Natural Treatments for Autoimmune Diseases

Autoimmune Paleo Cookbook

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

Autoimmune Paleo Cookbook Summary

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Author: Samantha Miller
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My Autoimmune Paleo Cookbook Review

Highly Recommended

Of all books related to the topic, I love reading this e-book because of its well-planned flow of content. Even a beginner like me can easily gain huge amount of knowledge in a short period.

All the modules inside this ebook are very detailed and explanatory, there is nothing as comprehensive as this guide.

DNA vaccination for central nervous system autoimmune diseases

Conceptually, gene therapy has been used as an efficient methodology to circumvent genetic deficiency by transfection of cDNA encoding the appropriate functional gene product. It is therefore conceivable that the best candidates for this form of therapy would be genetic diseases associated with a single gene mutation, such as X-linked agammaglobulinemia (XLA) or cystic fibrosis (CF). Paradoxically, it appears that gene therapy needs to confront similar levels of technological challenges when encountering genetic disorders, such as XLA or CF, to those a involved in a successful intervention in multifactorial diseases. Yet, while genetic disorders that involve a mutation in a single gene are rare, multifactorial diseases comprise a major cause of illness and death in the developed countries. This has motivated scientists to explore gene therapy strategies in multifactorial disorders. This chapter discusses the use of a modification of gene therapy named DNA vaccination to provide novel...

Rationale for HDAC Inhibitor Therapy in Autoimmunity and Transplantation

Abstract While there are currently more than 70 ongoing clinical trials of inhibitors of so-called classical HDACs (HDACi) as anticancer therapies, given their potency as antiproliferative and angiostatic agents, HDACi also have considerable therapeutic potential as anti-inflammatory and immunosuppressive drugs. The utility of HDACi as anti-inflammatory agents is dependent upon their proving safe and effective in experimental models. Current pan-HDACi compounds are not well suited to this role, given the broad distribution of target HDACs and their complex and multifaceted mechanisms of action. In contrast, the development of isoform-selective HDACi may provide important new tools for therapy in autoimmunity and transplantation. This chapter discusses which HDACs are worthwhile targets in inflammation and progress toward their therapeutic inhibition, including the use of HDAC subclass and isoform-selective HDACi to promote the functions of Foxp3+ T regulatory cells. Keywords...

HSPs and Autoimmunity in Atherogenesis

Hypothesized that T cells are involved in the initiation of disease and the humoral response plays a facilitating role 153 . It is possible that HSP27 and-90 are putative autoantigens involved during atherogenesis 154, 155 . Furthermore, autoimmunity to HSPs may lead to a systemic inflammatory response associated with elevated CRP which may also promote atherogenesis.

Myasthenia Gravis

Myasthenia gravis is a neuromuscular disease characterized by weakness and marked fatigability of skeletal muscle exacerbations and partial remissions occur frequently. The defect in myasthenia gravis is in synaptic transmission at the neuromuscular junction, such that mechanical responses to nerve stimulation are not well sustained. Myasthenia gravis is caused by an autoimmune response primarily to the ACh receptor at the postjunctional endplate. These antibodies reduce the number of receptors detectable by receptor-binding assays and electrophysiological measurements of ACh sensitivity. The similarity of the symptoms of myasthenia gravis and curare poisoning suggested that physostigmine might be of therapeutic value 40 years elapsed before this suggestion was tried, successfully.

Differential Diagnosis

Many disease processes present with pain, thus associated pain syndromes should be part of the physician's differential diagnosis (Overcash et al. 2001). Diabetic neuropathy (Tesfaye et al. 1994) is a frequently encountered pain, characterized by burning, muscle cramps, lancinating pain, metatarsalgia, hyperalgesia, allodynia, loss of proprioception, tingling, and numbness in lower extremities. Human immunodeficiency virus (HIV) patients present with pain including neuropathic, somatic, visceral, and headache symptoms. Patients suffering from autoimmune disease will often present with joint pain associated with inflammation, achiness, and stiffness. Post-surgical pain is commonly encountered and is usually somatic or visceral in nature. Infectious processes involving intra-abdominal organs are more likely to present with visceral pain while infectious processes involving the skin (e.g., herpes zoster) will present with somatic or neuropathic pain.

Effects of Ageing and Antioxidant Status on Immune Functions

Immune function impacts on the health and well being of all individuals, but is especially critical in the elderly because immune responses generally decline with age (Miller, 1994 Chandra, 1995). The consequences of suboptimal immune responses are particularly detrimental in the elderly, who have an increased risk of infections as well as immune-mediated cancers, adverse hospital outcomes and increased risk of autoimmune diseases (Meydani and Blumberg, 1993 Bogden and Louria, 1997).

Matrix metalloproteinases and their inhibitors in brain injury and repair

Matrix metalloproteinases (MMPs), a family of zinc-dependent proteolytic enzymes, together with their endogenous tissue inhibitors, TIMPs, are involved in remodeling of the extracellular matrix (ECM) under a variety of physiological conditions. Recent studies, however, have implicated MMPs in various pathological conditions such as tumor invasion and metastasis, arteriosclerosis, and inflammatory and autoimmune diseases.

MMPs In Multiple Sclerosis

The involvement of MMPs in the pathogenesis of MS appears to include a number of mechanisms, among which are degradation of cerebral vascular basement membrane leading to disruption of the BBB integrity, brain edema and immune cell infiltration into the CNS.26 An increase in cerebral vascular permeability, demonstrated following MMP-2 injection into rats, and a decrease of this phenomenon following co-injection of both MMP-2 and its inhibitor, TIMP-2, supports a direct role of MMPs in BBB damage.27 MMPs may also be involved in the demyelination process owing to their ability to degrade myelin basic protein, a major component of central myelin.28 This process of demyelination is followed by release of new immunogenic peptides which may lead to spreading autoimmunity.29 Additionally, MMPs are also

Clinical applications

The majority of clinical experience using diphtheria-based fusion protein toxin constructs has been with the IL-2 receptor targeting constructs. The specific expression of the high affinity IL-2 receptor on only activated and proliferating T cells makes DAB389IL-2 a potential therapeutic for the treatment of both T-cell mediated malignancies and autoimmune diseases. The progression of disease in both states often results in the emergence of resistance to chemotherapy and subsequent treatment failure, and highlights the need for the development of new therapeutic agents. In the context of malignant disease, IL-2 receptor expression is reported in various subsets of hematopoeitic malignancies of T-cell origin, such as cutaneous T-cell lymphoma (CTCL), low and intermediate grade non-Hodgkin's lymphoma, HTLV-1 associated adult T-cell leukemia lymphoma, and chronic lymphocytic leukemia (Foss et al., 1998). Signaling pathways mediated by the IL-2 receptor are a requirement for T-cell...

Blistering Diseases in the Elderly

Blistering diseases in the elderly are a rare group of diseases mediated through the immune system, induced by drugs or arising from other primary systemic physiological aberrations. Pathogenetically, they are autoimmune diseases which affect the cutaneous and mucosal tissues. Treatment requires an arsenal of approaches, including localized and systemic therapies. Localized treatments involve care of the local area of the blister (topical care) through diverse means. Of those, crucial is soaking of the blister in an antiseptic solution. For that, the two major chemicals used are potassium permanganate and aluminum subacetate.54 Aluminum subacetate (a basic aluminum acetate solution) is used locally on the skin and mucous membranes as an astringent and plays the role of the topical antiseptic. Solutions of the same chemical are also used as a wet dressing in a number of other skin diseases.

Isoforms Of Nitric Oxide Synthase

Inducible isoform (iNOS) is calcium-insensitive and is stimulated by endo-toxins, cytokines, interferon-y, and lipopolysaccharides. iNOS binds calmodulin tightly. For this reason, it does not require the presence of Ca2+, making it insensitive to fluctuations in cytoplasmic calcium levels (31). iNOS is present in glial cells in the CNS (8,19). In glial cells, cytokines such as interleukin-1p (IL-10) and tumor necrosis factor-a (TNF-a) are produced following acute ischemic stress. iNOS induction occurs in autoimmune diseases and septic shock. Once expressed, iNOS is continuously active and leads to a long-lasting (several hours to days) NO generation compared to calcium-dependent NO synthesis lasting a few minutes (31). By inhibiting iron-containing enzymes in parasitic target cells and causing DNA fragmentation, iNOS exerts its cytotoxic effects. On the other hand, it is suggested that NO iNOS is involved in neuronal apoptosis. The iNOS induction was detected primarily in astrocytes...

