes in the quantity of different interleukins. In some strains of inbred mice these changes can result in a decrease in humoral response. In other strains of mice a marked decrease in suppressor cells for the humoral response can result in autoimmune disease. Having examined aging in T, NK and B cells, it remains to summarize the reason for the increase in autoimmunity in aging human populations. In part this may be attributable to the loss of suppressor capacity as has been found in some strains of inbred mice. In part it may be due to accumulation of denatured proteins which is the consequence of the age-related decrease in proteolytic...

Andor Mononuclear Phagocytes of the CNS

Additionally we have to point to another cell population within the CNS with similar functional properties as microglia dendritic cells. Dendritic cells are a subclass of antigen-presenting cells critical in the initiation and regulation of adaptive immunity against pathogens and tumors as well as in the triggering of autoimmunity (for review see Pashenkov et al. 2003). Dendritic cells are present in normal meninges, choroid plexus, and CSF, but absent from the normal brain parenchyma. Inflammation is accompanied by recruitment and or development of dendritic cells in the affected brain tissue.

Monoclonal antilymphocyte antibodies

A problem is the production of anti-antibodies which counteract the effect of the administered mAb (Figure 1). It is a smaller problem when using polyclonal ALS, and is to some extent prevented by the use of concomitant immunosuppression. The problem with antiantibodies may be circumvented by changing to a mAb against a different epitope or by using mAbs with a human type of molecular structure. In an experimental system, pretreat-ment with ALS was found to suppress formation of neutralizing antiantibody to a mAb administered later. Only mAbs against CD4 seem to avoid stimulating the production of antiantibodies by the recipient. This may reflect the unique ability of CD4-spe-cific mAbs to induce tolerance. A humanized CD4-specific mAb has been used in clinical trials on patients with autoimmune disease. The effect of mAbs may be modified by removing the Fc fragment, which is of importance for the elimination of the target cells by phagocytes. Thus, CD3-specific mAbs...

The case of CD8 T cells

Most epithelial, vascular and mesenchymal cells do not express class II MHC molecules or costimulatory molecules however, there are exceptions thymic epithelium normally expresses class II MHC molecules, and some mucosal cells of the gastrointestinal tract and proximal tubular cells of the kidney also express some levels of class II MHC molecules. During inflammation, as a result of local IFNy production, many cells are made to express class II MHC molecules. Whether this aberrant expression is involved in tissue autoimmunity needs to be settled. Tissue cells express limited amounts of costimulatory molecules which makes them poor APCs for initiating T cell activation.

Assessment Of Patients

Circumstances, a patient with an anticipated difficult airway or an ASA classification of 3 or 4 may require consultation with an anesthesiologist. Patients with underlying neurologic diseases such as cerebral palsy, myasthenia gravis, or mental retardation may be much more sensitive to sedatives and consultation is suggested in such cases.

Methods for identifying autoantibodies

If autoantibodies are present, they will bind to the appropriate antigen. Excess serum is washed away. A second reagent, antihuman immunoglobulin conjugated to a fluorescent dye (usually fluorescein isothiocyanate, FITC), is then incubated with the tissue section. Unbound reagent is again washed away. Autoantibodies are detected using a microscope (transmission or incident light illumination) with an appropriate light source (usually mercury vapor or halogen quartz) and filter system that will enable the fluorescent markers to be seen. IIF can detect multiple antibodies on a single tissue or on a multiple tissue block, and thus has considerable value as a screening test. It is particularly valuable in testing for autoantibodies for which the antigen has not yet been characterized or for unexpected antibodies. These latter antibodies may be missed by an assay employing only purified antigens. With IIF, the reaction site can be seen, and thus the location...

Acetylcholine receptor

Autoantibodies to acetylcholine receptor (AchR) are present in 80-95 of sera from patients with myasthenia gravis. Variations in the reported incidence of these antibodies are due to the different methods (complement fixation, passive hemagglutination, and various RIAs and ELISAs) used for their detection. In addition, there are heterogeneous specificities of antibodies to AchR i.e. some that react to determinants other than the neurotoxin-binding site, others that react with the neurotoxin-binding site or the extra junctional receptors, and others that are species specific. Since the cross-reactivity of human antibodies to AchR with receptors from other species is limited, human skeletal muscle is preferred as the source of AchR.

Experimental Autoimmune Encephalomyelitis

EAE is a model in experimental animals that, due to similarities in the clinical and pathological features, is considered by many investigators to reflect human MS. EAE is probably the most intensively studied autoimmune disease model. The experimental animal (mouse, rat, guinea pig, or monkey) is injected with a protein from the central nervous system (CNS) myelin (myelin basic protein, proteolipid protein, or myelin oligodendrocyte glycoprotein) in a suitable adjuvant a material added to the antigen to enhance the immune response (containing oil and bacterial products). Ten to 14 days after the injection, the animal shows signs of neurological damage, including paralysis of the tail and posterior and anterior paws and loss of urinary sphincter control. This neurological disease

Abnormalities of capping

Various alterations of capping are found in cases of immunodeficiency and or autoimmunity, or following cell treatment with pharmacological agents known to show immunomodulatory properties. Various agents or conditions, which may be physiological, pharmacological or genetic factors and are known to modulate the immune responsiveness, are also found to alter the rate of capping. Thus, capping of B cell mlg occurs at different rates for mice of different strains and shows different susceptibilities to pharmacological agents immature, fetal or neonatal B cells cap faster than mature, adult B cells peripheral blood lymphocytes from elderly human beings show decreased capping rates in comparison with young adults and cyclosporine-treated B cells show a faster capping.

Cardiac Disease Autoimmune

In contrast to the extensive experimental and clinical knowledge that has accumulated concerning immunological and autoimmune mechanisms in the pathogenesis of tissue injury and dysfunction, notably the kidney, the concept that autoimmunity might play an important role in cardiac disease is just beginning to emerge. The slow progress in this area is, in part, due to the lack of good experimental models of autoimmune heart disease and also perhaps because of the difficulty of direct accessibility to the target organ itself. With the advent of the endocardial biopsy and other technological advances in cardiology, the ability to study cardiac tissue '* situ' has improved considerably and should provide the investigator with reasonable amounts of material for study similar to that seen since the advent of the renal biopsy.

Immune Theory of Aging

Original immunologic theory of aging suggests that aging in mammals is a self-destructive process leading to a decline in immune response. The failure in immune homeostasis is associated with a consequent rise in autoimmunity (Walford, 1987). Age-related phenomena such as increased prevalence of autoantibodies and monoclonal immunoglobulins reflect dysregulation of the senescent immune system rather than a simple decline in responsiveness. The age-related changes primarily occur in the T-cell-dependent immune system and are associated with increased susceptibility to infections and incidence of autoimmune phenomena in the elderly. One of the characteristics of all somatic cells is a finite life-span. Cells may proliferate until they reach a point, after which they can no longer produce daughter cells. This observation is central to the clonal exhaustion hypothesis, a mechanism cited to explain age-associated immune dysfunction. In this hypothesis, repeated division of lymphocytes...

