Autoimmune Diseases Cure Diet

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! Read more...

Autoimmune Paleo Cookbook Summary

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Highly Recommended

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

This ebook does what it says, and you can read all the claims at his official website. I highly recommend getting this book.

The Skin in Systemic Autoimmune Diseases

Volume 1 The Heart in Systemic Autoimmune Diseases Edited by Andrea Doria and Paolo Pauletto Volume 2 Pulmonary Involvement in Systemic Autoimmune Diseases Edited by Athol U. Wells and Christopher P. Denton Volume 3 Neurologic Involvement in Systemic Autoimmune Diseases Edited by Doruk Erkan and Steven R. Levine Volume 4 Reproductive and Hormonal Aspects of Systemic Autoimmune Diseases Edited by Michael Lockshin and Ware Branch Volume 5 The Skin in Systemic Autoimmune Diseases

Gene discovery in human autoimmune disease an engine of hypothesis generation

The example of PTPN22 suggests that further research in human genetics is likely to open up many new avenues of investigation in autoimmune diseases. The era of whole genome association studies is now upon us, a clear example of a 'discovery driven', as opposed to a 'hypothesis driven', approach to biomedical research. As noted above, the identification of PTPN22 as a susceptibility allele for RA was a result of a discovery approach. Future understanding of the mechanism of action of PTPN22 will likely involve additional discovery driven experimentation on genom-ic and proteomic platforms. Thus, a continuing interaction between hypothesis, exploratory discovery and technology development forms a kind of engine of hypothesis generation, as illustrated in Figure 3. Human genetics is now in the middle of a remarkable acceleration, largely driven by dramatic advances in the technologies for both producing and analyzing genetic data. Studies involving thousands of subjects and millions of...

Outcome Measures in Cutaneous Autoimmune Disease Dermatomyositis and Lupus Erythematosus

Introduction to outcome measures in cutaneous autoimmune disease The ability to measure, to describe, to classify and to diagnose diseases is the prerequisite for successful clinical research. Diagnosis and classification of cutaneous autoimmune diseases have made enormous progress during the latter half of the last century. In general, we now have a solid frame of reference for clinical research even though some of the diagnostic criteria are still being refined, and we are likely to see new and important markers of autoimmune diseases that will be introduced into clinical practice. However, comparative trials depend on outcome instruments that measure the extent and severity of a disease and can be used to compare the baseline status with the condition of the disease after treatment has been initiated. These are largely missing for the skin. The assessment of treatment success or the natural history of chronic skin diseases, particularly autoimmune diseases, has to allow measurement...

Narcolepsy And Autoimmunity The Evidence

Table 1 summarizes the evidence for and against an autoimmune basis for narcolepsy. The tight association between narcolepsy and HLA-DQB1*0602 is generally greater than HLA associations observed with known autoimmune disorders such as multiple sclerosis or type I diabetes mellitus (a notable exception may be ankylosing spondylitis and HLA-B27) Furthermore, like most autoimmune diseases, narcolepsy tends to affect younger individuals (peripubertal onset). Unlike most autoimmune diseases, which tend to affect females more, however, narcolepsy is seen equally in both sexes (1). Also, there is no known clustering of narcolepsy with known autoimmune diseases. Levels of inflammatory markers such as C-reactive protein and erythrocyte sedimentation rates, as well as CD4 CD8 lymphocyte subsets, have all been reported to be within the normal range. (1,16-19). This could be because by the time narcolepsy is clinically apparent, the initial inflammatory response may have disappeared or the immune...

Approach To Evaluati On Of The Thyroid Patient

Age > 60 years Hyperthyroidism Other autoimmune disease Addison's disease Pernicious anemia Diabetes mellitus (type 1) Subacute thyroiditis (overt or silent) Head neck cancer (treated) Family member with thyroid disease Medication use Lithium carbonate Amiodarone Iodine (any form) Routine tests (if previously done)

Project Title Fine Specificity Of Scleroderma Autoantibodies

Progressive fibrosis of specific target organs, such as the skin, lung, heart, gastrointestinal tract, and kidney. Although the underlying pathophysiology of this disorder remains an enigma, the presence of antinuclear antibodies in scleroderma patients is nearly universal. Targets of these autoantibodies include topoisomerase 1 (Scl-70), nuclear ribonucleoproteins (nRNP), centromere, PM-Scl, and Ku. Anti-topoisomerase-1 (topo-1) autoantibodies are quite specific for scleroderma. and are present in precipitating levels in 20-40 of patients. Anti-topo 1 is associated with diffuse skin thickening, lung involvement, and the development of lung, colon, and brain cancer. Scleroderma patients with anti-nRNP autoantibodies may have a more cutaneous form of the disease and universally suffer from Raynaud's phenomenon. Over the past decade we have extensively characterized the immunochemistry of lupus autoantigens. These previous studies provide the technical background for this proposal....

Treatment and Outcome

Polymyositis and dermatomyositis are very serious illnesses. Before corticosteroids were discovered 50 percent of patients died from their disease. With modern treatment, nearly 90 percent of patients can be expected to be alive five years after the onset of the disease, excluding those with a malignancy. There are differences in outcome between the subgroups of disease. The outcome is best for those whose myositis is associated with another autoimmune disease (85 percent alive at five years), second best for dermatomyositis (80 percent), and worst for cancer associated myositis (55 percent). As mentioned, particular autoanti-bodies give some information on response to treatment and outcome. Patients with anti-Mi-2 or anti-PM-Scl have a 95 percent chance of being alive at five years, those with antisynthetase antibodies a 65 percent chance, and those with anti-SRP, a 30 percent chance.

Definition of the Disease

Goiter with hyperthyroidism, exophthalmos, and pretibial myxedema are the pathognomonic triad of Graves disease. Graves disease is a classic organ-specific autoimmune disease where there is a humoral autoimmune response to the TSH receptor. In Graves disease goiter i.e., hyperplasia of the thyroid with palpable (and often visible) gland enlargement and hyperthyroidism (i.e., hyperfunction of the thyroid) result from IgG autoantibodies that bind to and stimulate the TSH receptor. Such agonist autoantibodies i.e., thyroid-stimulating immunoglobulins (TSIs) can be identified in 80-100 of subjects with Graves disease. In contrast, TSIs are detected in 0-10 of control populations and up to 20 of subjects with Hashimoto thyroiditis.

Aetiology Pathogenesis

Sjogren's syndrome is a systemic autoimmune disease characterized by dryness of the eye and mouth resulting from the lymphocytic infiltrates of the exocrine glands. The etiopathogenesis of the disease is generally thought as multifactorial involving a genetic predisposition, ambiental factors and disimmunity but, at present, remains broadly unknown (Delaleu et al., 2005). Table 1 summarizes the pSS etiopathogenetic process. Sex hormones appear to play an important role as modulators of autoimmune disease onset perpetuation. Steroid hormones are implicated in the immune response, with estrogens as enhancers at least of humoral immunity, and androgens and progesterone (and glucocorticoids) as natural immune suppressors (Cutolo et al., 2003). It is not a case then, if, as other autoimmune disease, pSS occurs more frequently in female than in male. Concerning the role of estrogens in autoimmunity, animal models showed controversial results. From one side it has been described that...

Inflammatory Lesions and Lymphoma

Thyroiditis comprises a diverse group of inflammatory thyroid lesions and is one of the most common endocrine disorders in clinical practice. The most frequently encountered form is chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), first described in 1912, and a major cause of goiter and hypothy-roidism in the United States. Clinically, patients are young to middle-aged women who present with a moderately enlarged nodular thyroid that is nontender. Approximately 90 of patients have high circulating titers to thyroid peroxidase and, to a lesser extent, thyroglobulin. Hashimoto's thyroiditis is an autoimmune disorder that is thought to be caused by a derangement of suppressor T lymphocytes. Possible contributing factors to this disease include genetic associations with HLA-DR3,HLA-DR5, and HLA-B8 viral and infectious factors have also been proposed.Approximately 10 of cases are the fibrosing variant of Hashimoto's thyroiditis that presents as severe hypothyroidism in elderly...