Class ADisease Specific

Another example that is applicable to this category is a disease such as Myasthenia Gravis where specific antibodies that block the acetylcholine receptors cause progressive muscle weakness. Specific neutralizing agents to these antibodies are likely to provide high efficacy in treating the disease with the likelihood of fewer adverse effects14 since such antibodies are not physiologically present in human beings. These examples are typical for Type 1 class A target validation. The biomarkers that need to be established for this Type 1 class A category should focus on validating the specificity of the target to the disease state.

Mitoxantrone And Related Quinones

Mitoxantrone is active in breast cancer, acute promyelocitic or myelogenous leukemias, and androgen-independent prostate cancer. Although early reports seemed to indicate that its cardiotoxicity was lower than that of the anthracy-clines,56 this claim has been subsequently challenged.57 Mitoxantrone has been recently approved for treatment of secondary progressive multiple sclerosis (MS).58 The rationale for this application stems from the fact that MS is considered to be an autoimmune disease where a heightened immune action results in the destruction of the myelin of the central nervous system, causing nerve impulses to be slowed or halted and leading to the symptoms of MS. Since chemotherapeutic

Fatigue As A Symptom In

Although fatigue is a common symptom in many diseases encountered in clinical practice (Tables 15.2 and 15.3), its definition and objective evaluation have always been difficult. The physiological definition of fatigue, which is the inability to sustain a specified force output or work rate during exercise, has often been termed 'objective fatigue'.8 Neuromuscular disorders like myasthenia gravis and metabolic myopathies are the best examples of this type of fatigue. To date, there is insufficient neurophysiolog-ical evidence of peripheral neuromuscular failure (involving peripheral nerves, neuromuscular junction or muscles) as the cause of persistent fatigue in CFS patients.9 Current evidence strongly supports a dominant central mechanism of fatigue in CFS,10-12 and the oxidative defects in muscle metabolism earlier observed in these patients are likely to be due to impaired bloodflow to the exercising muscles,13 as a result of dysregulated autonomic control.14,15 The majority of CFS...

Elaboration on Apoptosis and Necrosis

Apoptosis or programmed cell death (PCD) is a response to physiologic or pathologic stress, in which cell death is completed in an orderly manner, via activation and synthesis of gene products, aiming at cell destruction. There is disarray in the balance between the rate of cell division and elimination. Apoptosis provides the means by which organisms remove unwanted or useless cells 41 . If the process of apoptosis is disrupted, various pathologic conditions such as cancer, acquired immunodeficiency syndrome and autoimmune diseases may arise. The biochemical basis of the apoptotic machinery exists by constitution in all mammalian cells and is activated by various extra- and intra-cellular signals 27 . Apoptosis and necrosis are two forms of cell death with distinct morphological and biochemical characteristics 42 . However these two types of cell death may occur simultaneously in the cells 43-46 . The intensity of the stimulus determines the type of cell death 47 . The intracellular...

HDACs and Tumor Immune Responses

Dysfunction of the immune system is one way for tumor cells to escape attack from immune cells. HDACs may play roles in the regulation of immune system. HDAC inhibition can negatively regulate the functions of dendritic cells, important types of immune cells, by regulating the acetylation of signal transduction and activation of transcription 3 (STAT3), a crucial transcription activator which responds to the stimuli of cytokines, such as interferon, growth factors, and hormones (Sun et al. 2009). STAT3 is implicated in the regulation of immune cells and a variety of autoimmune diseases by regulating immune cell growth and apoptosis (Yang et al. 2007). HDAC1 binding to STAT3 in an interleukin-6 (IL-6)-dependent manner is required for the nucleocytoplasmic distribution of STAT-3, and affects the responsiveness of STAT3 target genes (Ray et al. 2008). A mutant of STAT3 defective in acetylation blocked STAT3-mediated NF-kappaB p100 processing to p52 and also acted as a dominant negative...

Antiphospholipid Syndrome And Antiphospholipid Antibodies

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent venous and arterial thrombosis, fetal loss and thrombocytopenia in association with elevated titers of circulating auto-antibodies directed against phospholipids, including lupus anticoagulant.1 Antiphospholipid antibodies (aPL) are crucial for diagnosis and represent a very heterogeneous group, as multiple specificities against various phospholipids are found. The anti-cardiolipin ELISA assay, introduced in 1983, is the most established and standardized method for detecting aPL, since other aPL directed to phosphatidylserine, phos-phatidylethanolamine, phosphatidylcholine, phos-phatidylglycerine, phosphatidylinositol and recently lysobisphosphatidic acid2 have been investigated less frequently. Moreover, in 1990 three independent groups reported the requirement of a protein cofactor, p2 glycoprotein I (p2-GPI), for efficient binding of 'autoimmune' antibodies to the phospholipids, in contrast to...

Sea Anemone Toxins Interacting with Kv1 Channels

All these toxin-channel interaction studies have assisted in the design of new types of toxins, such as ShK-Dap22 a mutant peptide where K22 has been replaced by a diaminopropionic acid. Binding and electrophysiological studies have shown that ShK-Dap22 is a highly potent and selective blocker of the Kv1.3 channel with a 100-fold decreased affinity for Kv1.1, Kv1.4 and Kv1.6 channels (Kalman et al. 1998). NMR studies have shown that the overall structures of ShK and ShK-Dap22 are quite similar, but there are differences in the side chains involved in Kv1.3 binding (Kalman et al. 1998 Norton et al. 2004). A high expression level of Kv1.3 is considered as a marker for activated effector memory T cells (TEM cells), which are involved in the pathogenesis of autoimmune diseases. Therefore, the selective suppression of autoreactive TEM cells with Kv1.3 blockers might constitute a novel approach for the treatment of multiple sclerosis (MS) and other autoimmune diseases such as type-1...

In Vivo Effects And Physiological Relevance Of Deltaselective Inverse Agonists

Theoretically, inverse agonists may be useful agents for the treatment of disease symptoms caused by constitutive receptor activity. Covalent modifications of the receptor protein, pathological increase in receptor or G protein densities, or inherited or somatic point mutations may lead to increased constitutive receptor activity. For example, certain inherited point mutations in rhodopsin have been shown to cause retinitis pigmentosa. The involvement of inherited, constitutively activating receptor point mutations has also been demonstrated in certain forms of hyperthyroidism, in male precocious puberty, and in Jansen-type metaphyseal chondrodysplasia 8 . Constitutive G protein activity may also be an important factor in autoimmune diseases 9 .

Class A Disease Specific Target

Another example that is applicable to this category is a disease such as myasthenia gravis, where specific antibodies that block the acetylcholine receptors cause progressive muscle weakness. Specific neutralizing agents to these antibodies are likely to provide high efficacy in treating the disease, with the likelihood of fewer adverse effects 9 since such antibodies are not physiologically present in human beings. These examples are typical for type 1 class A target validation. The biomarkers that need to be established for this category should focus on validating the specificity of the target to the disease state.

Immune Interventions of Human Diseases through Toll Like Receptors

Toll-like receptors (TLRs) are the immune sensors for infections, triggering robust innate immune activation followed by protective adaptive immunity against various infectious diseases. Recent evidence, however, has suggested that TLRs are involved in the pathogenesis of many diseases, including not only infectious diseases but also autoimmune diseases, allergy and atherosclerosis. Therefore, prophylactic or therapeutic application of TLR-based immune interventions should be potent, but their safety must be demonstrated using experimental animal models as well as human resources, including analysis of single nucleotide polymorphisms. Here, we focus on recent advances in understanding of the protective and pathogenic roles of TLRs in human diseases. An important role of the innate immune system in the first-line defense against pathogens, and the underlying molecular and cellular mechanism(s) involved not only in infectious diseases but also in cancer, allergy, autoimmune diseases and...

Degeneration In The Cns Involves Common Mediators Of Toxicity

Taken together, our findings in connection with neuroprotective autoimmunity thus appear to ascribe a hitherto unrecognized function to the immune system. Up to now, the adaptive immune response has been viewed as a defensive mechanism that evolved to provide a versatile backup when the innate immune response (involving macrophages) is unequal to the task. Our studies provide evidence that stressful conditions, caused by a pathological increase in potentially toxic compounds (e.g. glutamate), might prove too overwhelming for the nervous system to cope with, and thus alert the adaptive immune system (expressed here by the response to self-antigens) to provide neuroprotective immunity. An inadequate autoimmune response will lead to loss of beneficial autoimmunity and therefore accelerated degeneration, and perhaps also to destructive autoimmunity and hence a predisposition to autoimmune disease. immunity in Lewis rats does not develop spontaneously. First, how can rats that fail to...

