Cure Myasthenia Gravis

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!

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Injury and Autoimmunity

In experiments in the rat, lesioning of the hippocampus or anterior olfactory nucleus does not generate antineurofilament antibodies, whereas they are produced after lesioning of the olfactory bulb and the grafting of PC12 cells in all sites,68 indicating again that the site within the brain strongly determines the immunological outcome. Antineurofilament antibodies are not considered to be pathogenic since the target antigen is intracellular. However, intracellular injection of antibody against the intermediate neurofilament protein into cells of the early Xenopus embryo leads to later axonal abnormalities,69 and an anti-large neurofilament antibody isolated from a case of ALS also reacted with neuronal surface proteins.70 Previous head injury is a factor in the development of Alzheimer's7172 and epilepsy.73 74 Activation of microglia is found in both of these conditions and autoantibodies are elevated in about 50 of Alzheimer's patients,64 but at present specific autoimmunity is not...

Autoimmune Diseases in Hybrid Mouse

Several F1 hybrid mice have been used for the investigation of autoimmunity. The (NZWxBXSB)F1 mouse, which develops lupus nephritis with myocardial infarctions, is a model of idiopathic thrombocytopenic purpura (Oyaizuet al. 1988), and also shows serologic features resembling human antiphospholipid syndrome (Monestier et al. 1996). The (NZBxBXSB)F1 mouse is also a model of lupus nephritis (Merino et al. 1994). These studies gave new insights and a better understanding into the role of the Yaa gene in lupus development (Table 16.2). Although several other hybrid strains, including the (SWRxSJL)F1 mouse, in which both parental strains show lymphadenopathy, splenomegaly, and hyper-y-globulinemia (Vidal et al. 1994), have been proposed as models of SLE, there is little information available on lupus dermatoses.

Abnormal Clearance of Apoptotic Cells Renders Individuals Susceptible to Initiation of Systemic Autoimmunity

Apoptotic cell clearance is a complex process that actively inhibits the initiation of inflammation and immune responses, in part through the release of antiinflammatory cytokines (Henson et al. 2001, Savill and Fadok 2000). Clearance involves numerous components on both the phagocytic cell (including CD14, the PS receptor, CD36, and scavenger receptor class A) and the cell being engulfed (e.g., PS). Although numerous cell surface receptors on macrophages seem to be responsible for binding of the apoptotic cell, recent studies have demonstrated that ligation of the PS receptor by surface PS on the apoptotic cell is responsible for inducing the rapid and efficient uptake of the bound cell through stimulated macropinocytosis (Fadok et al. 2001, Hoffmann et al. 2001, Somersan et al. 2001). Recent studies have also implicated soluble components of the innate immune system in the efficient clearance of, and the induction of immune tolerance to, apoptotic material (Botto et al. 1998,...

Inflammatory Cells in Photosensitive Autoimmune Disease The Link to Antigen Presentation

We explained how during the physiologic turnover of apoptotic cells, autoantigens are displayed to the immune system for the maintenance of tolerance or, when there is an imbalance in the system, the production of autoimmunity. Furthermore, during the normal uptake of apoptotic debris, antigens can be processed to bind to MHC I or MHC II molecules to activate CD4+ or CD8+ T cells. It is still unclear how the inflammatory response in CLE is initiated and maintained, but there is evidence to support that it is an antigen-driven response. First, cutaneous lesions contain a patchy infiltrate of activated T cells that are predominantly CD4+ (David-Bajar 1993). Second, there is a selective expansion of V 8.1 CD3+ cells in the skin of patients with CLE (Furukawa et al. 1996). Third, sequencing of T-cell receptor clonotypes from skin suggests an antigen-driven response (Kita et al. 1998). Fourth, APCs in skin from DLE, SCLE, and CLE express B7-1 and B7-2 surface molecules that bind to CD28+,...

Mechanisms of Thyroid Autoimmunity

The other known genetic loci associated with thyroid autoimmunity, namely HLA, CTLA-4 and PTPN22, are shared between these 2 thyroid conditions, as well as many other autoimmune diseases reviewed in 3 . Several environmental factors have been delineated but some of these remain controversial and of unknown action, such as smoking and stress 4, 5 . Evidence for the involvement of infections is lacking (thyroid autoimmunity rarely follows subacute thyroiditis, for instance), but there does appear to be an association between congenital rubella infection and subsequent thyroid autoimmunity 6 . Genetic and environmental factors predispose to autoimmune disease through their effects on immunological tolerance (table 1). It is well established that most autoreactive T cells are deleted in the thymus, and this involves the intrathymic expression of self-antigens during development. This process is most clearly demonstrated in autoimmune polyglandular syndrome type 1, in...

Experimental Autoimmune Myasthenia Gravis in the Mouse

Myasthenia gravis (MG) is a T cell-dependent antibody-mediated autoimmune neuromuscular disease. Antibodies to the nicotinic acetylcholine receptor (AChR) destroy the AChR, thus leading to defective neuromuscular transmission of electrical impulse and to muscle weakness. This unit is a practical guide to the induction and evaluation of experimental autoimmune myasthenia gravis (EAMG) in the mouse (see Basic Protocol), the animal model for MG. EAMG is most frequently detected by clinical evaluation of muscle weakness of the mouse and the ability of neostigmine (an acetylcholinesterase inhibitor) to reverse the manifestations of disease. AChR can be extracted from the electric organs of Torpedo californica, or eel, and affinity purified (see Support Protocol 1) to be used as an immunogen to induce autoimmunity to AChR, thus causing EAMG. Purification requires a neurotoxin 3-agarose affinity column (see Support Protocol 2). The defect in neuromuscular transmission can also be measured...

Induction of Autoimmune Disease by Depletion of Regulatory T Cells

Organ-specific autoimmune diseases can be induced in rodents that do not normally spontaneously develop autoimmunity by using procedures that render the animals partially T cell deficient. Using a protocol of adult thymectomy followed by four doses of sublethal y irradiation, insulin-dependent diabetes can be induced in normal PVG.RT1u rats, an inbred congenic strain that has the same major histocompatibility complex (MHC) allotype as the spontaneously diabetic BB rat. Onset of the disease ranges from 3 to 18 weeks after the final dose of irradiation, with 98 of male and 70 of female animals becoming diabetic. The animals develop an acute and rapidly fatal syndrome with severe weight loss and hyperglycemia. Using this protocol, 50 to 60 of PVG.RT1u animals may develop anti-thyroid antibodies but they have no adverse effect. Female rats of the strain PVG.RTIc will also develop diabetes if treated by this protocol, but with a much lower incidence (10 to 53 ).

The Day3 Thymectomy Model for Induction of Multiple Organ Specific Autoimmune Diseases

Autoimmune diseases of the ovary and the stomach are major components of the murine autoimmune polyendocrinopathy syndrome that occurs following experimental perturbation of the normal immune system. Several methods of perturbation can lead to autoimmune disease, and the disease occurs in multiple organs in association with autoantibodies to tissue-specific antigen of the respective organs. As shown in Table 15.16.1, the autoimmune diseases develop in a variety of laboratory mouse strains that are not prone to spontaneous autoimmune diseases. This unit describes the induction of autoimmune disease of the ovary and the stomach in mice by thymectomy at the age of day 3 (day-3 thymectomy see Basic Protocol) and methods for evaluating disease histologically and serologically (Support Protocols 1 and 2).

Choice of Assays in Assessing Murine Autoimmune Disease

All of the SLE models mentioned above develop antibodies to chromatin and ssDNA. The chromatin specificity is probably the most useful because the preparation contains DNA, histones, and multiple nuclear proteins, making it an excellent screening test for systemic autoimmunity. Antibodies to double-stranded DNA are generally found only in the NZB NZW, NZB SWR, and MRL lpr mice, and rheumatoid factor is found in MRL lpr and B6 lpr. In addition to the serological markers, proteinuria, renal histology, and mortality are useful markers for disease.