PTPN22 is a negative regulator of early Tcell signaling events

Knocking out the murine homolog of PTPN22 (PEP), resulting in lowered thresholds for T-cell receptor signaling in these animals 51 . PEP knockout mice on a non-autoimmune background (C57 Bl6) exhibit a variety of phenotypes consistent with T-cell hyper-responsiveness, including enlargement of spleen and lymph nodes due to T-cell proliferation. This becomes more prominent in older mice, with the spontaneous development of germinal centers that appear to be largely dependent on the enhanced T-cell function present in the PEP- - animals. Increased T-cell proliferative capacity is primarily found within the effector memory cell compartment in both CD4 and CD8 subsets, and this is accompanied by enhanced phosphorylation of activating tyrosine residues in both Lck and ZAP70. Although there were increases in the levels of certain Ig isotypes in these knockout animals, autoantibodies did not develop, nor were there signs of overt autoimmune disease. Thus PEP deficiency alone does not lead to...

Refractory Epilepsy A Progressive Intractable but Preventable Condition

Summary The authors propose a hypothesis for the conceptual understanding and prevention of refractory epilepsy based on accumulated laboratory findings and an improved knowledge of the natural history of treated epilepsy. Refractory epilepsy can be recognized as a distinct condition with multifaceted dimensions, including neurobiochemical plastic changes, cognitive decline and psychosocial dysfunction, leading to dependent behavior and a restrictive lifestyle. The biological basis of refractoriness may be multifactorial, and may include the severity of the syndrome and or underlying neuropathology, abnormal reorganization of neuronal circuitry, alteration in neurotransmitter receptors, ion channelopathies, reactive autoimmunity, and impaired antiepileptic drug (AED) penetration to the seizure focus. Recurrent seizures may be the cause of some of these changes. The authors hypothesize that refractory epilepsy may be prevented by interrupting this self-perpetuating progression....

Conclusions Future investigations and therapeutic potential

Innate immunity represents an attractive source of therapeutic targets because it is linked directly to development of atherosclerosis, and also because of its strategic position in controlling inflammation, autoimmunity, and antibody responses. Lig-ands for specific TLRs are already being developed and evaluated in clinical trials as vaccines or adjuvants 93, 94 . Innate immune cells, particularly DCs, are being evaluated for possible roles in delivering antigen and inducing antitumor immunity 95 and in controlling autoimmunity 96 . Therapies aimed at tipping the Th1 Th2 balance toward a Th2 response may be a fruitful area of investigation among these are molecules that target specific aspects of TLR signaling 93 . NK cells and NK T cells may be useful in treating cancer 97 , and since both have been recently linked to atherosclerosis 98, 99 , the possibility arises that cellular therapy utilizing these lineages might also prove useful in atherosclerosis. Although still in early...

Genital secretions 197

Biopharming represents another point on the continuum. In general, biopharming appears to be a creature of giant corporations, not family farms. Boosters of biopharming insist that their products will be cheaper than current drugs. Examples include edible vaccines against disorders such as hepatitis B and diarrhea, in the form of genetically modified (GM) bananas, corn, tomato juice, lettuce, and potatoes. These foods must be eaten raw (cooking would destroy the vaccines). The use of edible vaccines to treat autoimmune diseases is currently being studied. Enthusiasts insist that edible vaccines could be valuable in developing countries that lack facilities to refrigerate and deliver standard vaccines. Critics point out that it will be hard to provide consistent doses. In discussions of drugbearing plants, concerns over safety and environmental damage have been and continue to be expressed.

Diverse Uses for Mouse Models of Cancer

Screening for Autoimmunity Immune-Based Therapy Vaccination has been an effective defense against both bacterial and viral diseases. Research to develop vaccine-based cancer immunotherapy targeting tumor-associated antigens (TAAs), although still at an early stage, is proceeding with the assistance of transgenic mouse models. A major concern in the development of such therapeutics is that because TAAs are self-antigens, the benefit of an antitumor effect must not be outweighed by a pathological autoimmunity particularly with the addition of costimulatory molecules to increase vaccine potency. Carcinoembryonic antigen (CEA) overexpression, for example, has been associated with a variety of carcinomas, but does exhibit a limited normal tissue expression and is thus considered both a TAA and self-antigen. In a series of studies, a mouse model engineered to correctly express the human CEA has proved useful in evaluating autoimmune reactions. The model permitted a comprehensive...

Project Title Rna Binding Proteins In Epilepsy And Neurologic Disease

Finding is consistent with the high incidence of seizures in fragile X patients. Since FMRP-deficient animals represent a second example of a situation in which abnormalities in an RNP result in seizures, we suggest that RNP dysfunction may be more general disease mechanism in epilepsy. Due to the potential importance of RNPs in epilepsy, the focus of our current grant application is to study the cellular role of Jerky, Jerky-like proteins, and FMRP. We propose I) to analyze the RNA binding properties of the human JERKY protein and a similar human protein HHJRK, II) to identify the cellular binding targets of JERKY and FMRP (by a method recently developed in our laboratory) and to assign functions for these targets, and 3) to employ Jerky autoantibodies as tool to study Jerky-RNA complexes. These proposed experiments will establish the jerky family as a distinct group of RNPs with a novel RNA binding motif. Also, specifying targets for JERKY and FMRP will allow us to link these...

Hepatic steatosis See steatosis

Hepatitis Hepatitis is an irritation or inflammation of the liver with a variety of causes, including viral infections, bacterial infections, autoimmune diseases, and chemical and medication toxicities. The leading worldwide cause of inflammation of the liver or hepatitis is viral in origin. A common misperception is that one virus causes hepatitis actually there is a diverse group of hepatitis viruses lettered A through G, except the letter F hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), hepatitis E (HEV), and hepatitis G (HGV-C). All of the hepatitis viruses have different size, genetic structure, routes of transmission, and ability to produce chronic infection. Despite these differences, hepatitis viruses have the propensity to produce acute symptoms of fatigue, loss of appetite, intermittent nausea, abdominal pain, fever, jaundice, dark-colored urine, chills, and liver enlargement. Several of the hepatitis viruses can evade the elaborate defenses of...

Immune suppressive therapies See immunosuppression

The immune system is involved in five major activities in the body. It defends the body against foreign substances, such as viruses and bacteria. It identifies and rids the body of abnormal cells to prevent their growth into tumors. It also eliminates old and deteriorating cells and rejects cells from other organisms that might enter the body. Finally it is sometimes involved in inappropriate responses to harmless substances, which lead to allergies, and, if it attacks itself, it results in an autoimmune disease.

Clinical Neurophysiology

For the procedure-oriented clinician, this extremely popular subspecialty, involving both EEG and EMG, allows the neurologist to incorporate a greater number of procedures into his or her practice. By mastering how to perform and to interpret these tests, you will become a better diagnostician of epilepsy, sleep disorders, and neuromuscular disease. Clinical neurophysiologists often monitor EEG rhythms and interpret evoked potentials prior to and during surgical procedures. They also are sometimes trained in the evaluation of sleep studies. These neurologists become well-versed in the evaluation and treatment of patients with epilepsy, peripheral neuropathies, muscular dystrophy, myasthenia gravis, and amyotrophic lateral sclerosis. Clinical neurophysiology is a highly sought after fellowship, particularly by those interested in private practice.

Neuromuscular Junction Disorders

Neuromuscular junction disorders, too, give rise to a simple pattern, limited to dysfunction of the motor system. Unlike myopathy, myasthenia gravis is a disorder of fatigue more than of constant weakness. Symptoms fluctuate and are worse at the end of the day. Signs may become apparent only after repeated testing that fatigues what may initially be an excellent response. Invariably there are cranial nerve signs weakness of facial and extraocular muscles, including the eyelids. In early cases, these can be very asymmetric.