Studies On Etiology And Pathogenesis As A Basis For Development Of Biomarkers For Diagnosis And Prognosis In Ra

Any understanding of a complex, partly genetic disease is based on an understanding of how genes and environment interact in giving risk to immune reactions that contribute to the joint destruction and other inflammatory reactions in RA. In healthy subjects, the major role for the immune system and subsequent inflammatory reactions is to defend us against pathogens, but in RA the immune system has partly changed focus to attack our own tissues, primarily the joints, and is thus denoted as an autoimmune disease.

Broader Applications of Enzyme Inhibitors

The utility of enzyme inhibitors extends well beyond the clinic. The same acetylcholine esterase inhibitors for treating myasthenia gravis (the auto-immune disorder linked to the destruction of acetyl-choline receptors at neuromuscular junctions) are also powerful insecticides. Likewise, the herbicide glyphosate (marketed in the US as Round-Up ), the extraordinarily potent homogentisate pathway inhibitor, is used every day on the farm and in the garden to eradicate weeds and other nuisance plants.

Pharmacological Models

In summary, genetically modified animals are instrumental in understanding complex in vivo interactions, in the normal and the pathological forms. This knowledge is indispensable for the identification of drug targets for the intervention with not yet understood processes as well as with diseases with undefined onset and slow progression, as for instance autoimmune diseases or Alzheimer's disease.

Botulinum Toxin Botox Injection

Botulinum toxin (both A and B types) has been invoked in the treatment of cervical dystonia, migraine headache, tension headache, temporomandibular joint disorders, and chronic back pain (Argoff2005). Multiple series of injections may be required to achieve maximal analgesia. Contraindications include pregnancy, concurrent aminoglycoside antibiotic use (e.g., gentamicin, tobramycin), myasthenia gravis, Eaton-Lambert syndrome, and known sensitivity to toxins. Clinical resistance brought on by development of antibodies to toxins may reduce clinical efficacy after repeated administrations.

M Propafenone Hydrochloride

Indications ventricular arrhythmias paroxysmal supraventricular tachyarrhythmias which include paroxysmal atrial flutter or fibrillation and paroxysmal re-entrant tachycardias involving the AV node or accessory pathway, where standard therapy ineffective or contra-indicated Cautions heart failure elderly pacemaker patients potential for conversion of paroxysmal atrial fibrillation to atrial flutter with 2 1 or 1 1 conduction block great caution in obstructive airways disease owing to beta-blocking activity (contra-indicated if severe) interactions Appendix 1 (propafenone) Driving May affect performance of skilled tasks e.g. driving Contra-indications uncontrolled congestive heart failure, cardiogenic shock (except arrhythmia induced), severe bradycardia, electrolyte disturbances, severe obstructive pulmonary disease, marked hypotension myasthenia gravis unless adequately paced avoid in sinus node dysfunction, atrial conduction defects, second degree or greater AV block, bundle branch...

What Is Herpes Zoster

VZV-specific CMI may also fall below a threshold necessary to prevent clinical virus reactivation as a result of disease (e.g. lymphoma, human immunodeficiency virus (HIV)), therapeutic immune suppression (e.g. after organ transplant, for autoimmune disease), or as a result of treatment of malignancy (e.g. radiotherapy, chemotherapy). However, younger individuals may develop HZ with no coexisting disease process. Prodromal pain usually lasting three to five days is followed by a typical unilateral rash in a dermatomal distribution. The rash progresses from ery-thematous patches to vesicles, pustules, and scabs. Healing occurs typically within three weeks, often leaving hyper- or hypopigmented scars and sensory changes. HZ cannot be contracted from contact with varicella, but varicella may occur after contact with HZ although the force of infection is low ( 0.1 percent)3 compared with that for contracting varicella from another person with varicella (...

Precautions And Contraindications

Chloroquine is not recommended for treating individuals with epilepsy or myasthenia gravis. The drug should be used cautiously if at all in the presence of hepatic disease or severe GI, neurological, or blood disorders. The dose must be adjusted in renal failure. In rare cases, chloroquine can cause hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Chloro-quine should not be used in patients with psoriasis or other exfoliative skin conditions because it causes severe reactions. It should not be used for malaria in patients with porphyria cutanea tarda but is used in smaller doses for treatment of the underlying disease (see Chapter 63). Chloroquine inhibits CYP2D6 and interacts with a variety of drugs. It should not be given with mefloquine because of increased risk of seizures. Most important, this antimalarial opposes the action of anti-convulsants and increases the risk of ventricular arrhythmias from coadministration with amiodarone or halofantrine....

Pharmacological Effects

Action on Skeletal Muscle Quinine increases the tension response to a single maximal stimulus delivered to muscle, but it also increases the refractory period of muscle so that the response to tetanic stimulation is diminished. The excitability of the motor end-plate region decreases so that responses to repetitive stimulation and to acetylcholine are reduced. Thus, quinine can antagonize the actions of physostigmine on skeletal muscle. Quinine also may produce respiratory distress and dysphagia in patients with myasthenia gravis.

MBPPE40 chimeric protein for treatment of multiple sclerosis

Although IL2-PE40 suppresses effects against specific antigen-activated cells, these effects are not limited to the specific pathogenic cells and it cross-reacts with all IL2R-bearing cells. Therefore, in cases of autoimmune diseases in which the antigen is known, elimination of the specific lymphocyte population(s) that recognize(s) the specific antigen allows the other IL2R expressing cell populations of the immune system to be preserved. Thus, we constructed a chimeric protein, representing a novel class of chimeric proteins antigen peptide-toxin chimeras, fusing cDNA encoding a selected antigen, to sequences coding for PE, for the treatment of MS.

Other measures to reduce cardiovascular risk

Pregnant women are at high risk of developing preeclampsia if they have chronic kidney disease, diabetes mellitus, autoimmune disease, chronic hypertension, or if they have had hypertension during a previous pregnancy these women are advised to take aspirin (section 2.9) in a dose of 75 mg once daily unlicensed indication from week 12 of pregnancy until the baby is born. Women with more than one moderate risk factor (first pregnancy, aged > 40 years, pregnancy interval > 10 years, BMI > 35kg m2 at first visit, multiple pregnancy, or family history of pre-eclampsia) for developing pre-eclampsia are also advised to take aspirin 75 mg once daily unlicensed indication from week 12 of pregnancy until the baby is born.

Neuropathic Orofacial Pain

In fact, the trigeminal system seems to have unique features compared to the spinal system with respect to its propensity to develop neuropathic pain following a nerve injury.71 There are unfortunately no operationalized criteria for the diagnosis of NOP, but a hierarchical system for general neuropathic pain conditions has been proposed72 and is currently being adjusted for NOP and tested.73 In this paragraph, emphasis is on procedures and trauma which potentially may induce NOP, although many other diseases can also cause lesions to the nervous system, for example autoimmune diseases, metabolic diseases, infections, vascular diseases, and cancer.

Immune Mechanisms Involved in RHD

All these works suggested that the major role of degeneracy of T cells is to maintain the physiological immunity, in view of the large number of foreign antigens that an individual can encounter and respond to it in his life. However, the mechanism used by degenerate T cells in order to recognize selected peptides without pathological potential, and on the other hand, how the degenerate T cell reactivity may lead to pathological autoimmunity in individuals with genetic susceptibility remain unknown.

Introductionbackground

Recent reviews list more than 400 biotechnology-based pharmaceutical formulations either registered in clinical trials or undergoing review by the regulatory agencies for the treatment of nearly 150 diseases including cancer, infectious diseases, autoimmune diseases, and AIDS HTV (1,2). Biotechnology-based pharmaceuticals already on the markets include recombinant blood factors, recombinant hormones, cytokines, vaccines, monoclonal antibody-based products, and therapeutic enzymes.

Forcing pathogenic cells to undergo apoptotic suicide by novel chimeric proteins the next generation of targeting

Apoptosis, or programmed cell death (PCD), is an intrinsic mechanism possessed by every cell in the human body, which plays an important role in development and homeostasis (Hengartner, 2000 Nagata, 1997). Disturbances in the regulation of apoptosis illustrate its importance in normal homeostasis (Kerr et al., 1972). Abnormal resistance to apoptosis induction correlates with malformations, autoimmune diseases or cancer (Kerr et al., 1993 Thompson, 1995 O'Reilly and Strasser, 1999). In contrast, enhanced apoptotic decay of cells occurs in acute pathologies (infection by toxin-producing microorganisms) as well as in chronic diseases such as AIDS (Thompson, 1995). Initially shown in C. elegance (Liu and Hengartner, 1999), there are three protein families involved in promoting or inhibiting apoptosis, including the Bcl-2 family (Kroemer, 1997 Gross et al., 1999), Apaf-1 (Zou et al., 1997 Cecconi et al., 1998) and the Caspases (Nunez et al., 1998 Earnshaw et al., 1999 Budihardjo et al.,...