UV Light Apoptosis and Autoimmunity

The link between photosensitivity and the induction of autoimmune disease can be understood through a model centered on the apoptotic cell. Apoptosis is a process of programmed cell death during which intracellular antigens are translocated to the cell surface, allowing for detection by the immune system (Casciola-Rosen and Rosen 1997, Casciola-Rosen et al. 1994, 1995, 1999, Schultz and Harrington 2003). Because apoptosis is required for the development and maintenance of tissue homeostasis in multicellular organisms, the immune system has developed mechanisms to cope with the removal of apoptotic debris. Under noninflammatory conditions, immature dendritic cells (DCs) or local macrophages phagocytose apoptotic cells and prevent the development of autoantibodies in a process of tolerance (White and Rosen 2003).If the balance is distorted by an increase in the production of apoptotic cells, by an increase in the amount of inflammatory cytokines, or by a deficiency in the proteins...

Genetic analysis of systemic autoimmunity

Even for complex diseases with high rates of monozygotic twin concordance, disease-associated alleles remain elusive. One explanation is that multiple common genetic variants with weak effects cause these diseases and identification of any single allele requires large cohorts. Conversely, if the allelic spectrum of complex disease is heterogeneous, strong effects of rare variants might be offset by their presence in only a small proportion of the patient population. Lupus (SLE) is a systemic autoimmune disease, with significant monozygotic twin concordance, protean clinical manifestations, and production of high-affinity pathogenic autoantibodies. This complex phenotype and results from genome scans point to multiple molecular defects. Contrary to this expectation, our analysis of ENU-mutagenized mice indicates that homozygous mutations frequently cause anti-nuclear antibodies (ANAs), and can account for a full blown lupus phenotype. The best characterized example is the...

Drugs That Can Aggravate Myasthenia Gravis

Table 74 Ancillary tests in myasthenia gravis (p. 342) Table 74 Ancillary tests in myasthenia gravis (p. 342) 1 Short-term inhibition of cholinesterase, given intravenously for diagnostic purposes. 2 Ocular myasthenia gravis. 3 Generalized myasthenia gravis. 4 Example Repeated stimulation of accessory nerve (3 sec for 3 seconds) and recording of activity in trapezius muscle. 5 CT (contrast-enhanced) or MRI (younger patients, better differentiation of thymic hyperplasia).

The Thyroid and Autoimmunity in Children and Adolescents

Thyroid autoimmunity is the commonest disease process to affect thyroid function. The prevalence of thyroid autoimmunity increases throughout life, with a possible decline in frequency in the very old as a 'healthy survivor' effect. The mere presence of thyroid autoimmunity, as demonstrated by the presence of thyroid autoantibodies or focal thyroiditis, for example, does not equal thyroid disease, since the majority of people with focal thyroiditis do not become hypothyroid 1 . On the other hand, as far as we know the formation of thyroid-stimulating antibodies (TSAb) leads to Graves' disease in the great majority of subjects, even if in rare cases their levels may oscillate and be associated with a fluctuating clinical course. After a brief review of the basic immunological mechanisms which underlie autoimmune thyroid diseases, this chapter will focus on the comparatively few studies which have looked specifically at the pathogenic mechanisms in these disorders in children and...

Myasthenia Gravis

For myasthenia gravis, there are not so much diagnostic criteria as a set of diagnostic tests with varying sensitivity and specificity. These tests include characteristic clinical course, response to In the diagnostic criteria for neuropsychiatry systemic lupus erythematosus (one of many disorders associated with myasthenia gravis), there are diagnostic criteria for myasthenia gravis, but the extent to which the wider medical community or specialists in neuromuscular diseases adhere to this case definition is unclear.

Current Clinical Neurology

Vitek, and Andres M. Lozano, 2003 Myasthenia Gravis and Related Disorders, edited by Henry J. Kaminski, 2003 Seizures Medical Causes and Management, edited by Norman Delanty, 2002 Clinical Evaluation and Management of Spasticity, edited by David A. Gelber and Douglas R. Jeffery, 2002

Autoimmuneneuromuscular disorders

A number of autoimmune neuroinflammatory disorders (see 6.09 Neuromuscular Autoimmune Disorders) affect either the central or peripheral nervous system. Many of these disorders are exceptionally rare such as Moersch-Woltman syndrome (stiff-man), Lambert-Eaton myasthenic syndrome, and myasthenia gravis (MG). While uncommon, these disorders tend to be highly debilitating as they directly alter neuromuscular transmission. The most common of these disorders is MG which affects an estimated 60 000 people in the USA. The primary pathology underlying MG appears to be the production of autoantibodies directed against the alpha subunit of the neuromuscular nicotinic acetylcholine receptor. Through direct interference and complement-mediated lysis of the postsynaptic muscle membrane, the autoantibodies cause disruption in the motor endplate that leads to a weakness in skeletal muscle throughout the body. The autoimmune disorder systemic lupus erythematosus (SLE) and the neuroinflammatory...

Basic Mechanisms and Concepts

In 1901, Ehrlich postulated that organisms possess certain contrivances by means of which the immune reaction is prevented from acting against (its) own elements. Such contrivances constitute what in modern terms is designated as tolerance and, still in Ehrlich's words,. are of the highest importance for the individual. Several decades later, when autoimmune diseases were described, they were interpreted as the result of a breakdown or failure of the normal tolerance to self, resulting in the development of an autoimmune response. Ehrlich's hypothesis was apparently supported by the definition of pathogenic mechanisms for different diseases considered as autoimmune in which the abnormal anti-self-immune reaction played the main role. In the 1940s, Owen, a British biologist, was involved in ontogeny studies using bovine dizygotic twins, which share the same placenta. Under these circumstances, each animal is exposed to cells expressing the genetic markers of the nonidentical twin...

Systemic Lupus Erythematosus

SLE is a complex autoimmune disease involving several organs. The main effectors of disease pathology are the diverse autoantibodies, immune complexes, and auto-reactive cells. Altered biology of immune cells, keratinocytes, and endothelial and possibly other cells invariably contributes to the expression of the disease. At the pathogenic level, the disease presents unprecedented complexity involving an as-yet-unspecified number of genes, immunoregulatory aberrations, and environmental and hormonal factors. Previous and current research efforts have elucidated the complex array of genetic, environmental, hormonal, and immunoregulatory factors thought to interplay in the pathogenesis of the disease.

Membrane Mediated Signal Transduction in Lupus Immune Cells

Fresh circulating lupus T cells (whole T cells, CD4+ cells, and CD8+ cells) as well as lupus T-cell lines and autoantigen-specific lupus T-cell clones displayed significantly increased free intracellular Ca2+ responses compared with the responses of T lymphocytes, T-cell lines, or autoantigen-specific T-cell clones from healthy individuals or patients with systemic autoimmune diseases other than SLE.

Environmental Factors

Molecular mimicry between autoantigens and antigens expressed by viruses and other pathogens have been extensively considered in the pathogenesis of autoimmune diseases. Epitopes of the SLE-associated 60-kd Ro SSA autoantigen share sequences with the vesicular stomatitis virus (VSV) nucleocapsid protein,which may explain the presence of anti-Ro SSA antibodies. In addition, immunization of animals with VSV proteins causes production of anti-Ro SSA autoantibodies and anti-VSV antibodies. Additional examples of molecular mimicry include that between the B B' component of the Sm antigen and the human immunodeficiency virus type 1 p24 gag protein and the D component of the Sm antigen and the EBV nuclear antigen type 1 protein of EBV.