Neuromuscular Junction Diseases

Disordered function of the neuromuscular junction (NMJ) usually results from myasthenia gravis, an autoimmune disease characterized by antibodies to the nicotinic acetylcholine receptor, which mediates transmission between nerve and muscle. This disease can be associated with malignant thymoma, so a chest computed tomogram (CT) is crucial in these patients. Both myasthenic patients and those with myopathies can present with proximal muscle weakness. Patients with myasthenia almost invariably have cranial nerve (bulbar) signs such as ptosis, diplopia, and facial weakness. Elevation of blood levels of creatine kinase is not a feature of myasthenia gravis but can be associated with certain myopathies. Another neuromuscular junction disease is Lambert Eaton syndrome, which is clinically similar to myas-thenia gravis but is associated with antibodies to the presynaptic calcium channels and malignant small-cell cancer of the lung.

Repetitive Nerve Stimulation

Pletes the nerve terminals of acetylcholine, resulting in a decremented response that is specific for myasthenia gravis. In actual practice, a weak patient first undergoes nerve conduction testing. If this is normal, EMG is performed to look for the presence of a myopathy (small motor units). If this is normal, repetitive stimulation is performed to evaluate the presence of myasthenia gravis. One important rule of electrodiagnostic testing is to limit the study to weak muscles because normal muscles will give normal results.

Differential Diagnosis

The initial diagnosis, based on the history and initial laboratory data, was anemia of chronic disease (ACD). This is a large group of conditions second only to iron deficiency as a cause of anemia. This class of anemias can be due to chronic infectious or inflammatory conditions, carcinoma, autoimmunity, or chronic renal disease.1 Patients with ACD typically have a mild, normocytic anemia and inappropriately low reticulocyte response. Cytokines, including interleukin-1 (IL-1), interferon gamma (IF-g), and tumor necrosis factor a (TNF-a), produced in response to chronic inflammatory states, such as gout, cause anemia through multiple mechanisms, including direct suppression of erythropoi-esis, blunted renal production of erythropoietin (EPO) in response to anemia, and increased uptake and sequestration of iron within macrophages. A key effecter of iron sequestration is hepcidin, a peptide synthesized by hepatocytes in response to IL-6 and

Lubricants and Moisturizers

Vaginal dryness can occur as estrogen levels fluctuate. Dryness occurs commonly with aging. However, in some women, vaginal dryness can occur during pregnancy, while nursing, or at certain times in the menstrual cycle. In addition, some disease states can cause vaginal dryness, such as Sjogren's syndrome, an autoimmune disease, which affects the body's moisture-producing glands.

Exacerbation Of Autoantibodymediated Diseases In Ldvinfected Mice

The pathogenicity of polyclonal rabbit anti-mouse platelet antibody was strongly exacerbated in mice acutely infected with LDV.7,8 This led to severe thrombocytopenia and to the development of purpuric lesions reminiscent of human thrombocytopenic purpura.7 A similar enhancement of antibody pathogenicity was observed in LDV-infected mice that received monoclonal anti-mouse platelet autoantibodies, derived either from (NZB x BXSB)F1 mice or from animals that developed an autoimmune anti-platelet response after immunization with rat platelets.9 Infection with mouse hepatitis virus (MHV) resulted in the same enhancing effect of autoantibody pathogenicity.7 Moreover, anemia induced by an anti-erythrocyte monoclonal antibody was also strongly exacerbated in mice infected with LDV.10 Interestingly, this consequence of LDV infection was found with an IgG2a autoantibody that induces anemia through phagocytosis, but not with an IgG1 autoantibody that lead to a similar disease through distinct...

Cysteine proteinase inhibitors

Sloane et al. (1990) reviewed some of the literature where reductions in stefin levels have occurred with tumour progression and have speculated that this might be responsible for the enhanced levels of cyteine proteinase activity associated with tumour progression, as discussed above. The view that endogenous inhibitors may regulate the activity of proteinases, and thereby control cancer cell invasion, is amply supported by the abolition by the cysteine proteinase inhibitor E-64 of the in vitro invasion by EJ bladder carcinoma, and by the inhibition in vivo of vascular dissemination and formation of metastasis by EJ cells (Redwood et al., 1992). Stefins have been isolated from several forms of human cancer and stefin A, and not stefin B, appears to be responsible for the inhibition of cathepsin B activity in sarcomas and ovarian carcinomas (Lah et al., 1989, 1990). In lung cancers, cathepsin B is found in the bronchoalveolar lavage fluid, partly in complex with stefins A and B....

Developments in Detection of Neuroendocrine Cancers and their Metastases in SLNs using Vlabeled and 123I or 131I

Taiodobenzylguanidine (MIBG) as indicators, it was found that both radionuclides used with the compounds mentioned are sensitive indicators of neural crest tumors. The specificity in diagnosis and also the indications for therapy are different. In contrast to MIBG, 111In-pentetreotide is not specific for detection of neuroendocrine tumors and their metastatic spread, because positive scintigraphic results are also obtained in other tumors, in granulomas, and in autoimmune diseases. On the basis of these experiences recorded by his own group, Hoefnagel (1994) suggested that 131I-MIBG was not effective only in diagnosis but also in therapeutic efforts for several neural crest tumors, but the biodistribution of 111In-pentetreotide does not allow the use of this compound for radionuclide therapy.

The Antiphospholipid Syndrome

The antiphospholipid syndrome (APS) is a noninflammatory autoimmune disease defined by the presence of antiphospholipid antibodies APA in the plasma of patients with venous or arterial thrombosis, or complications of pregnancy (Table 63.1). APS occurs predominantly in young women and is characterized by recurrence and high morbidity.

Treatment And Prognosis

Therapy.12,25 In the unresponsive cases of CBD stenosis to steroid therapy, surgical operation is often necessary to be differentiated from malignancy as well as the relief of symptoms.13 Eleven of our 20 patients were successfully treated with prednisolone, 2 with pancreatectomy, and 4 without medication. The long-term prognosis of AIP is unknown. As the clinical and laboratory findings of most cases are reversible after steroid therapy,12,13,19 the prognosis of AIP may depend on the severity of complicated diseases, such as other autoimmune diseases or diabetes mellitus.

Pathophysiology Of

Occasional coexistence of pancreatitis with other autoimmune diseases suggests that there may be common target antigens in the pancreas and other exocrine organs such as the salivary gland, biliary tract, and renal tubules. We observed that several autoantibodies such as antinuclear antibody (ANA), antilactoferrin antibody (ALF), anticarbonic anhydrase-II antibody (ACA-II), rheumatoid factor, and antismooth muscle antibody were frequently detected in patients with AIP. LF, a nonenzymatic protein, is also detected in the various human tissues, including the lactating breast bronchial, salivary, and gastric glands and the pancreatic acinus.19 The high prevalence of these antibodies suggests that CA-II and LF may be the candidates for the target antigens in AIP. However, it is noted that these antibodies are not necessarily specific for AIP because ACA-II can be detected in some patients with SjS or systemic lupus erythematosus and ALF in ulcerative colitis or PSC.

Deletion or Unresponsiveness of Antitumor Effector Cells

The T regulatory cell (T-reg), vital for maintaining peripheral tolerance against autoimmunity, has been shown to play a negative role in antitumor immunity (22). Recent evidence suggests that the tumor might utilize the host T-reg cell to suppress immune response. Wang and colleagues identified a tumor antigen-specific CD4+ CD25+ T-reg cell clone generated from human tumor-infiltrating lymphocytes (TILs) and demonstrated that the T-reg clone could strongly suppress T-cell response (23). Depletion of CD25+ T-reg cells with antibodies abrogated the unresponsiveness of CTL to syngeneic tumors in vivo and in vitro and led to regression of various tumors in animal models (24-27). These studies support the T-reg cell as an emerging target for cancer immunotherapy.

