Latest Treatment of Autoimmune Diseases

The Autoimmune Bible System

The Autoimmune Bible system was developed by Mark Steve, who was suffering from an autoimmune disease that is not treatable. He tried other medicine and did not work, but after turning to the Bible, he was able to get the best healing for the disease. The product discusses in detail the Bible recipes and also the ingredients which come with it, which can be used to fight the diseases. God has provided the people with healing through the readily available things which can be found in the grocery, and it only needs one to follow them strictly, and you will get healed. The Bible has specific herbs, which it has mentioned, which could be used to heal the various disease which we are suffering which include the autoimmune disease and diabetes which continue to be a problem to many. The program can be accessed through the e-book, and some bonuses come with the program and maximum benefits from the program. You don't need any technical skills or other intermediate skills to use the product since it entails using the Bible. Read more...

The Autoimmune Bible System Summary


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The Key Role for B Lymphocytes in Autoimmune Diseases

For some time, autoimmune diseases have been considered to be mediated essentially by T cells. Of late, emerging data suggest that B cells play an important role in these diseases than previously thought. While it has long been known that levels of autoantibodies such those directed to the thyroid stimulating hormone receptor that correlate with disease severity and progression in Graves disease, and those directed to double-stranded DNA that are often elevated in lupus disease, it is becoming appreciated that B cells play more than one role in these diseases (12). Not only are they the precursors of antibody-secreting plasma cells, but they also act as remarkably effective antigen-presenting cells, suggesting that they may play a potential role in autoimmunity via abnormal autoantigen presentation. B cells can also secrete cytokines, such as TNFa, that exacerbate the autoimmune and inflammatory responses. In addition, autoreactive B cells express ligands that bind costimulatory...

The Role of the Complement in Autoimmune Diseases

In addition to its important roles in the innate immune system to foreign antigens, the complement system is increasingly recognized to be causally involved in tissue injury during ischemic, inflammatory and autoimmune diseases (28,29). Studies of human diseases have provided clinical evidence for activation of the alternative pathway. Indeed, the presence of activated C3 or C4 fragments and other activated components of the alternative pathway in target organs has been described in several clinical settings (29). The involvement of the complement in RA has been suggested by the observation that the complement activity of the joint fluid from patients is significantly lower than that of control subjects. In addition, significant increases in soluble complement activation fragments in the joint fluid, as well as enhanced local production of complement proteins in synovial tissue, are found (30).

Autoimmunity In Chronic Lyme Disease

Although an immune response to heat shock proteins in patients with Lyme disease has been demonstrated in the various studies cited above, there is no evidence that molecular mimicry between the homologous B. burgdorferi and host heat shock proteins leads to an autoimmune response. Three lines of evidence will be presented to demonstrate that neurological Lyme disease may be an autoimmune disease resulting from molecular mimicry between B. burgdorferi flagellin and human hsp 60. These include (1) immunostaining of nerve tissues and neuroblastoma cells, (2) identification of the cross-reacting epitopes, and (3) a proposed pathological mechanism of neuronal dysfunction.

Who Is Vulnerable to Autoimmune Disease

Generally, anyone can develop an autoimmune disorder. Some diseases are hereditary, while other diseases, although not directly hereditary, run strongly in families. This is referred to as a genetic tendency or inherited predisposition. Most autoimmune diseases seem to have a genetic tendency with several members of the family showing the same or similar types of autoimmune diseases. Autoimmune thyroid disease is no exception. Often, multiple family members and generations of family members, particularly in female members, will have one or more types of autoimmune thyroid disease. This suggests that there are significant genetic changes related to this disease, but it is far more complex than would be seen in simple directly hereditary situations. There is some evidence to suggest that stress is one factor that may contribute toward triggering an autoimmune disorder. Clearly, when you are under unusual or extreme stress, many hormonal changes occur in the body, particularly between...

The Contradictions Of Hsp 60 Autoimmunity

The conservation of stress proteins throughout evolution may be explained by their performance of essential functions and by the dependence of this performance on particular structures encoded in unique amino acid sequences to maintain the functions of stress proteins, evolution, during its meandering course, has had to preserve their key sequences. Other chapters in this book discuss the functions and structures of stress proteins. Whatever these functions may be, the conservation of the amino acid sequences of stress proteins and their universal expression in apparently all cells makes these proteins immunologically interesting any parasitic cell, prokaryote or eukaryote, will express stress proteins that are sure to have epitopes similar or identical to those expressed by the cells of the host. Therefore, stress proteins challenge the host's immune system to distinguish between the invader and the self (6). An example is hsp 60, in which the mammalian host and its prokariotic...

Hsp 60 Autoimmunity Can Amplify Or Restrain Inflammation

My colleagues and I are beginning to investigate the immunology of natural autoimmunity to hsp 60 by constructing transgenic mice with hsp 60 hyper-expressed under the regulation of different promoters. We are also studying the effects of natural autoimmunity to hsp 60 on the immune response to bacterial antigens. These studies are not yet completed, but it appears that natural autoimmunity to hsp 60 can indeed modify significantly both autoimmune diseases and immune responses to foreign antigens. Interestingly, autoimmunity to hsp 60 can manifest seemingly contradictory effects Some immune responses can be enhanced and others inhibited. Since expression of hsp 60 is upregulated by the stress of inflammation, it is not surprising that natural autoimmunity to hsp 60 can help the initiation of immune responses to other antigens that happen to be at the site of any hyper-expression of hsp 60. The high frequency of anti-hsp 60 T cells present from birth (9) guarantees that some of these...

Autoimmune Disease

The role of chaperonins in autoimmune disease is controversial. At one end of the spectrum is the argument that although infection immunization with chaperonin-containing organisms is universal, and healthy people have T cell responses to self-chaperonins, classical autoimmune disease is quite uncommon. So the presence of immune reactions to chaperonins may be incidental and unimportant. At the other end of the spectrum is the idea of molecular mimicry (Cohen and Young, 1991). The theory is based upon the observation that there is a high level of amino acid sequence conservation between chaperonins of microbial and mammalian origin. It proposes that during infection with a wide range of microbes chaperonin epitopes that are shared between microbes and mammals stimulate T lymphocytes. A high level of chaperonin presentation of shared chaperonin epitopes breaks tolerance to self-chaperonins and autoimmune disease develops (Kaufmann, 1990). A refinement of this idea (Cohen, 1991 Cohen...

The Unique Role of Heat Shock Proteins in Infections

For both lymphocyte subsets specificity is generated by somatic genetic rearrangements, and antigen stimulation leads to the activation of a particular clone expressing a unique receptor. In principle, the receptors have to recognize epitopes derived from nonself antigens, and to ignore self epitopes. To achieve this goal, lymphocytes undergo selection processes. Most T lymphocytes recognizing self are deleted in the thymus before they mature, and self reactive clones which evade deletion are inactivated in the periphery (3). It is this inac-tivation of physically existing T cells expressing self-reactive TCR which bears the potential risk of autoimmune disease. B cells are deleted, but not positively selected, in the bone marrow when pre-B cells encounter membrane-bound antigens on adjacent cells. Evading self-reactive B cells are rendered anergic in the periphery and have a remarkably short life span. After antigenic contact, mature B cells undergo another phase of specificity...

Hsps Are Unique Targets Of Autoimmune Responses

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

Pancreasderived Stem Cells

Much of the impetus to isolate a pancreatic islet stem cell is for the development of a therapy for patients with type I diabetes, whose insulin-secreting p cells are destroyed by a poorly understood autoimmune response. Today, some of these patients are eligible for whole organ or islet cell transplantation, but the number of cadaver organs available is limiting. If islet stem cells could be isolated from cadaver organs that were capable of unrestricted growth and differentiation in vitro, it would facilitate the treatment of many more patients than is currently possible. One might envision a scenario in which a bank of pancreatic islet stem cells derived from nondiabetic cadaver donors was created, each line with a different histocompatibility. Similar to the current situation with human ES cell lines, there are ethical and scientific considerations for the development of such a group of cell lines however, the isolation of an endocrine pancreatic stem cell would be a major advance...

Receptormediated Mechanisms Of Caspase Activation

These TNF-family receptors include TNFR1, Fas (CD95), DR3 (weasle tweak), DR4 (trail receptor-1 Apo2), DR5 (trail receptor-2) and DR6 (Figure 2). The conserved cytosolic domain is known as the 'death domain' (DD) and is comprised of a six a-helical bundle which forms trimers and possibly higher-order oligomers in response to ligation of the extracellular domains or simply when these receptors are overexpressed in the absence of their cognate ligands. Hereditary loss-of-func-tion mutations or trans-dominant inhibitory mutations in the DD of Fas (CD95) have been associated with a lym-phoproliferative disorder and autoimmunity in the Iprllpr strain of mice and in humans with autoimmune lympho-proliferative syndrome (ALPS). Similarly, somatic mutations in the death domain of Fas have been detected in certain human neoplasms, including myelomas, lymphomas, leukaemias and carcinomas of the lung and bladder.