Nucleic Acid Immunizations

The direct inoculation of antigen-expressing DNAs represents a powerful new approach to eliciting immune responses. The antigens are synthesized in transfected cells and obey the trafficking, modification, and antigen-presentation rules of eukaryotic cells. Very low levels of antigen expression (typically nanograms) induce both antibody and cytolytic T cell responses. This easy method of immunization may be used for testing the immuno-genicity of novel recombinant molecules and screening DNA libraries. Potential applications include the development of protective vaccinations, the control of tumors, and the manipulation of allergies and autoimmune disease. DNA-based immunizations readily raise polyclonal and monoclonal antibodies, invoke helper T cells (TH), and activate cytolytic T cells (Tc). The use of DNA for immunization also holds promise for basic studies on immune responses.

The Epidemiology of Lupus Erythematosus

Lupus erythematosus (LE) is an autoimmune disorder that includes a broad spectrum of clinical forms, ranging from those with lesions confined to the skin to others with more generalized involvement, then termed systemic LE (SLE). Although previously considered a rare disease, LE now seems to be relatively common in certain groups, probably owing to the development of several immunologic tests that identify many atypical or benign cases that otherwise might not be diagnosed. Furthermore, since the introduction in 1982 by the American College of Rheumatology (ACR) of a set of more sensitive criteria for SLE classification, more cases are now being detected. It is noteworthy that cutaneous manifestations account for 4 of the 11 revised criteria for the classification of SLE.

Fetal Maternal Relationships

Thyroid hormone transport proteins particularly TBG (thyroxine-binding globulin) increase due to enhanced hepatic synthesis and a reduced degradation rate due to oligosaccharide modification. Serum concentration of free thyroid hormones has been reported to be decreased, increased or unchanged during gestation by different groups depending on the assays used 9 . However, there is general consensus that there is a transient rise in free thyroxine (FT4) in the first trimester due to the relatively high circulating hCG concentration and a decrease of FT4 in the second and third trimester albeit within the normal reference range. Recently, it has become apparent that there is a need for normative trimester-specific reference ranges for thyroid hormones 10 . Ideally these should be derived from iodine sufficient women who do not have any evidence of thyroid autoimmunity 11 . Changes in free triiodothyronine (FT3) concentration are also seen in which they broadly parallel the FT4, again...

Epidemiology of the Cutaneous Manifestations of Lupus Erythematosus

SCLE occurs in 10 -15 of patients with SLE and includes the papulosquamo-sus (psoriasiform) and annular-polycyclic variants. These lesions are usually widespread, symmetrical, and nonscarring. They occur in a characteristic, photoexposed distribution, with an LE-specific histopathology. A few patients may have a combination of psoriasiform and annular lesions, although most predominantly have either one or the other subtype (Sontheimer 1989). Approximately, 50 of patients with isolated SCLE subsequently develop SLE. Patients in this subset of LE frequently have anti-Ro antibodies (Sontheimer et al. 1982) and are HLA-B8-DR3 2 positive (Johansson-Stephansson et al. 1989). SCLE may be associated with other systemic autoimmune diseases, and photoactive medications may induce lesions of SCLE.

Additional Resources Books

Chinese herbs as immunomodulators and potential disease-modifying antirheumatic drugs in autoimmune disorders. Curr Drug Metab 2004 5 181-192. Lai JH. Immunomodulatory effects and mechanisms of plant alkaloid tetrandrine in autoimmune diseases. Acta Pharmacol Sin 2002 23 2093-1101.

Evaluation of Eyelid Malpositions

Snapback Test

A history of slow progression is not uncommon with most involutional eyelid changes, but this usually occurs over several years. Almost all patients with ptosis or dermatochalasis will report some increase in droopiness late in the day or when tired this does not usually indicate myasthenia gravis. The occurrence of an eyelid malposition with orbital pain is always worrisome and demands investigation to rule out neoplasm or pseudotumor. Any such association requires radiographic study. Any patient with a history of significant worsening of ptosis late in the day or when tired should be suspected of having myasthenia gravis. This is especially true if the eyelid appears near normal in the morning, or the condition is associated with difficulty in swallowing, generalized weakness, or diplopia. A levator fatigue test can be performed easily without risk. The patient is asked to look upward for several minute without blinking. The position of the eyelid is measured before and immediately...

Formation of phosphate conjugates

The unexpected (and mostly unexplored) activity of phosphotransferases toward xenobiotic substrates is forcefully illustrated by the recently reported activation of FTY720 (37, Figure 14), a novel immunomodulator showing great promise in transplantations and to treat autoimmunity.71 The agent itself appears inactive, being phosphorylated in rats and humans to the active monophosphate. Recent studies have implicated spingosine kinases as the catalysts and have shown that the reaction is highly product enantioselective. Indeed, FTY720 itself is prochiral (it bears two enantiotopic -CH2OH groups), and the enzymatic reaction results exclusively in the phosphorylated enantiomer of (S)-configuration (38), which is also the only active one.

Background Information

1987), treatment of autoimmune diseases (Wofsy and Seaman, 1985, 1987 Christadoss and Dauphin e, 1986 Shizuru et al., 1987, Depending on the nature of the experiment, extended treatment schedules may be required. In experiments aimed at testing the long-term effect of CD4+ T cells on the development of autoimmune diseases, depletion of CD4+ T cells for periods up to 5 months have been achieved (Wofsy and Seaman, 1985 Wofsy, 1986). In some long-term treatment protocols, injected mice sometimes produced anti-rat IgG antibodies when certain hybridomas or treatment schedules were used, causing serum sickness and accelerated mortality. Because no mouse monoclonal antibodies against CD4 are available, this problem is difficult to avoid for experiments aimed at long-term CD4+ T cell depletions. However, for unknown reasons, not all in vivo treatments with the GK1.5 hybridoma elicit responses to rat IgG (Benjamin et al., 1986 Gutstein et al., 1986 Wofsky, 1986 Wof-sky and Seaman, 1985), and...

Monitoring of the Fetus in a Mother with Graves Disease

In areas of iodine deficiency the circulating maternal thyroxine concentrations are low although TSH is usually in the normal range. In this situation the incidence of thyroid abnormalities is higher and in particular thyroid autoimmunity may be associated with diminished thyroid reserve and an increase in spontaneous abortion.

Animal Models of Acute and Chronic Graft VersusHost Disease

Graft-versus-host disease (GVHD) represents a special situation in transplantation immunology in which immunocompetent donor cells are engrafted into recipients that are incapable of rejecting them due to tolerance (parent offspring, or P F1), immaturity (adult neonate), or radiation- or chemotherapy-induced immune deficiency (donor irradiated host). Donor T cells encountering allogeneic stimulators become activated, secrete cytokines, proliferate, and differentiate into effectors this in vivo immune response is known as the graft-versus-host reaction (GVHR). The systemic effects of this initial donor anti-host reaction comprise a multiorgan syndrome, graft-versus-host disease (GVHD). Murine GVHD experiments have been utilized to model the clinical disorders of acute and chronic GVHD (AGVHD and CGVHD) that occur after allogeneic bone marrow transplantation, and also to study T cell regulation, induction of tolerance, and autoimmune diseases.

Findings that elevate suspicion of MI

Pericarditis look for viral upper respiratory infection prodrome. EKG shows diffuse ST segment elevation. Other signs include elevated erythrocyte sedimentation rate and low-grade fever.lire most common cause is viral (coxsackie virus) others include tuberculosis, uremia, malignancy, and lupus or other autoimmune diseases.

Acute Rheumatic Fever Introduction

Acute rheumatic fever is an autoimmune disease responsible for cardiac valve disease or rheumatic heart disease. It is associated with infections caused by the group A streptococcus and occurs about 2 to 6 weeks following a streptococcal upper respiratory infection. It is prevented by adequate treatment of the infection with appropriate antibiotic therapy within 9 days of onset of streptococcal infection before further complications can occur. Because rheumatic heart disease does not occur after only one attack and children are susceptible to recurrent attacks of rheumatic fever, it is vital that an initial episode is diagnosed and treated, and that long-term prophylactic therapy (5 years or more) is given following the acute phase. There is no specific test for rheumatic fever the diagnosis is based upon the manifestations using the revised Jones criteria as a guideline. Jones criteria consist of major manifestations (polyarthritis, carditis, chorea, subcutaneous nodules, and...