Agents targeting Bcells

The CD20 B-cell surface antigen is expressed only on pre-B as well as mature B cells and is lost before differentiation of B-cells into plasma cells. A murine monoclonal antiCD20 antibody (tos-itumomab) as well as a chimeric antiCD20 monoclonal antibody (rituximab), both of which cause a selective transient depletion of the CD20+ B-cells, have been introduced for the treatment of CD20 + low grade or follicular non-Hodgkin's lymphoma (Boye et al., 2003 Zelenetz, 2003 Stern and Herrmann, 2005). Similarly, epratuzumab, an antibody to CD22, a marker of mature B-lymphocytes, which also induces the targeted deletion of B-cells, is currently investigated in clinical trials in patients with non-Hodgkin's lymphoma (Leonard et al., 2004). In addition, targeting B-lymphocytes appears to be a promising approach for the treatment of autoimmune diseases. There is

Cytokines causing immunodeviation

In patients with SLE an increased production of IL-10 by peripheral blood mononuclear cells was found to be associated with overproduction of pathogenic autoantibodies. Therefore, it seemed reasonable to investigate whether blocking IL-10 may provide a useful approach to treat autoimmune diseases such as LE. Accordingly, six steroid-dependent patients with SLE were treated for 21 consecutive days with intravenous infusion of anti-IL-10 (20 mg day). The patients experienced a significant decrease in disease activity and were able to reduce concomitant steroid medication. In addition, a significant improvement of vasculitis and skin lesions was observed. Clinical scores remained stable through a follow-up of 6 months and no significant adverse events have been reported (Llorente et al., 2000).

Jason C Rouse Joseph E McClellan Himakshi K Patel Michael A Jankowski and Thomas J Porter

Recombinant protein pharmaceuticals have revolutionized the treatment of a variety of medical ailments, including cancer, autoimmune diseases, and hemostatic disorders. Proteins manufactured with eukaryotic expression systems may be complex and heterogeneous because of posttranslational modifications (PTMs) and differential proteolytic processing. At one time, detailed characterization and definition of the protein structure were difficult, and the manufacturing process defined the product. If process changes were made, clinical trials were required to demonstrate product equivalence prior to regulatory agency acceptance of the product manufactured by the modified process. To adopt new manufacturing processes in a timely manner, the biopharmaceutical industry and regulatory agencies have worked together over the last few years to develop new guidance documents based on knowledge gained from industry experience in the manufacture and clinical testing of protein pharmaceuticals (1,2)....

Experimental allergic encephalomyelitis eae

An autoimmune disease that can be induced in various experimental animals by the injection of homogenized brain or spinal cord in Freund's adjuvant. The antigen appears to be a basic protein present in myelin, and the response is characterized by focal areas of lymphocyte and macrophage infiltration into the brain, associated with demyelination and destruction of the blood-brain barrier. Sometimes used as a model for demyelinating diseases, although whether this is entirely justifiable is not clear.

Calcineurin inhibitors

Agent in many kinds of organ transplantations (Starzl et al., 1989 Wong et al., 2005). However, the experience with the systemic use of tacrolimus in autoimmune diseases is limited to some severe cases in which 'all other medications' have been tried unsuccessfully. In the 1990s, tacrolimus was also introduced as a topical agent producing favourable results in various skin disorders (Ruzicka et al., 1999). Meanwhile, safety and efficacy data of the topical formulation are available for more than 10 years from at least 20,000 cases worldwide (Assmann et al., 2001 Gupta et al., 2002). Tacro-limus ointment is generally well tolerated and all studies have shown a very good safety profile. The most common side effects are the sensation of skin burning and pruritus at the site of application, which are mostly of short duration and of mild or moderate severity. Sometimes, its application also leads to local erythema, skin infections, and, in rare cases, to flu-like symptoms and headache. In...

Role in central nervous system diseases

A role for the macrophage in both the induction and effector phases of multiple sclerosis (MS) (see Chapter 8) has been suggested. Inappropriate induction of antigen-specific helper T cells resulting in altered regulation of the immune response is postulated to be one of the factors in the mechanism of autoimmune disease. In MS (Bar-Or et al., 1999), once autoreactive T cells have been presented with the relevant antigen and received the appropriate cytokine stimuli, they become activated and cross into the CNS across the blood-brain barrier. Subsequent proliferation of these autoreactive T cells may occur following presentation by indigenous macrophages, microglia or possibly astrocytes. CNS damage and edema following the release of cytokines and macrophages, which are known to strip myelin from nerve sheaths, play a role in the subsequent demyelination. See also Chapter 13 for a more detailed examination of the role of macrophages in the CNS.

B lymphocyte stimulator

B lymphocyte stimulator (BLyS) is a 285-amino acid member of the tumor necrosis factor (TNF) ligand superfamily, which stimulates B cells to develop in mature plasma B lymphocytes (Stohl, 2002). Studies indicate that increased levels of BLyS may contribute to the pathogenesis of autoimmune diseases, such as SLE, and a significant

Tolllike receptors as pharmacological targets

The toll-like receptors (TLRs) are the first responders in the major pathway by which the immune system detects infection or damaged tissue. Through the recognition of microbial products and endogenous molecules released from injured tissue, TLRs provide a critical link between the innate and the adaptive immunity 1 . Since the first human TLR was identified in 1997 2 , ten additional TLRs have been described in mammals 3, 4 . Furthermore, more than 30 molecules from Xenopus, Drosophila and plants were added to what is now collectively known as the inter-leukin 1 receptor (IL-1R) TLR superfamily 5 . Considerable information has been collected on the structure, function and signaling of the TLRs. The biological function of these receptors as sensors of infection and tissue damage makes them attractive drug targets for designing vaccine adjuvants and for the treatment of immune related disorders including inflammation, infections, autoimmunity, allergies and cancer.

Special considerations

Orally administered antigens stimulate a strong secretory immune response with immunoglobulin A (IgA) and IgM antibodies, while the systemic immune response is inhibited. Thus the live polio vaccine and vaccines against salmonellae and Vibrio cholera are administered orally. Orally administered autoantigens may induce selective immunological tolerance and could be used to treat autoimmune diseases, such as multiple sclerosis, although results of clinical trials have so far been discouraging.

Conclusion and outlook

The enormous progress in biotechnology as well as in the improved understanding of the underlying pathomechanisms of several autoimmune diseases has paved the road for the development of novel, more specific, and hopefully more efficient therapeutics strategies. In many cases, biologics have already given the physician novel, highly potent, and often patient-friendly drugs at hand in additional to the already existing armamentarium for autoimmune disorders. At present, the number of drugs being evaluated for their efficacy and safety in the treatment of various autoimmune disorders are rapidly increasing. It is clear that even in the current era of biologics autoimmune diseases cannot be cured until the precise cascade of patho-genetic events and the ultimate molecular mechanisms of such diseases are unravelled. However, in addition to offering novel alternative treatment strategies biologics will undoubtedly contribute to our current pathogenetic understanding of autoimmune disorders...

Adultonset diabetes and chromium

Autoimmune disorder, type 2 diabetes results from insulin resistance, the body produces and releases insulin normally however, the insulin signal is not properly transmitted into cells. With time, however, the beta cells of the pancreas break down resulting in reductions in insulin production. The cause of the disease at a molecular level has only been elucidated in a tiny fraction of cases. Consequently, any mechanism by which insulin signaling could be stimulated has possible value in the treatment of the symptoms of type 2 diabetes.

Neurologic Diagnosis Technology At Its Best

For peripheral nerve and muscle disorders as well as radiculopathies (pinched nerves due to a slipped disk within the spine). Debilitating diseases such as myasthenia gravis are picked up by special EMG studies that make use of repetitive stimuli and single-fiber stimulation. By guiding the physician specifically to the affected muscle, the EMG allows for more effective treatment of patients with dystonia and severe muscle spasms.

Myositis and Myopathy

Penicillamine, a drug occasionally still used to treat RA and scleroderma, can cause inflammatory myositis that can be difficult to differentiate from DERMATOMYOSITIS AND POLYMYOSITIS. The risk of developing myositis does not seem to be related to the dose or duration of treatment. Affected patients most often complain of proximal muscle weakness, but features thought to be typical of autoimmune disease such as a rash and difficulty swallowing can occur. Elevated muscle enzymes and symptoms rapidly revert to normal when the drug is stopped.

