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 Overview

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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...

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.

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...

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...

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...

Myasthenia gravis

And respiratory muscles in severe cases. MG appears to affect all races, the prevalence in the Western world being about 5-9 per 100000 with an annual incidence of about 4 per million. It may occur from early childhood to extreme old age. Other autoimmune diseases occur at increased frequency, especially thyroid disease, and other autoantibodies are common. About 8 of babies born to myasthenic mothers have a transient neonatal myasthenia due to placental transfer of AChR-specific antibody, and in a small proportion there may be limitation of intrauterine movement with development of arthrogryposis multiplex congenita. Experimental autoimmune myasthenia gravis The discovery by Patrick and Lindstrom that rabbits immunized with AChR, purified from the electric organ of electric eel Electropborus, developed a myasthenia-like illness (experimental autoimmune myasthenia gravis, EAMG) provided an animal model for the human disease. The clinical features of EAMG bear a striking resemblance to...

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...

Immunogenetics and disease association

Adrenal autoimmunity may be a heterogeneous condition, as suggested by reports that Addisons disease is inherited in at least three different fashions autosomal recessive, autosomal dominant with decreased penetrance and X-linked recessive. Inherited susceptibility to autoimmune Addisons disease is linked to HLA-DR3 and or DR4, except when the disease occurs as part of type 1 autoimmune polyglandular syndrome. A high prevalence of other autoimmune diseases (ovarian failure, Graves disease, Hashimoto's disease, hypothyroidism and insulin-dependent diabetes mellitus) is associated with Addisons disease (see Table 1).

Programed and Genetic Theories

However, the genetics of longevity have not been as revealing in mammalian studies. In mouse systems genes involved with immune response have been implicated in longevity, as has the 'longevity gene p66shc, which is involved in signal transduc-tion pathways that regulate the cellular response to oxidative stress. In humans, a number of mitochon-drial DNA polymorphisms are associated with longevity. Linkage analysis in humans systems has associated certain genes on chromosome 4 with exceptional longevity. Further support for human longevity genes may be provided by the observation that siblings and parents of centenarians live longer. The major histocompatibility complex (MHC), the master genetic control of the immune system, may also be one of the gene systems controlling aging, since a number of genetic defects that cause immunodeficiency shorten the life span of humans. Certain MHC phenotypes have also been associated with malignancy, autoimmune disease, Alzheimer's disease, and...

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...

Working things out on the basis of mechanism and logic

Many physicians base clinical decisions on an understanding of the aetiology and patho-physiology of disease and logic.10,11 This paradigm is problematic because the accepted hypothesis for the aetiology and pathogenesis of disease changes over time, and so the logically deduced treatments change too. For example, in the past 20 years, hypotheses about the aetiology of psoriasis have shifted from a disorder of keratinocyte proliferation and homeostasis, to abnormal signalling of cyclic AMP, to aberrant arachidonic acid metabolism, to aberrant vitamin D metabolism, to the current favourite a T-cell-mediated autoimmune disease. Each of these hypotheses led to logically deduced treatments. The efficacy of many of these treatments has been substantiated by rigorous RCTs, whereas other treatments are used even in the absence of systematically collected observations. We thus have many options for treating patients with severe psoriasis (for example UVB, Goeckerman treatment, psoralen-UVA,...

Anemia Autoimmune Hemolytic In Animal Models

Autoimmune hemolytic anemia (AIHA) is a classic example of an antibody-mediated autoimmune disease. It is well documented how autoantibody-coated red blood cells (RBCs) can be destroyed by splenic macrophages, but by contrast, the mechanisms that initiate the production of RBC autoantibodies remain unclear. The New Zealand Black (NZB) strain of mice spontaneously develops AIHA. RBC-bound immunoglobulin G (IgG) autoantibodies can be detected by Coombs' test from 3 months of age and the mice develop signs of anemia 2-3 months later. For two decades after these mice were first bred in 1959, a flood of papers appeared documenting the specificity of the autoantibodies and attempting to pinpoint lesions in particular cells which could result in the generation of RBC autoantibodies. Many of these results are now open to re-evaluation in the light of recent studies.