Drug Discovery Some Remarks

Among the natural products, pharmaceutical industries have rekindled the interest in peptides, due to current novel technological accomplishments, strategy developments, advances in the areas of formulation, and enhanced drug delivery technology for peptides. Peptides as drugs show unique characteristics (high biological activity, high specificity, and low toxicity), thereby making them particularly attractive therapeutic agents 14 . The major obstacles that peptides face in becoming active pharmaceutical ingredients (APIs) are the lack of oral bioavail-ability and low stability under physiological conditions. Thus, the interest shown by the pharmaceutical industry in peptide research has declined and more efforts have been made in the field of small molecules that mimic peptides. Advances in the fields of formulation, drug delivery technology, and chemical modifications have rekindled the interest in peptides, thereby leading to highly successful peptide drugs such as the agonists of...

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Using a proteomics approach, we showed that T cells recognize vimentin, reinforcing the role of this protein as a putative autoantigen involved in the rheumatic lesions. In addition, we identified myocardial and valvular autoantigens that were recognized by heart-infiltrating and peripheral T cells from RF RHD patients. Novel heart-tissue proteins were identified, including disulfide isomerase ER-60 precursor (PDIA3) protein and a 78-kDa glucose-regulated protein precursor (HSPA5). The role of PDIA3 in RHD pathogenesis and other autoimmune diseases is not clear (Table 4) 65 . Cytokines are important secondary signals following an infection because they trigger effective immune responses in most individuals and probably deleterious responses in patients with autoimmune disease. Three subsets of T helper cytokines are currently described. Antigen-activated CD4+ T cells polarize to the Th1, Th2, or Th17 subsets, depending on the cytokine secreted. Th1 is involved with the cellular immune...

Oxidative Stress and Pancreatic pCell Destruction in Insulin Dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM) is considered to be an autoimmune disease (1,2). Recent reports suggest that reactive oxygen species (ROS) participate in the development of IDDM (3,4). Thioredoxin (TRX) is a small (12 kDa) reduction oxidation (redox) protein (5,6) and has protective effects on cells against oxidative stress by scavenging ROS (5-7), by repairing DNA and proteins damaged by ROS (5-8), and by blocking apoptosis induced by ROS (6,9).

Molecular Mechanisms ofApoptosis

Apoptosis plays a critical role in development, tissue homeostasis and defense against pathogens by eliminating redundant, damaged or infected cells. Tight control appears essential, since dysregulation of the apoptotic program can have dramatic consequences and may lead to severe pathological conditions such as cancer, autoimmunity and degenerative disorders 10, 11 . As a consequence, interest in the molecular control of apoptosis has grown exponentially, with the hope of designing new therapeutic strategies.

Interstitial cystitis

That a systemic autoimmune disease is presenting as a local manifestation as has Clorpactin (a derivative of hypochlorous acid in a buffered base)77 with success rates ranging from 50 to > 90 percent. A controlled comparison of intravesical DMSO with intravesical saline by Perez-Marrero et al.65 demonstrated improvements in symptomatology in 53 percent of the DMSO-treated group and only 18 percent of the saline-treated group. DMSO produces a distinct taste and smell in the patient's breath, so blinded comparisons were not performed. Based on the hypothesis that IC is a local manifestation of a systemic autoimmune disease, immu-nosuppressant therapies such as systemic cyclosporine67 and intravesical Bacillus Calmette-Guerin immuno-therapy68 have been utilized in controlled trials with good success rates for the former and insignificant success rates reported for the latter.

Are Changes In Immune Function Causally Or Coincidentally Consequences Of Stress Or Depression

The association between cancer, autoimmune diseases, myocardial infarction, stroke and dementia with depression and the activation of the immune system, particularly involving the proinflammatory cytokines, has been the subject of considerable discussion in recent years. The initial studies indicating that patients suffering from major depression had decreased cellular immune response compared to healthy controls (Kronfol and House, 1985 Schleifer, Keller, Siris, Davis, and Stein, 1985) helped to lay the scientific basis whereby psychosocial factors could profoundly affect the development of physical and psychiatric disease. However, in well over 30 studies in the last 15 years, the consistency of the immune changes in depression is uncertain, with some investigators findings impaired immunocompetence while others do not. This situation led Miller, Spencer, McEwen, and Stein (1993) to review all the published studies regarding the changes in differential white blood cell counts,...

Novel alternative immunotherapeutic approaches using chimeric proteins not intrinsic toxins

A chimeric protein has been generated involving the fusion of streptavidin, a protein produced by Streptomyces avidin, and the IgG-binding domains of protein A, ST-PA fusion protein) (Figure 9.1). This chimeric fusion protein can be abundantly expressed in bacterial systems and is easily purified. The ST-PA fusion protein, which has both biotin- and IgG-binding ability, forms a tetramer which can bind four biotin and four IgG molecules. The protein A portion of the conjugate binds to the Fc domain of an antibody, allowing flexibility with regard to the targeting antigen. The potential of biotin to be easily incorporated into a wide range of macromolecules without affecting their biological activities suggests that the ST-PA fusion protein may be a useful carrier for a variety of biotinylated proteins. Hence, the final molecular complex that would be used as a therapeutic would consist of a targeting antibody and a biotinylated toxin (or other effector molecule) bridged by the ST-PA...

Summary and perspective

Immune-mediated (autoimmune) human diseases are caused by antigen-reactive T lymphocytes or immunoglobulins, with variable activation of accessory effector pathways. Since antigens which trigger autoreactive lymphocytes are mostly unknown, a variety of new therapeutic approaches are directed at inhibition of lymphocyte activation, proliferation, or differentiation through use of rationally designed chimeric proteins, many containing cytotoxic moieties. Most of these agents target cell-surface receptors or antigens that are selectively expressed in antigen-presenting dendritic cells or in antigen-activated lymphocytes. For example, IL-2R or transferrin receptors and a variety of co-stimulatory counter-receptor proteins such as B7 CD28, ICAM-1 LFA-1 or CD40 CD40L are direct targets of specific agents. Much of the work preceeding the use of fusion toxins and chimeric toxins in autoimmune diseases has been based in treatment of neoplastic leukocytes (and other types of cells) with agents...

Perspectives And Future Directions

Adequate washout periods can be difficult to design and conduct. With the advent of therapeutic biological products, the use of these products in clinical conditions such as leukemia, lymphoma, solid tumor cancers, organ transplants, and autoimmune diseases is rapidly growing. The patients with aforementioned disease states may also require concurrent use of other medications. As a result, there is always a potential for drug interactions therefore, a more routine investigation of pharmacokinetic drug-drug interaction studies for new therapeutic biological products is necessary.

Chronic Liver Diseases Of Interest For Drug Targeting

As mentioned before, drug targeting to the liver may be a promising therapeutic approach for hepatic diseases with a chronic character. Examples of such diseases are liver cirrhosis, viral hepatitis and other infectious liver diseases, liver carcinomas or metastases of tumors, and hepatic autoimmune diseases (hemochromatosis, Wilson's disease, and a antitrypsine deficiency). The problem with the available pharmacotherapy in these diseases is that most drugs are not liver-specific and often exhibit undesirable toxicity. In the next paragraphs, we describe the pathosis of chronic liver diseases that are the subject of experimental therapies based on the application of drug delivery systems. This knowledge is important for the development of specific carriers and for the identification of molecular regulatory pathways that may serve as targets for therapeutical interventions.

Errare Humanum Est What Causes Cancer and How to Selectively Fight Tumors

Almost 400 biotech medicines are currently undergoing trials in the US, with the majority (close to 50 ) being directed against cancer in one or more of its many manifestations, and a significant number being directed towards infectious disease, autoimmune disease and HIV. A significant proportion of all materials in the cancer and infectious disease areas are vaccines of one type or another, and the second largest class of biopharmaceuticals under development are mAbs, with the largest numbers being directed towards cancer and autoimmune diseases. The authors demonstrate the current and future potential of the search in nature for biologically active peptides and proteins, and the ability to express these agents in homologous and or heterologous hosts. The ability to manipulate the gene sequences in order to produce subtle modifications of existing active agents and the potential for semisynthesis to modify the basic properties of the initial agents is amply demonstrated in the...

Dietary Restriction The Cheapest The Best

Dietary restriction is an anti-aging therapy that dates back further than antioxidant administration, and, importantly, it is also more interesting due to its effectiveness. The first studies about dietary restriction were made in the 1930s by McCay and co-workers 232 , and since then, their work has been replicated 233 . In rodents, the most studied model, a 40 reduction in dietary intake can increase the MLSP by 50 234 . Of significance, dietary restriction not only increases the mean and maximum life spans but it also delays the onset of most diseases associated with aging, such as cancer, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases and diabetes 235 . This shows that delaying aging is also useful in delaying the development of aging-associated diseases.