Dysarthrias Characteristics and Classification

Mixed dysarthrias reflect combinations of two or more of the single dysarthria types. They occur more frequently than any single dysarthria type in many clinical settings. Some diseases are associated only with a specific mix for example, flaccid-spastic dysarthria is the only mix expected in ALS. Other diseases, because the locus of lesions they cause is less predictable (e.g., multiple sclerosis, traumatic brain injury), may be associated with virtually any mix. The presence of mixed dysarthria is very uncommon or incompatible with some diseases (e.g., myasthenia gravis is associated only with flaccid dysarthria), so sometimes the presence of a mixed dys-arthria can make a particular disease an unlikely cause or raise the possibility that more than a single disease is present.

Histological characteristics

Images Vasculitis The Bowels

Moderate RV results from limited small vessel vasculitis involving the postcapillary venules. Histopathologically, it is also a leukocytoclastic vasculitis. Patients most often present with cutaneous lesions, most characteristically, palpable purpura, on dependent sites. Cutaneous small-vessel vasculitis can be seen in many disease states and can be caused by infection, drugs, foreign protein, or immune complexes (autoimmune diseases). Moderate RV is believed to be an immune complex-mediated vasculitis in patients with high-titer RF that represents IgM (or IgA) IgG immune complexes.

Anas Younes MD and Andrea Cerutti MD

The tumor necrosis factor (TNF) family members are membrane-bound and soluble proteins that play an important physiological role in lymphocyte homeostasis, immunity, inflammation, and calcium metabolism. Abnormalities in the expression or function of these ligands and their receptors have been linked to several human diseases, including autoimmunity and cancer. These observations provided the background for exploring this system to design novel treatment strategies for autoimmune diseases, bone disorders, and cancer. Because the systemic administration of some TNF family members is toxic to normal cells, only a few have a potential therapeutic value. In this concise review, we focus on the potential role of six TNF family members in cancer therapy CD30 ligand, CD40 ligand, receptor activator of nuclear factor-kB (RANK) RANK ligand, TNF-related apoptosis-inducing ligand (TRAIL) Apo-2L TRAIL, BAFF, and APRIL and their receptors.

Human herpesvirus 5 See cytomegalovirus

Human herpesvirus 6 Herpesvirus that infects lymphocytes, including CD4 cells. HHV-6 infection generally occurs early in life and may cause fever and exanthem (roseola, a red skin rash) in infants. HHV-6 is associated with neuropathology, chronic fatigue syndrome, multiple sclerosis, and certain autoimmune diseases.

The validation process

Who can use a validated instrument The validation of the instrument has to reflect the setting and the raters who will use the instrument in clinical trials, and cannot be extrapolated to related but unvalidated populations of raters. There are a variety of possibilities raters can be trained dermatologists only (Carrol et al., in press), trained dermatologists and residents (Albrecht et al., 2005) or dermatologists, residents as well as nurses (Lucky et al., 1996). For autoimmune diseases it may be desirable to enable rheumatologists to score the patients so that it could be used for collaborative studies. However, it has been demonstrated that even for a more common and less complex disease like atopic dermatitis, scores by dermatologists were significantly better than those of nondermatologists (Oranje et al., 1997). Therefore, even a well-validated instrument would need to be revalidated with rheumatologists. While

Riccardo Rondinonea Stefania Banob Luca Iaccarinoa Andrea Doriaa

Lupus erythematosus (LE) is a multisystemic autoimmune disease that can occur with a wide spectrum of clinical manifestations. The skin is frequently involved, either as an isolated finding, i.e. when no other sign or symptom of systemic involvement can be disclosed, or as a part of a complex syndrome with multiple organ involvement.

Stefano Bombardieri Chiara Baldini

Sjogren's syndrome is a chronic autoimmune disorder of unknown aetiology characterized by the dysfunction and destruction of exocrine glands (Ramos-Casals et al., 2005). Sjogren's syndrome is one of the most common systemic autoimmune diseases and it may occur alone, as a primary condition (primary Sjogren's syndrome pSS), or in association with other connective tissue diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), as secondary variants (secondary Sjogren's syndrome). In both cases salivary and lachrymal glands are the major target organs, typically associated with focal lymphocytic infiltrates, leading to dry mouth (xerostomia) and dry eyes (xerophthalmia) (Skopouli and Moutsopoulos, 1994). Although the sicca symptoms are the hallmarks of the syndrome, during disease progression any organ or mucosal surface may be involved. Thus, pSS presents as a heterogeneous non-organ-specific autoimmune entity, encompassing a wide...

Other biological compounds

Cytokines of the IL-12 (IL-12) family including IL-12, IL-23, and IL-27 are known to regulate Th1-cell responses. In addition, it recently turned out that IL-23 via stimulating T-cell IL-17 production plays an important role in autoimmune inflammation (Hunter, 2005). Accordingly, a monoclonal antibody to the human IL-12 p40 subunit (anti-IL-12p40), which is shared with IL-23 has been developed for the treatment of autoimmune diseases. In a first clinical trial, this antibody was evaluated for its efficacy and safety in the treatment of moderate-to-severe psoriasis. Anti-IL-12p40 was well tolerated and 67 of the patients achieved at least a 75 improvement in PASI between 8 and 16 week after a single application of the medication (Kauffman et al., 2004). These very promising results need to be confirmed by the ongoing long-term trials. Targeting directly molecules of the B7 family which are crucial for providing costimulatory signals required for T-cell activation may be another...

Separate measurements of disease activity and damage

This chapter is part of a book on autoimmune diseases and the skin. The development of two skin-specific outcome instruments for autoimmune diseases within 1 year is an important step forward. However, this small step only makes painfully clear that these instruments are lacking for all the other diseases discussed in this book. We hope that this discussion and the workshop will motivate others to extend the range of instruments available to more of cutaneous autoimmune diseases and that these instruments will be used frequently. It is important to note that from the beginning the development of a new outcome instrument for a disease must be an interactive process in as broad a disease community as possible. The experience with SLE illustrates that a large community can develop a variety of instruments. This abundance makes the comparison of clinical trials more difficult and limits the experience with each instrument. To avoid this, an open and interactive development process is...

Idiopathic thrombocytopenic purpura See thrombocytopenia

The cause of many rheumatological conditions, for example RA and SLE, is not known. However, because antibodies (rheumatoid factor and antinuclear antibody (ANA), respectively) against normal components of the body occur, they are considered autoimmune diseases. The presence of autoanti-bodies does not automatically imply the presence of an autoimmune disease, for example low levels of ANA are common in healthy people. Some autoantibodies do not cause damage directly but may do so when they bind to complement and lodge in tissues such as the kidney. others directed against a patient's cells can damage them. For example antiplatelet antibodies can cause thrombocytopenia. Why autoantibodies develop and cause disease in some people is not clear. one theory is that autoreactive T cells that are normally destroyed in the thymus gland escape destruction and trigger an autoimmune response. Another is that the ability of the immune system to tolerate self-antigens is broken down. Primary...

Definition of Disease13

Usually enlarged, and aminotransferase elevations are 2-4X ULN with AST usually > ALT. Histological examination of the liver seldom can distinguish between wilsonian cirrhosis or chronic active hepatitis and other causes (e.g., viral, autoimmune diseases, or drug toxicity). Copper studies are essential for the differential diagnosis of these patients. Fulminant liver failure due to Wilson's disease is also difficult to differentiate from other causes since serum ceruloplasmin can be low and urinary copper excretion high in other forms of fulminant liver disease. However, in Wilson's disease, liver failure appears to be associated with relatively low serum alkaline phosphatase activities and very high bilirubin values, so that an alkaline phosphatase bilirubin ratio of < 2.0 (alkaline phosphatase in U L bilirubin, total in mg dL) has been proposed as evidence for wilsonian fulminant liver failure.