Specificity and characterization of T cells

CD4+ T cells can be classified into two types, TH1 and Th2, depending on the cytokines they produce. For example, TH1 cells typically secrete interferon 7 (IFNy) and TH2 cells interleukin 4 (IL-4). The type of cytokine secreted by helper T cells affects the iso-type of antibody produced, and in mice THl-domi-nated responses are associated with IgG2a antibodies and Th2 with IgGl. Whilst there is now a consensus that pathology of cell-mediated autoimmune diseases is linked to the stimulation of TH1 autoreactive cells, it might be expected and indeed it has been suggested that T(I2 responses may be important in initiating and driving antibody-mediated autoimmune disorders such as AIHA. However, NZB T cells stimulated with band 3 produced high levels of IFN-y, but little or no IL-4, IL-5 or IL-10. Similar patterns were produced by NZB T cells responding to a spectrin preparation from the RBC membrane skeleton, or to mycobacterial heat shock protein (hsp) 65 following immunization of mice...

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...

Pathologic conditions related to Ig secretion

Mott cells are plasma cells defective in Ig secretion found in multiple myeloma and certain chronic inflammatory and autoimmune conditions. Mott cells are characterized by cytoplasmic inclusions normally containing immunoglobulin molecules, called Russell bodies, and representing dilated cisternae of the ER. Mott hybridomas have been obtained by fusing splenocytes from NZB mice, a strain highly susceptible to autoimmune diseases. Since these hybridomas express several membrane antigens, a general defect in the secretory pathway may be excluded. That the Mott cell phenotype is due to mutations in the Ig chains is indicated by the observation that Russell bodies are formed upon transfec-tion of certain mutated heavy chains into myeloma cells. Not all nonsecretable chains induced the Mott phenotype. Thus, Russell bodies probably reflect the presence of nontransportable molecules resistant to pre-Golgi degradation.

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.

Apoptosis in immunity

The small minority of thymocytes that are positively selected exit the thymus and migrate to the peripheral lymphoid organs. Here they are faced with the possibility of reacting with previously unencountered self-antigens. Should this happen, the autoreactive mature T cell, all going to plan, should then undergo apoptosis, probably as a result of receiving an inappropriate activation signal (such as TCR engagement in the absence of CD28 costimulation). Should this peripheral deletion process fail for any reason, then autoimmunity can result. Unlike in the thymus, CD95-CD95L interactions do appear to be important for peripheral deletion, as both lpr and gld mice are impaired in peripheral deletion and develop a systemic lupus erythematosus (SLE)-like autoimmune disease as a result. B cells that manage to persist also run the gauntlet of apoptosis during affinity maturation in the germinal centers. During the germinal center reaction, activated B cells acquire point mutations in the V...

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...

Other endocrine organs

Autoimmunity also develops against other endocrine organs such as the adrenal gland, pancreas islet cells, parathyroid, pituitary and ovary. The autoantibodies are much less prevalent than with thyroid disease but, if present, help in diagnosis. The reactivities, assays and primary associated disorders are summarized in Table 1.

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

Therapeutic Interventions

The understanding that the autoimmune disease is 2. In addition to the TCR contacting its appropriate peptide in the MHC, efficient T cell activation needs an interaction called ''the second signal'' or T cell costimulation. In other words, the signal delivered to the T cell by the interaction of its TCR with the peptide-MHC complex is not sufficient to cause activation, and another trigger to a simultaneously bound surface molecule on the T cell is needed to enable the stimulation to proceed. This second signal is termed a costimula-tory signal. Blocking this interaction by decoy molecules prevents T cell costimulation. Such interventions in animal models of autoimmune disease result in prevention or cure of the disease. 7. Once the pathogenic T cells have reached the target tissue, the damage is inflicted in part by cytokines secreted by these cells. Thus, one way to treat autoimmune diseases involves the neutralization of cytokine effects (e.g., anti-tumor necrosis factor...

Treating The Human Disease

Current treatments for many human autoimmune diseases are largely based on immunosuppression, usually by giving medications such as corticosteroids, cyclophosphamide, azathioprine, or cyclosporin A, which inactivate or kill all classes of lymphocytes. In many patients these medications are effective in the short term only their administration does not usually alter the natural history of the disease, and the toxicity of these drugs is considerable. This toxicity is related to nonselective immunosuppression, which results in susceptibility of the patient to infections and malignancies. In addition, these medications have considerable side effects (such as in the case of corticosteroid drugs elevated glucose levels, hypertension, obesity, osteoporosis, and psychiatric disturbances). Thus, the ideal therapy for autoimmune disease should affect the pathogenic clone or clones specifically without suppressing the entire immune system it should be devoid of toxicity and it should be easily...