Evaluation Guidelines Table132

Disorders of speech and swallow suspected to be due to neuromuscular disorders such as motor neuron disease or myasthenia gravis may be evident on electrophysiological testing. Repetitive stimulation on nerve conduction studies, and single fiber assessment of jitter may aid in the diagnosis of myasthenia. Electromyography (EMG) of the tongue or limb muscles may demonstrate denervation indicative of motor neuron disease. The location of a nerve lesion producing vocal cord paralysis may be established by EMG testing of the thyroarytenoid Other Tests. Patients with voice disorders should undergo careful otolaryngological evaluation of the neck and pharynx, and visualization of the vocal cords by either indirect or direct laryngoscopy. Paresis of the left vocal cord may result from disease processes in the chest involving the recurrent laryngeal nerve, such as an expanding aortic aneurysm, mediastinal adenopathy, or lung neoplasm. Chest radiographs, and possibly CT,...

Polymorphism Of The Hsp 702 Gene As A Susceptibility Marker In

A role in the development of autoimmunity in SLE. Indeed, several groups have reported an increase in the frequency of the Pstl 8.5-kb allele of the hsp 70-2 gene associated with a C4A deletion in type I diabetes and Graves' disease (41,42). In addition, Pociot et al. (43) have observed decreased hsp 70-2 mRNA expression in individuals who are homozygotes for the pstl 8.5-kb allele as compared with homozygotes for the pstl 9.0-kb allele. Using pH 2.3 and Pstl in studies of hsp 70 gene polymorphism in SLE, genomic DNA from 49 individuals with SLE and 45 healthy controls with no family history of autoimmune disease have been analyzed. As expected, we observed two alleles, 8.5 and 9.0 kb, resulting in three genotypes (9.0 9.0, 9.0 8.5, and 8.5 8.5). There was a statistically significant association between the absence of the 9.0-kb allele and SLE (p 0.0474). Conversely, the presence of 8.5-kb allele was associated with SLE (p 0.039), and its allelic frequency was increased in patients...

Myopathic Syndromes

As is often the case in medicine, there are exceptions to these general rules. The distal muscles may be weaker than the proximal muscles (e.g., myotonic dystrophy, inclusion body myositis), or a motor neuron disorder may affect the proximal musculature more than the distal, mimicking a myopathy (Kugelberg-Welander syndrome). Some myopathies affect the cranial and ocular muscles rather than limb muscles, as in, for example, the chronic progressive external ophthalmoplegia (CPEO) syndrome. The abnormal eye movements can be differentiated from those in myasthenia gravis in CPEO eye movements are restricted symmetrically and diplopia is not a complaint, whereas in myasthenia gravis double vision is a common symptom.

Indirectacting Cholinomimetics

Clinical use of reversible inhibitors is directed to eye, skeletal muscle, neuromuscular junctions, gastrointestinal tract, urinary tract, respiratory tract, and heart and used in treatment of glaucoma (an ocular disease caused by increased intraocular pressure due to inadequate drainage of aqueous humor at filtration angle), myasthenia gravis (an autoimmune disease

Bioartificial Organ Rejection

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

PCell Neogenesis Is Curtailed In Islets Of Nod Mice

However, the progenitors found in islets of NOD mice failed to generate PDX-1 SOM IN+ or Glut-2 IN+ cells and eventually vanished during progression of the autoimmune disease. We speculate that intra-islet precursors of NOD mice, like those of their nondiabetic counterparts, are capable of regenerating the p-cell population and will do so if the immunologic insult to the islets is circumvented.

Thyroid Disease in Pregnancy and After Delivery

Autoimmune thyroid diseases, such as Hashimoto's disease (see Chapter 5) or Graves' disease (see Chapter 6), frequently strike during the first trimester of a pregnancy or within the first six months after delivery. That said, you should note that preexisting autoimmune thyroid disease as well as other autoimmune diseases tend to improve during a pregnancy but can worsen after delivery. Although the reasons for this are not known, these changes parallel the changes in estrogen levels in the pregnant woman high levels of estrogen are associated with improvement in the thyroid problem. Thyroid nodules and thyroid cancer can also be first discovered during a pregnancy, and in those cases, there are particular management strategies we'll discuss.

Abnormal EMG Activity

In disorders with abnormal neuromuscular transmission, such as myasthenia gravis, motor unit action potentials vary in amplitude and area during continued activity and, in addition, there is an excess of small, short-duration potentials in affected muscle. The variability of the potentials reflects the reduced safety factor for neuromuscular transmission, as a consequence of which there is variation in the number of muscle fibers firing with each discharge of the unit. Single-fiber electromyography is a technique in which action potentials are recorded from two or more muscle fibers belonging to the same motor unit by means of a special electrode, and the temporal variability (or jitter) between the two action potentials at consecutive discharges is measured. y This jitter reflects variation in neuromuscular transmission time in the two motor endplates involved. An increased jitter is therefore to be expected in patients with diseases of neuromuscular transmission, and impulse...

After the Baby Is Born

During pregnancy, your immune system is naturally suppressed to prevent your body from rejecting the fetus. After pregnancy, your immune system turns on again. But this has a rebound effect in that the immune system is so alert that it is almost too powerful and can develop autoantibodies that attack normal tissue. This is what's known as an autoimmune disorder (see Chapter 5) and may be one reason why women are more prone to thyroid autoimmune disorders after pregnancy. I (Sara) liken the scenario to having a guard dog tied up for nine months (during the pregnancy) and then let out. The dog will be feistier and may even attack his owner.

Hsp Reactivity Of Lymphocytes Isolated From Heterotopic Rat Cardia Allografts

Thus far, our studies on the hsp reactivity of allograft lymphocytes have been done with recombinant protein preparations of mycobacterial rather than mammalian origin. In various autoimmune disease models, the reactivity of mycobacterial hsp-specific lymphocytes may reflect recognition of antigenic determinants shared with host self-proteins (16-19). Throughout evolution, the molecular structures of the different types of hsps have been highly conserved between the species (41). Sequence homologies have been reported between hsp

Summary and future considerations

It is clear that a better understanding of our immune system and the way it can differentiate between self-antigens and non-self-antigens will have a huge impact on different areas of clinical medicine. Such developments could help treatment of patients with cancer, infection, autoimmune diseases and allergies, as well as those patients undergoing organ transplantation or requiring aggressive forms of chemo- or radiotherapy.

Physiological Factors

Diminishing temperature results in slower opening and closing of the Na+ channel pore but, because closing time is relatively more affected, the net result is that cooler temperatures produce a net increase in the total time the Na+ channel remains open. The slower opening time causes delay in regeneration of the action potential at each node of Ranvier and results in prolonged distal latencies and slower conduction velocities. The net increase in sodium channel open time results in a longer duration action potential and, as more Na+ ions enter the intracellular space, a larger amplitude potential is produced. Warming beyond the physiological range reverses this pattern and can result in faster conduction velocities and reduced amplitude. Studies attempting to document these changes in during routine NCS conditions have produced variable results because of differences in how cooling was applied. However, in clinical practice, the important effects of cold temperature in routine NCS...

Stress Proteins in Inflammatory Liver Disease

The liver is not only involved as a bystander organ in many systemic diseases, it is also, more than most other organs, the focus of many chronic inflammatory diseases. Hepatitis B virus infection is the most prevalent infectious disease in the world, and chronic hepatitis C appears to be similarly common worldwide, although with a different geographical distribution. Alcoholic hepatitis as the inflammatory lesion in many patients with alcoholic liver disease is thought to be largely immune mediated. Although systemic autoimmune diseases like lupus erythematosus rarely affect the liver, the liver itself is the target organ of autoimmune attack in autoimmune hepatitis (which in itself is probably a heterogeneous group of diseases), primary biliary cirrhosis, amd primary sclerosing cholangitis. Expression of and immunity to hsp 60, as explained elsewhere in this book, has been thought to play a critical role in the immunopathogenesis and prepetuation of autoimmune diseases. In liver...