Photosensitivity in Lupus Erythematosus

Lupus erythematosus (LE) represents an autoimmune disease with great clinical variability in which photosensitivity is a common feature for all forms and subsets. Cutaneous LE lesions often arise in sun-exposed areas and it is well reported and recognized that sun exposure may also exacerbate or induce systemic manifestations of this disease (Dubois and Tuffanelli, 1964 Nived et al., 1993 White and Rosen, 2003). The original concept of photosensitivity in LE dates back to the first description by Cazenave (1851) and early observations since the beginning of the 19th century, where the role of environmental factors were related to disease activity and even induction of the disease. Of the different external factors that have detrimental effects on disease activity, the sun's radiation has been best studied. Hutchinson (1888) reported in his Harveian Lectures on Lupus, that patients with LE did not tolerate the sun. LE represents an autoimmune disease characterized by UV-sensitivity,...

Thiopurine Metabolism and Toxicity

And immunosuppressive agents to treat inflammatory bowel disease, rheumatic and hematologic autoimmune diseases, and following solid organ transplant. Thiopurine drugs are inactive and require metabolism of the prodrug to thioguanine nucleotides (TGN) for cytotoxic and immunosuppressive action. TGNs are formed after a series of enzymes modify the prodrug (Fig. 74.1) beginning with hypoxanthine guanine phos-phoribosyl transferase (HGPRT). While the exact mechanism of the effects of these drugs is unknown, theories include TGN incorporation into and interference with DNA and RNA synthesis and chromosomal replication, inhibition of T and B cell proliferation, and interference with natural-killer (NK) cell cytotoxicity.4'5

Erosive Lichen Planus

Lichen planus is an autoimmune disease that can occur anywhere on the body. When it occurs in mucous membranes, such as the oral mucosa and the vulvovaginal area, it tends to be erosive in nature (Fig. 18) (28). These erosions are quite painful during urination and daily activities, as well as with coital activity. There is usually a profuse white to yellow to greenish discharge present that patients often describe as sticky. Examination of the mucous membranes of the mouth, vulva, and vagina demonstrate erythematous erosions. A lacy white pattern, known as Wickham's striae, can be present on the mucosal surfaces.

The pharynx

The pharynx is critically important in ensuring that the upper airway is protected from aspiration of food, saliva and drink during swallowing and vomiting. Thus neurological disorders, including stroke, motor neuron disease, myasthenia gravis or reduced conscious level associated with intoxication, anaesthesia or coma can cause aspiration into the lungs, and pneumonia. Upper respiratory tract infections often cause pharyngitis and may cause tonsillitis. Common pathogens include viruses, such as influenza and the Epstein-Barr virus, and bacteria, such as streptococci. Group A b-haemolytic streptococci may also cause rheumatic fever, a systemic autoimmune disorder that can affect the skin, heart and brain. Diphtheria is a serious cause of pharyngitis that is preventable by immunization.

Aetiology of RA

There is a genetic influence in RA, but the concordance in identical twins (15 ) 46 is the lowest for all autoimmune diseases, suggesting that there is a role for other stimuli. Antigen presenting cells use major histocompatibility complex (MHC) class II antigens to present antigenic peptides to CD4+ T cells. In RA CD4+ T cells infiltrate the joint. MHC class II antigens have been associated with RA 47 . In particular, the human leukocyte antigen (HLA)-DR molecule chains HLA-DRB1 *0404, *0401, *0405, *0101 and *1402 which all share a common epitope 48 . This suggests that there may be antigen presentation of a viral bacterial pathogen or endogenous proteins such as a citrullinated protein 49 or human cartilage glyco-protein 39 50 , in the initial immune response of RA.

Value SI Units

As organ-specific autoimmune diseases, both Graves disease and Hashimoto thyroiditis are commonly associated with pernicious anemia and even type 1 (autoimmune) diabetes mellitus. Less commonly Graves disease or Hashimoto thyroiditis can be associated with autoimmune Addison disease or adrenal autoantibodies. The association of AITD (or type 1 diabetes mellitus) and Addison disease adrenal autoantibodies is termed autoimmune polyglandular syndrome type 2. The older literature referred to the association of adrenal and thyroid autoimmunity as Schmidt syndrome. The coexistence of AITD, Addison disease adrenal autoantibodies, and type 1 diabetes mellitus was termed Carpenter syndrome.

Etiology

Hashimoto's thyroiditis (lymphocytic thyroiditis) is the most frequent cause of primary hypothyroidism in developed countries, occurring with a prevalence of approximately 15 in women aged 18-24 and in 25 of women between the ages of 55 and 64. It is about a third as common in men. Hashimoto's thyroiditis is characterized by lymphocytic infiltration of the thyroid gland and the production of antibodies that recognize thyroid-specific antigens. It is currently believed that the disease occurs as a consequence of abnormalities in suppressor T-lymphocyte function that cause a localized cell-mediated immune response, although the pathogenesis is still not completely understood.2 The study of Hashimoto's thyroiditis has served as a general model for inquiry into the mechanisms of autoimmune disease. Most patients with Hashimoto's thyroiditis present with some thyroid enlargement (goiter) that has a bosselated texture on palpation. There is usually some degree of hypothyroidism, although...

Deficiency

The most important causes of Bj2 deficiency are the various forms of intestinal malabsorption of which the autoimmune disease, pernicious anaemia, is the most common. Autoantibodies are produced against the parietal cells of the stomach so the cells can no longer produce IF or hydrochloric acid (HCl). Patients with hypochlorhydria, such as the elderly and postgastrectomy patients, may exhibit malabsorption of dietary cobalamin and a lack of IF prevents absorption of vitamin B12.

Prevalence

The prevalence of pSS in the general population varies widely from 0.05 to 4.8 due to the different 'classification criteria' used (Drosos et al., 1988 Jacobsson et al., 1989 Zhang et al., 1995 Thomas et al., 1998). In fact, various classification criteria sets for pSS have been proposed in the last 30 years, from the ''Copenhagen Criteria'' (1976) (Manthorpe et al., 1986) to the ''San Diego Criteria'' (1986) (Fox et al., 1986) to the Preliminary European Classification Criteria (1993) (Vitali et al., 1993). None of them was universally accepted till the recent elaboration of the ''Revised International Classification Criteria (2002) by an American and European Consensus Group (Vitali et al., 2002). It was thus difficult until recently to establish the real prevalence of pSS, since according to some criteria, the diagnosis of pSS can be made in the absence of objective evidence of inflammation and autoimmunity, while other criteria restrictively require both the presence of biopsy...

Type 1 Diabetes

The relevance of further sub-classifying type 1 diabetes may appear less immediately apparent than for type 2. After all, once total beta-cell destruction has occurred then insulin replacement therapy will have to be used irrespective of the cause. However, certain genetic sub-types may be at much higher risk of other autoimmune diseases or complications, for example, and the identification of these at an early stage would be highly relevant. The real importance of sub-phenotyping in type 1 diabetes will be in the research effort to identify at risk and presymptomatic individuals and to intervene in their autoimmune

Jay S Skyler

This chapter will review evidence concerning interventions designed to interdict the type 1 diabetes disease process. To facilitate the discussion, the evolution of the disease can be divided into a number of stages, depicted in Figure 4.1, through which individuals progress. Interruption of the sequence at any stage is likely to be important13. The stages are (1) genetic susceptibility, modulated by genetic protection, identified by finding of susceptibility genes without dominant protective genes (2) initiation of autoimmunity, presumably by an environmental trigger, with a cellular immune response leading to immune-mediated islet infiltration (insulitis), with the stage identified by the presence of circulating autoantibodies (3) impairment of B-cell function resulting in loss of first-phase insulin response (FPIR) during an intravenous

Risk Identification

The identification of individuals at risk of type 1 diabetes, the ability to predict disease development, is crucial for studies of disease prevention. In family members, testing for autoantibodies (i.e. identification at stage 2) is usually used, and in this circumstance genetic testing is of limited value. On the other hand, genetic testing may be useful for identifying individuals in the general population or in infant relatives for prospective follow-up for the appearance of autoantibodies or for recruitment into trials aimed at prevention of initiation of autoimmunity. Indeed, there are several studies underway involving screening of newborns or infants for genetic markers22-26 with the goal of following these subjects (with or without intervention) for the appearance of autoimmunity. In addition, there are studies following offspring of diabetic parents for the appearance of autoimmunity27.