Future Directions

The major force in the introduction of new and effective treatment for autoimmune diseases is our enhanced understanding of immunology in general and control of immune cell activation in particular. As we discover the key players in T cell activation and the molecular tools to abort an immune response in its early stages without adversely affecting the millions of other beneficial immune cells, we will be able to introduce novel and more effective treatments. Since these diseases cause considerable suffering and loss of life, the sense of urgency has shortened the time in which clinical applications of inventions in the laboratory are carried out.

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...

Etiology Pathogenesis

Investigations of human biopsies together with research using animal models and in vitro cell culture systems have generated some understanding of the underlying etiologic and pathogenetic mechanisms of lupus nephritis (23-27). The findings indicate that disturbed Fas-FasL-mediated apoptosis is a cause of autoimmunity in SLE (28-31). Subsequent breakdown in immunologic tolerance leads to the production of autoreactive B and T cells that, through either direct infiltration or their secretory products, initiate inflammation (32). Selective polyclonal B-cell expansion possibly related to disturbances in the idiotype network and genetic factors may be of primary importance in the initiation and development of autoim-

Nutrition Intervention

Fish oils are rich in the long-chain ra-3 polyunsaturated fatty acids (PUFAs), eicosapentanoic (20 5ra-3) and docosahexaenoic (22 6ra-3) acids. Linseed oil and green plant tissues are rich in the precursor fatty acid, a-linolenic acid (18 3ra-3). Most vegetable oils are rich in the ra-6 PUFA linoleic acid (18 2ra-6), the precursor of arachidonic acid (20 4ra-6). Arachidonic-acid-derived eicosanoids such as prostaglandin E2 are proinflammatory and regulate the functions of cells of the immune system. Consumption of fish oils leads to the replacement of arachidonic acid in cell membranes, diminishes lymphocyte proliferation, T-cell-mediated cytotoxicity, NK cell activity, macrophage-mediated cytotoxicity, monocyte and neutrophil chemotaxis, major histocompatibility class II expression, and antigen presentation, production of proinflammatory cytokines (IL-1, IL-6, TNF), and adhesion molecule expression. Studies on animal models indicate that fish oil reduces acute and chronic...

Epidemiology of Celiac Disease

Diagnosed celiac disease appears to be more common in women than men. However, in those individuals who are identified by population-based screening, the prevalence of the disease appears to be equal between genders. The explanation for this is unclear, however, presentation of disease may be more common in women because of the nutritional challenges posed by pregnancy and menstruation, especially when producing iron deficiency anemia. The predisposition of women to autoimmune disease may also increase the likelihood of the occurrence of symptomatic celiac disease.

Liverspecific autoantigen

A liver-specific autoantigen as the target for immune-mediated damage in autoimmune hepatitis has not yet been identified. Crude preparations of liver cells and liver cell membrane preparations have been examined in various ways for reactivity with serum or peripheral blood T cells from patients with autoimmune hepatitis with promising but not unequivocal results. No liver-specific autoantigen has yet been identified by techniques applied successfully in other autoimmune disease, namely immunoblotting on electrophoreticaily separated liver cell membrane preparations, or probing gene expression libraries, using serum from cases of autoimmune hepatitis. Claims for ASGP-R as a liver-specific autoantigen relevant to autoimmune hepatitis need more substantiation.

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.

Inappropriately applied laboratorybased tests

It has been suggested that food immune complexes may play a role in those who claim a delayed (> 2 hours) adverse response to foods. These are able to be detected using solid phase radioimmunoassay. Even within autoimmune diseases that rely on their presence as diagnostic, their role is unclear. Their clinical relevance is doubtful for two further reasons. They have not been

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.

Clinical Description

Antibodies to factor XI are rare and have mostly been described in nondeficient patients as a complication of autoimmune disease. 6 Recently, however, a number of patients who were given plasma replacement therapy were diagnosed with acquired inhibitors to factor XI. They had a mean factor XI activity level of about 1 and were all homozygous for the Glu117stop (type II) mutation, indicating that mutations associated with a very low factor XI level may be risk factors for development of an inhibitor after plasma replacement.1-11-1

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

Peripheral nerve disease

In 1955, Waks-man and Adams described an autoimmune disease of the peripheral nervous system, experimental autoimmune neuritis (EAN), which they induced in rabbits immunized with sciatic nerve tissue in adjuvant EAN serves as a model for Guillain-Barre syndrome. Animals with EAN develop cellular immunity and antibodies to the P2 protein, an autoantigcn found in peripheral nerve myelin. P2 is a basic protein containing 131 amino acid residues, which is structurally and antigenically distinct from the CNS MBP molecule. EAN has been transferred with CD4* T cells from donors immunized with either P2 protein, or synthetic peptides corresponding to the P2 ncurito-genic epitopes. See also Autoimmune diseases Autoimmunity Multiple sclerosis Neurological autoimmune diseases T cell receptor, ap T cell vaccination Tolerance, peripheral.