Variable Stimulation Of The Immune System Of Primates Under Different Conditions

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

Ivhow Was Hsp Considered To Be Involved In Atherosclerosis

As mentioned above, atherosclerotic lesions bear many similarities to chronic inflammatory conditions, the most striking of which are accumulation of macrophages and T lymphocytes (reviewed in refs. 3-5). It was not known, however, which pathogens and or antigens might elicit the response of these immune cells in atherogenesis. Our theory that atherosclerosis might be immunologically mediated was aroused by the increasing reports in the literature, partially cited above, centering around the humoral and cellular immunological phenomena in this disease (14-21,26-39), including the involvement of antibodies to modified low-density lipoprotein (LDL) (40), and bacteria (41). Our approach to this issue was based on our previous experience with various animal models of experimentally induced and spontaneous autoimmune diseases (42), as well as the role of changes in lymphocyte lipid metabolism in the altered immune responsiveness during aging (43,44).

Congenital Myasthenias

The onset of myasthenic symptoms at birth or in patients with a family history of this disease has always made congenital forms of myasthenia a diagnostic possibility. With the advent of the acetylcholine receptor (AChR) and the calcium channel antibody test as markers for myasthenia gravis and Lambert Eaton myasthenia, it has become apparent that congenital myasthenia, like the congenital myopathies, may present later in life and, in some cases, without a family history.

Cell Depletion Therapy

The important role of B cells in SLE and RA etiologies is supported by the encouraging results of clinical trials aiming to eliminate B cells in affected patients. B-cell development is characterized by a series of changes of surface phenotypic markers. One of them CD20 is expressed at intermediate stages and is lost during terminal differentiation to immunoglobulin-producing plasma cells. A chimeric monoclonal antibody (MAb) against human CD20, called Rituximab, is now used in clinical trials of several autoimmune diseases. Its mode of action remains under investigation, but the available evidence suggests that this antibody acts via complement-mediated and antibody-dependent, cell mediated-toxicity, and induction of apoptosis (13).

The Inhibitory Coreceptor FcyRiib A Potential Target

Previous work has demonstrated that the expression of the inhibitory Fc receptor FcyRIIB is required for the maintenance of self-tolerance (25). C57BL 6 mice deficient in this receptor develop spontaneous lupus-like autoimmunity. Several other stains of mice that develop spontaneous autoimmune disease, such as NZB, NOD, BXSB, and MLR, have also been shown to express reduced levels of FcyRIIB on activated or germinal center B cells. This reduced expression results from a polymorphism in the promoter of the corresponding gene. These results suggest that the levels of FcyRIIB expressed on some B cells may regulate their ability to maintain tolerance, and that relatively small changes in the expression of this inhibitory receptor may permit the survival and expansion of autoreactive cells (26). Thus, changes in the surface expression of this receptor appear to be critical for determining disease progression, and these changes provide a rational basis for a therapeutic approach based on...

Disruption of the Interferon Activating Pathway

An important clue that interferon (INF) might contribute to lupus comes from a series of studies in patients who received INFa as a therapeutic agent for viral hepatitis or carcinoid tumors. Nearly a quarter of INFa-treated subjects (22 ) developed a positive antinuclear antibodies blood test (34), and one in five (19 ) developed overt autoimmunity, including a small number who developed SLE (35).

Presentation and diagnosis

Systemic vasculitis is characteristically a multifocal disease with a variety of clinical manifestations according to the size of the blood vessel involved and the organs affected. It is classified according to the size of the smallest vessel involved.1 Alveolar haemorrhage results from small vessel vasculitides involving the lungs these include Wegener's granulomatosis, microscopic polyangiitis and, rarely, Churg-Strauss syndrome. They can present at any age but occur most commonly in patients in their 50s and 60s and there is a slight male predominance.2 3 There are reports of vasculitis occurring in families,4-7 but most cases arise sporadically and, unlike most autoimmune diseases, so far no consistent HLA associations have been identified,8 although there are associations with certain complement alleles and alleles of aj-antitrypsin.9-12 Environmental factors such as silica exposure,13-15 drugs,316 and infections17-19 may play a part however, although these may be important in...

Autologous Hsct In Recentonset Autoimmune Type 1 Diabetes Mellitus

Loss of islet p cells occurs over a time span of 3-5 years and is initially balanced by regeneration however, persistent autoimmunity eventually exhausts or overwhelms the regenerative capacity of pancreatic stem cells (27). Clinical symptoms manifest when the number of islet p cells falls below the threshold necessary to maintain glycemic control, but before complete ablation of islet p cells. Patients with residual islet p cells have better metabolic control, are less likely to experience acute hypoglycemic or ketotic episodes, and are less likely to develop chronic complications (28). Therapeutic intervention designed to control autoimmunity in patients with recent onset type 1 diabetes may preserve remaining islets and thus improve disease management. In patients with recent-onset type 1 diabetes, immunosuppressive therapy with corticosteroids or cyclosporine delays the onset of insulin-dependency nevertheless, chronic immunosuppressive therapy slows but does not halt autoimmune...

Pancreas And Islet Transplant For Autoimmune Type 1 Diabetes Mellitus

In contrast to HSCT for rheumatic autoimmune diseases, HSCT for patients with type 1 diabetes cannot provide relief from clinical symptoms of chronic disease. Frequently, clinical presentation of type 1 diabetes is subsequent to autoimmune-mediated damage to islet p cells therefore, damaged or destroyed endocrine tissue must be regenerated or replaced in order to alleviate clinical manifestations of disease. Conversely, islet or pancreas transplant may lead to recurrent autoimmune-mediated destruction of donor tissue, and thus HSCT may be necessary to cure autoimmunity before endocrine tissue replacement. Although the markedly improved success of islet transplantation with the Edmonton protocol is promising, both the high number of donor islets (requiring two to three donor pancreases per transplant recipient) and the necessity for chronic immunosuppressive therapy remain barriers to widespread clinical application. Also, although indications for islet transplant include severe...

Who Is Most Likely to Suffer from Dry Eyes

Dry eyes are often a woman's problem since so many autoimmune diseases, which plague women in particular, are associated with dry eyes. Aside from Graves' disease, women can also be plagued with Sjogren's syndrome, which impairs lacrimal gland function and the formation of watery tears (90 percent of Sjogren's syndrome sufferers are women). Hormonal changes during pregnancy and menopause can also cause dry eyes, while in the general population asthma, glaucoma, blepharitis (chronic inflammation of the eyelids), cornea surgery, and corrective surgery for nearsighted-ness are other causes.

Diseases Affecting

Postsynaptic Disorders of NMT 3.2.1. Myasthenia Gravis MG is an autoimmune disorder in which polyclonal antibodies are directed against the nicotinic acetylcholine receptor of skeletal muscle. This results in degradation of the NMJ, with simplification of the secondary synaptic clefts, loss of acetylcholine receptors, and failure of NMT. The loss of receptors results in a MEPP that has decreased amplitude, leading to a decreased EPP. The clinical hallmark of the disease is fatigable weakness, usually after repetitive action, causing intermittent symptoms, such as ptosis, diplopia, dysphagia, dysarthria, and facial and limb muscle weakness. Respiratory compromise can occur in severe cases. The disease has a bimodal peak incidence, affecting older men and young women of childbearing age.

Suggested Reading

AAEM Professional Practice Committee, Chiou-Tan FY, Gilchrist JM, Tim RW. Practice parameter for repetitive nerve stimulation and single fiber electromyographic evaluation of adult patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome summary statement. Muscle Nerve, 2001. Engel AG, ed. Myasthenia Gravis and Myasthenic Disorders. Oxford University Press, New York, NY, 1999. Gilchrist JM. Myasthenia gravis. In Current Diagnosis in Neurology (Feldmann E, ed.). Mosby, myasthenia gravis. Muscle Nerve 1992 15 720-724. Sanders DB, Stalberg EV. AAEM minimonograph 25 Single fiber electromyography. Muscle Nerve 1996 19 1069-1083.

Animal Species for the Model

Rodent models for genetic diseases have also originated through spontaneous mutations as opposed to genetic manipulation. The NOD mouse model represents a naturally occurring model genetically predisposed to autoimmune diseases including type 1 DM (64). NOD mice generally develop diabetes between 12 and 16 weeks of age. Given the reliable and early onset of diabetes and the No autoimmunity Nonhuman primates such as baboons and Old World macaques have long been used as animal models for basic and preclinical studies (74,75,77-81). By virtue of their anatomic, physiological, and genetic similarities to humans, studies have been performed during the entire spectrum of development from embryonic to pubertal and from adult to aging. For the most part, the research results can be translated readily to human biology, and in some cases to clinical trials. However, only a few nonhuman primate models are available for therapeutic studies limiting the potential needs of stem cell-based trials....