Summary

Large-scale LD mapping has been successful at identifying RA-associated polymorphisms. Interestingly they seemed to identify RA-specific gene(s) and also gene(s) that contribute to multiple autoimmune diseases. Another important issue in the investigation of disease-associated polymorphisms is that polymorphisms vary among ethnic groups therefore genetic studies should be carefully and extensively carried out with special attention paid to ethnic variations in polymorphisms and combinations of multiple genes.

Impairment 251

Immunosuppressive A drug that significantly impairs (suppresses) the functions of the body's immune system. In some cases, immunosuppression is an intended drug effect. In other cases, it is an unwanted side effect, as in the long term use of cortisone-like drugs suppressing the immune system sufficiently to permit reactivation of a dormant tuberculosis. Immunosuppressant drugs are being used to treat several chronic disorders that are thought to be autoimmune diseases.

Neuroimmunology

Specialists in neuroimmunology concentrate on patients with autoimmune neurologic disease, particularly multiple sclerosis. According to the AAN, roughly 350,000 to 500,000 people suffer from multiple sclerosis in the United States. The neuroimmunologist also evaluates and treats patient with other autoimmune neurologic problems, such as myasthenia gravis, lupus, and Sjogren disease. Due to the complexity of these diseases, neuroimmunologists are also knowledgeable in their complications, including depression, psychosis, spasticity, incontinence, sexual dysfunction, and pain.

Mechanisms

Increased motility can increase the frequency of defecation, and when it is severe there may be insufficient time for normal reabsorption of fluid from the stool, resulting in increased stool volumes. Dysmotility may occur with autonomic neuropathy, for example, in diabetes mellitus. Other causes include thyrotoxicosis and motility-stimulating drugs, such as acetylcholinesterase inhibitors used to treat myasthenia gravis (see Chapters 15 & 17).

Lockjaw See tetanus

Lupus An autoimmune disease in which a person's immune system mistakenly works against the body's own tissues. Systemic lupus erythematosus (SLE), the most common type of lupus, typically develops during the 20s, 30s, or 40s mbut about 15 percent to 17 percent of people with systemic lupus first notice symptoms during childhood or adolescence. Most of these are children 10 years or older it is extremely rare in children under five. Experts estimate that between 5,000 and 10,000 children in the United States have SLE.

Contraindications

BTX-A is contraindicated in areas of active infection and in patients with known hypersensitivity to the drug. It should be administered with caution to patients with neuromuscular disorders, such as myasthenia gravis, or those with peripheral motor neuropathies. Caution should also be used in patients taking medicines that interfere with neuromuscular transmission because these can increase the effect of the toxin. Common examples of these agents include calcium channel blockers, penicillamine, quinine, or aminoglycoside antibiotics. BTX-A is pregnancy category C and is not recommended for pregnant or lactating women (3).

Phosphorylate

Photophoresis A process by which a light-sensitive drug called psoralen is used to treat various autoimmune diseases. The drug is injected into the body after an interval blood containing psoralen is removed from the body and exposed to ultraviolet light, thus activating the drug in white blood cells. Finally, the blood is returned to the body by reinfusion. The whole procedure is usually performed on two consecutive days at monthly intervals and takes about four hours per session. Photophoresis is an approved therapy for a skin cancer called cutaneous t-cell lymphoma. In the test tube, it has been shown to work to inhibit viruses that involve RNA and DNA including HIV.

TTPPathophysiology

Most patients with sporadic idiopathic TTP have very low or undetectable ADAMTS13 activity at presentation. Inhibitory antibodies against ADAMTS-13 are detected in some, but not all, patients, which may be due to the insensitivity of current assay methods. As is seen in other autoimmune diseases, there is an increased incidence of sporadic idiopathic TTP, ADAMTS-13 deficiency, and autoantibodies in African- American women. In patients diagnosed clinically with HUS, however, ADAMTS13 activity is usually normal or only moderately decreased, and autoantibodies are not detected.

Gastric cancer

Gastric cancer is particularly prevalent in Japan, but the incidence is decreasing worldwide. Environmental factors, such as smoked foods, play a role and chronic gastritis, caused by autoimmune disease, or more commonly by Helicobacter pylori infection, predisposes to both adenocarcinoma and gastric lymphoma (see Chapter 31).

Perspectives

Nonreplicating canarypoxvirus (ALVAC) vector expressing both human carcinoem-bryonic antigen (CEA) and the B7-1 costimulatory molecule was used as cancer vaccine to treat patients with advanced CEA-positive adenocarcinomas in two phase I trials (116, 117). Cancer progressions in three out of six patients were stabilized with increased CEA-specific precursor T-cells in vivo. As discussed earlier, in two other recent phase I trials, combination of CTLA-blocking mAb with GM-CSF treatment or tumor antigen vaccines were tested. Administration of CTLA-4 antibody (MDX-CTLA4) induced moderate antitumor response and led to tumor stabilization in several metastatic melanoma and ovarian carcinoma patients while unfavorably inducing significant autoimmunity (66,67). More complicated combined strategies such as using tumor vaccine transfected with recombinant viral vector expressing multiple costimulatory molecules, given along with immune stimulatory cytokines, are currently under clinical trial.

CD40 and CD40L

CD40 ligand (CD40L, CD154) is predominantly expressed by activated T-lymphocytes (more frequently in CD4+ than in CD8+ lymphocytes), but can also be expressed by activated B-lymphocytes, natural killer (NK) cells, monocytes, basophils, eosinophils, dendritic cells, and platelets, in addition to nonhematopoietic cells, including endothelial and smooth muscle cells (10). Solube CD40L (sCD40L) is detected in sera of patients with lymphoma, chronic lymphocytic leukemia, autoimmune disease, and essential thrombo-cythemia (25-27). Recently, a new gene called AKNA was reported to regulate the expression of both CD40 and CD40L (28).

Creactive protein

CRP, a member of the pentraxin family, was first detected in 1930 by Tillett and Francis (3). It received its name because of its ability to precipitate the somatic C-polysaccharide or cell-wall teichoic acid of Streptococcus pneumonia. CRP is a nonspecific biochemical marker of inflammation, which, in addition to its involvement in the prediction of CV risk, has also served for many years as an indicator of a variety of pathological processes including infections, tissue damage, autoimmune diseases, or cancer. In healthy individuals, only trace levels of CRP can be detected in circulation. There is no apparent circadian variability with CRP, as has been observed with other acute-phase reactants such interleukin-6 (IL-6) or for plasminogen activator inhibitor-1 (PAI-1) (4,5), and there is also no evidence for seasonal variations as seen with fibrinogen (6,7). Under acute conditions, concentrations of CRP increase during the first 6-8 h and can reach peak levels approaching 300mg L...

Cd40cd40l

Multiple myeloma, autoimmune disease Multiple myeloma, malignancy-associated As discussed earlier, several mouse studies, such as BAFF-transgenic mice and TACI-deficient mice, develop lymphoproliferative disorders, including marginal zone (MZ) B-cell lymphoma (44,53). This tendency increases in the absence of TNF-a (164). Recently, dysregulated BAFF and APRIL have also been observed in patients with lymphomas. Soluble BAFF is increased in patients with certain types of non-Hodgkin's lymphoma (NHL), including germinal center B cell-derived follicular lymphoma. Soluble BAFF and APRIL are also increased in patients with CLL and multiple myeloma (MM) (165, 166). Interestingly, soluble BAFF is also increased in patients with autoimmune diseases such as Sjoegren's syndrome, which is often associated with low-grade B-cell lymphoma (53). Moreover, the chromosomal 13q32-34 region, which encompasses the BAFF gene, is often amplified in non-Hodgkin's lymphomas (NHLs).