Mechanism of Action

In the case of insulin the effectors and second messenger are not known. It has been established that hormone deficiency effects can exist even in the presence of above-normal levels of hormone. The receptors appear to be resistant to the hormone. One likely reason for this is decreased receptor availability as well as lowered sensitivity by them. Several diseases are believed to involve the development of antibodies to membrane receptors, so they do not function normally toward their ligands. Among such autoimmune diseases are myasthenia gravis, multiple sclerosis, and possibly schizophrenia.

RNAi Approaches to Inhibit HIV Replication

Control of disease-associated genes makes RNAi an attractive choice for future therapeutics. Basically every human disease caused by activity from one or a few genes should be amenable for RNAi-based intervention. This list includes cancer, autoimmune diseases, dominant genetic disorders and viral infections. RNAi can be triggered by two different pathways

Antibodies Against Serotonin And Gangliosides In Major Depression And

Several authors have show the occurrence of antinuclear, antiphospholipid and antiserotonin, antihistone, antibodies in depression (Villemain, 1988 Irwin et al., 1990 Maes et al., 1991 Schott et al., 1992). Some autoimmune disorders have been related to the induction of antihormone and anti-receptor antibodies (Cohen and Cook, 1986). We have recently reported the occurrence of antibodies against serotonin and gangliosides in major depressed patients (Sluzewska et al., 1997d). Antibodies against gangliosides have been shown to be part of the serotonin receptor complex (Fishman, 1988). Patients with major depression showed a significant antibody reactivity of IgG or IgM type to serotonin (55 of the patients) and to gangliosides (50 of the patients). In most patients the antibody against serotonin was associated with the antibody against gangliosides. 73 of the major depressed patients with antibodies against serotonin and 70 major depressed patients with gangliosides antibodies were TRD...

Localization and Some Physiological Roles of Esterases

Acetylcholinesterase (acetylcholine acetylhydrolase, EC 1.1.1.7) has a high specificity for acetylcholine, a marked reduction in catalysis being seen between propionylcholine and butyrylcholine. The enzyme is mainly associated with nerve tissue and, particularly, with cholinergic synapses. It is membrane-bound notably on postsynaptic membranes, but it is also found in striated muscle and erythrocytes. Acetylcholinesterase plays a central role in neuromuscular transmission by hydrolyzing the acetylcholine released upon depolarization of the presynaptic nerve terminal 112 . A number of acetylcholinesterase inhibitors are used in clinical practice, e.g., donepezil and ga-lanthamine in Alzheimer's disease, and physostigmine in the management of myasthenia gravis. The function of acetylcholinesterase in red blood cells is not clear, but it might be correlated with cell differentiation.

Human Antibodies Promote Remyelination In Tmevinfected Mice

Antibody treatment is currently being explored as a therapy for human demyelinating disease. Intravenous immunoglobulin (IVIg) has been used successfully to treat a variety of autoimmune neurologic diseases, including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuro-pathy, multifocal motor neuropathy, polymyositis, and myasthenia gravis.26 Clinical studies in MS indicate that IVIg may be effective in stabilizing the course of the disease.27 Given the demonstrated ability of a subset of mouse antibodies to promote CNS remyelination, and the potential efficacy of IVIg as therapy for MS in humans, we tested pooled human immunoglobulin for its ability to promote remyelination in the mouse TMEV model.

Neurotoxin From Conus Snails

Neurotoxin From Conus Snails

Become a drug candidate for treating host-graft (transplantation) immune rejection and certain autoimmune diseases (Beeton et al. 2006). Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM, Penniington MW, Kolski-Andreaco A, Wei E, Grino A, Counts DR, Wang PH, LeeHealey CJ, Andrews BS, Sankaranarayanan A, Homerick D, roeck WW, Tehranzadeh J, Stanhope KL, Zimin P, Havel PJ, Griffey S, Knaus H-G, Nepom GT, Gutman GA, Calabresi PA, Chandy KG (2006) Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc Nat Acad Sci USA 103 17414-17419.

Drug Discovery Evolution

The time frame between the initial discovery of a potential drug candidate and the market launch of a new therapeutic agent usually is 10-14 years (Fig. 1). For this reason it is difficult to measure the real trend in the drug discovery programs during the last two decades. However, the worldwide pharmaceutical natural product patents trend show a decline from 1990 to 1999 and a recent increase of patenting up to 2001 The interest in discover new natural products declined when new technologies became more attractive for the pharmaceutical industry to be implemented in their search for new drug candidates. The evolution of molecular techniques allowed the identification and isolation of purified protein targets. The use of defined molecular targets combined with automatization, modern robotic instruments, sensitive detectors, data processing and control software allowed the development of tests using microvolumes for the screening of libraries of chemical structures the high-throughput...

Biogenic Amines in Neurodegenerative and Neuropsychiatric Diseases

Dopaminergic neurons in the substantia nigra undergo neurodegeneration. In HD neurodegeneration occurs in striatal medium spiny neurons and motor neurons located in the anterior part of spinal cord degenerate in ALS. Although, the exact cause and molecular mechanism of neurodegenerative diseases are fully understood, but it is becoming increasingly evident that multiple factors and mechanisms may contribute to the pathogenesis of disorders 39 . The most important risk factors for neurodegenerative diseases are old age, positive family history, unhealthy life style, endogenous factors, and exposure to toxic environment 39 . Other risk factors for neurodegenerative diseases include neuroinflammation, autoimmunity, cerebral blood flow, and blood-brain barrier dysfunction 40 .

Role of Leptin in Inflammation and Its Possible Connection to Obesity in Schizophrenia

Irrespective of the cause, epidemiological evidence suggests that obesity increases the risk of autoimmune disease and such immune related diseases as asthma. It has been speculated that this arises due to the decrease in immunological tolerance associated with the increase in the pro-inflammatory cytokines and leptin, and the decrease in adiponectin 47 . It has been demonstrated that both IL-6 and leptin downregulate the regulatory T cells thereby reducing antigen surveillance. Thus, obesity, through the induction of chronic low-grade inflammation and decreased immu-nological tolerance to antigens, increases the activity of the Th-2 humoral pathway thereby increasing the risk of allergies and immune-related disorders. Such changes are a common feature of schizophrenia.

Effects of Upstream and Downstream Processes

Several publications describe the association of coding polymorphisms in FCGR3A with responses to rituximab in oncology and autoimmunity trials (101105). Similar findings have been reported for FCGR2A, although it may be that these associations result from linkage within the genetic region encoding several FcRs (103). In vitro studies have shown that the FCGR3A variant 158V has higher affinity for IgG than the 158F variant, effectively broadening the concentration range in which Fc engagement activates ADCC in NK cells (106,107). Likewise, it has been observed that the anti-TNF mAb drugs may act as cell-targeting agents, since TNF-a is produced in a transmembrane form before release from the cell surface by cleavage (108). Recent studies of FCGR3A and infliximab therapy demonstrated that patients homozygous for the high-affinity 158V allele had a greater decrease in C-reactive protein, a PD marker in Crohn's disease, compared with 158F carriers. A follow-up study demonstrated that...

Miscellaneous Immunosuppressant And Antiinflammatory Agents

Mycophenolate mofetil is used increasingly to treat inflammatory and autoimmune diseases in dermatology in doses ranging from 1 to 2 g day orally. Mycophenolate mofetil is particularly useful as a corticosteroid-sparing agent in the treatment of autoimmune blistering disorders, including pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, and pemphigus foliaceus. It also has been used effectively in the treatment of inflammatory diseases such as psoriasis, atopic dermatitis, and pyoderma gangrenosum.

Painful bladder syndrome interstitial cystitis

There is good evidence that there is a disruption of the normal urothelial barrier in most if not all IC patients. The etiology of the breakdown in the urothelial barrier and the consequences of this breakdown in IC are, as yet, unknown. One theory proposes that the breakdown of the urothelial barrier results from a failure to maintain adequate formation of glycosaminoglycans, the protective coating of the urothelium. Another theory proposes that IC is a systemic autoimmune disease presenting as a local manifestation with associated immunologic dysfunction, including possible abnormal mast cell activity. The most mechanistic theory to date relates the breakdown of the urothelial barrier to the presence of a specific peptide present within the urine of IC patients that impairs urothelial regrowth. Named the antiproliferative factor (APF), this low molecular weight peptide is a member of the Frizzled 8 protein family 62 . APF has been identified in over 90 of rigorously diagnosed IC...