Immunopharmacological Drugs

Undoubtedly, inflammation is also an immune response. Drugs described in other chapters, such as antihistamine agents, nonsteroid anti-inflammatory agents, antiserotonin drugs, and many others can also be formally grouped with immunopharmacological agents. However, only the drugs having a direct effect on cells that have immune functions, such as lymphocytes, plasma cells, and subtypes of these cells will be examined in this chapter. It should be noted that the vital functional products of these cells themselves, such as lymphokines, interferons, and interleukins, are very important immunopharmacological drugs. The immune system has an enormous number of antigens that differentiate between 'own' and 'alien' molecules. It plays a huge role in autoimmune diseases, hypersensitivity reactions in the body to certain irritants, and in transplant rejections.

AntiCD40 Ligand Therapy

Several tissue injuries and immune-mediated pathologies were found to involve CD40-CD40L signaling. Disruption of this pathway in animal models led to the improvement of graft survival. CD40-CD154 interactions were also shown to play a significant role in the progression of autoimmunity, and the production of auto-antibodies in SLE (47). High-level expression of CD154 (48) has been detected in T cells from patient with SLE, RA, and other autoimmune disease,

Randall S Sung Jeffrey D Punch

Transplant Rectum

Insulin-dependent diabetes mellitus (IDDM, also known as type I diabetes mellitus) is an autoimmune disease resulting from destruction of the islets of Langerhans. It usually occurs in lean, young persons and is characterized by an absence of insulin secretion in response to hyperglycemia and a tendency toward ketosis. Hyperglycemia leads to deleterious secondary complications including retinopathy, neuropathy, and fll

Case Study Insulin Production Systems

Type I diabetes mellitus is a disorder affecting over 80 million people worldwide. At present exogenous insulin delivery via injection or pumps equipped with glucose sensors cannot provide the minute-to-minute normoglycemia needed to prevent the complication associated with this autoimmune disorder. The sensor pump technology also lacks durability, with device function often limited to only hours. The exacting requirement placed on insulin dosage and timing of administration in diabetic patients, as well as the many years of safe and reliable treatments expected from the insulin delivery technology, have pointed to the advantages of implantable systems in which insulin would be synthesized as needed and made available to the organism on demand. Four alternatives have been considered and have undergone clinical evaluation whole organ transplantation, human islet and xenogeneic islet transplantation, immunoisolation of normal or tumoral insulin-secreting tissue, and transplantation of...

Important Findings In The Pediatric Emg Laboratory

Disorders of neuromuscular transmission are caused by impaired transmission of acetylcholine across the neuromuscular junction. In children, the most common causes of these disorders are myasthenia gravis (of which there are three types neonatal, congenital, and juvenile) and botulism. Lambert-Easton myasthenic syndrome is rare in this age group. In neonatal myasthenia gravis, maternal antibodies to the acetylcholine receptor cross the placenta and enter the fetal circulation. This occurs in 12 of infants born to mothers with symptomatic or quiescent autoimmune myasthenia gravis. Soon after birth, an affected neonate develops respiratory distress, feeding difficulties, and weakness. In one-third of cases, ventilatory support and nasogastric tube feedings are required until the baby clears the antibodies from the circulation, which usually takes several weeks. Oral pyridostigmine may be helpful in severe cases. Congenital myasthenic syndrome is caused by genetic mutations affecting the...

Neuromuscular Disorders

Nonviral neuromuscular diseases occurring with some frequency include myasthenia gravis, myotonic dystrophy, and Duchenne's muscular dystrophy. Myasthenia gravis is a neuromuscular junction disorder caused by an autoimmune response that blocks the nicotinic receptors in the extraocular and facial muscles and is associated with thymus gland abnormalities. The disorder, which typically affects young women and older men, results in fluxuating and asymmetric muscle weakness, but causes no cognitive symptoms. The symptoms of myasthenia gravis include facial and neck muscle weakness, difficulty controlling neck and shoulder muscles, difficulty swallowing, and poor respiratory functioning. In severe cases, this disorder may result in quadriplegia and respiratory distress.

The First Line Of Body Defence

Small protein hormones that can stimulate or inhibit many normal cell functions but are less specific and more localized than endocrine hormones (Table 8.2). Cytokines can be divided into several families, including interleukins, interferons, tumour necrosis factors, colony stimulating factors and chemokines, which regulate the migration of cells between and within tissues. For example, there are around 22 different interleukins (ILs), numbered IL-1 to IL-22. Of these, IL-1 is secreted by macrophages and monocytes and can stimulate an inflammatory response and activate lymphocytes (Table 8.2 and Figure 8.2). IL-2 is produced by T-helper lymphocytes and stimulates the proliferation of T-helper cells, cytotoxic T-cells and B-lymphocytes, and activates NK cells. On the other hand, IL-10 and transforming growth factor- (TGFP) are immunosup-pressants and inhibit the cytotoxic response of the immune system (T-cells and macrophages) against the antigens from tumours and infectious agents...

Physiology of Gastrointestinal Disorders

Paralysis of the Swallowing Mechanism. Damage to the 5th, 9th, or 10th cerebral nerve can cause paralysis of significant portions of the swallowing mechanism. Also, a few diseases, such as poliomyelitis or encephalitis, can prevent normal swallowing by damaging the swallowing center in the brain stem. Finally, paralysis of the swallowing muscles, as occurs in muscle dystrophy or in failure of neuromuscular transmission in myasthenia gravis or botulism, can also prevent normal swallowing. Gastric Atrophy. In many people who have chronic gastritis, the mucosa gradually becomes more and more atrophic until little or no gastric gland digestive secretion remains. It is also believed that some people develop autoimmunity against the gastric mucosa, this also leading eventually to gastric atrophy. Loss of the stomach secretions in gastric atrophy leads to achlorhy-dria and, occasionally, to pernicious anemia.

Ocular Misalignment Syndromes

Patients with myasthenia gravis (see Chapter.50 ) can present with failure of adduction in one eye with dissociated nystagmus of the other eye. The dissociation between medical rectus function on lateral gaze compared with near convergence is, however, not typical of myasthenia gravis. Nonetheless, any patient presenting with the motility pattern that characterizes a pure MLF lesion, either unilateral or bilateral, without other signs suggestive of demyelinating or ischemic brain stem diseases, should have an edrophonium chloride (Tensilon) test as part of the workup (see Chapter15 ).

Systemic Considerations

Tracheal repair is inadvisable in a few diseases. If a patient with myasthenia gravis gives a history of frequent exacerbations, which led to respiratory failure and need for ventilation, then it makes little sense to reconstruct the trachea. Such a patient is better managed with a tracheostomy or T tube, so that when the next and predictable episode occurs, a tracheostomy tube can be replaced for ventilation without difficulty. If, on the other hand, the disease seems to be well controlled, then reconstruction is appropriate, with cautionary statements to the patient about what might occur in the event of respiratory failure. A similar approach is taken to patients whose stenosis was due basically to chronic pulmonary disease.

The Immunoregulatory Role of Mesenchymal Stem Cells

This is strengthened by the facts that MSCs are relatively easy to expand in vitro and their use does not involve ethical issues. This chapter discusses the biology of MSCs and examines in depth their various effects on immune cells, including, their potential for therapy of autoimmune diseases. The clinical efficacy of MSC for tissue repair has been documented. The various properties outlined in the previous sections make MSC an extremely attractive therapeutic tool also with a view to reducing unwanted immune responses such as graft-versus-host disease (GVHD), graft rejection, autoimmune diseases and other inflammatory conditions. The efficacy of bone marrow transplantation for the treatment of autoimmune diseases is now well known both in experimental systems and in the clinical setting. A possible critical role for MSC in the therapeutic effect of bone marrow transplant (BMT) has been suggested by Kushida et al.60 who reported that the removal of adherent cells from the bone...

Dermatitis herpetiformis

Dermatitis herpetiformis is a rare, chronic, markedly pruritic, papular, vesicular, and bullous skin disease of unknown etiology. It is probably an autoimmune disease and activated via the alternate complement pathway. The patient describes the itching of a new blister as a burning itch that disappears when the blister top is scratched off. The severe scratching results in the formation of excoriations and papular hives, which may be the only visible pathology of the disease. Individual lesions heal, leaving an area of hyperpigmentation that is very characteristic. The typical distribution of the blisters or excoriations is on the scalp, sacral area, scapular area, forearms, elbows, and thighs. In severe cases, the resulting bullae may be indistinguishable from pemphigus or bullous pemphigoid.