Spd 756 455

Somatic cell gene therapy A genetic treatment that involves the insertion of genes into somatic cells for therapeutic purposes, for example, to induce the treated cells to produce a protein that the body is missing. It has been used in the treatment of autoimmune diseases and cancer. Inserting a particular gene into somatic cells affects only the patient being treated. It does not affect the genetic makeup of a patient's offspring and generally does not change all, or even most, cells in the patient. Therefore, it is considered an extension of normal medical care and does not generally fall under the moral and legal controls of other genetic engineering. It is being studied for potential use in the treatment of HIV.

The Immune Response

In organ-specific autoimmune diseases, resident cell types are involved in regulating tissue-specific autoimmunity (Unanue and Allen, 1987). It has been proposed that maintenance of the autoimmune state is achieved by presentation of autoantigens by resident cells aberrantly ex- The question as to whether M ller cells function as APC in experimental allergic uveitis (EAU) has been studied extensively by Robert Nussenblatt and his associates at the National Eye Institute. EAU is a CD4+, T-lymphocyte-mediated autoimmune disease, which has served as a useful paradigm for human ocular inflammatory diseases such as sympathetic ophthalmia (Gery et al., 1986). EAU can be readily induced in animals by immunization with retinal S-antigen and other retinal proteins, and presents itself as a delayed, hypersensitive reaction, resulting in ocular inflammation and loss of photo- M ller cell involvement in the immune response is further supported by the studies of Mano et al. (1991) who showed that...

Thymosin alpha

Some treatments have been tried that would maintain or increase the size of the thymus, thereby hopefully increasing production of T cells. These have been unsuccessful so far. Some practitioners of natural medicine believe stimulating the thymus through massage of the area, or vibratory rapping on the chest, can stimulate activity and maintain the thymus's health. Patients with myas-thenia gravis, an autoimmune disease of the muscles and nerves, often have the thymus removed as it becomes tumorous.

Interferon alpha

A link between interferon alpha (IFN alpha) and SLE was first evaluated by the induction of the disease during an IFN alpha therapy and the finding that many patients with SLE have increased serum concentrations of type I interferons. The main producers are plasmacytoid dendritic cells that are diminished in the circulation of SLE patients, but found in large numbers stimulated in e.g. skin lesions. The high concentrations of IFN alpha in the sera of patients with SLE were found to activate dendritic cells to trigger T cell-mediated autoimmunity and promote the differentiation of B cells into antibody-producing plasma cells (rev. by Colonna et al., 2004).

Conclusion

The above-mentioned substances are just examples of new topical and systemic therapeutic options in the therapy of SLE and other systemic autoimmune diseases, which indicate the enormous development in this area. However, one important future step will be the initiation of optimized clinical trials, which need to take into account the heterogeneous expression of SLE and the lack of proven standardized therapy for specific organ manifestations, such as CNS and skin. Recently, the American College of Rheumatism (ACR) developed standardized response criteria to measure the overall disease activity in SLE (Liang et al., 2004) providing a common basis for comparing treatment options, permitting more diverse patients to be studied and to be compared statistically, and facilitating qualitative and quantitative (meta-analysis) synthesis of different clinical trials. Similar instruments have to be developed for other systemic autoimmune disease to answer the important question, does a...

Intelligibility

Treatment focused on improving articulation often uses the hierarchical practice of selected syllable, words and phrases (Robertson, 2001). However, because artic-ulatory imprecision may be due to reduced respiratory support, velopharyngeal insufficiency, or rate control, the treatment of articulation is not always focused on improving the place and manner of articulatory contacts. When specific work on improving articulatory function is warranted, behavioral approaches involve focusing the speaker's attention on increased effort for bigger and stronger movements. Compensatory strategies such as using a different place of articulation or exaggerating selected articulatory movements may be used (DeFao and Schaefer, 1983). The use of minimal contrasts (tie sigh) or intelligibility drills (having the speaker produce a carefully selected set of stimulus words) focus the speaker's attention on making specific sound contrasts salient and clear. Strength training is sometimes advocated, but...

AntiB cell therapy

Specific autoantibodies are the serological hallmark of SLE. Therefore, it is quite logic to address B lymphocytes, the precursors of immunoglobulin-producing plasma cells, in therapeutic intervention. In systemic autoimmune diseases, B cells are thought to play a major role, and animal models indicate that such diseases are blocked in mice deficient in B lymphocytes. Furthermore, B cells may

Streptozotocin

Glycogen Streptozotocin

Induced NO production has received special attention. It has been suggested that these agents damage rat islets in vitro, but their effects on cultured human islets are less pronounced, despite the production of similar amounts of NO.46 Eizirik and coworkers85 investigated the differences between humans and rodents and have found that human p-cells are resistant to nitroprusside (a NO donor),86 STZ, or alloxan (a generator of free radicals)87 at concentrations that decrease survival and function of rat or mouse p-cells. It is reported that human fetal islets grafted into nude mice were not destroyed by injections of STZ, in spite of the adequate uptake of the drug by the human tissue.88 It is well known that the time between the appearance of islet autoimmunity and the clinical onset of insulin-dependent diabetes mellitus (IDDM) is much longer in humans than in mice (non-obese diabetic mice) and, in particular, rats. Because the degree of resistance to various toxins suggested from...

Ofer Markman

Identification and characterization of antibiotic agents that affect bacterial cell wall synthesis, plasma protein glycans, growth factor and cell surface receptor structures involved in viral disease, and autoimmune diseases such as insulin dependent diabetes. Rheumatoid glycans have also been used in the development of biomaterials for contact lenses, artificial skin, and prosthetic devices. Furthermore, glycans are used in a number of non-medical fields, such as the paper industry. Additionally, of course, the food and drug industry uses large amounts of various polysaccharides and oligosaccharides.

Types of Hepatitis

The liver responds to any injury in three different ways (1) inflammation, generically called hepatitis, which can be of different nature (leukocytic, lymphocytic, plasmo a cytic, etc.) (2) cholestasis, which represents an impairment of the bile flow at any point from the sinusoidal membrane to the extrahepatic bile ducts and (3) a combination of both. Cholestasis can be caused by drugs, toxins, virus, and blockage of the biliary tree at any level and from multiple causes (stones, strictures, tumors, etc.). A cholestatic injury is characterized by elevation of alkaline phosphatase and bilirubin, which is normally secreted into bile. Cholestatic injury may occur in a pure form with no evident parenchymal damage or may be accompanied by hepatocellular damage.1 A hepatitic injury is characterized by an elevation of transamin-ases and represents hepatocellular damage and necrosis. It can be related to multiple causes such as bacteria, drugs, toxins, virus, autoimmunity, metabolic...

CD30 and CD30 Ligand

CD30 is a 120-kDa type I transmembrane protein that contains six extracellular cys-teine-rich domains (Fig. 1) (9). CD30 is shed in a soluble form (sCD30), which can be detected in sera of patients with CD30+ tumors, autoimmune disease, and viral infection 17p11 B-Cell proliferation and autoimmunity

Angiogenic Disorders

After birth, angiogenesis still contributes to organ growth, but during adulthood most blood vessels remain quiescent angiogenesis only occurs in the cycling ovary and placenta during pregnancy. However, endothelial cells (ECs) retain the remarkable ability of dividing rapidly in response to a physiological stimulus, such as hypoxia and inflammation. Angiogenesis is also reactivated during wound healing and repair. In many disorders, however, this stimulus becomes excessive, and the balance between stimulators and inhibitors is disturbed, resulting in an angiogenic switch. The best-known conditions in which angiogenesis is switched on are malignant, ocular and inflammatory disorders, but many additional processes are affected-such as atherosclerosis, asthma, diabetes, cirrhosis, multiple sclerosis, endometriosis, acquired immunodeficiency syndrome (AIDS), bacterial infections and autoimmune diseases (Table 1). In obesity, adipose tissue may also show excessive growth. A high-fat diet...

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