Introduction and Epidemiology

Neonates are not sufficiently immunologically competent to develop IgG autoanti-body-mediated disease independently. However, IgG autoantibodies from the mother transmitted in utero can initiate disease in susceptible individuals. In a small percentage of fetuses and neonates exposed to maternal autoantibodies of the Ro SSA family, an autoimmune disease called neonatal lupus erythematosus (NLE) will develop (Lee 1993,2001). It may be argued that NLE is misnamed, as many of its clinical findings are not shared by systemic LE (SLE) of children or adults, but the name NLE remains in common use. The main features of the syndrome are cutaneous lupus lesions, cardiac disease (primarily complete congenital heart block), hepatobiliary disease, and hematologic cytopenias. Many affected individuals have only one manifestation of NLE, but any combination of these findings may occur.

MicroRNAs and other nonproteincoding RNAs

The CAGE technology enabled the detection of many weakly expressed non-protein-coding RNAs (ncRNAs) and tissue cell-specific transcription initiated at the stem-loop of micro RNAs (miRNAs). Thus far, miRNAs derived from introns of protein-coding pre-mRNAs have been known only as sequence-specific regulators on a post-transcriptional level. For example, miR-375 suppresses glucose-induced insulin secretion via its target mRNA myotrophin (Poy et al 2004). The findings reported by the FANTOM3 consortium together with recent computational estimates of 200 miRNAs, on average, per target mRNA (Krek et al 2005) imply a critical role of miRNAs in gene regulatory networks. Further investigations along the lines of Ramkissoon's (2006) work which demonstrated different expression patterns of haematopoietic cell-specific miRNAs in normal and malignant cell lineages should yield new insights into the regulation of cancer and autoimmunity.

Biology of microglia

These areas are concentrated around the subven-tricular zones where active neurogenesis occurs. These ameboid tissue macrophages then migrate throughout the entire brain parenchyma and differentiate into resident microglial cells. In the mature CNS, microglia are ubiquitously present as highly ramified cells (resting microglia) 5,6 . They respond to changes in the CNS microenvironment in a variety of disorders with or without the participation of the systemic monocytes. Although in degenerative disorders such as AD and Parkinson's disease there is little evidence to support recruitment of monocytes from the periphery, in infectious and autoimmune diseases such as HIVE and multiple sclerosis (MS) and in stroke, there is frank infiltration of monocyte-derived macrophages as well as other inflammatory cells. Even in these diseases in which monocytes are known to contribute significantly to the disease process, studies using sensitive markers of...

Manipulators Of The Developing Immune System

Ability of the body to defend against pathogens (Bardare et al. 1993 Devereux et al. 2002). The majority of immunocompromised individuals in the world simply lack nourishment (Janeway Jr. et al. 1997a). Studies implicate maternal diet in development of atopic disease (Bardare et al. 1993 Devereux et al. 2002). Other maternal behaviors such as breastfeeding can decrease risk of allergy, asthma, and autoimmune disease (Bjorksten 1999a Hanson 1998). The benefits of breastfeeding indicate that the neonate's diet plays a significant role in maturation of immune system function. Likewise, the third area, exposure to toxins, offers insight into vulnerable periods during development. Much work needs to be done on assessment of toxicant exposure in early life and the development of disease particularly autoimmune disease in later life. Popular opinion generates diffuse anxiety about scientific advances (such as offered through genetically modified foods) because of the unknown effect on...

Principles of the Immune System

Autoimmunity, allergy, immunosuppression The immune system can be divided into the nonadaptive (or innate) part and the adaptive immune system. The adaptive immune system has 'memory,' i.e., it can react faster and better on a renewed contact with the chemical, even after years of not having had any exposure. The cells of the innate immune system use surface receptors to recognize bacterial structures, and initiate defense reactions against them directly. Moreover, the innate defense reaction may include recruitment and instruction of cells of the adaptive immune response, for instance via secretion of cytokines or chemokines. Adaptive immune responses by T cells and B cells can in principle respond to any given structure, i.e., any protein (Tcells and B cells), lipid (some specialized Tcells, B cells), sugar chain, or chemical substance (B cells only), and mount a humoral or cellular response. Antibody producing B cells, cytokine producing helper Tcells, and killer Tcells capable of...

The Two Basic Immunotoxic Action of Chemicals Unwanted Activation

Secondly, chemicals or their metabolites can act by the immune system. This means they interfere with the response mediated by the specific antigen receptors of B and or Tcells. Chemicals may be recognized as antigen and elicit immune responses, or they may directly or indirectly change self antigens and thus break tolerance. It is generally accepted by now that T cells are the major players in xenobiotic-induced autoimmunity and allergy. Chemicals acting by the immune system lead to sensitization and a memory response. Memory lymphocytes can expand and mediate a stronger immune response on second contact with the chemical, even if it occurs long after the first contact. Adverse immune reactions of this type may lead to allergy or autoimmunity.

Lupus Erythematosus Profundus

Lupus Profundus

LEP, historically referred to as Kaposi-Irgang disease or also known as lupus pan-niculitis, is a rare variant of CCLE in which pathologic changes occur primarily in the lower dermis and subcutaneous tissue. In 1883, subcutaneous nodules associated with LE were first described by Kaposi (Kaposi 1883), but the term lupus profundus was coined by Irgang (Irgang 1940) in 1940. Subsequently, different authors reported new cases and contributed to define the clinical and histopathologic characteristics of this disease (Arnold 1956, Sanchez et al. 1981, Tuffanelli 1971, Winkelmann 1970). Middle-aged women are predominantly affected however, in a recent study it has been shown that LEP in Asian patients is more frequent in a younger age group compared with the Caucasian population (Ng et al. 2002). The course of this subtype of CCLE is usually chronic and characterized by periods of remission and exacerbation. The major morbidity is usually disfigurement and disability related to pain, and...

Natural Antibodies To Cytokines

Natural Ab against IFN in humans were first reported in 1981 as a case of neutralizing IFN-a Ab in a patient with varicella-zoster (13). Later, IFN-a Ab were found in patients with other viral infections, with neoplastic and autoimmune diseases, and in a patient with chronic graft versus host disease (6,7,13-24). The prevalence of IgG anti-IFN-a Ab in these patients is about 10 .

Chemical Suppression And Susceptibility

Environmental agents can affect the immune system in various ways. Effects tend to include immunosuppression, possibly resulting in altered host resistance against infections or neoplastic agents hypersensitivity or autoimmunity and uncontrolled proliferation of immune components, i.e., lymphoma or leukemia. Quantification of T cell-dependent antibody responses is known to be an extremely reliable indicator of immunotoxicity and could very well be used to predict changes in host resistance as they develop (Luster et al. 2002).

Inhibition of Complement

It is known that patients with genetic deficiencies in the complement system, especially C2 and C4, have a high incidence of lupus and other autoimmune diseases, presumably because this leads to defects in the clearance of immune complexes (Dubois and Wallace 1987). Hydralazine and several other drugs interact with C4 and inhibit binding of C4 to C2, and it was proposed that this could represent the mechanism of drug-induced lupus (Sim and Law 1985). The hydroxylamine of procainamide also binds to C4 (Sim et al. 1988), but the concentration of this metabolite in vivo is unlikely to be sufficient to have much of an effect.