Is there tolerance to ocular antigens

Central to the understanding of the mechanisms of ocular autoimmunity is the special localization of the ocular antigens in relation to the immune system. It has long been known that the eye is an 'immunologically privileged' organ, such that histoincompatible tissue grafts placed in the anterior chamber of the eye are not rejected. The reason for this immune privilege has been attributed mainly to the fact that there is no lymphatic drainage of the interior of the globe, and to the existence of a blood-ocular barrier Table 1 Animal models of autoimmune diseases affecting the eye

Forssman specificity and disease

Forssman-specific antibodies have been found to be associated with autoimmune diseases such as Graves' disease and Hashimoto's disease. The role of Forss-man-specific antibodies in patients with Guillain-Barre syndrome is under discussion. Forssman determinants are also expressed in certain human cancer tissues - for example, in adenocarcinoma of the stomach and colon in individuals whose tissues are normally Forssman negative.

Phenotypic expression due to multifactorial inheritance

Similarly, there are several examples of monogenic and polygenic immunological diseases which can be summarized as follows. HLA, the major histocompatibility complex, comprises multiple closely linked genes, which are highly polymorphic, and inheritance of a certain group of alleles at these loci is found to be associated with specific diseases in response to environmental changes. Some diseases associated with specific HLA alleles include type 1 insulin-dependent diabetes mellitus, ankylosing spondylitis and hemochromatosis, and several autoimmune diseases. Similarly, genetic predisposition to several immune complex diseases are associated with com

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.

Pathology and dysfunction

The previous paragraphs stressed the normal anatomy and function, and touched on the problems one might encounter with hepatobiliary disease. The systematic review of all liver diseases is beyond the scope of this chapter however, our focus will be on surgical pathologic states and the most commonly encountered problems on clinical rotations. What soon will be apparent is that many diseases converge in common pathways. Infectious diseases such as hepatitis B and C lead to hepatocytes damage and subsequent destruction of the liver architecture. Cholestasis as a result of obstructing stone disease, but also secondary to tumors, autoimmune disease or cystic disease leads to destruction of hepatocytes and liver architecture as well. With the loss of normal hepatic architecture and function, characteristic signs of liver failure surface can easily be understood based on the anatomy and function as discussed previously. For the sake of this chapter, we will divide liver disease in four...

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...

Immunodeficiency Primary

Mutations in the CD3 7 chain gene have been reported, one dying from severe autoimmune disease in infancy, while the other remains healthy at 10 years this was associated with about 50 of normal expression of the CD3 TCR complex. One child with recurrent lung infections is reported with inherited defects in the CD3 e gene. Since the CD3 e chain is crucial for normal T cell development, the residual 10 of normal expression of the CD3 TCR complex in this patient was presumably enough to provide partial T cell immunity.

Development of immunosuppressive therapy

Immunosuppressive therapy during the 1960s and 1970s consisted of combinations of different agents intended to produce maximal suppression while keeping the side-effects as few as possible. The most common immunosuppressive protocol was the combination of azathioprine and corticosteroids, which significantly improved allograft survival but also created a variety of severe side-effects, especially long term, among which were overwhelming, sometimes fatal infections, direct organ toxicities, slow wound healing, anemia, leukopenia, diabetes, osteoporosis, stunted growth in children, and even malignancies. The average 1 year kidney survival rate from all transplantation centers reached about 50 using this protocol while in outstanding centers the figures reached 80 and higher. Under those conditions, liver transplantation remained an experimental procedure and heart transplantation, which had enjoyed a transient burst of activity in the late 1960s, was abandoned in all but three centers...