Possible mechanisms of complement and disease associations

It has been shown that the intact classical pathway is needed to prevent formation of insoluble immune complexes (ICs) the components of the classical pathway play an important role in this function. In cases of deficiency, ICs may not be cleared by the reticuloendothelial system and therefore recirculate until being deposited at capillary or basal membranes, leading eventually to tissue damage. This mechanism could be envisaged in some forms of vasculitis and glomerulonephritis, as well as autoimmune disease in the presence of nuclear antibodies.

Nitric oxide synthase and reproductive ageing

An alternative hypothesis is that ageing is associated with an excessive synthesis of NO resulting in the accumulation of its cytotoxic metabolites such as peroxynitrite, leading to neuronal apoptosis. The process might affect the hypothalamic neurons including those that secrete GnRH. Such cytotoxic effects ofexcessive levels ofNO could result in accelerated apoptosis ofother components of the reproductive axis such as the testes. The high NO levels in tissues of ageing animals may occur as a result of excessive stimulation of nNOS by activation of NMDA receptors or the spontaneous expression of inducible NOS (iNOS), the NOS isoform that is induced during autoimmunity, inflammation and degeneration. In normal physiological conditions iNOS is undetectable in the organs of adult laboratory animals and is expressed in high levels only after exogenous cytokine stimulation and in inflammatory or infectious processes. To study the role of NOS in reproductive ageing, our laboratories...

Giant cell myocarditis

Within a week unless cardiac transplantation is available. There are irregular areas of myocardial necrosis, at the margins of which are large giant cells but no organised granulomas such as occur in sarcoid. No virus has been implicated. The only known association is with autoimmune disease and thymomas, although the majority of cases occur suddenly in subjects who have no other pre-existing disease. Recurrence of the giant cell myocarditis in donor hearts can occur.

Encephalitogenic antigens

Experimental evidence to support the hypothesis that CNS tissue contains organ-specific antigens capable of eliciting an immune response was first provided by Witebsky and Steinfeld in 1928. Thus, once the EAE model had emerged, a widespread search was initiated to identify the relevant organ-specific antigens responsible for this autoimmune disease. It is known today that two myelin structural proteins, myelin basic protein (MBP) and proteolipid protein (PLP), are the major encephalitogenic antigens (Figure 1). MBP, which constitutes 30 of the total myelin protein, was first reported to induce EAE by Marian Kies in the early 1960s. This antigen actually

Graftversushost disease

Clinically, graft-versus-host disease can appear as one of two distinct forms. Acute graft-versus-host disease has its onset early following the infusion of donor immunocompetent cells and is characterized by the cytolytic destruction of the recipient epidermal cells, hepatocytes and gastrointestinal cells, producing a characteristic cutaneous erythroderma, elevation in hepatocellular enzymes and diarrhea. A high rate of fatality is found in both animals and humans with severe acute graft-versus-host disease due to the denudation of the gastrointestinal tract, epidermal sloughing, sepsis and bleeding. Individuals, who do not die from acute graft-versus-host disease, are at risk of developing chronic graft-versus-host disease, which has many similarities to autoimmune diseases, including sclerodermatous skin changes, the production of autoantibodies, etc. In model animal systems, graft-versus-host disease is usually produced by the infusion of homozygous donor immunocompetent cells...

Clinical presentation and diagnosis

The clinicopathologic features of y-HCD vary, with a lymphoplasmacytic proliferation similar to that of Waldenstrom's macroglobulinemia in 40 of cases and, in other cases, various forms of lymphoid proliferations, including lymphomas and chronic lymphocytic leukemia (CLL), or no detectable lymphoproliferative disorder. Association with autoimmune diseases is not uncommon. p-HCD is rare. It presents with the same variety of immunoproliferative disorders as y-HCD, typically CLL with vacuolated bone marrow plasma cells. Although truncated HCs (structurally different from HCD proteins) are able to deposit in tissues in amyloidosis and heavy chain deposition disease, there is no documented tissue deposition in HCD (a single case of amyloidosis of unknown composition was reported in y-HCD).

Manipulated responses Passive immunization

See also Acute inflammatory reaction Affinity Affinity maturation Agglutination Antibody-dependent cellular cytotoxicity Antigen-binding site Autoimmunity Mast cells B lymphocyte differentiation Cell-mediated immunity Helper T lymphocytes Complement receptors Cytokines Diversity, generation of Fc receptors Germinal center Hypersensitivity reactions Immune adherence Immunoglobulin class switching Immunoglobulin, functions Immunoglobulin structure Lymphocytes Memory, immunological Neutralization of biological reactions by antibodies Opsonization Phagocytosis Vaccination, methods of administration.

Pressureaugmented immunogenicity

Pressurized tumor cells, as well as pressurized autoimmune cells, were both demonstrated to possess a high and specific immunogenicity. Such pressure-treated cells were successfully used in pre-vaccination trials in murine models of cancer and autoimmune diseases. These observations open novel approaches for both the diagnosis and treatment of cancer and autoimmune disease, which are currently under investigation.

The Physiological Roles Of The Bcl2 Family Proteins In Development And Homeostasis

The Bcl-2 family proteins are important in enabling organisms to perform their physiological functions in their responses to certain endogenous or exogenous stimuli. One example is that shortlived T-cells, when activated by foreign antigens, begin to express Bcl-xL, which allows the activated T-cells to survive for a sufficient period of time to mature for their immune functions (119). An expression of a prodeath gene, bim, may ensure the death of these cells later on to avoid autoimmunity (120). Mice with the deletion of the bim gene actually manifest autoimmune symptoms (121). In

Activation versus tolerance

While orchestrating its defenses, the immune system must also take steps to prevent cellular damage which accrues via friendly fire (autoimmunity). In contrast to activation, which leads to the stimulation and expansion of certain lymphocytic clones, immunological self tolerance is achieved by the selective elimination from its armament of the lymphocytes which are reactive with dominant determinants on self antigens. At least three mechanisms have been described for the induction of tolerance clonal deletion, clonal anergy and active suppression via cytokines or regulatory lymphocytes which recognize certain immunoglobulin or TCR molecules. Clonal deletion is accomplished in part during the establishment of centra) tolerance, where high-affinity, autoreactive T and B cells are physically removed during thymic and bone marrow selection, respectively, via antigen-induced apoptosis. However, negative selection in the primary lymphoid organs alone is not sufficient for the maintenance of...