More Than Adequate Iodine Intake

Carried out 7 years previously in the same area. A total of 302 schoolchildren (12-18 years of age) from a mountainous area of northwestern Greece were examined for the presence of goiter, and blood and urine samples were collected for assessment of thyroid function, antithyroid antibodies and urinary iodine excretion. Median urinary iodine concentration in the children was 200 xg l. Thyroid function was normal in all but 7 children, who had subclinical hypothyroidism (2.5 ). Antithyroid antibodies (antithyroid peroxidase and or antithy-roglobulin) were positive in 32 children, including those with subclinical hypothyroidism (10.6 ). Twenty-nine of these children (9.6 ) also had the characteristic hypoechoic pattern of thyroiditis on ultrasound studies and were diagnosed to have autoimmune thyroiditis (AIT). It was concluded that iodine prophylaxis has resulted in the elimination of iodine deficiency in this region of Greece but this has been accompanied by an increase in the...

Summary And Concluding Remarks

Those reacting with neurofilament proteins are pathogenic, there is evidence that not all antibodies are equal. It should be borne in mind that in antibody-mediated autoimmune diseases severity is rarely related to antibody titre. This fact, combined with the neuron's propensity to endocytose proteins, including immunoglobulin, may mean that some antibodies could have an influence on neurons following injury and their entry into the brain.

Gender Ethnicracial And Life Span Considerations

Cushing's syndrome in infants usually results from adrenal carcinoma. Primary disease is often linked to a familial autoimmune disorder and is seen in children and young adults of both genders. Secondary disease is more common than primary disease in children older than 6 or 7 and, as in adults, is usually the result of overproduction of ACTH. In adults, secondary Cushing's syndrome that results from pituitary disease is most common in females aged 30 to 50 years. Secondary Cushing's syndrome that results from increased ACTH secretion is more common in males, possibly because of the higher incidence of bronchogenic carcinoma that is caused by smoking. There are no known racial and ethnic considerations.

Heart Pacemaker Cellm2 Receptor Activation

The Effect Nicotine Receptor Sites

The quaternary carbamate neostigmine is employed as an indirect parasympathomimetic in postoperative atonia of the bowel or bladder. Furthermore, it is needed to overcome the relative ACh-deficiency at the motor endplate in myasthenia gravis or to reverse the neuromuscular blockade (p. 184) caused by nondepolarizing muscle relaxants (decurarization before discontinuation of anesthesia). The tertiary carbamate physostigmine can be used as an antidote in poisoning with para-sympatholytic drugs, because it has access to AChE in the brain. Carbamates (neostigmine, pyridostigmine, physos-tigmine) and organophosphates (para-oxon, ecothiopate) can also be applied locally to the eye in the treatment of glaucoma however, their long-term use leads to cataract formation. Agents from both classes also serve as insecticides. Although they possess high acute toxic-ity in humans, they are more rapidly degraded than is DDT following their emission into the environment. Tacrine is not an ester...

Disclaimer Not for patient use To be used as a research guide only

Disease biomarkers are usually based on large population studies that monitor diseases such as cancer (CEA, PSA),69 diabetes (hemoglobin A1c), and autoimmunity (rheumatoid factor).73 These markers not only allow the possibility for early detection that may influence success of treatment, but also serial analysis to potentially indicate whether disease

Guillain Barre syndrome

While GBS occurs throughout the world, the axonal forms of the disease are much less common in Europe and North American, and more common in China, Japan, India, and Central America. Contrary to many autoimmune diseases, males are more commonly affected than females.10 Age distribution is bimodal - with peaks in young adults and the elderly. There are no reliable serological markers.

Chronic inflammatory demyelinating polyradiculoneuropathy

CIDP is thought to be an autoimmune disorder caused by either humoral or cell-mediated immunity to axonal, myelin, or other Schwann cell antigens. The autoantigens associated with CIDP are generally unknown. However, MMN is associated with anti-GM1 IgM antibodies, the levels of which decrease with clinical improvement.

Pathophysiology of Photosensitivity in Lupus Erythematosus

Despite these general possibilities of UV-induced autoimmunity, more specific pathogenetic pathways have been experimentally demonstrated. Thus, Furukawa et al. (Furukawa et al. 1990) could show in the absence of apoptosis the cellular redistribution of the Ro SSA antigen on UV irradiation, which enables its presentation to the immune system as a possible first step in the autoimmune response cascade. Although the four-step model for the pathogenesis of UV-induced LE based on the translocation of the Ro SSA antigen, which was developed by Norris and Lee (Norris and Lee 1985), has been widely referred to and agreed on, it is limited to the Ro SSA-positive forms of LE, such as subacute CLE (SCLE) and neonatal LE (NLE). value, that is, as additives in sunscreen products to prevent UV-induced LE lesions (McVean and Liebler 1997, Steenvorden and Beijersbergen van Henegouwen 1999, Tebbe et al. 1997, Trevithick et al. 1992). A potentially crucial role in the initiation of the autoimmune...

Selective Adhesion Molecule Inhibitors

In Crohn's disease, an organ-specific autoimmune disease in which the immune system attacks the intestinal mucosa, the therapeutic target of natalizumab is a4 7 integrin, which, like a4pl integrin, is recognized by a4 integrin-specific antibodies. This integrin has multiple functions, including mediating migration of gut-homing T cells via its counter-receptor in the gut, MadCAM.

Costimulatory molecule inhibitors

In the adaptive immune response, nonspecific signals are generated from the interaction of pairs of receptors, so-called co-stimulatory molecules.30 Inhibition of the co-stimulatory signal results in suppression of the immune response. The CD28 B7, CTLA4 B7, and CD40 CD40L receptor ligand pairs of co-stimulatory molecules have been the targets of drug development for autoimmune disease. There are two conceptually different approaches to blocking co-stimulation by inhibiting either the induced expression of co-stimulatory molecules or the transmission of their specific intracytoplasmic signal. The latter approach is described here.

Therapeutic Vaccines and Toleragens

While vaccines have traditionally been used as prophylactics, they are increasingly being used as therapies for already established chronic disease.31 For autoimmune disease therapy, a peptide similar to that causing the disease is administered to the patient in theory, the vaccine then stimulates an immune response to the T cells reacting in the disease. This presumes that the autoantigen(s) is known, and that the disease is caused by one or a few antigens. An advantage to this hypothetical mechanism is that the anti-Tcell response should, in theory, be specific for the T cells contributing to disease pathogenesis. Glatiramer acetate is the first vaccine that has been used to treat an autoimmune disease - in this case RRMS32 it was approved by the US FDA in 1996. It is a mixture of many synthetic peptides - random polymers - that mimic the antigenic portion of MBP. It reduces the relapse rate in RRMS, impacts MRI markers of disease activity, is well tolerated, and does not appear to...

Identification of B Cell and T Cell Epitopes Using Synthetic Peptide Combinatorial Libraries

Synthetic combinatorial libraries have been found to be valuable tools for the study of protein-protein interactions. Of the many different combinatorial library methods developed, the one described in this unit consists of the synthesis and screening of mixture-based synthetic combinatorial libraries (SCL) of peptide molecules. These libraries are systematically arranged into mixtures containing a total of hundreds of thousands to trillions of individual peptides. The understanding of B cell and T cell specificity has been advanced significantly by the development and use of SCL composed of millions of synthetic peptides. The use of peptide SCL has led to the identification of high-affinity ligands for both T cells and mAbs with known and unknown specificities. These peptides can result from the combinations of the amino acids that do not necessarily correspond to sequences in known proteins. In addition, the native ligand and potential cross-reactive sequences can be identified from...

Etiologies of Hypoglycemia

Pathophysiological Endocrinopathy (Addi-son's disease, Sheehan's syndrome) neoplasms (insulinomas, multiple endocrine adenomatosis MEA type I) liver disease (alcoholism, cirrhosis) chronic renal failure (CRF) and hemodialy-sis miscellaneous (AIDS, autoimmune diseases, pregnancy).