The Immunological Homunculus

The paradoxes of hsp 60 autoimmunity can be ascribed to a principal misconception of the classic clonal selection theory the behavior of the immune system is not controlled solely by chance contacts with antigens it is no less constrained by the internal organization of the immune system (24). This organization reflects the evolutionary experience of the species. For example, the capacity of the receptor repertoire to interact with particular antigens is dictated by various elements encoded in the germ-line, such as the machinery of antigen processing and presentation, and the major histocompatibility complex This cognitive theory of the immune system proposes that the system, through its internal organization, is programmed to respond to certain molecules in certain contexts. The details of this view of the immune system have been outlined elsewhere (24,27,28). The point I wish to stress here relates to natural autoimmunity hsp 60 and the other members of the stress protein families...

Prevention Strategies

Because dividing cells are more sensitive to the cytotoxic effects of alkylating agents than are cells at rest, it has been hypothesized that inhibition of the pituitary-gonadal axis by gonadotropin-releasing hormone (GnRH) agonists may protect the ovarian germinal epithelium from the cytotoxic effects of chemotherapy. In a mixed teenage and young adult group of women treated for lymphoma, leukemia or autoimmune disease, Blumenfeld and colleagues 47, 48 reported a significant benefit in the concomitant use of GnRH agonist treatment with cytotoxic chemotherapy. Pereya and colleagues evaluated the role of GnRH analogs with respect to the prevention of early onset ovarian insufficiency following chemotherapy in adolescent females. Their study compared prepu-bertal females treated with GnRH analogs prior to chemotherapy with a control group of prepubertal patients who were not given GnRH analogs. Pereya and colleagues found that GnRH analog treatment before and during chemotherapy might...

Functions Of Chaperonins

The biological significance of the chaperonins does not end with their roles in protein assembly. The GroE chaperonins are some of the most potent stimulators of the immune system yet discovered, and indeed are the dominant immunogens in all human bacterial infections studied. There is thus considerable medical interest in the possible role of the chaperonins in human disease, especially in protection against infection, cancer, and autoimmune disease (see Chapter 10).

Chronic Progressive External Ophthalmoplegia and Kearns Sayre Syndrome

Conditions to exclude include other mitochondrial diseases, primarily MERRF and MELAS any disease causing ophthalmoplegia when that is the sole presenting symptom, especially myasthenia gravis other diseases that cause multisystem involvement, such as collagen vascular diseases, particularly systemic lupus erythematosus and in the appropriate setting, Lyme disease (caused by infection with Borrelia burgdorferi) or Whipple's disease. Ihe ultimate diagnosis is made by muscle biopsy and mtDNA analysis. Ihere is no proven specific treatment, although coenzyme Q10 and carnitine have been used. Implanted cardiac pacemakers can be used for conduction defects. Associated endocrine abnormalities--growth hormone deficiency, diabetes mellitus, or hypoparathyroidism--can be treated medically. Although these conditions are considered chronic, complete heart block may result in sudden death.

Neurological Examination

Several disorders of the motor system are associated with sleep alterations. Strength should be examined, specifically the strength of the neck and respiratory muscles. Patients with myopathies, neuropathies, and neuromuscular junction disease can have significant chest wall weakness. In acute or chronic demyelinating polyneuropathy (Guillain-Barre(c) syndrome), tendon reflexes are lost and there may be additional bulbar cranial nerve weakness. In patients with myasthenia gravis, initial inspiration and expiration volumes may be normal, but repeated testing demonstrates rapid fatigability and poor aeration. In the condition multiple system atrophy, a diffuse degenerative condition with numerous areas of the nervous system affected, typical signs include parkinsonism in the form of bradykinesia and rigidity and gait dysfunction, along with cerebellar dysfunction-like dysmetria, ataxia, or tremors. Spinocerebellar atrophies are also associated with sleep...

Evaluation Guidelines Table95

AT, Ataxia-telangiectasia CSF, cerebrospinal fluid CT, computed tomography EMG, electromyography HD, Huntington's disease HIV, human immunodeficiency virus MG, myasthenia gravis MRA, magnetic resonance angiography MRI, magnetic resonance imaging N A, not applicable NCV, nerve conduction velocity TFTs, thyroid function tests. AT, Ataxia-telangiectasia CSF, cerebrospinal fluid CT, computed tomography EMG, electromyography HD, Huntington's disease HIV, human immunodeficiency virus MG, myasthenia gravis MRA, magnetic resonance angiography MRI, magnetic resonance imaging N A, not applicable NCV, nerve conduction velocity TFTs, thyroid function tests.

Streaming Pancreas Islet Cell Kinetics Zajicek G Et Al

Seung E, Iwakoshi N, Woda BA, Markees TG, Mordes JP, Rossini AA, Greiner DL. Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD Lt mice. Blood 2000 95 2175-2182.

The Clonal Selection Paradigm

The classic clonal selection theory proposed that tolerance to self-antigens required that the repertoire be purged of all cells bearing receptors capable of recognizing self-molecules (4). The recent demonstration of negative selection in the thymus is seen as the modern vindication of the classic notion of clonal deletion of anti-self reactivity as the cornerstone of self-tolerance (5). Thus, the potentially open-ended receptor repertoire of the immune system is hedged by a developmental bias against autoimmunity. But the bias against self-recogni-tion does not weaken the classic view that the structure of the immune system is in the hands of the arrant antigens that select those clones of lymphocytes bearing complementary receptors. The fundamental view of the clonal selection paradigm is that the immune response is regulated by two factors the concentration of available antigen and the concentration of lymphocytes with specific receptors. A. The Clonal Selection View of...

What Happens in Graves Disease

In Chapter 5, we described what happens in autoimmune disease and how the autoimmune response is triggered. With Graves' disease, an abnormal antibody is produced, called TSA (thyroid stimulating antibody), also known as TSI (thyroid stimulating immunoglobulin). TSA stimulates the thyroid gland to vastly overproduce thyroid hormone. Normally controlled by the pituitary gland, the thyroid's triggers are tricked into being stimulated by abnormal antibodies. This particular trigger is the thyroid follicular cell's receptor for TSH, stimulated by TSI instead of TSH. The result is hyperthy-

Hsp 60 As A Pcell Antigen In Iddm

Hsp 60 has been implicated in several autoimmune diseases (39) because of its immunodominance and the high degree of homology between mammalian and microbial hsp 60 65. This hypothesis is referred to as molecular mimicry (40), and it incorporates immune cross reactivity between environmental microorganisms and mammalian stress proteins expressed by the target cell.

Clinical Characteristics

Analysis of a group of our early patients with stenosis following tracheostomy for respiratory care showed an equal gender distribution and a mean age of 47 years (range 16 to 79 years). The causes of the original respiratory failure were diverse, including chest trauma, drug ingestion, myasthenia gravis, polyneuritis, head injury, pickwickian syndrome, pneumonia, and following cardiac surgery. Tracheostomy had been required in these patients for periods ranging from 2 to 119 days, with a mean duration of 42 days. Several different types of tracheostomy tubes had been used in this group of patients, but metal tubes (silver or stainless steel) with rubber cuffs, or plastic tubes with plastic cuffs, predominated in this era prior to the development of low-pressure cuffs. In many cases, at least two kinds of tube and cuff had been used. In most, an endotracheal tube had been employed for a period up to 4 or 5 days prior to tracheostomy. In 3 patients, the inflatable cuffs had been used...

Treating Hyperthyroidism

The most common autoimmune thyroid disease is Hashimoto's thyroiditis, also known as Hashimoto's disease. It is important to note, however, that there are other types of thyroiditis that are not autoimmune disorders (discussed further on). In medical circles, Hashimoto's disease is referred to as chronic lymphocytic thyroiditis because the thyroid gland contains lymphocytes that are attacking it. The disease is named after Hakaru Hashimoto, the Japanese physician who first described the condition in 1912. This chapter outlines autoimmune disease in general, and then discusses symptoms, diagnosis, and treatment of Hashimoto's disease. We also discuss other forms of thyroiditis as well as other autoimmune diseases that are commonly seen with autoimmune thyroid disease.