Antibodies to sperm membrane antigens

The occurrence of sperm-specific antibodies in 60-70 of vasectomized men shows that occlusion of the efferent ducts can induce autoimmunity, and infections may also stimulate immune responses, possibly through an adjuvant effect. However in most cases no explanation for the immune response can be found. Male laboratory animals immunized with homologous sperm in complete Freund's adjuvant develop orchitis with destruction of the germinal tissue, but in men the autoimmunity apparently does not affect spermatogenesis. Apart from modest deposits of immunoglobulin around seminiferous tubules, testicular histology has been normal in most men with sperm-specific antibodies who (for other reasons) have had testis biopsies performed, and semen samples often show normal sperm counts and normal motility. However, the presence of antibodies on motile sperm can be demonstrated by simple techniques such as the immunobead-binding test, in which particles covered with anti-immunoglobulin attach to...

Immunopathology Humoral immunity

The role of cell-mediated autoimmunity in the pathogenesis of IDDM has been extensively studied in animal models. Evidence exists that supports the hypothesis that macrophages and T cells arc clearly involved in the destruction of (3 cells. T cells There is much evidence to indicate that T cell-mediated autoimmunity is involved in the destruction of p cells. Neonatal thymectomy prevents diabetes in the BB rat. The lymphocytes from diabetic BB rats transfer disease to young diabetes-prone BB rats. BB rats treated with monoclonal antibodies (OX19) directed against antigens expressed on the surface of all T cells do not develop diabetes. T cell lymphopenia, characterized by a reduced level of CD4+ T cells and a substantial decrease in the number of CD81 T cells, is observed in the BB rat. In contrast, the BB rat exhibits a relative increase in the number of NK cells (OX19- OX8). The proliferative response of T cells to mitogens, such as con A, phytohemagglutinin (PHA), and the production...

Environmental factors

Autoantibody evidence that the disease process has started begin finally during infancy or early childhood (Figure 1). The role of viral or dietary triggers of (5 cell autoimmunity have long been postulated, but not clearly identified. Proposed pathogenic mechanisms have included direct islet cell viral infection, resulting in either altered self molecules or release of previously sequestered antigens from damaged (3-cells, and or a superantigenic event. Alternatively, molecular mimicry between a viral or dietary protein antigen and an islet autoantigen may provide the inductive event.

Key Nutrients Involved in Host Resistance to Infection

Ascorbic acid (vitamin C) Ascorbic acid is rapidly mobilized and utilized in infection and high levels of ascorbic acid are found in leucocytes. Studies in humans and animals have found a reduced T-cell response, delayed cutaneous hypersensitivity, and reduced epithelial integrity in vitamin C deficiency. Vitamin C supplementation is associated with increased lymphocyte proliferation in response to mitogen, increased phagocytosis by neutrophils, and decreased serum lipid peroxides. A role for vitamin C has been suggested in the treatment of autoimmune diseases as well as in delaying the progression of HIV to AIDS however, further research is required to confirm such a role. The effectiveness of ascorbic acid in preventing and reducing the duration of acute respiratory infection also remains controversial. Claims that high intakes of vitamin C can prevent the common cold have not been corroborated, although there is evidence of a decrease in duration and alleviation of symptoms of the...

Wrong diagnosis or more than one diagnosis

It is possible that the patient being treated for infective endocarditis and not doing well may have been given a wrong or incomplete diagnosis. The patient may have been regarded as having culture negative infective endocarditis or the positive cultures may have been misleading or not have grown a typical organism. If vegetations are seen, they may not be caused by infective endocarditis and in reality may be sterile thrombotic vegetations in a patient with adenocarcinoma or systemic lupus. The fever and rise in acute phase reactants may be caused by lymphoma, tuberculosis, opportunistic infection in AIDS or active autoimmune disease or, rarely, the patient may have a fever producing portal of entry such as ulcerative colitis, or carcinoma or Hodgkin's disease in addition to infective endocarditis.

Genetic disruption of IL2R subunits

As IL-2 is required to maintain the growth and viability of T cells in vitro, one might expect disruption of the genes encoding IL-2 or any of the IL-2R subunits to significantly impair T cell development or expansion. However, mice lacking the IL-2, IL-2Ra or IL-2R(3 genes demonstrate apparently normal development of T, B and NK cells and, rather than showing reduced lymphocyte expansion, frequently demonstrate hyperproliferation of lymphocytes and development of T cell-dependent autoimmune disorders such as hemolytic anemia and inflammatory bowel disease. In contrast, yc- mice show severely impaired lymphocyte development, consistent with the involvement of yc in other cytokine receptor complexes. Indeed, the IL-7 receptor utilizes yc and has been shown to be essential for B cell and thymocyte development. Collectively, these results suggest that in the absence of IL-2 or a functional IL-2R, other yc-dependent cytokine receptors can mediate lymphocyte development and expansion in...

Immune modulation by IL12

THl-type responses to autoantigens are considered to be characteristic for several organ-specific autoimmune diseases. It could be demonstrated that in certain mouse models of antigen-induced or spontaneous autoimmune diseases administration of IL-12 can accelerate the development of disease. But IL-12 could also inhibit or delay disease development if higher doses or a different application regimen were employed. Furthermore, in some of the models IL-12-specific antibodies, when applied therapeutically, led to a reduced incidence and severity of the disease.

Recent advances in mechanisms underlying the Arthus reaction

See also Acute inflammatory reaction Adhesion molecules Anaphylatoxins Autoimmune diseases Mast cells Chemokines Cobra venom factor Complement, classical pathway Cytokines Fc receptors Histamine Hydrostatic pressure, effect on immune system Immune complexes integrins Intercellular adhesion molecules ICAM-1, ICAM-2 and ICAM-3 Interleukin 8 and its receptor Neutrophils Nitric oxide Phagocytosis Platelet-activating factor (PAF) Prostaglandins Selectins (CD62-E UP) Serotonin Systemic lupus erythematosus, experimental models Tumor necrosis factor a Chemotaxis of neutrophils.

Bacterial Pericarditis On Echocardiogram

Early Echo Signs Endocarditis

Pericarditis is the most common affliction of the pericardium and reflects inflammation that can result from a broad variety of local and systemic disorders. Most causes can be assigned to one of six categories infectious, idiopathic, metabolic, collagen vascular autoimmune disease, postinjury, and neoplastic. Metabolic, e.g., uremia, myxedema Collagen vascular autoimmune disease Trauma direct or indirect, e.g., surgery, postmyocardial infarction, radiation Autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, and scleroderma may cause acute pericarditis as the first manifestation of the systemic illness. Acute rheumatic fever can involve the pericardium as part of a pancarditis. Certain drugs may

Nonspecific mechanisms

Following the observation that type 1 diabetes-prone NOD non-obese diabetic) mice raised in nonspecific pathogen-free (non-SPF) conditions had a lower incidence of diabetes, NOD mice were exposed to BCG and again the incidence of autoimmunity was diminished. Although this is not a general phenomenon in autoimmune disease, these findings have led to BCG trials in identified high-risk relatives of patients with diabetes with early results pointing to a modest prolongation of the 'honeymoon' (i.e. remission) period. to treat a number of autoimmune diseases, especially systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The aim has been to reverse the immune imbalance believed to be associated with the disease process. The results, however, have been disappointing and none of these agents has secured a regular place in therapy. In a sense, this is hardly-surprising as the physiological role of these compounds, extracted or synthetic, in normal T cell maturation in the thymus...