Photosensitivity in Murine Experimental and Inbred Lupus Models

Photosensitivity is one of the major symptoms of SLE and related diseases, including subacute CLE and neonatal LE. Although it remains unclear how photosensitivity can be examined using laboratory tests, experimental models have been developed and inbred SLE-prone mice have been investigated for a better understanding of the photosensitivity phenomenon in relation to autoimmunity (reviewed by Sontheimer 1996). It is well known that patients with LE show hypersensitivity to UVB light (Epstein et al. 1965, Kochevar 1985). In NZB mice, the relationships between autoimmunity, chromosomal abnormalities, and clastogenic factors have been discussed by a few investigators (Emerit 1982, Halpern et al. 1972, Reddy et al. 1978), and the UV sensitivity of NZB cell lines has also been reported (Zamanski et al. 1980). The clastogenic factors were reported to be sensitive to near-UV light (360-400 nm) (Emerit 1982), but the significance of this finding has not been completely understood. B W F1...

Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) is a relatively new syndrome of clinical and histologic findings and has also been described as 'lymphoplasmocytic sclerosing pancreatitis with cholangitis', 'nonalcoholic duct-destructive chronic pancreatitis' and 'chronic sclerosing pancreatitis'. A number of features can be found, including hypergammaglobulinemia, elevation of serum IgG4, IgG4-containing immune complexes and a number of antibodies, such as antinuclear antibodies, antibodies against lactoferrin, carbonic anhydrase type II, and rheumatoid factors. Histological features include fibrosis with lym-phoplasmacytic infiltration of interlobular ducts. The majority of lymphocytes are CD8+ and CD4+ T-lympho-cytes, while B-lymphocytes are less frequent. In general, diagnosis of AIP is established by clinical signs and laboratory and morphological findings. An association with other autoimmune disease such as Sjogren-syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, Crohn's...

SCID Mouse as a Model of Systemic Lupus Erythematosus

Because the SCID mouse is deficient in active T and B lymphocytes, this mutant can be reconstituted with different allogeneic as well as xenogeneic hematopoietic and lymphoid cells. Indeed, studies using SCID mice as the recipients of peripheral blood lymphocytes from patients with SLE or experimental SLE mice have been reported (Duchosal et al. 1990, Reininger et al. 1992, Segal et al. 1992,Vladutiu 1993). Dixon and associates reported that SCID mice reconstituted with peripheral blood lymphocytes from patients with SLE showed the long-term presence of donor-type autoantibodies in their sera, as well as human immunoglobulin deposits in their renal glomeruli (Duchosal et al. 1990). The development of autoimmune disease can also be induced in SCID mice populated with long-term in vitro proliferating B W F1 pre-B cells (Reininger et al. 1992). This SCID model for SLE allows us to directly evaluate the effects of cellular and humoral function in the progression of SLE and enables us to...

Lupuslike Syndromes Related to Drugs and Environmental Factors

Autoimmunity develops in relation to many environmental agents, including drugs, chemical agents, dietary factors, and infectious agents (Mongey and Hess 1996). Until now, more than 70 drugs have been related to the onset of drug-related lupus. In general, skin manifestation is not frequently observed in patients with drug-related lupus, although there are no specific diagnostic criteria. Approximately 25 of

Summary and Conclusion

Needless to say, mouse models are not identical, but are similar, to human diseases. However, they are important in the search for the underlying pathogenesis of autoimmune diseases on the basis of careful evaluation of the similarities and differences between human diseases and these models. If such studies are steadily performed, then inbred or experimental models will become more promising tools for the investigation of CLE.

The Specific Autoantibody Response as a Probe of Disease Mechanisms in Systemic Lupus Erythematosus

There is a growing consensus that the highly specific humoral immune response to autoantigens in systemic autoimmune diseases is T-cell dependent and that flares of disease result when this primed immune system is rechallenged with self-antigen (Diamond et al. 1992, Radic and Weigert 1994). The molecules targeted in SLE are ubiquitously expressed in most nucleated cells but seem to share nothing in common in terms of structure, function, or subcellular distribution in control cells (Casciola-Rosen et al. 1995, Rosen and Casciola-Rosen 1999). The mechanisms responsible for initiation and propagation of the immune response to this highly specific group of autoantigens remain unclear (Bach and Koutouzov 1997). Several years ago, we postulated that although these autoantigens have no apparent unifying characteristics, they likely satisfied the stringent criteria for initiation of a primary immune response at the onset of disease (e.g., presentation in a proimmune context of suprathreshold...

UVR Light Causes Exposure of Autoantigens to the Immune System

SCLE and neonatal LE are associated with the presence of antibodies to Ro SSA and La SSB (Mond et al. 1989, Sontheimer et al. 1982). The importance of anti-Ro SSA antibody in the pathogenesis of SCLE is demonstrated by the fact that the lesions of neonatal LE resolve within a few months of onset, likely with the degradation of maternal antibodies (Lee and Farris 1999). These antibodies are necessary but insufficient for the development of SCLE, demonstrating that there are multiple factors required for the development of autoimmunity.

Decreased Clearance of Apoptotic Cells

There is growing evidence in patients with SLE and autoimmune mouse models that defects in the clearance of apoptotic cells may be important in triggering the immune response. First, in the absence of apoptotic cell uptake, multiple apoptotic bodies can be found in tissues, and these remnants are often associated with the presence of autoimmune disease (Botto et al. 1998, Potter et al. 2003, Scott et al. 2001). Second, deficiencies in the receptor tyrosine kinases Tyro 3, Axl, and Mer lead to autoimmunity (Cohen et al. 2002, Lu and Lemke 2001), and Mer knockout mice have impaired phagocytosis and clearance of apoptotic cells, leading to increased numbers of nuclear autoantibodies (Scott et al. 2001). Third, there is abnormal clearance of apoptotic lymphocytes and fragments by macrophages in SLE (Hermann et al. 1998). Finally, there is impaired uptake of apoptotic cells and macrophages in germinal centers in some patients with SLE (Baumann et al. 2002), and uptake of apoptotic...

Hypochromic Infectious or Toxic Anemia Secondary Anemia

Skin Infection Cytology Image

Among the various causes of lack of iron for erythropoiesis (see Fig.44, p. 129), a special situation is represented by the internal iron shift caused by iron pull of the reticuloendothelial system (RES) during infections, toxic processes, autoimmune diseases, and tumors. Since this anemia results from another disorder, it is also called secondary anemia. The MCH is hypochromic, or in rare instances, normochromic, and therefore erythro-cyte morphology is particularly important to diagnosis. In contrast to exogenous iron deficiency anemias, the following phenomena are often observed, depending on the severity of the underlying condition

In Cutaneous Lupus Erythematosus

Lupus erythematosus (LE) is an autoimmune disorder associated with specific and nonspecific skin lesions, UV sensitivity, anti-DNA antibodies, and increased interferon (IFN)-a p production. Although the histopathology of LE is well defined, the pathogenesis of skin lesions in LE is still insufficiently understood and does not explain all the clinical aspects of LE. Approximately 55 of patients with systemic LE (SLE) develop clinically distinctive skin lesions, whereas patients with specific LE skin disease, such as subacute cutaneous LE (SCLE) or chronic discoid LE, may never develop systemic manifestations (Dubois and Tuffanelli 1964).LE is considered an autoimmune disease. Because several autoimmune processes have been described in LE, it also has been assumed that the cutaneous lesions are based on an autoimmune etiology.

Primary Biliary Cirrhosis

Primary biliary cirrhosis is an autoimmune disease where cytotoxic T-cells attack biliary endothelium causing granulomatous destruction of intrahepatic bile ducts. This destruction leads to cholestasis, then progressive cirrhosis, portal hypertension, and liver failure. Patients often complain of fatigue and pruritus and jaundice is evident. This process is most prevalent in middle-aged women, especially in those with other preexisting autoimmune disorders. Laboratory evaluation elicits an elevated alkaline phosphatase level and positive antimitochondrial antibody. Hepatic transplantation is the only method of long-term treatment.