Islet Replacement Therapy

This method resulted in insignificant side-effects, and is favourable to the transplantation of a whole pancreas as it avoids major surgery. There has been a subsequent exponential increase in clinical islet transplantation, although follow-up investigations have revealed a progressive attrition of the grafted islets, with only 50 of patients remaining insulin-free after 5 years, possibly due to a mixture of slow rejection, recurrence of the autoimmune disease or exhaustion of the f cells.7

Clinical Evaluation Using Efferent Stimulation

In some diseases, such as myasthenia gravis, the adequacy of release of acetylcholine (the neurotransmitter at the myoneuronal junction) is compromised. In diagnosing this deficiency, it is common to test with a series of four or five Mmax stimuli closely spaced in time (interstimulus rate can range from 3 to 50Hz Walton, 1987). The later stimuli in the time series result in markedly reduced M waves in the EMG in the patient with transmitter deficiency, compared to the healthy person. This contrasts with the availability of glutamate at the Ia-motoneuronal synapse. In the latter case, even as few as two closely spaced stimuli will result in the second H-reflex being much reduced in magnitude or even nonexistent. This is the phenomenon of homosynaptic depression (Capek & Esplin, 1977).

Autoimmune Endocrine Diseases

The majority of autoimmune endocrine diseases are characterized by immune destruction of endocrine tissue leading to glandular dysfunction and hormonal imbalance. Endocrine autoimmune diseases include hypophysitis, Graves' disease, thyroiditis, autoimmune disease of the adrenal gland (Addison's disease), hypoparathyroidism, autoimmune type 1 diabetes mellitus, and autoimmune polyendocrine syndromes. These diseases have complex etiologies, which are unique to each disease, and, to some extent, unique to each patient. With the exception of autoimmune polyendocrine syndrome type I, genetic susceptibility to the development of endocrine autoimmune diseases is associated with multiple polymorphisms in the major histocompatibility complex genes (11). Genetic susceptibility alone, however, is insufficient to elicit autoimmune disease. Studies of autoimmune disease manifestation in identical twins show a lack of concordance, suggesting that specific (environmental or stochastic) immune...

Allogeneic Hsct In Recentonset Autoimmune Type 1 Diabetes Mellitus

In contrast to autologous HSCT, allogeneic HSCT may cure autoimmunity, and consequently preserve remaining pancreatic islets in patients with recent-onset type 1 diabetes. The rationale for allogeneic HSCT for patients with recent-onset type 1 diabetes is based on the following observations (1) allogeneic HSCT will halt autoimmune-mediated destruction of islet p cells (2) preservation of intact islet p cells is beneficial to the patient even in the absence of full metabolic control (3) because hyperglycemia is more easily managed in patients with functional islet p cells, chronic complications are less likely to develop and (4) there is a low probability of disease relapse or recurrence after allogeneic HSCT. The strongest genetic determinants of type 1 diabetes are particular polymorphisms of the MHC class II DQ and DR alleles approximately 20-50 of familial aggregation is associated with specific DQ and DR haplotypes (45). Because genetic susceptibility to the development of type 1...

Foreword to the Fourth Edition

Recombinant cytokines provide useful laboratory probes for studying the cell biology of innate and adaptive immunity and inflammation. Cytokines are the major orchestrators of host defense processes and, as such, are involved in responses to exogenous and endogenous insults, repair and restoration of homeostasis. Microbial pathogens have operated on these principles far longer than immunologists and have been shown to produce variants of proinflammatory cytokines, their receptors and chemokine antagonists that subvert and suppress the host immune and inflammatory defenses. Deletion of these products reduces the pathogenicity of these viruses. In addition to their role in host defense, cytokines appear to play a major role in development and some of them may account for as yet unidentified embryonic inductive factors. The study of cytokines is also elucidating the mechanisms underlying pathophysiological processes. Cytokines mediate not only host responses to invading organisms, tumors...

Abnormal Findings and Clinical Uses of Repetitive Nerve Stimulation

Repetitive nerve stimulation is a useful technique for evaluating neuromuscular transmission. In diseases in which such transmission is impaired, the muscle response to repetitive nerve stimulation may show abnormal alterations in size or area. In myasthenia gravis, a progressive decrement in the response may occur with repetitive stimulation (especially at 2 to 3 Hz), or an initial decrement may be followed by a leveling off of the response at a reduced size. Abnormalities are more likely to be found in proximal rather than distal limb muscles and in facial rather than limb muscles. Normal findings do not exclude the diagnosis. By contrast, in patients with Lambert-Eaton myasthenic syndrome or botulism, the response to a single stimulus is abnormally small and stimulation at a slow rate leads to a further reduction in response size with rapid rates of stimulation, a progressive increase in size of the response occurs.

Hashimotos Thyroiditis

Like other autoimmune diseases, a tendency for Hashimoto's disease is also inherited, but much of the time Hashimoto's disease strikes adults over age thirty (though many younger women have also been diagnosed with it), and it is much more frequently diagnosed in women. Statistically, one in five women will likely develop Hashimoto's disease in her lifetime.

Foetal Cell Microchimerism

Foetal cells may play a role both in the mother's peripheral circulation and in her tissues during gestation. During pregnancy, foetal cells have been shown to reflect the biology of pregnancy by being associated with dermato-logic disorders, such as polymorphic eruption of pregnancy56 and systemic disorders, such as pre-eclampsia.57 Foetal microchimeric cells were also present in higher numbers in women with some autoimmune diseases, such as systemic sclerosis, than in control groups58-62 and non-autoimmune disorders, such as hepatitis C63 and cervical cancer.64 Thus, foetal cells were associated with the maternal response to injury as opposed to causing disease. A non-invasive procedure based on the retrieval of microchimeric foetal cells circulating within the maternal blood for antenatal genetic analysis would enable foetal testing without risking the pregnancy. Male and female foetal cells cross the placenta in equal numbers. However, it is quicker and easier to detect the...

Autoimmune Type 1 Diabetes Mellitus

Of the endocrine autoimmune diseases, autoimmune type 1 diabetes mellitus (hereafter referred to as type 1 diabetes) is the most extensively studied because of both disease prevalence and severity. In 2002, approximately 13 million people in the United States (6.3 of the population) suffered from diabetes, and approximately 5-10 of these cases were diagnosed as type 1 diabetes (15). Furthermore, in the year 2000, diabetes was the sixth leading cause of death listed on death certificates in the United States (15). Thus, despite supportive therapy, diabetes mellitus causes significant morbidity and mortality. Although there is a lack of consensus regarding autoimmune-triggering events, it is clear that autoimmunity toward islet p cells is T cell-mediated and, at least primarily, results from failure of peripheral tolerance mechanisms. A dual checkpoint peripheral tolerance failure model has been proposed to explain the pathogenesis of type 1 diabetes in genetically susceptible...

Partially Characterized Syndromes

A positive AChR antibody test excludes a congenital myasthenia, but because cases of AChR antibody-negative myasthenia gravis exist, a negative test is less helpful. A positive edrophonium (Tensilon) test confirms the presence of a myasthenic syndrome but does not differentiate congenital myasthenia from myasthenia gravis. It may be negative in some patients with congenital myasthenia in whom there is a deficiency of acetylcholinesterase. EMG studies may show a decrement in the compound muscle action potential to repetitive stimulation but at 10 Hz rather than the typical 3 Hz. Single-fiber EMG may show excess jitter and blocking. Morphological, immunostaining, and immunochemical techniques and in vitro neurophysiological tests on intercostal muscle containing motor end plates are research methods for confirming and characterizing the nature of a congenital myasthenia. y , y Genetic analysis may show, for example, mutations of genes encoding for subunits of AChR.y

Alexias And Agraphias Languagerelated Disorders

Lips and impairs enunciation of labial consonants (B, M, P). Neurological examination may reveal atrophy and fasciculations of the tongue and weakness of the palate and the facial muscles. When a history of variable dysarthria or dysphonia, with prominent fatigability is elicited, a neuromuscular junction disorder such as myasthenia gravis may be present.

Absorption Distribution and Elimination

Deficiency include a decreased release of acid or decreased secretion of intrinsic factor by gastric parietal cells (secondary to gastric surgery), autoimmune diseases (antibodies to intrinsic factor) or various intestinal diseases leading to ileal damage. Some absorption of pharmacologic levels of B12 can be mediated by a separate diffusion-type mechanism.1

A 64kDa AntigenGAD

Humoral autoimmunity to GAD 65 was initially identified in newly diagnosed patients with IDDM (69) and in prediabetic individuals (72). More recent publications have demonstrated a proliferative T-cell response to GAD 65 both in NOD mouse (56,73) and in human IDDM (74). In the NOD mouse, CD4+ T-cell response to GAD 65 have been suggested to be the earliest event in the autoimmune cascade, although T-lymphocyte responses against other antigens, including hsp 60 can also be demonstrated simultaneously. The administration of GAD 65 in a nonimmunogenic form to NOD mice resulted in tolerization to GAD 65 and the prevention of IDDM in a significant proportion of the population. In addition, this resulted in tolerization to other p-cell autoantigens.