Behavioral Effects Of Infectious Diseases And Cytokine Administration In Animals

Similar symptoms, as well as increased anxiety behavior were also reported, using a mouse model of autoimmune disease (systemic lupus erythematosus) (Schrott & Crnic, 1996), indicating that behavioral changes can also accompany non-infectious conditions. Alterations in pain perception accompany inflammation, infection, autoimmune diseases and nerve injury. Proinflammatory cytokines, associated with these conditions, were found to activate neural circuits which modulate pain perception (Watkins, Maier, & Goehler, 1995b). Typically, cytokine secretion results in an immediate phase of hyperalgesia (increased responsiveness to painful stimuli) (Watkins et al., 1995b), which is later followed by a prolonged analgesic phase (Romanovsky, Kulchitsky, Akulich, Koulchitsky, Simons, Sessler, & Gourine, 1996 Yirmiya et al., 1994).

Profiling of in Immune Biomarkers

Today, multiplex assays have all but replaced traditional enzyme-linked immunosorbent assays (ELISA) for cytokines allowing us to simultaneously measure proinflammatory cytokines, Th1- vs. Th2-type cytokines, growth-promoting as opposed to suppressive cytokines, and so on, in a small (0.5 ml) sample of body fluid. Multiplex bead immunoassays designed to work in conjunction with a Luminex-type instrument utilize sets of distinct fluores-cently labeled microspheres, each covalently linked to a cytokine-specific antibody 20, 21 . A combination of different color-coded beads (up to 100) in one tube allows for a simultaneous assessment of several cytokines. A flow-based instrument equipped with a reporter and classifying lasers and associated optics measures reactions that occur on the surface of colored microspheres. A high-speed digital signal processor efficiently manages the fluorescent output. The intensity of measured fluorescence is directly proportional to the concentration of the...

Regulation of Receptors

DISEASES RESULTING FROM RECEPTOR MALFUNCTION Alteration in receptors and their immediate signaling effectors can be the cause of disease. The loss of a receptor in a highly specialized signaling system may cause a relatively limited, if dramatic, phenotypic disorder (e.g., deficiency of the androgen receptor and androgen insensitivity syndrome see Chapter 58). Deficiencies in widely employed signaling pathways have broad effects, as are seen in myasthenia gravis and some forms of insulin-resistant diabetes mellitus, which result from autoimmune depletion of nicotinic cholinergic receptors (see Chapter 9) or insulin receptors (see Chapter 60), respectively.

Consequences Of Antibodies To Therapeutic Proteins

TNF inhibitors such as etanercept cause injection-site reactions by a T-cell-mediated delayed-type hypersensitivity reaction. Antibodies against etanercept have been shown not to be correlated to adverse events. Skin reactions probably are a class effect of TNF inhibitors. Blockade of TNF can stimulate certain forms of autoimmunity by increasing T-cell reactivity to microbial and self-antigens 13 .

Other chimeric neurotoxins and novel approaches

To study the localization and function of neuronal targets of neuropeptide hormones, a variety of chimeric toxins of ricin A chain with oxytocin, atrial natriuretic peptide or gelonin with corticotrophin releasing factor have been prepared and characterized (Schwartz and Vale, 1989 Samson et al., 1992 1993 1995 Blackburn et al., 1995). Myelin basic protein (MBP) is an important component of myelinated neurons. Antibodies against MBP are generated in autoimmune diseases of the nervous system such as multiple sclerosis. Very promisingly, a chimeric toxin combining MBP and Pseudomonas exotoxin (MBP-PE40) blocked the clinical symptoms of inflammation and demyelination typical of this disease, providing a new immunotherapeutic tool (Brenner et al., 1999) for autoimmune nervous system diseases in which a known antigen is involved. The poor prognosis associated with

Collagen Vascular Diseases in Critical Care An Overview

Conditions most frequently encountered are Goodpasture's syndrome (GPS) and glomerular basement membrane disease (GBH) Wegener's granulomatosis (WG) polyarteritis nodosa (PAN) and systemic lupus erythematosis (SLE). Other, less common, diagnoses include microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and antiphospholipid antibody syndrome (APS). Most of these disorders are inflammatory and have evidence of autoimmunity, which can range from targeting of a single specific organ to many organs in the body. The author briefly reviews the symptoms of each type, then summarizes general principles of treatment. Treatment should treat underlying infection support vital organs (lung and kidney failure are common to many of these conditions) ensure adequate nutrition modify the immune response with steroids, azathioprine or cyclophosphamide and remove immune complexes and antibodies, using plasma exchange. A brief posttest is appended to the article. 2 figures. 3 tables. 19...

HDACi and Foxp3 Tregs

Our focus on selective HDACi arose from our findings in testing several HDACi compounds for their effects in murine models of colitis, including dextran sodium sulfate (DSS)-induced colitis and the T-cell-dependent CD45RBhi adoptive transfer model (Tao et al. 2007 de Zoeten et al. 2010). Two pan-HDACi compounds, trichostatin-A (TsA) and suberoylanilide hydroxamic acid (SAHA), but not MS275, a potent and long-acting HDAC class I-specific inhibitor, blocked development of colitis as shown by prevention of weight loss and associated blood in the stool, diarrhea, and histologic injury. Likewise, in T-cell-dependent adoptive transfer models, both pan-HDACi but not MS275 were effective in preventing the development of colitis, and in promoting the resolution of established colitis. The beneficial effects of pan-HDACi were dependent upon the presence of Foxp3+ T regulatory (Treg) cells, since Treg depletion or use of Scurfy mice with a mutation in Foxp3 abrogated any therapeutic benefit of...

Transmembrane Adaptor Proteins

Lat Protein

The importance of the LAT-PLCy interaction in immune homeostasis is dramatically illustrated in knock-in mice where the PLCy binding site is mutated to phenylalanine (Aguado et al. 2002 Sommers et al. 2002). T cells from these mice display similar defects in signaling, as seen in cell lines with the same mutation characterized by reduced phosphorylation of PLCy and an inability to induce intra-cellular calcium release after TCR stimulation. This results in a severe defect in T-cell development and supports the notion that the LAT-PLCy interaction is necessary for pre-TCR signaling. Surprisingly, these mice develop a polyclonal lymphoproliferative disease and autoimmunity involving constitutively active CD4+ cells in the periphery, a high amount of T-helper-2 (TH2) cytokines secreted and induced B-cell maturation. Interestingly, the activation of Erk was relatively normal in these mice, suggesting additional mechanisms for signal regulation of the Ras-Erk pathway. Another (and very...

Amyotrophic Lateral Sclerosis

Multiple mechanisms have been postulated to be the cause of the sporadic form of the disease, including excitotoxicity (118,119), oxidative injury (120), cytoskeletal abnormalities with aggregates containing SOD1 (121), and autoimmunity (122,123). Up to 70 of sporadic cases have varying loss of the glutatmate transporter, EAAT2 (118,124). Aberrant EAAT2 mRNA species seem to account for the regional selective loss of EAAT2, most likely the result of RNA processing errors (125).

Targeting Amyloid Pathologies

The trial was suspended due to detection of meningoencephalitis in 6 of the patients treated with the Aft vaccine 110 . Despite this adverse reaction, there were signs of efficacy as suggested by reduction in CSF tau (normally elevated in AD subjects) and improvement in the neuropsychological test battery 111,112 . Passive immunization in animal models with cerebral amyloid angiopathy has been shown to cause cerebral hemorrhage 113 . A balance of efficacy and safety against autoimmunity and cerebral hemorrhage will be the challenge for the future of Aft immunotherapy.

Protein Assembly Linking TCR to NFkB Activation

Transcription of immune regulatory genes involves the coordinated action of several transcription factors, including NFAT, NF-kB, API and members of the forkhead box family (Coffer and Burgering 2004 Kuo and Leiden 1999). It is therefore relevant to examine how receptor proximal events are linked to these mediators and how specificity in the regulation of the different transcription factors is maintained. There is accumulating evidence demonstrating that fine-tuning of signals at this level in the signaling cascade is as complex as the fine-tuning of signals proximal to the immune receptors and that scaffolding proteins again are essential for signal integration to occur. This is well illustrated by the molecular mechanisms connecting the T-cell receptor to NF-kB activation (Fig. 3) (Bonizzi and Karin 2004). Engagement of the TCR results in the nuclear translocation and activation of NF-kB, which regulates various aspects of lymphocyte development, homeostasis, survival and functions....