Ubiquitine Proteasome and Signal Transduction Pathways

Ikb Phospho

Lysosomal proteases are mainly responsible for the degradation of proteins taken up from the cell surface and are involved in 20 of normal protein turnover. Therefore, a nonlysosomal proteolytic enzyme complex, the proteasome, degrades most cellular proteins. Proteasomes, which are localized in both the cytosol and nucleus, represent up to 1 of all cellular proteins in eukaryotes.1 It specifically degrades cytoplasmic and nuclear proteins previously tagged with Ub in an adenosine triphosphate (ATP)-dependent manner. The Ub-proteasome pathway (UPP) is involved in processing and functional modifications of proteins implicated in essential cellular processes,2 such as survival, function, and cell cycling of normal cells. Indeed, intracellular proteolysis is necessary for physiological regulation of transcription, cell cycle, antigen processing, and signal transduction.3 Thus, a deregulation may contribute to tumor progression, neurodegenerative or autoimmune diseases, drug resistance,...

Studies in Experimental Animal Models

The suppressive effect of GA in EAE is a specific one, since GA lacked any suppressive effect on the immune response in several systems - humoral and cellular immune responses to a variety of antigens and vaccination against various induced infections. GA treatment also did not suppress other experimental autoimmune diseases, including myasthenia gravis, thyroiditis, diabetes, and systemic lupus erythematosus.5,17 However, it has been reported to inhibit another autoimmune disorder, namely experimental uveoretinitis,18 a disease interrelated with MBP and EAE. Recently, GA was also shown to be effective in the case of experimental colitis.19 In addition, GA also had an effect on a murine model for graft-versus-host disease, as well as in three systems of graft rejection.20

Elevated Eosinophil and Basophil Counts

Reactive Bronchial Cells

Bacterial and viral infections are both unlikely ever to lead to eosinophilia except in a few patients with scarlet fever, mononucleosis, or infectious lymphocytosis. The second most common group of causes of eosinophilia are allergic conditions these include asthma, hay fever, and various dermatoses (urticaria, psoriasis). This second group also includes drug-induced hypersensitivity with its almost infinitely multifarious triggers, among which various antibiotics, gold preparations, hydantoin derivatives, phenothiazines, and dextrans appear to be the most prevalent. Eosinophilia is also seen in autoimmune diseases, especially in scleroderma and panarteritis. All neoplasias can lead to paraneoplastic eosinophilia, and in Hodgkin's disease it appears to play a special role in the pathology, although it is nevertheless not always present. A specific hypereosinophilia syndrome with extreme values (usually > 40 ) is seen clinically in association with various combinations of...

Childhood Hyperthyroidism

Central to considering the use of radioactive iodine and other treatment options in Graves disease in the pediatric population, is recognition of the natural history of the autoimmune disorder. One must also consider how long antithyroid drug therapy should be continued before moving on to definitive therapy.

Introduction Therapeutic Immunosuppressant Use In Women Of Childbearing

Women receiving organ transplants or suffering from cancer or autoimmune disease are the most common candidates for therapeutic immunosuppressive drug regimens during pregnancy (Forastiere et al. 2003 Tournigand et al. 2003 Hurtova et al. 2001 Millan et al. 2003). The chemotherapeutic drugs used to treat cancer are not administered with the intent of causing immune suppression. However, many chemotherapeutic agents (e.g., cyclophosphamide, chlorambucil, methotrexate, melaphalan) have potent immunosuppressant properties (Furst et al. 1989 Folb et al. 1990 Connell and Miller 1999), which has led to use of some of these agents in humans for therapeutic immune suppression. The widely employed antineoplastic agent cyclophosphamide is perhaps best recognized in this regard, having also been used as an immunosuppressant for maintaining organ transplants and regulating autoimmunity (Deweys et al. 1970 Calabresi and Parks, 1985). Additional classes of powerful immunosuppressive drugs are...

Experimental Autoimmune Encephalomyelitis in the Mouse

Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell-mediated autoimmune disease. The disease is characterized by perivascular CD4+ T cell and mononuclear cell inflammation and subsequent primary demyelination of axonal tracks in the central nervous system, leading to progressive hind-limb paralysis. EAE provides a powerful model for the study of the pathogenesis and immune regulation of CD4+ TH1-mediated tissue damage and is generally considered to be a relevant model for the human immunemediated demyelinating disease multiple sclerosis. In the SJL (H-2s) mouse, the disease is characterized by a relapsing-remitting course of paralysis, which allows assessment of the efficacy of various immunoregulatory strategies in a progressive autoimmune disease setting. In other mouse strains, such as PL J (H-2u) and B10.PL (H-2u), the disease is normally acute and self-limiting, and is not characterized by clinical relapses.

The BB Rat as a Model of Human Insulin Dependent Diabetes Mellitus

Two inbred lines of BB have been used in the majority of published studies using this model system these rats are designated as diabetes prone (DP-BB Wor) and diabetes resistant (DR-BB Wor). DP-BB Wor rats of both sexes spontaneously develop IDDM between 55 and 110 days of age. They are severely deficient in circulating T lymphocytes that express the maturational alloantigen RT6. Transfusion of histocompatible normal rat T cells to young DP recipients prevents spontaneous disease provided that RT6+ T cells become engrafted. In contrast, DR-BB Wor rats have normal levels of circulating RT6+ T cells and do not develop spontaneous autoimmunity. Several intervention strategies can be used to induce the disease in DR-BB Wor rats. In vivo depletion of RT6+ T cells using a cytotoxic monoclonal antibody, together with certain immunostimulatory agents, induces IDDM in > 90 of treated animals. The two basic protocols describe diagnosis (see Basic Protocol 1) and prevention (see Basic Protocol...

Adoptive Transfer Of Iddm

This protocol describes the adoptive transfer of insulin-dependent diabetes mellitus (IDDM) to athymic nude rats by diabetes-resistant (DR)-BB rat cells (McKeever et al., 1990). Recipients are histocompatible (RT1u) WAG nu nu rats that are free of spontaneous autoimmune disease and lack thymus-derived T cells. Donor cells are peripheral lymph node cells from DR-BB rats made diabetic by treatment with anti-RT6.1 antibody and poly(IC) (see Alternate Protocol 1). The adoptive transfer of diabetes is mediated by diabetogenic T cells from DR-BB rats, and is cell dose-dependent (Whalen et al., 1994). DR-BB rats are chosen as donors because, unlike diabetes-prone (DP)-BB donors, successful transfer of diabetes does not require large cell doses or prior in vitro activation of T cells (see Critical Parameters). The basic adoptive transfer protocol described here can also be used to study not only those RT6- T lymphocyte subsets active in induction of IDDM, but also RT6+ T cells involved in...

Retraction of the Eyelid

Graves Orbitopathy

INTRODUCTION Eyelid retraction may be seen as a sequel to trauma, surgery, or orbital disease. The most common cause is Graves' disease. This is a systemic autoimmune disease in which the primary target of the immune response is directed toward the TSH receptor of the thyrocyte. Extrathyroidal manifestations principally involve specific fibroblasts of the orbit and of the pretibial dermis. The immune reaction is mediated by anti-TSHR T-cells and results in the release of a Th-1 cytokine profile, proinflammatory mediators, and growth factors that cause deposition of glycosaminoglycans, adipose proliferation, and collagen synthesis with chronic fibrosis. Through the phenomenon of epitope spreading, adjacent tissues become involved, including the extraocular and eyelid muscles, and connective tissue sheaths and fascia.

Experimental Autoimmune Uveoretinitis in the Rat and Mouse

Experimental autoimmune uveoretinitis (EAU) in rats and mice is a prototypic T cellmediated autoimmune disease that targets the neural retina and related tissues. The model is used to represent human sight-threatening inflammatory eye diseases that are believed to have an autoimmune etiology, and to study basic mechanisms of tolerance and autoimmunity to organ-specific antigens from immunologically privileged sites. EAU is an induced, as opposed to spontaneous, autoimmune disease model. It can be elicited by peripheral immunization with a number of purified retinal proteins or peptides derived from them (uveitogens) in adjuvant, or by adoptive transfer of lymphocytes specific to these antigens. The hallmarks of EAU are onset of ocular inflammation, disruption of the retinal architecture, and partial to complete destruction of the photoreceptor cell layer. The type, number, and size of lesions serve as a basis for a semiquantitative grading system used to score disease severity. A...