TABLE 2311 Drugs that Can Cause Hypocalcemia

Idiopathic Hypoparathyroidism Idiopathic hypoparathyroidism is probably an autoimmune disorder in which pernicious anemia, exostoses, moniliasis, Hashimoto disease, sterility, and Addison disease may be seen. This syndrome may also be associated with cataracts, mental retardation, intracranial calcifications, and papilledema due to increased intracranial pressure.

Systemic lupus erythematosus

Several sets of criteria have been proposed for the diagnosis of SLE, but the simplest requires the presence of two seropositive manifestations of autoimmunity and a significantly titred serum ANA. SLE is considered to be a rare, multisystemic, autoimmune disorder that most frequently involves the musculoskeletal, haematopoietic, cutaneous and urinary systems. Cutaneous manifestations of feline SLE are exceptionally rare and may include generalised alopecia, scaling and crusting, involving the face, pinnae, neck, ventrum and limbs, and crusting of all digital pads. The histological features may include interface dermatitis, interface folliculitis, epidermal basal cell and follicular basal cell vacuolation with necrosis. The immunological basis for the latter changes is thought to involve keratinocyte apoptosis mediated by T-lymphocytes that infiltrate the epidermis evidence for this process is lacking in the cat. In addition, there is often...

Selection of the T cell repertoire involvement of minor H antigens

An example of non-MHC genes which may encode polymorphic proteins affecting the propensity to develop autoimmunity has been found from studies of the NOD (non-obese diabetic) strain of mice. A number of chromosomal localizations of genes predisposing to susceptibility or resistance to diabetes have been identified from the extensive backcross studies of Todd and Wicker. It is possible that some of these may act by affecting T cell repertoire selection, for example by negative selection, similar to that caused by the expression of a cross-reactive self-antigen of BALB c (H2'1) origin causing clonal deletion and thus nonresponsiveness to the

Therapeutic applications of monoclonal antibodies

Transplant rejection autoimmune disease In the case of autoimmune disease which is generally not life threatening, such drastic measures are usually inappropriate and much interest has centered on the removal of specific compartments of the immune system to downregulate the autoimmune response without destroying that patient's ability to fight routine infections. Monoclonal antibodies to CD2, CD5, CD7 and CDw52 have all been put through preliminary clinical trials, as have antibodies to various cytokines and their receptors, but no clear candidate therapy has emerged and for any that may do so, the cost per patient will be a relevant issue.

Considering biologic response modifiers

Medications called biologic response modifiers, such as adalimumab (Humira), infliximab (Remicade), and etanercept (Enbrel), have been used for many autoimmune diseases, but are still under investigation for endometriosis. Biologic response modifiers inhibit cytokines, which decrease pain and inflammation.

Therapeutic interventions

See also Autoantigens Autoimmune diseases Autoimmunity Experimental autoimmune encephalomyelitis (EAE) H LA class II Immunopathology Immunosuppression Interferon p Interferon 7 MHC restriction Molecular mimicry T cell receptor, p T cell receptor, 78 T cell vaccination Tumor necrosis factor a.

Chemokine Receptors and Multiple Sclerosis

MS is an autoimmune disease of the CNS characterized by relapse and remittance of clinical signs and the presence of inflammation and demyelination in the white matter. Accumulating evidence has suggested that these findings represent the first stage of the disease followed by a chronic irreversible phase due to degeneration of the myelin sheath and the underlying axon. As the suppression of the relapse during the course of MS with immunotherapy is extremely important to prevent the development of the subsequent irreversible stage of the disease, it is essential to clarify the mechanism of disease relapse using an animal model, that is, Encephalomyelitis (EAE). EAE is a T-cell-mediated inflammatory demyelineating disease of the CNS that functions as a mouse model for human MS. Upon immunization of susceptible mice with myelin proteins (McRae et al., 1992 Trotter et al., 1987), EAE neuroinflammation follows with the subsequent invasion of leukocytes into the CNS through the blood-brain...

Central nervous system

MS is most commonly viewed as an autoimmune disease, but no antigen against which the immune response is thought to be directed has been identified. Periodically, interest in a viral causation for MS resurfaces, but to the present no virus has been identified that links to the disease despite diligent search. Nonetheless, there is reason to believe that an MS-rclevant antigen does exist. This rare disease is characterized by axial and limb rigidity and painful spasms. More cases occur in men than in women. Stiff man syndrome occurs both sporadically and as a remote effect of cancer. Most sporadic cases, but not all, have high titer circulating antibodies to glutamic acid decarboxylase (GAD). The enzyme catalyzes the formation of gamma amino butyric acid (GABA) from glutamic acid. GABA is a major inhibitory neurotransmitter and GABA agonists ameliorate the symptoms of stiff man syndrome. Ten per cent of cases have epilepsy. GABA agonists are antiepileptic. Antibodies to GAD are a...

Future directions

Although it is clear that oral antigen can suppress autoimmunity in animals and results to date suggest that this approach may have utility in humans and is safe, much remains to be learned about the immunologic mechanisms associated with antigen-specific mucosally driven tolerance. Important areas of investigation include cytokine milieu, antigen presentation, costimulation requirements, routes of antigen processing, form of the antigen, role of the liver, the effect of oral antigens on antibody and CTL See also Autoimmune diseases Cytokines Immunotherapy of autoimmune diseases Mucosal immunity Mucosa-associated lymphoid tissue (MALT) Multiple sclerosis Neurological autoimmune diseases T lymphocytes Transforming growth factor p (TGFp).