Toxicities Of Alkylating Agents Bone Marrow Toxicity

Ifosfamide, cause acute myelosuppression, with a nadir of the peripheral blood granulocyte count at 6-10 days and recovery in 14-21 days. Cyclophosphamide has lesser effects on peripheral blood platelet counts than do the other agents. Busulfan suppresses all blood elements, particularly stem cells, and may produce a prolonged and cumulative myelosuppression lasting months or even years. For this reason, it is used in preparation for allogeneic bone marrow transplantation. Carmustine and other chloroethylnitrosoureas cause delayed and prolonged suppression of both platelets and granulocytes, reaching a nadir 4-6 weeks after drug administration and reversing slowly thereafter. Both cellular and humoral immunity are suppressed by alkylating agents, which have been used to treat various autoimmune diseases. Immunosuppression is reversible at doses used in most anticancer protocols.

Clinical Responses and Monitoring of Phase I and Phase II Neuromuscular Blockade by Succinylcholine Infusion

TOXICOLOGY The important untoward responses of the neuromuscular blocking agents include prolonged apnea, cardiovascular collapse, those resulting from histamine release, and, rarely, anaphylaxis. Related factors may include alterations in body temperature electrolyte imbalance, particularly of K+ (discussed earlier) low plasma butyrylcholinesterase levels, resulting in a reduction in the rate of destruction of succinylcholine the presence of latent myasthenia gravis or of malignant disease such as small cell carcinoma of the lung (Eaton-Lambert myasthenic syndrome) reduced blood flow to skeletal muscles, causing delayed removal of the blocking drugs and decreased elimination of the muscle relaxants secondary to reduced renal function. Great care should be taken when administering these agents to dehydrated or severely ill patients.

Advances in the Treatment of Lupus Nephritis

Summary Systemic lupus erythematosus (SLE) is an autoimmune disease that leads to the formation and deposition of immune complexes throughout the body, which are pathogenic (causing disease) for SLE. Different forms of glomerulonephritis (inflammation of the filtering units of the kidney) can occur in patients with SLE and can contribute significantly to the associated morbidity (illness and complications) and, ultimately, mortality (death) from the disease. Over the past two decades, there have been significant strides in the understanding of the disease and in treatments that attempt to control the formation and deposition of anti-DNA auto-antibodies and immune complexes, as well as the subsequent inflammatory cascade mediated through various cellular and humoral pathways leading to progressive renal (kidney) damage and end stage renal disease (ESRD). This article reviews the current understanding of the pathogenesis and treatment of lupus nephritis in its various stages and...

Metabolism And Inactivation

Insulin resistance (with hyperinsulinaemia and various degrees of hyper-glycaemia) is associated with several rare syndromes, either congenital or acquired, including acanthosis nigricans, leprechaunism and lipoatrophy. Insulin resistance with acanthosis nigricans is subdivided mainly into Type A (hereditary) and Type B (autoimmune) syndromes. The Type A syndrome, due to various genetic defects in the insulin receptor, predominantly affects young women who are grossly hyperinsulinaemic, markedly glucose-intolerant and usually virilized. Type A variants (including the Type C syndrome) are clinically similar but result from a post-receptor defect. The Type B syndrome, due to antibodies (usually IgG) directed against the insulin receptor, also mainly affects women who often have other features of generalized autoimmune disease. Most patients are hyper-glycaemic but specific receptor-stimulating antibodies in a few may cause hypoglycaemia. Type B variants include other rare conditions...

Neuroimmune Diseases

Only a few neurologic disorders fulfill the criteria of an autoimmune disease, that is (1) the presence of specific immune (T- or B-cell-mediated) reactivity against a well-defined autoantigen (2) the existence of a known pathogenic mechanism by which these antibodies or T-cells induce clinical and or histopathologic features of the disease and (3) the feasibility of inducing a similar disease in laboratory animals by immunization with the putative auto-antigen. Such definite neuro-autoim-mune diseases include myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS) and anti-MAG (myelin associated glycoprotein) demyeli-nating polyneuropathy (Table 1.1). In these diseases, the rationale for immunosuppressive therapy is obvious, and the results of treatment with plasma-pheresis, IVIG, corticosteroids and azathioprine and cyclophosphamide have usually been very satisfactory.

Xerostomia

Pilocarpine is administered orally in 5-10-mg doses given three times daily for the treatment of xerostomia that follows head and neck radiation treatments or that is associated with Sjogren's syndrome, an autoimmune disorder occurring primarily in women in whom secretions, particularly salivary and lacrimal, are compromised. Side effects typify cholinergic stimulation, with sweating being the most common complaint. Bethanechol is an oral alternative that produces less diaphoresis. Cevimeline (evoxac) has activity at M3 muscarinic receptors, such as those on lacrimal and salivary

Diagnosis

Although the diagnosis of autoimmune myasthenia gravis usually can be made from the history, signs, and symptoms, its differentiation from certain neurasthenic, infectious, endocrine, congenital, neoplastic, and degenerative neuromuscular diseases can be challenging. Myasthenia gravis is the only condition in which the muscular weakness can be improved dramatically by anti-ChE medication. The edrophonium test for evaluation of possible myasthenia gravis is performed by rapid intravenous injection of 2 mg of edrophonium chloride, followed 45 seconds later by an

Treatment

Pyridostigmine, neostigmine, and ambenonium are the standard anti-ChE drugs used in the symptomatic treatment of myasthenia gravis. All can increase the response of myasthenic muscle to repetitive nerve impulses, primarily by the preservation of endogenous ACh. The optimal single oral dose of an anti-ChE agent is determined empirically. Baseline recordings are made for grip strength, vital capacity, and a number of signs and symptoms that reflect the strength of various muscle groups. The patient then is given an oral dose of pyridostigmine (30-60 mg), neostigmine (7.5-15 mg), or ambenonium (2.5-5 mg). The improvement in muscle strength and changes in other signs and symptoms are noted at frequent intervals until there is a return to the basal state. After an hour or longer in the basal state, the drug is readministered at 1.5 times the initial amount, and the functional observations are repeated. This sequence is continued, with increasing increments of one-half the initial dose,...

Scleroderma

Scleroderma is an autoimmune disease that manifests itself in the skin, resulting in fibrosis and damage to the vasculature. It is thought that IBs play a major role in the course of the disease and therefore should be good targets for both therapeutic intervention and diagnostic prognostic development. Recently, Duan et al. 8 have compared the serum IB patterns of scleroderma patients with controls using the RBM testing approach, measuring 188 different biomarkers. In addition, this group compared the serum protein expression patterns with the messenger RNA expression from the monocytes and lymphocytes isolated from these patients' peripheral blood.

Conclusions

Their modulation as drug targets themselves has also become a core theme for many of the autoimmune diseases. Finally, innovative products designed for the clinical trial setting, such as the TruCulture whole-blood culture system, will help bring immune-related biomarker patterning into the everyday realm of clinical drug development and companion diagnostics.

Toll Like Receptors

The immediate response to an invading organism is coordinated by the innate immune system. The pathogens are sensed by a family of germ line-encoded receptors recognizing conserved molecular patterns shared by large groups of pathogens. These types of ligands are often referred to as pathogen-associated molecular patterns (PAMPs) and are mainly derived from the microbial nucleic acids or cell walls. The PAMPs are recognized by members in the family of Toll-like receptors (TLRs), expressed in monocytes, macrophages, and dendritic cells. Functional TLRs are essential for our defense against microbes and initiate the inflammatory reactions. Uncontrolled TLR signaling may lead to life-threatening complications such as systemic inflammatory response syndrome (SIRS also often referred to as septic shock), chronic inflammation, and autoimmunity. The TLR family consists of at least 10 members in humans, where they sense microbial compounds such as lipopolysaccharide (TLR4) and lipoproteins...

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.

Calcitriol Rocaltrol

In addition to controlling calcium and phosphate metabolism, calcitriol also has an immunomodulating effect that may be useful for the treatment of autoimmune diseases. It has already been approved for the topical treatment of immune-mediated skin disease, such as psoriasis. Calcitriol also has been found to induce apoptosis (biochemically-programmed cell death) in some cancer cells.

Immune Events

Rheumatic fever (RF) is an autoimmune disease caused by the Gram-positive bacteria Streptococcus pyogenes following an untreated throat infection in susceptible children. Rheumatic heart disease (RHD), the most serious complication, occurs in 30-45 of RF patients and leads to chronic valvular lesions. Here, we focus on the genes that confer susceptibility for developing this disease. Molecular mimicry mediates the cross-reactions between streptococcal antigens and human proteins. Several autoantigens have been identified, including

Concluding Comments

Channels like ASICla and ASIC3 which are expressed in nociceptive neurons, have been implicated in inflammation and in various pain processes (Mazzuca et al. 2007). Voltage dependent K+ channels are key elements in the repolarization phase and duration of action potentials, consequently they are very important in a number of physiological processes. Dysfunctions of K+ channels often correspond to diseases such as episodic ataxia (Kvl.l), cardiovascular disorders (KCNQ1, HERG), neonatal convulsions (KCNQ2, KCNQ3) and deafness (KCNQ1, KCNQ4). It is very important to find molecules that are able to selectively interact with these channels. The most important sources of such molecules are animal venoms. SAK toxins which block some Kv channels, by their original mode of action and their particular structural properties, are important additions to the currently known panel of natural Kv inhibitors isolated from other animal venoms. SAK toxins target Kv1, HERG and Kv3 channels subfamilies,...