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

The other mechanism for virus-induced diabetes involves the triggering of 3 cell-specific autoimmunity, leading to the autoimmune destruction of 3 cells. Kilham rat virus (KRV) causes autoimmune diabetes in DR-BB rats without the distinct infection of 3 cells. Since KRV widely infects peripancreatic and other lymphoid tissue, but not pancreatic 3 cells, it has been suggested that KRV triggers autoimmune diabetes by perturbing the immune system of genetically predisposed DR-BB rats, although the exact role KRV plays in the induction of diabetes in DR-BB rats is not known.

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.

Central Nervous System

One of the most interesting side effects of NSAID use is aseptic meningitis. The literature reports cases in which patients repeatedly present with symptoms of headache, fever, neck stiffness, and fever within hours of taking NSAIDs. Cerebrospinal fluid analysis in these patients reveals elevated white blood cell, elevated protein, and normal or decreased glucose levels. Symptoms resolve after NSAID use is stopped and can be elicited with repeat NSAID challenges. This phenomenon is most often seen with patients who have underlying autoimmune diseases, such as systemic lupus erythematosus. The phenomenon is thought to be a hypersensitivity reaction. A complete workup to rule out infectious meningitis must be undertaken before the diagnosis of NSAID-induced aseptic meningitis is entertained.4

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.

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...

The relevance of environmental mycobacteria

Saprophytic mycobacteria are extraordinarily common in the environment, and can be detected in soil samples or scrapings of waterpipes by direct staining and microscopy. Their persistence in the environment is partly attributable to the massive cell wall structure described above. Mycobacteria appear not to be part of the normal commensal microbial flora, but they are ubiquitous, resistant to degradation, and very immunogenic, so skin-test surveys reveal that individuals are sensitized to the species characteristic of their own environment. It is now clear that this is relevant to the variable efficacy (0-80 protection in different trials) of vaccination against mycobacterial diseases with BCG, because preimmunization by environmental saprophytes that prime a T,,l pattern of response is protective, but experimentally, immunization with such saprophytes using doses and routes that prime a TH2 cytokine pattern, actually increases susceptibility to the disease. It may be that variable...

Lambert Eaton myasthenic syndrome

This disorder is much less common than myasthenia gravis. It is characterized by proximal muscle weakness, depressed tendon reflexes, post-tetanic potentiation and autonomic changes, including dry mouth and constipation. Onset can be in adolescence, but is usually after 40 years of age. Other autoimmune diseases may associate, notably thyroid disease and vitiligo, and other autoantibodies occur at increased frequency. The physiological abnormality is presynaptic, in contrast to myasthenia gravis. Quantal release of acetylcholine by the nerve impulse depends on the opening of voltage-gated Ca2 channels (VGC.'Cs) and the consequent local influx of Ca2f into the nerve terminal in LEMS, the calcium-dependent release of transmitter is greatly reduced, and freeze-fracture electron microscopy shows loss of active

Hematologic malignancy

Corticosteroids are commonly used in the treatment of lymphoid malignancies, but are also used as an anti-inflammatory agent in nonmalignant conditions such as autoimmune diseases. They act in these conditions in part by suppressing cell-mediated immunity (T cell responses), but their beneficial effects are at the expense of a risk of infection, particularly reactivation of latent herpes virus. Particular care must be taken in patients who have not previously had varicella (chickenpox). Primary chickenpox infection in patients with impaired cell-mediated immunity -including those on steroids - is frequently severe and potentially fatal. Early visceral dissemination is common and may be the presenting feature. Special care should therefore be taken in children, who may not previously have been exposed to chickenpox.

Disorders of the Neuromuscular Junction

Myasthenia gravis is discussed in Chap 226. Botulism Ingestion of foods contaminated with Clostridium botulinum toxin causes botulism, an acute disease marked by weakness and gastrointestinal slowing. Adults whose disease is caused not by bacterial infestation but by ingestion of botulinum toxin may report exposure to foods such as home-canned vegetables in the preceding 1 to 2 days. Unlike adults, infants, whose guts are not colonized fully, are susceptible to infection with viable bacteria that elaborate toxin. Parents of infants should be questioned for possible ingestion of C. botulinum spores, commonly transmitted by feeding honey. Infants may present with poor sucking. Botulism caused by infection through a wound is rare. On examination, mentation is normal, but there may be bulbar weakness. The extraocular movements are sometimes abnormal, and an important diagnostic clue is the absence of the pupillary light reflex, which distinguishes this disorder from myasthenia gravis....