Interactions Between Cytokines

Along with their roles in host defence, polarized Thl and Th2 responses can also contribute to the pathogenesis of immune-mediated diseases. Thl responses are involved in organ-specific autoimmune diseases while Th2 responses are implicated in allergic disorders in genetically susceptible individuals. A key question has therefore concerned the molecular basis for polarization. Both Thl and Th2 cells are derived from a common precursor termed ThO. The issue of polarization therefore lies at the heart of cellular differentiation, and discoveries in this area are proving informative to other areas of biology. The cytokine IL-12, which is produced by antigen-presenting cells, promotes differentiation into Thl cells, whilst IL-4 produced by ThO cells promotes their differentiation into Th2 cells . CD28 is expressed on the surface of Thl and Th2 cells and is an important costimulus to promote activation of both cell types, while a homologue of CD28, termed ICOS, may selectively promote...

Spontaneous Remission of Graves Disease

Thyroid experts have theorized that removing certain stressors, which may have triggered the autoimmune disease in the first place, could help lead to spontaneous remission. Although unproven, it is helpful to review some of the stress-reduction techniques described in Chapter 22.

Are There Natural Therapies for Graves Disease

In the case of hyperthyroidism, such a diet could theoretically work to block the effects of thyroid hormone, but reality is not so obliging. It seems easier to take a methi-mazole tablet twice a day than to eat twenty pounds of raw cabbage, chew cassava, and follow a strict low-iodine diet (see Chapter 20) each day. Also, a goitrogenic diet cannot cure the autoimmune disease that is causing thyrotoxicosis.

Stress Proteins As Targets Of Immune Responses

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

Evaluation Guidelines Table156

Edrophonium chloride (Tensilon), a short- acting cholinesterase inhibitor, is used in the diagnosis of myasthenia gravis (Tensilon test). As explained earlier in the discussion of fatigability, a symptomatic muscle that is most amenable to semiquantitative testing is chosen for the measurement of fatigability before and after the intravenous injection of edrophonium. This test is sometimes done in conjunction with injection of a saline placebo. However, because muscarinic as well as nicotinic receptors are stimulated by the accumulation of acetylcholine in the synaptic cleft, this test is difficult to perform in a blinded fashion because intestinal cramping and muscle fasciculations in the eyelids are generally produced by the edrophonium. The muscarinic effects may also cause a bradycardia that is sufficiently severe to induce fainting, and rarely asystole occurs in what appears to be an idiosyncratic reaction. Therefore, a small test dose of 0.2 ml is given first to...

Development Of A Working Model For The Role Of Hsps In Transplant Immunity

Stressed target cells in the transplanted tissue respond by upregulation of the production of various hsps, especially the hsp 60 and hsp 70 families (phase 2). Although hsp 60 operates as a molecular chaperone primarily within the mitochondrial compartment, there has been convincing evidence that hsp 60 can be recognized by T lymphocytes, and that mycobacterial and or mammalian hsp 60-specific immune responses play an important role in several autoimmune diseases (16-20). Increased hsp production by stressed cells might be associated with positive and negative influences on transplant immunity (phase 3). The positive signals deal with the recognition and activation of lymphocytes, especially hsp-reactive T cells, which now have been amply demonstrated in various immunologically mediated inflammatory lesions in autoimmune disease, in tumor immunity, and as our data show, in transplant rejection. T cells might react directly with hsp molecules expressed on the cell surface or they...

Differential Diagnosis

The incidence of misdiagnosis may be declining. Watson and Buranen (1979) found after a 10-year follow-up period that 25 of diagnoses of conversion disorder were in fact false-positive diagnoses. In a more recent 4-year follow-up study, Kent et al. (1995) found that only 13 of patients were initially misdiag-nosed. Even though the rate of misdiagnosis has declined, these studies confirm that medical illness continues to be the cause of the original presenting complaint in a substantial number of patients initially diagnosed with conversion disorder. For this reason, it is imperative that patients thought to have conversion disorder receive a thorough neurological and medical evaluation. Conversion disorder should not be considered a diagnosis of exclusion. Rather, it is a well-defined entity that mimics neurological processes. On the other hand, the presence of a neurological condition does not preclude the diagnosis of conversion disorder. In fact, as previously noted, some studies...

Diathesisstress Models

For instance, exposure to stressors for some individuals produces gastrointestinal (GI) dysfunction (ulcers, colitis, etc.), while others may manifest immunological disturbances (frequent infection due to stress-induced immunosuppression, increased occurrence or worsening of autoimmune diseases, etc.). Such disparities in physiological outcomes of stressor exposure has led many researchers to postulate that individuals vary in the organs or brain systems that are constitutionally weakest and thus more susceptible to adverse health outcomes during times of stress. In this regard, one could attempt to explain the recurrence of chronic colitis in relation to stressor exposure by

Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy can be distinguished from inclusion body myositis, which presents as dysphagia. It also has rimmed vacuoles, but the filaments seen are larger and are present in the cytoplasm as well as the nucleus and there are no ocular palsies. Ocular myasthenia gravis without waxing and waning of symptoms may produce weakness in the same distribution as oculopharyngeal muscular dystrophy, but it generates demonstrable neuromuscular junction transmission defects on EMG and neuromuscular junction abnormalities on morphological studies. Although late onset of the mitochondrial myopathy, Kearns-Sayre syndrome, or oculocraniosomatic disease may present with ptosis, histochemical and ultrastructural studies of muscle show biochemical defects in the respiratory chain and mitochondrial DNA deletions.

Neuromuscular Junction Syndromes

MYASTHENIA GRAVIS The defect in neuromuscular transmission in myasthenia gravis (see Chapter 50 ) produces a pure muscular weakness without the atrophy, fasciculations, or reflex changes seen in motor neuron disease.y Myasthenia gravis also causes a pattern of weakness in the ocular and cranial muscles that is different from that seen in amyotrophic lateral sclerosis. A weakness of the extraocular muscles and eyelids producing diplopia and ptosis is common in patients with myasthenia gravis but rare in those with amyotrophic lateral sclerosis (see Table.15-2 ). Facial weakness is also common in myasthenia gravis, and the combination of ptosis and weakness of eye closure may be duplicated only by an acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome), which has a very different temporal profile. The other characteristic feature of myasthenia gravis is fatigability. The myasthenic muscle rapidly weakens with continued or repetitive use. The physiological...


Eric Gershwin, MD is a distinguished professor of medicine as well as the Jack and Donald Chia professor of medicine. He is also chief of the division of allergy and clinical immunology at the University of California School of Medicine in Davis. Dr. Gershwin graduated from Stanford Medical School in 1971 and subsequently trained in internal medicine and then immunology at Tufts University-New England Medical Center and the National Institutes of Health. He joined the UC Davis faculty in 1975 and has been division chief since 1982. Dr. Gershwin has been continuously funded by NIH since 1975 and currently has published more than 20 books, 600 experimental papers, and 200 book chapters or review articles. He is editor of the Journal of Autoimmunity and Clinical Reviews in Allergy and Immunology and on the editorial board of multiple other journals. His major contributions revolve around the theme of autoimmune disease. Dr. Gershwin was the first individual to clone an autoantigen and...


There are many types of thyroid diseases and disorders. This section covers the scope of common thyroid problems you have likely encountered, including autoimmune diseases, such as Hashimoto's disease or Graves' disease, and the symptoms of hypothyroidism or hyperthyroidism. All possible diagnostic and laboratory tests used in thyroid disease are covered in this section, as are all medications and treatments used in thyroid disease.


We have tried to outline the unparalleled features of hsps, as compared with ordinary proteins, in relation to host defense against microbial pathogens on two levels (1) their chaperone functions in the pathogen and in the host, (2) their high conservation causing cross-reactive immune responses. The effects of hsps as chaperones and antigens following infections with microbial pathogens are summarized in Figure 1. Because hsps contribute to the survival of pathogens, hsp-gene deletions could be useful for attenuating pathogens to be used as vaccines. This assumption is based on the chaperone function of hsps, where microbial hsps refold proteins during host defense and thereby promote survival of the invader. Owing to boosting of anti-hsp immune responses by frequent encounter with different microbes expressing hsps of high sequence similarity, hsps can rapidly mobilize immunity against pathogens. This is being exploited for protein-vaccines, where hsps serve as immunogenic carriers...


The factors of age group and gender are also important, for several diseases are often related to age or gender. The autoimmune disorder known as Sjogren's syndrome, for example, is common in menopausal women, while mumps, parotid swelling due to paramyxoviral infection, usually occurs in children between the ages of 4 and 10 years.