Rheumatoid Arthritis

It is considered to be one of the autoimmune diseases with the joint damage primarily found in the synovial tissue (APS, 2002 Danter, 2009). There have been many theories as to the cause of the disease, including Epstein-Barr virus or mycobacterial infection and environmental factors (APS, 2002).

Glucocorticoids

Therapy of IBD with methotrexate differs somewhat from its use in other autoimmune diseases. Most important, higher doses (e.g., 15 25 mg week) are given parenterally. The increased efficacy with parenteral administration may reflect the unpredictable intestinal absorption at higher doses of methotrexate.

Abstract

In the past years, it has been shown that kynurenines pathway is a regulator of both the innate and the adaptive immune responses. Particularly, the initial enzyme of this pathway, indoleamine 2,3-dioxygenase (IDO), is implicated in maintaining tolerance during pregnancy, and also can be expressed in tumors to avoid the immune attack. In this chapter, we will describe how the kynurenine pathway affects the immune system with important implications both in physiology and in pathology. The incorrect activation or blockade suppressive properties of the kynurenine pathway are also implicated in a number of other diseases such as AIDS or autoimmune diseases.

Hsp90

HSP65 is one of the most highly conserved proteins 97 homology among prokaryotes and more than 70 homology between prokaryotic and human HSP65 100 . Heat-shock proteins can promote, as well as regulate, autoimmunity. Therefore, antimicrobial HSP65 antibodies may cross-react with self-HSP65 101 . It is thus difficult to clearly establish which antigen was originally responsible for the production of anti-HSP60 65 antibodies (microbial or self-source).

Telithromycin

Untoward effects Telithromycin generally is well tolerated. Nausea, vomiting, and diarrhea occur in 3-10 of treatment courses. Slowed accommodation can cause visual symptoms. Reversible hepatic dysfunction with elevated transaminases or hepatitis and pseudomembranous colitis has been reported in some cases, the hepatotoxicity has been severe and even fatal. Telithromycin is not recommended for routine use in patients with myasthenia gravis due to possible disease exacerbation.

Medical Applications

In clinical medicine, diagnostic tests for determining serum antibody titers to a number of infectious agents, autoantigens, or other exogenous molecules have been used for many years. These tests are commonly performed one at a time in the clinical laboratory and require a large quantity of serum and reagents. All of these tests could potentially be miniaturized by immobilizing the antigens (proteins or peptides) in a microarray format. Antibodies, specific to cytokines or other biological molecules, can be immobilized on chips, which can then be used as diagnostic tools to evaluate a patient's serum, or serve as research tools in pro-teomics.122,123 It is conceivable that biochips will be available for clinical diagnosis within a decade. Biochips could test hundreds to thousands of compounds using only a small amount of a blood sample. Recent studies also suggest that pep-tide or small molecule microarrays are useful tools in the discovery of biomarkers for various diseases, such as...

Immunosuppression

In transplantation, the major classes of immunosuppressive drugs are (1) glucocorticoids, (2) cal-cineurin inhibitors, (3) antiproliferative antimetabolic agents, and (4) biologics (antibodies). These drugs have achieved a high degree of clinical success in treating conditions such as acute immune rejection of organ transplants and severe autoimmune diseases. However, such therapies require lifelong use and nonspecifically suppress the entire immune system, exposing patients to considerably higher risks of infection and cancer. The calcineurin inhibitors and glucocorticoids are nephrotoxic and diabetogenic, respectively, thus restricting their usefulness in a variety of clinical settings.

Tolerance

Immunosuppression has concomitant risks of opportunistic infections and secondary tumors. Therefore, the ultimate goal of research on organ transplantation and autoimmune diseases is to induce and maintain immunologic tolerance, the active state of antigen-specific nonresponsiveness. If attainable, tolerance would represent a true cure for conditions discussed above without the side effects of the various immunosuppressive therapies. The calcineurin inhibitors prevent tolerance induction in some, but not all, preclinical models. In these same model systems, sirolimus does not prevent tolerance and may even promote tolerance induction. In contrast to immunosuppressive agents that inhibit the immune response in transplant rejection and autoimmunity, a few immunostimulatory drugs have applicability to infection, immunodeficiency, and cancer.

Overview of HDACi

This chapter will summarize current data as to the therapeutic applications of HDACi in inflammation and autoimmunity, including the key cellular targets of HDACi, associated mechanisms of action, data from clinical studies and animal models of disease, and the rationale for therapeutic development of HDAC isoform-selective agents for use in inflammation and autoimmunity. Additional details are available from recent reviews on this topic (Blanchard and Chipoy 2005 Halili et al. 2009 Glauben et al. 2009 Mai 2007 Adcock 2007 Huang 2006 Wang et al. 2009a Villagra et al. 2010).

Dipyridamole

Indications see notes above and under Dose Cautions rapidly worsening angina, aortic stenosis, recent myocardial infarction, left ventricular outflow obstruction, heart failure may exacerbate migraine hypotension myasthenia gravis (risk of exacerbation) coagulation disorders concomitant use of drugs that increase risk of bleeding interactions Appendix 1 (dipyridamole) Pregnancy not known to be harmful Breast-feeding manufacturers advise use only if

Other Examples

Peptoid glycopeptide dendrimers containing four dansyl groups as fluorescence label were synthesised by Jin and co-workers 172 . The trisaccharide building block was formulated using major antigenic epitope of pectic polysaccharides from the root of the plant Bupleurum falcatum L. The roots serve as traditional Chinese and Japanese medicine for the treatment of autoimmune diseases, chronic hepatitis and nephrotic syndrome.

Therapeutic Uses

The most common form of cobalamin deficiency, known as pernicious anemia, is now known to be an autoimmune disorder that results from parietal cell destruction. This results in insufficient production of gastric acid and IF and the ensuing malabsorption of cobalamin. Other less common causes of insufficient absorption are hypochlorhydria, gastrectomy, ileo-cecal resection, celiac disease, and chemical incompatibilities with drugs in the gastric milieu. A deficiency of cobalamin can also result from nutritional deficiencies, increased requirements as is seen in pregnancy, as well as a strict vegetarian diet without adequate supplementation. The symptoms of cobalamin deficiency primarily result from potentially irreversible nerve damage, involving sensory, motor, and cognitive functioning, and the megaloblastic anemia that can be confused with that seen in folate deficiency. The ability of folic acid to reverse megaloblastic anemia seen in cobalamin deficiency, without affecting nerve...

Perspective

With the understanding of the structure-function relationship of bacteria protein toxins, we are able to apply genetic engineering techniques to delete the active site of a toxin without affecting the antigencity. The useful portion of a toxin can then be selected to serve as adjuvants and antigen deliver systems in new vaccine designs. Thus, structure-based vaccine designs have allowed us to induce specific types of immunity against selected structures, or small peptide epitopes, rather than the disease-causing whole bacteria or virus. This has led our future development program of vaccines to a new perspective dimension. Certain risks associated with inactivated whole-organism vaccines could also be overruled. We hope with the input of structure-based vaccine designs, to not only develop vaccines to prevent infectious diseases, but also to turn vaccine development in another dimension for the treatment of cancer, autoimmune diseases, and allergies.

Thalidomide

Although most vaccines have targeted infectious diseases, a new generation of vaccines may provide complete or limited protection from specific cancers or autoimmune diseases. Because T cells optimally are activated by peptides and costimulatory ligands that both are present on antigen-presenting cells, one approach for vaccination has consisted of immunizing patients with APCs expressing a tumor antigen. intravenous immunoglobulin Indications for the use of intravenous immunoglobulin (IVIG) have expanded beyond replacement therapy for agammaglobulinemia and other immunodeficiencies to include a variety of bacterial and viral infections and an array of autoimmune and inflammatory diseases as diverse as thrombocytopenic purpura, Kawasaki's disease, and autoimmune skin, neuromuscular, and neurologic diseases. The mechanism of action of IVIG in immune modulation is unknown. Although IVIG is effective in many autoimmune diseases, its spectrum of efficacy and appropriate dosing (especially...

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