Role of Methylation in Organisms

Histone methylation plays a central role not only in epigenetic chromatin modification in eukaryote cells, but also in cell differentiation, development, gene expression, genome stability, and cancer research. Other types of protein methylations and methyltransferases are also vital to organisms. Aberrant protein methylation or mutation in methyltransferase always leads to disease. For instance, monomethylated arginine and asymmetric dimethylated arginine are NOS inhibitors. These kinds of modifications have already been discovered in many patients with heart disease. Arginine methylation is not reversible, which will influence NOS activity. Several methlylated proteins are found in autoimmune diseases. For example, the antibody

Costimulation and coinhibition are physiologically related to polyclonal activation and inhibition

Synergistic interactions between a clonally restricted antigen receptor and a polyclonal receptor form the basis of costimulation. This is a physiologic process in which receptor-ligand interactions occur, allowing different types of cells to communicate with each other. T cells are activated by signals transmitted via the antigen receptor and other signals transmitted via a second receptor or class of receptors. The classical costimulator of T cells is the receptor CD28 whose ligand is B7 (CD80 86), but there are many others. B cells are activated by signals transmitted via the antigen receptor and other signals transmitted via a second receptor or class of receptors. The classical costimulatory receptor for B cells is CD40 whose ligand is CD40L which is found on T cells. CD40L also acts as a receptor for T cell signaling, so that a given cell surface element can serve as both receptor and ligand. Other costimulatory receptor-ligand systems have been defined, and evidence suggests...

Anti Cholinesterases General Mechanism of Action

The anti-cholinesterases inhibit the breakdown of acetylcholine by binding to the acetylcholinesterase enzyme in a competitive manner. This raises the background concentration of acetylcholine near the neuromuscular junction, which in turn overcomes the reduced number of functional nicotinic receptors on the muscle end plate whether due to a reduced number of receptors (myasthenia gravis) or due to blockade of existing receptors (non depolarizing muscle relaxants). They can be classified as either reversible anti-cholinesterases or organophosphorus compounds. While all anti-cholinesterases act on acetyl and plasma cholinesterase the specific interaction with the enzyme varies between individual drugs.

Immune responses of the host

Pathogenesis of viral central nervous system disease Pathogenesis and immunity of viral myocarditis Gastrointestinal infection and immunity Respiratory infection and immunity Viral induction of autoimmunity Delineation of the anti-idiotypic network Induction of autoimmune diabetes

Neuromuscular and Cutaneous Syndromes

The idiopathic inflammatory myopathies are systemic autoimmune diseases characterized by chronic inflammation leading to progressive weakness of the proximal muscles. In 7 - 66 of cases of adult dermatomy-ositis, different malignant tumors can promote the difficult cascade mechanisms at the cell level, leading to rapid weakness of skeletal muscles (Mooney et al. 2006). A case with all characteristic signs of acute, se-

Sex Hormones And Immunity

In addition to their profound effects on sexual differentiation and reproduction, sex steroids also influence the immune system's function. The effects of these hormones on the immune system initially attracted the attention of investigators working on autoimmunity, as a sexual dimorphism exists in human autoimmune diseases - that is, one gender is often more susceptible than the other. Although the precise mechanisms through which sex steroids interact with the immune system remain unknown, we do know that these hormones can act directly on certain of the system's cells, or indirectly either through cells controlling the immune system's growth and development or through organs eventually destroyed by autoimmune diseases. Understanding such mechanisms will allow new insight into autoimmune diseases and also into the normal development and function of the immune system and its responses to challenge.

Acquired neuromyotonia Isaacs syndrome

Acquired neuromyotonia is a rare disorder characterized by widespread muscle twitching (myokymia) and cramps, sometimes associated with muscle hypertrophy, stiffness, weakness, increased sweating and central effects. Onset can be from adolescence to old age. There is an association with thymoma, with myasthenia gravis, and probably also with lung cancer. See also Autoantigens Autoimmune diseases Autoimmunity Idiotype network Immunosuppression Neurological autoimmune diseases Plasmapheresis Thymus.

The etiological role of viruses

In common with other autoimmune diseases, it is believed that polygenic genetic susceptibility factors interact with environmental factors to induce SS. Potential viral triggers include sialatropic and lym-photropic viruses such as the herpesviruses, in particular Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus type 6 (HHV-6). Evidence for involvement of any of these viruses has been conflicting, with some studies finding elevated titers of antibodies to all three viruses in patients with SS but others finding them normal. EBV has been detected in parotid and labial salivary glands by DNA hybridization techniques. Salivary epithelium can contain up to 50 copies of EBV DNA per cell in healthy people without inducing an immune response, suggesting that the gland is an important site of persistence. The extent of EBV infection load in salivary glands in SS is still controversial with conflicting reports. While these inconsistent data may

Finding Chemically Safe Products

Will cutting down on chemical exposure help control endometriosis The jury is still way out on whether chemical exposure causes autoimmune diseases like endometriosis. But reducing contact with some chemicals certainly can't hurt. (See Chapter 4 for more on chemical exposure and endometriosis.)

Type V hypersensitivity

See also Acute inflammatory reaction Allergens Anaphylatoxins Antiglobulin (Coombs') test Arthus reaction Atopic allergy Autoimmune diseases Blood transfusion reactions Cell-mediated immunity Contact hypersensitivity Delayed-type hypersensitivity Eczema Food allergy Granuloma Hemolytic disease of the newborn Immune complexes Rhinitis, allergic Sarcoidosis.

The pathophysiology of breathlessness as it relates to neurological disease

In patients with disorders such as amyotrophic lateral sclerosis or myasthenia gravis, the mechanical properties of the respiratory system maybe normal, but the weakened respiratory muscles require greater neural drive for activation.3 This has been demonstrated in patients with myasthenia gravis, who show greater electromyography activity, and higher airway pressures, as compared to controls.4 This greater neural drive increases sense of respiratory effort, and hence induces dyspnoea. The sense of effort is related to the ratio of the pressure generated by respiratory muscles to the maximum pressure-generating capacity of those muscles.5 Whenever there is muscle weakness, fatigue or paralysis, the maximum pressure-generating capacity is reduced, which increases the central motor command to the respiratory muscles, raises the sense of respiratory effort, and so induces dyspnoea. The greater neural drive may also add to 'mismatch' between the outgoing motor command, and incoming...

Historical background

Lymphocytes in the spleen and lymph nodes that could specifically transfer the tolerance to a recipient animal. Conversely, fresh T lymphocytes (antigen primed or unprimed) transferred into a tolerant recipient were unable to break the tolerant state and also became tolerant. These results had two consequences first, it was demonstrated that tolerance could be both antigen specific and dependent on the presence of a specific population of lymphocytes, namely T cells secondly, it laid to rest the notion that the shutdown or negative control of an immune response was solely the result of antibody-dependent feedback mechanisms. Other workers, at the same time, using syngeneic murine tumor models were demonstrating that tumor-bearing animals possessed fully immunocompetent antitumor cells. Nonetheless, these mice not only failed to respond to the tumor, but contained T cells that prevented the host from making an antitumor response. Yet another converging line of studies came from...