There are two forms of this disease, known as type I and type II diabetes. Type I diabetes is an autoimmune disease in which the white blood cells attack and destroy the P cells of the pancreas. This form of the disease is sometimes called juvenile diabetes because it occurs predominately in teenagers, although it can strike at any age. Type II diabetes affects older people, usually when they are 50 to 60 years of age. In this case, the disease may be due to a genetic predisposition to short-lived P cells, or it may be due to P cell burnout, brought on by a lifelong preference for a diet that is heavy on sweets. This may account for the fact that nearly 80 percent of those suffering from type II diabetes are overweight. At last count, 10 genetic loci were known to be associated with the onset of both types of diabetes.

Th1Th2 Cells

There has been a great deal of recent interest in a subset of CD4+ regulatory T cells (Tregs) that depend for their production on the transcription factor FoxP3 and that are characterized by high surface expression of CD25 (reviewed in Ref. 82). Tregs inhibit the activation of T cells and innate immune cells, apparently to suppress autoimmunity. To modulate responses in the periphery, Tregs must home to the site of inflammation, and Tregs have been shown to express a variety of chemokine receptors that would serve this function, including CCR4, CCR5, CCR6, and CCR8 (83-86). Consistent with a role for these chemokine receptors in Tregs function, deficiency of CCR5 on these cells exacerbated experimental graft versus host disease (85) in mice. Chemokine receptors important in defining and characterizing pathways of T-cell differentiation are listed in Table 1.


While Sjogren's syndrome often has a characteristic se-rology, including anti SS-A, anti SS-B, and occasionally ANA and rheumatoid factor, the pathogenesis of the disease is not entirely clear and is multifactorial as with most autoimmune diseases 224 . In addition to HLA-DR associations, recent studies suggest that polymorphisms in genes, such as minor histocompatibility antigen HA-1, and TNF may play a role in the disease process. Humoral dysregulation and B-cell hyperac-tivity is thought to be another pathogenic mechanism for Sjogren's syndrome 224, 277 .

Multiple Sclerosis

The evidence that MS is an autoimmune disease, or for that matter, an immunologically mediated disease, is circumstantial. Numerous laboratories tried to find immune responses to myelin and other antigens that were unique to patients with MS, but none succeeded. Persons with MS do have increased immune responses to a variety of myelin antigens, including myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein (18-24), and


In idiopathic narcolepsy less than 15 of the normal number of cells in this area are functioning, possibly because they are inactivated or because too few were present at birth, because of a developmental abnormality, but more probably because of cell damage and death later in life. This may have an autoimmune basis, particularly in view of the HLA association, but little evidence for this has been detected histologically. Auto-antibodies are no more frequent than in the general population and there is no evidence for any organ-specific autoimmunity. Narcolepsy is no more frequent in women than in men, unlike other autoimmune diseases, and there is no association with any other autoimmune diseases. Humoral immunity appears to be normal and inflammatory markers, such as C reactive protein, are normal.


In addition to their prime role in fighting infectious agents, it is clear that the immune system plays an important role in a number of pathological conditions, e.g. abnormal immune responses against a harmless substance (e.g. food, pollen) or self-antigens have been associated with allergies and autoimmune diseases. In contrast, normal immune responses against a tissue or organ transplantation from an incompatible individual are associated with transplant rejection (Buckley, 2003). The immune cells in transplanted organs and tissues may also attack and destroy the tissues of the host causing graft-versus-host disease (Gulbahce et al., 2003).


Although other agents, both infectious and noninfectious, have been more easily dismissed as etiological culprits (reviewed in refs. 1 and 17), the idea that sarcoidosis might be, at least partially, an autoimmune disease has been more pervasive (2,8,17). With the discovery of bacterial stress proteins (SPs) as major antigens for the T- and B-cell response to many pathogens, and the significant sequence homology between prokaryotic and eukaryotic SPs, a link between infectious diseases and autoimmunity was widely hypothesized (18-20). This was particularly true in those autoimmune diseases in which the critical target antigen (21) at the site of disease had not been clearly identified. Included in this category was sarcoidosis, where several possible mechanisms for a SP-driven autoimmune response could be considered. Thus, the initial event might involve (1) molecular mimicry or cross reactivity between SPs of the invading pathogen and the host (22,23), or (2) true autoreactivity...


The wealth of information obtained during the past 114 years of research in bacterial toxinology has provided a great deal of knowledge regarding the molecular structure, the genetic aspects, and the interaction of these fascinating molecules with the various cellular systems and tissues of the human and animal organisms. The study of the biological effects of bacterial toxins at the subcellular and molecular levels revealed their highly complex implications in a variety of physiological and metabolic processes. The key role of bacterial toxins in the pathogenesis of various acute, chronic, and certain autoimmune diseases afforded new insights in our understanding of infectious diseases. Many questions remain unanswered as yet. Novel toxins will be discovered and new achievements will certainly emerge in the coming years, particularly the design and use of novel therapeutic strategies (drugs, vaccines, adjuvants) in the management of toxin-induced diseases and prophylaxis of...

Stiff Person Syndrome

Stiff-person syndrome (SPS) is believed to be an idiopathic disorder in some patients and an autoimmune disorder with functional impairment of spinal neurons due to antibodies directed against the enzyme glutamic acid decarboxylase (GAD) in others. y This enzyme is essential for the conversion of glutamic acid to GABA, an inhibitory neurotransmitter found throughout the central nervous system. y In a paraneoplastic form of SPS, amphiphysin, a protein associated with synaptic vesicles, has been implicated, and this product's gene has been mapped to 7p13-14. y Neurophysiological studies show continuous excessive firing of the motor unit, suggesting that the disorder is due to disinhibition of the descending pathways to the Renshaw cells or gamma motor system.y Autopsy information, albeit limited, has failed to demonstrate any abnormalities in the brain stem, spinal cord, peripheral nerve, or muscle. autoimmune disorders (diabetes mellitus, thyroiditis,...

Subjective Objective

Myopathy can be a feature of hypothyroidism and manifests with proximal muscle weakness. Regardless of the cause of the hypothyroidism, weakness is observed in about one third of these patients.y Increased muscle size and firmness, which is most obvious in the limb musculature, as well as slowed muscle contraction are important features to identify. Exertional pain, stiffness, and cramps may be noted, and myoedema may be observed. Myoedema, a mounding of the muscle in response to direct percussion, is painless and electrically silent, and occurs in one third of hypothyroid patients. y Difficulty relaxing the hand grip and exacerbation by cold weather may suggest myotonia. However, unlike myotonia, hypothyroid myopathy involves a slowness of muscle relaxation and contraction, and resolves with correction of the hypothyroid state. y Although sleep apnea is usually of the obstructive type, other possibilities include a central abnormality, chest muscle weakness, and blunted responses to...


Most people can tolerate up to 1000 g iodine daily without adverse effects, but daily intakes of up to 2000 g are regarded as excessive and potentially harmful.5 Such intakes are unlikely to be obtained from normal diets of natural foods except where they are exceptionally high in marine fish or seaweed, or where foods are contaminated with iodine from iodine-containing medications or other adventitious sources. The effects of high iodine intake on thyroid function are variable and depend on the health of the thyroid gland. Dietary intakes of up 1000 g day have few long-term effects when the thyroid is healthy. Adverse effects include hypothyroidism and elevated TSH, goiter and increased incidence of autoimmune thyroid disease.66 People who have underlying autoimmune disease such as Grave's Disease or Hashimoto's thyroiditis, or who have previously been iodine deficient, may be more sensitive to iodine.8 Iodine-induced thyrotoxicosis (Jod-Basedow) has been described following the...

BAFF Antagonists

BAFF, also known as BLys, is a member of the TNF family that acts as an essential survival factor for B cells (19,20) and appears to play a central role in the development of some autoimmune diseases and B-cell malignancies. It has Two major avenues of evidence link BAFF to autoimmunity, namely studies in animal models and measurement of BAFF levels in patients with systemic autoimmune diseases. BAFF levels are elevated in autoimmune mice, notably the (NZB x NZW) F1 and MLR- pr strains (21). In patients with RA, SLE and other systemic autoimmune diseases, BAFF levels are also elevated (23). During the course of SLE, BAFF levels fluctuate (24), and BAFF has been proposed to be a biomarker for SLE disease activity. This information is suggestive of a link between BAFF and development of autoimmunity, and implicates BAFF in the etiology and progression of autoimmune diseases. As such, antagonism to BAFF may provide a novel therapeutic approach to the treatment of autoimmune diseases. Two...

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