Hematopoietic and Immune System

Exposure induces increases in the number of memory T cells, but with enhanced reactivity against self-antigens, priming the individual for autoimmune disease. In healthy adults, IgA concentration increases by 0.2 gl-1 per decade throughout life. The T lymphocytes, however, respond more poorly to ongoing antigen assault in later life. Thymic involution associated with neural and hormonal changes of aging is an impediment to T-cell maturation in older persons. The basis of intrinsic function deficits of memory cells, on the other hand, has been ascribed to defective signaling and includes hyporesponsive-ness to mitogen-stimulated proliferation and decrease in genetic suppression, allowing increased stimulation of inflammatory cytokines the balance between pro-and anti-inflammatory cytokines shifts with aging, favoring the inflammatory pole, especially with the greater expression of interleukin 6. This has a negative systemic effect on bone metabolism, as well as dysregulating overall...

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...

Primary Biliary Cirrhosis

These observations relating autoantigens to functional sites of proteins are of interest in that they are consistent with an emerging trend seen in a number of other autoimmune diseases. Autoantibodies to RNA synthetase in polymyositis sera are able to inhibit RNA aminoacylation and it has also been reported that synthesis of 28S and 18S RNA is inhibited by RNA polymerase I-specific antibodies in Although there have been significant advances based on cloning, antigen definition and epitope mapping, there has been relatively little insight into the relevance of T cell reactivity in patients. The identification of T cell reactivity will be critical. The characterization of T cell reactivity in other autoimmune diseases has likewise been difficult because of the low frequency of antigen-specific T cell activity in peripheral blood. Moreover, even when liver tissue is studied, the frequency of antigen-specific T cells may be low because of the irrelevant inflammatory response. All of the...

Neuromuscular and Cutaneous Syndromes

Myasthenia gravis is an autoimmune disorder of neural conduction in which the autoantigen is the nico-tinic acetylcholine receptor at the neuromuscular junction. There are few reported cases of carcinomatous neuromyopathies associated with renal cell carcinoma. Neurological manifestations frequently manifest before discovery of the primary tumor. Effective therapy of the primary malignancy is almost always associated with resolution of the symptoms. In one case, the

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

Antiphospholipid syndrome

APL are a heterogeneous group of antibodies which occur in certain autoimmune diseases, especially SLE, PAPS, syphilis and other infectious diseases, and in normal individuals. Autoimmune aPL include the LA and aCL and, as mentioned above, are associated with thrombosis, recurrent fetal loss and thrombocytopenia. Although aPL are heterogeneous in their specificities, those that react with anionic phospholipids and ( -glycoprotein 1 ( 32GP1) 02GPl-dependent aCL) are associated with the clinical manifestations of APS. In addition to LA and aCL, antibodies to the other anionic phospholipids include antibodies to PS (aPS), PI (aPI) and PA (aPA).

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...

Cell and molecular biological studies of suppressor cells

The studies mentioned above plus numerous others clearly established that the concept of cell-based negative regulation had merit. Furthermore, the phenomenology of suppression could be demonstrated in virtually all types of immune responses. The challenge became to establish the physiological, biochemical and molecular genetic basis of suppression. The major questions that required study-were as follows 1) Does there exist a phenotypically and biologically distinct population of lymphocytes whose sole function is to specifically suppress immune responses (i.e. 'professional' Ts cells) 2) What is the precise role of such cells in immunity (e.g. do they play a role in tolerance, autoimmunity, regulation of normal immune responses and tumor immunity) and what is the interplay between Ts cells and other regulatory elements 3) What is the biochemical and molecular basis of Ts cell function 4) What is the nature of the antigen receptor on Ts cells and how is it related to the...

Major histocompatibility complex MHC genes

Although lupus susceptibility is not restricted to a single MHC haplotype (Table 1), the major contribution of certain MHC alleles to lupus susceptibility has been clearly demonstrated. In BXSB mice there is a dominant role for H-2 while for NZ mice, heterozygosity of the MHC (H-2d z) appears to confer higher susceptibility. Yet, H-2d z heterozygosity is not the only factor contributing to accelerated autoimmunity in the F1 hybrid, as crosses of NZB with SWR (H-2q) or BXSB (H-2b) also develop a disease similar to that of (NZB x W)F1 and crosses of NZB with congenic BALB c.H-2z are devoid of disease. Additional studies of H-2 congenic NZB mice revealed that the H-2bml2 haplotype predisposes to early onset lupus similar in severity to that in (NZB

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

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