Motheaten mice and the protein tyrosine phosphatase gene

Mice homozygous for the recessive allele 'motheaten' me), and its milder variant 'viable motheaten' (mev) express multiple hematopoietic and immunologic abnormalities, including developmental or functional defects in macrophages, granulocytes, T cells, B cells and natural killer (NK) cells. These mice develop systemic autoimmunity with hypergammaglobulinemia and antinuclear autoantibodies, and the majority of B cells are of the B1 type (Ly-1 + ). The me mutation was initially mapped to the distal end of chromosome 6. Subsequent linkage analysis positioned the me locus at the same site on chromosome 6 to which the protein tyrosine phosphatase 1C (PTP1C) gene (hematopoietic cell protein tyrosine phosphatase (Hcph) gene) had been previously mapped. Cloning and sequencing of the PTP1C gene from me mice

Mechanisms of regulation

An open question is how the anti-idiotypic and anti-ergotypic regulatory cells arrest the autoimmune disease process. Specific autoimmune T cells persist in TCV-treated animals, suggesting that effective regulation of disease does not depend on total deletion of the autoimmune effector cells. Indeed, TCV was found to suppress inflammation without inhibiting the production of autoantibodies. The divergent effects of TCV on tissue damage and antibody production may be explained by the Tnl-TH2 dichotomy. TCV has been found to enhance a switch from a proinflammatory THl-type cytokine response to an anti-inflammatory TH2-type cytokine response. Following TCV, the treated animals still respond to the target self antigen however, instead of producing large amounts of interferon 7 and interleukin 2 (IL-2), the responding T cells produce low amounts of these cytokines and high amounts of IL-4, IL-10 and

Two theoretical concepts on self tolerance

The most accepted view on tolerance is based on the Burnet Lederberg theories (and developments thereof) which consider all autoreactivities as dangerous to the organism. All self reactive lymphocytes should therefore be physically eliminated (deletion) or irreversibly inactivated (anergy). Tolerance is thus established by 'default' (lack of self reactivities), that is, by 'ignorance' of what self is. For this concept, tolerance and (pathological) autoimmunity are problems which should be dealt with at the single cell or clonal level, and thus discards the notion of

Concluding remarks

The alternative theoretical concept here described has major implications in therapeutic approaches to autoimmune diseases and organ transplantation, as well as in tumor immunology. See also Autoimmunity Anergy, T cell Clonal deletion Clonal selection Idiotype network T lymphocyte differentiation T lymphocytes, autoreactive Thymus Tolerance, central Tumors, immune response to Tumors, immunological escape of Transplantation T cell vaccination.

Organization Of The Seminiferous Tubule

Spermatogenesis occurs within the seminiferous tubules of the testes (Figs. 1 and 2). The intertubular area includes a vascular supply and testosterone-producing Leydig cells. A basement membrane surrounds each tubule with an outer layer of peritubular cells and a basal lamina. Within each tubule is an epithelial layer of Sertoli cells, somatic cells that provide physical and metabolic support for developing germ cells and regulate spermatogenesis. Intercellular junctions form near the base of adjacent Sertoli cells, further separating the tubule into basal and adluminal compartments and forming a blood testis barrier. This barrier segregates diploid and haploid germ cells, thus restricting access of antibodies and preventing autoimmunity due to haploid gene expression. Germ cells

Negative regulation of expansion

Causes effector T cells to slowly upregulate the death receptor Eas and its counter-receptor Fas-ligand (FasL). This expression results in death of the T cell and other Fas4 cells, as Fas signaling triggers apoptosis. Interestingly, the mutant mouse strains lpr lpr and gld gld have defective Fas and Fasl , respectively, and their effector lymphocytes are resistant to AICD. This results in the accumulation of lymphocytes in these strains, which in turn appears to cause autoimmune disease. Thus, AICD may be essential to control the expansion of potentially deleterious effector cells.

Crucial selection events in T cell development are determined by actions of the preTCR and TCR

Before migrating to the periphery, developing thymocytes have to be screened for a second feature they must not recognize thymic MHC molecules too eagerly, because then they would, if allowed to mature and migrate out of the thymus, cause harmful autoimmunity. Self MHC plus self peptide-reactive T cells are therefore eliminated in the thymus by clonal deletion, and this 'negative selection' process plays a major role in the acquisition of self tolerance, at least for those antigens that are expressed in the thymus, or for circulating native self proteins that have access to the thymus. The first major breakthrough in the understanding of acquisition of tolerance was made in 1987 by Kappler, Roehm and Marrack, when it became clear that T cells expressing an ot(3 TCR with V 517a (identified with a specific mAb) exhibit preferential reactivity for a given class II MHC-peptide combination, regardless of the a TCR chain or J, N and D region sequences in their TCR. T Cells with such a Vpl7a...

Induction in mature animals

These latter models, however, do not readily lend themselves to understanding the mechanisms of tolerance induction involving the cytokine cascade, antigen presentation, roles of activation events and intracellular biochemical processes as well as the role of antigen processing. Another model, the unresponsive state induced in adult mice to monomeric forms of mammalian gamma globulin, more readily lends itself to the investigation of these latter events. An in vivo model of a central unresponsive state is presented in this review to delineate the conditions required for the induction and maintenance of self tolerance and the role of such induction and maintenance on susceptibility to autoimmunity. A classical in vivo model of tolerance which mimics a number of aspects of self tolerance has been studied in the past by several groups of workers using monomeric preparations of mammalian gamma globulin. In the model to be discussed below, tolerance is induced to human gamma globulin (HGG)...

Improving Immune Therapy

Immune therapy is still in its infancy in treating endometriosis. (See Chapter 12 for more about immunotherapy.) Although use of immune therapy for cancer treatment is common, doctors don't use it as much as they could to treat autoimmune diseases. This reluctance stems from the potentially serious side effects. After all, who wants to treat a disease and have side effects that are potentially life-threatening and worse than the disease itself New, less destructive and dangerous drugs may make immune therapy more acceptable for endometriosis.

Tolerance induction and TGFp

Oral administration of myelin basic protein iMBP) to rats effectively prevents EAE induced by immunization with MBP in Freund's complete adjuvant. Evidence has been presented that such tolerance is mediated by CD8+ T cells producing TGFp. TGF'P is also strongly upregulated in DA strain rats treated with low doses of MBP by the nasal route. Nasal tolerization with MBP efficiently prevents the induction of protracted-relapsing EAE in DA rats. In the acute Lewis rat EAE model, nasal administration of MBP or MBP peptides 63-88 or 89-101 resulted in increased levels of TGFp mRNA-expressing immune cells. TGFp-mediated bystander regulatory mechanisms are thought to be important for nasal tolerance induction. High numbers of TGFp mRNA-posi-tive mononuclear cells are also found in lymph nodes of rats tolerized to the mainly B cell-mediated experimental autoimmune myasthenia gravis (EAMG) by oral or nasal administration of the target antigen acetylcholine receptor (AChR). Such findings suggest...

The role of TNFa in development

The involvement of TNFa in development starts before embryogenesis. TNFa induces ovulation and enhances luteinizing hormone (l.H)-induced ovulation. Soluble TNFR is increased in the blood of pregnant women and also in amniotic fluid and umbilical serum. However, not only does TNFa have an effect on reproduction but also sexual hormones have an effect on TNFa production. Estradiol and progesterone enhance TNFa release by macrophages, whereas testosterone has no effect. This may be one possible reason for the higher incidence of autoimmune diseases in women.

Other childhood vaccines

More recently, the IOM has published findings on adverse events associated with a number of other childhood vaccines, to see whether any evidence bearing on causality could be established. Reactions to the diphtheria and tetanus toxoids, measles, mumps, polio, hepatitis B, and Haemophilus influenzae type B (Hib) vaccines, were examined. Evidence for neurological disorders (both demyelinating and nondemyelinating diseases) and a series of immunologic reactions (anaphylaxis, Arthus reaction, delayed-type hypersensitivity and autoimmunity in particular) was sought. After an exhaustive review of the available data, the findings suggested that these vaccines are remarkably safe.

Disorders of the neuromuscular junction

Myasthenia gravis (see chapter 8) Myasthenia gravis has been associated with thymoma and immune-mediated myositis. Ducote J.M. & Dewey C.W. (2001) Acquired myasthenia gravis and other disorders of the neuromuscular junction. In Consultations in Feline Internal Medicine. 4th edn (ed. August J.R.). WB Saunders, Philadelphia, PA, pp. 374-379.

The Evolution of Disease

Predispose individuals to physiological degeneration in mid-life, for example, through type II diabetes, gall bladder disease, autoimmune diseases, and hypertension, are examples of antagonistic pleiotropy, that is having opposite effects on fitness at different ages (Gerber & Crews, 1999, p. 446).

Introduction Clinical Setting

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown cause that can occur at almost any age, although it affects mostly women in their 20s. The annual incidence of SLE is 50 to 70 people per million of the population, and prevalence is 500 per million (1). Epidemiologic data show that the incidence of new cases and the survival of patients with SLE are both increasing (2). The disease is characterized by a large variety of organ disorders involving many different immune mechanisms. This is reflected in particular by the spectrum of glomerular lesions, resulting in a strong variation of the clinical symptoms of the renal disease. Clinical or morphologic involvement of the kidney in SLE occurs in 50 to 80 of lupus patients at any moment during the course of their disease. Moreover, renal alterations are found in almost 90 of lupus patients at autopsy. The lowest 5-year survival has been reported for patients with central nervous system and renal involvement (1).

Transforming Growth Factor p TGFp

Covered on characterization of a glioblastoma-derived T cell suppressor factor which, after cloning, was termed TGFp2. Mice deficient in the gene for TGFp , generated by knockout technology, die from a wasting syndrome accompanied by inflammation in multiple organs. Although TGFp belongs to the group of cytokines with anti-inflammatory effects, it may under certain circumstances also exhibit proinflammatory activities. TGFp participates critically in mucosal tolerance to experimental autoimmune encephalomyelitis (EAF.) and myasthenia gravis (EAMG) induced by oral or nasal administration of autoantigens, and could represent a powerful tool in the future abrogation and prevention of autoimmune diseases.

Considering Immunotherapy

Many doctors already use immune therapy in cancer patients as well as patients with autoimmune disease, a category it seems endometriosis may fall into. (See Chapter 4 for more on the immune system and endometriosis.) I New research shows women with endometriosis often have increased autoantibody levels, suggesting that endometriosis is an autoimmune disease. Common

Naming the two main treatment options

Immune therapy is successful with other types of autoimmune disease, and because of the link of endometriosis to autoimmune diseases, researchers suggest that immune therapy may work against endometriosis. Because the FDA hasn't approved any of these more aggressive treatments for endometrio-sis, we include them in this chapter. The two main treatments include 1 Intravenous immunoglobulin (TVIG) IVIG is a sterile protein preparation derived from human blood, given intravenously. IVIG is being used in other autoimmune disorders with some success, but some studies have found no real benefit to IVIG. The biggest problem with this treatment is the cost, 2,500 to 4,000 per treatment, which most insurance companies don't cover because IVIG isn't approved for use in endometriosis.

The immunological role of calcitriol

These findings suggest a role for calcitriol under physiological conditions as an important factor in sustaining normal functions of the immune system (which can be compromised by vitamin D deficiency). Because a large number of undifferentiated or low differentiated cancer cells have been shown to differentiate toward normal cell phenotypes, efforts to treat cancer with calcitriol have been developed. A potentially important clinical application of the antiproliferative effects of calcitriol on monocytes has been in the development of antileukemic agents. The use of vitamin D metabolites in myeloproliferative disorders in vivo has, so far, been less successful than related agents such as retinoic acid. This idea has stimulated an interest in the possible use of calcitriol in the treatment of other proliferative diseases such as psoriasis and also in the treatment of autoimmune disorders and in the prevention of graft rejection. However, the therapeutic...

Diseases caused by maternal antibodies

Autoimmune diseases Transfer of maternal IgG antibodies across the placenta may give rise to autoimmune diseases also in the fetus and newborn child. Such disease is most often transient, disappearing as the maternal antibodies are catabolized. These neonatal effects have been observed in a range of autoimmune diseases and the materno-fetal model has been crucial in confirming an autoimmune basis of many such disorders. The materno-fetal model also provides a unique, naturally occurring, experimental system which should be valuable in gaining an understanding not only of the pathogenic process in autoimmune diseases but also of the priming influence of the maternal immunity on the developing immune system. The incidence of fetal or neonatal disease in children to mothers with antibody-mediated autoimmune diseases is not 100 but ranges from 5 to 60 for the most common disorders, indicating that factors other than the maternal antibodies are of importance. Recent data in human...

Staphylococcal Enterotoxins

In addition to their nature as superantigens, SEs function as potent gastrointestinal toxins causing SFP, which has a major public health impact. 1,3-5 Superantigenicity and emesis activities of SEs have been shown to result from distinct regions of the toxin protein. SEs comprise a family of homologous but antigenically different exotox-ins, which are heat stable and resistant to inactivation by gastrointestinal proteases. SEs have also been implicated in several allergic and autoimmune diseases. The repertoire of SEs includes the five classical enterotoxins SEA through SEE and the more recently identified enterotoxins starting with SEG (Table 1). To date, the ''alphabet'' of SEs and their coding genes has reached the letter ''Q.'' However, some of the recently described SEs were shown to be nonemetic, thus actually lacking the defining property of SEs. Nevertheless, the standard convention hitherto has been to refer to proteins exhibiting sequence similarity to SEs as enterotoxins.

Contribution to Disease

Luxol Multiple Sclerosis

Damage to oligodendrocytes can occur in a variety of ways, including microbial infections, injury, autoimmunity, genetic defects, inflammation, and exposure to toxins. Although great strides have been made in understanding the core features of many of these demyelinating actions, the molecular events leading to damage of oligodendrocytes and, in many cases, dysmyelation or demyelination are not totally understood.

Physical Examination

Extraocular Muscles

Cranial nerve IV controls the superior oblique muscle, cranial nerve VI controls the lateral rectus muscle, all other extraocular muscles are controlled by cranial nerve III. Ocular motility can be impaired by restriction, interrupted or decreased innervation, or trauma. Examples of restriction include thyroid orbitopathy, myositis, and mechanical entrapment of a muscle secondary to an orbital blowout fracture. Cranial nerve palsies or paresis may be caused by cVAs, myasthenia gravis, diabetes, hypertension, tumors, aneurysms, infections, and trauma. Penetrating or blunt traumatic injury to an extraocular muscle can also result in motility disturbance. Diplopia may develop, especially when the patient is attempting to look in the direction of the malfunctioning muscle. Ocular alignment should be evaluated in primary gaze initially (looking straight ahead), followed by testing in all fields of gaze.

Consequences of invariant chain knockout

The activities of the Ii chain as a specific class II chap-erone have been extensively analyzed in transfection assays and mutant mouse strains produced using gene targeting techniques. Under physiological conditions, the loss of Ii chain expression has been shown to cause a dramatic reduction in surface class II expression. As a general rule, mutant spleen cells are defective in their ability to present intact protein antigens, and have greatly reduced numbers of thymic and peripheral CD4' T cells. However, exceptional antigens such as RNAase are presented in association with class II molecules via an Ii chain-independent pathway. Moreover, the extent of Ii chain influence on positive selection of individual CD4+ T cells is dependent on their receptor specificities. As yet, only limited information exists concerning the various functional contributions made by Ii chain to CD4 1 T cell responses in vivo. It will be interesting over future years to learn more about the structure and...

Color Vision Defects Associated with Other Diseases

Tritanopes

There is a class of autoimmune diseases that arise from cancers that express antigens, which are also expressed by photoreceptors. The immune system detects these antigens and reacts to them both on the cancer cells and on the photoreceptors. This class of diseases has been called cancer-related retinopathies. Some of these diseases are highly specific, involving only cones and not rods. Such subjects can lose all cone vision and consequently color vision. Recently, we found a subject who lost only L and M cones but not S cones or rods. These are examples of acquired achromatopsia.

Generation of immunological diversity and the need for tolerance

Early models of tolerance induction invariably invoked clonal deletion as the means by which self reactive cells were rendered tolerant. That is, self reactive lymphocytes were killed by interaction with self antigen. Numerous experiments dating from the 1970s, however, suggested that not all self reactive B cells were deleted. After Naor and Sulitzeanu described the enumeration of antigen-specific lymphocytes by their ability to bind radioactively labeled antigen, others used the same technique to determine whether antigen-specific B cells persisted in tolerant animals. In some instances a reduction in the number of such B cells was observed, while in others no change was seen, suggesting that B cell tolerance was not obligatorily associated with deletion. Using this technique it was possible to demonstrate in apparently healthy animals the presence of lymphocytes which could bind self antigens such as thyroglobulin. Yet other groups showed that polyclonal B cell activators such as...

Asthma allergies and autoimmune issues in endometriosis

There's growing evidence that endometriosis is an autoimmune disease. There's also growing evidence that people who have one autoimmune disease are more likely to have additional autoimmune problems. One large study of more than 3,000 women with endometriosis showed the following

Immune responses to antigenic material in immune privileged sites

Strong tissue-restricted autoantigens that can readily cause autoimmune disease. Immune privilege is considered to be one mechanism that is used by tissues with strong 'sequestered1 autoantigens to avoid destructive autoimmunity. See also Autoantigens Autoimmune diseases Autoimmunity Transplantation.

Pavlovian conditioning and immunomodulation

That conditioned immunopharmacologic effects are of biological importance is apparent from Ader and Cohen's observations that the development of a systemic lupus erythematosus (SLE)-like autoimmune disease in (NZB x NZW)F, hybrid mice could be markedly delayed by treating animals under a partial schedule of pharmacologic reinforcement. That is, by substituting conditional stimuli that had been paired with CY for a proportion of the trials on which animals would normally have received active drug therapy, conditioned mice showed a significant delay in the onset of lupus using a cumulative dosage of CY that was, by itself, insufficient to alter the course of the autoimmune disease. Moreover, conditioned mice repeatedly re-exposed to the taste stimulus that had been paired with CY following the termination of active drug therapy survived significantly longer than conditioned animals that received no 'medication'. Although in the not-too-distant future, conditioned immunopharmacologic...

Biochemical pathways leading to the synthesis and metabolism of the major neurotransmitters in the mammalian brain

Reversible anticholinesterases which are in clinical use. Both act in similar ways but they differ in terms of their lipophilicity, the former being able to penetrate the blood-brain barrier while the latter cannot. The main clinical use of these drugs is in the treatment of glaucoma and myasthenia gravis.

Effects on Particular Organs or Organ Systems

Immune System The immune system consists of various organs, including the bone marrow, spleen, thymus, and lymph nodes, plus specialized cells and plasma proteins produced by those organs which circulate in the blood and lymphatic system. The cells are the lymphocytes, or white blood cells, and include T cells and B cells. The proteins include the immunoglobulins, interleukins, and the complement system. Together they act to rid the body of chemical and biological contaminants. There are three types of immune system derangements. Immunosuppressants reduce immune response and render the body more vulnerable to foreign substances. Immunostimulants cause hypersensitivity reactions or allergies. Autoimmune disease is the condition where the immune system attacks its own substances as if they were foreign. Immunostimulants usually cause their reaction within 15 minutes of exposure. A first exposure does not cause a reaction since the immune system must generate immunoglo-bulin antibodies....

Recombinant vaccines expressing tumor associated antigens

The recent discovery of human CD4+CD25+ regulatory T cells (Tregs) has made it feasible to develop strategies that modulate the immunosuppressive effects of Tregs in a vaccination setting 73 . Tregs have been shown to play an important role in the repression of T cell responses to both self and foreign antigens, and the loss of Tregs leads to the development of autoimmunity. Experimental tumor models in mice have revealed that Tregs can inhibit antitumor immune responses as well depletion of such Tregs using anti-CD25 antibody permits the development of an antitumor immune response and tumor rejection 74 . Recent evidence indicates that Tregs may exist in high proportion in human cancer patients, possibly inducing or maintaining tolerance to tumors 75 . Vieweg et al. hypothesized that in vivo elimination of Tregs using the fusion protein denileukin diftitox (ONTAK) can enhance the efficacy of tumor RNA-transfected DC vaccines to stimulate a tumor-specific T cell response. They...

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