Induction Of Eau In The Rat By Active Immunization

The course of disease in the Lewis rat is typically acute and of short duration. The time of onset will vary depending on the severity of the developing disease and on the antigen and mode of induction used. The immunization protocol described here, using as antigen 30 Mg of peptide R16 of bovine IRBP (amino acids 1177-1191, sequence ADG-SSWEGVGVVPDV Sanui et al., 1989), typically results in disease onset on day 9 or 10. In contrast, immunization with 30 g of S-Ag in complete Freund's adjuvant (CFA) usually results in onset between days 12 and 14. If PTX is used as additional adjuvant, the time of onset will be earlier by up to 3 days and will usually be more uniform than without pertussis. B. pertussis is the cause of the childhood disease whooping cough, and its toxin has been known for over 30 years to enhance the expression of autoimmune disease in experimental animals. The adjuvant effect of PTX is complex and only partly characterized it includes inhibition of lymphocyte...

Induction Of Tolerance To Experimental Autoimmune Thyroiditis

Susceptible mice are normally unresponsive when immunized with mouse thyroglobulin (MTg) without adjuvant. However, they become resistant to experimental autoimmune thyroiditis (EAT) induction after pretreatment with two doses of deaggregated MTg (dMTg) given 7 days apart. Within 3 days after the second dose, EAT induction is virtually suppressed, and resistance lasts for > 73 days. Suppression is mediated by CD4+ cells. Thus, this protocol permits the study of regulatory T cell mechanisms in an autoimmune disease it simulates the endogenous release of circulatory MTg following thyroid-stimulating hormone infusion which also leads to CD4+ T-cell-mediated suppression. Note that two groups of mice are used tolerized and nontolerized mice.

Inducing And Evaluating Eamg

The nicotinic acetylcholine receptor (AChR) is purified from the electric organs of Torpedo californica (see Support Protocol 1), emulsified in complete Freund's adjuvant (CFA), and used to induce experimental autoimmune myasthenia gravis (EAMG). Clinical signs of myasthenia gravis (MG) usually become evident days to weeks after the second immunization, although some mice ( 10 ) will develop signs 20 to 30 days after the first immunization. Mice that demonstrate muscle weakness are injected with neo-stigmine, an acetylcholinesterase inhibitor, to test for temporary improvement in muscle strength. EAMG can be evaluated quantitatively by electromyography (see Support Protocol 3), by a radioimmunoassay for antibodies to AChR (see Support Protocol 4), or by measuring muscle AChR (see Support Protocol 5).

Use Of Therapeutic Immunosuppressants During Pregnancy

Many collective reports and considerable data are available, therefore, showing increased pregnancy complications in organ transplant recipients, although apparently healthy children appear to be the most common result of such pregnancies. Relatively few studies have monitored immune development in these children, however, and later-life immune dysfunctions, including deficits or exacerbated responses (e.g., increased autoimmune diseases), remain a concern (Holladay 1999 Prevot et al. 2002). Long-term follow-up data from infants exposed to therapeutic immuno-suppressive drug regimens throughout pregnancy also remain limited due to the relatively recent advent of this population, and will be required to determine if postpubertal or adult immune dysfunctions are more prevalent in humans exposed to immune-suppressive drugs during development.

Evaluating Eamg By Assaying For AntiachR Antibodies

Myasthenia gravis (MG) is primarily an antibody-mediated disease, so measuring serum levels of anti-acetylcholine receptor (AChR) antibodies by radioimmunoassay (Lindstrom et al., 1981 Christadoss and Dauphinee, 1986) can be used to evaluate mice with experimental autoimmune MG (EAMG). Because the antibodies that are pathogenic in EAMG are cross-reactive with mouse muscle AChR, it is appropriate to measure antibody to mouse muscle AChR. This assay can also be used to measure antibodies to Torpedo californica AChR to determine that a humoral response to Torpedo californica AChR has been established however, the presence of such antibodies is irrelevant to disease pathogenesis.

Developmental Immunotoxicity In Rodents Exposed To Therapeutic Immunosuppressants During Pregnancy

Tion, resulting in increased autoimmunity (i.e., syngeneic graft-vs.-host disease) in the host animals (Glazier et al. 1983). Such results raise clear questions about the ability of cyclosporine A to induce or exacerbate autoimmune disease in gestationally exposed individuals. In support of this possibility, newborn mice dosed daily with cyclosporine A for the first week of postnatal life developed organ-specific autoimmune disease (Sakaguchi and Sakaguchi 1988, 1989). Such disease elicited in rodents appeared to be related to interference by cyclosporine A with the production or expansion of self-reactive T cells in the thymus (Sakaguchi and Sakaguchi 1992). Similarly, Classen (1998) found that cyclosporine A exposure during pregnancy in mice greatly increased prevalence of autoimmune disease in the offspring. These collective observations in irradiated and perinatal rodent exposure models, where new immune systems are being established in the presence of cyclosporine A, may suggest...

Detection of AntiRoSSA Antibodies

Detection of ANA, immunofluorescence microscopy, represents a valuable tool for both the clinician to identify certain autoantibody specificities to diagnose subsets of systemic autoimmune diseases and the biomedical researcher to analyze the architecture and function of the cell nucleus. Immunofluorescence enables the visualization of antigens and the identification of structures in cells and tissues. The emitted signal of excited fluorochromes is viewed against a black background, thus providing high contrast. In addition, fluorescence imaging delivers superb specificity. These advantages of immunofluorescence techniques can be further enhanced by confocal laser scanning microscopy. Confocal microscopes differ from conventional (wide-field) microscopes because they fade out out-of-focus signals. In a confocal microscope, most of the out-of-focus light is excluded from the final image, which greatly increases the contrast and the visibility of fine details in the specimen. Thus,...

Cavernous sinus and orbital processes

An autoimmune disorder in which the extraocular muscles are enlarged and infiltrated with inflammatory elements, eventually leading to a restrictive oculomyopathy and motility disorder. The onset of the ensuing painful exophthalmos and chemosis, diplopia and lid retraction is rapid. The clinical picture needs to be differentiated in adults the condition results from idiopathic orbital inflammation, and in children it is caused by rhabdomyosarcoma or orbital cellulitis Myasthenia gravis

Treatment Approaches for Children

Based on what is now known about the risks and benefits of different treatments and the pathogenesis of Graves' disease, we can now be more selective in our approach to therapy. To reduce treatment risks and expedite cures, the treatment of the child or adolescent with Graves' disease can be guided by the patient's age and the nature of the intrinsic autoimmune disease.

Immunologic Observations In Children Of Organ Transplant Recipients

Pilarski et al. (1994) analyzed peripheral blood T lymphocytes from seven children exposed to cyclosporine A and four children exposed to azathioprine during development. A slight delay in T cell development was found in children exposed to cyclosporine A, a slight acceleration of such development in children exposed to azathioprine, and no T cell development affect in children exposed to both cyclosporine A and azathioprine. From 1 to 6 years of age the children exposed to cyclosporine A showed a decreased proportion of T cells expressing a high density of CD29, the bl-integrin linked to ability to respond to recall antigens and to home sites of infection. However, the study children showed no outward signs of immune deficiency, and the authors concluded that the developmental immunosuppressant exposure was not likely to cause immune deficiency or autoimmune disease. Recently, however, Scott et al. (2002) reported autoimmune complications in the pregnancy of a 23-year-old daughter of...

Lidocaine hydrochloride

Metabolites may contribute to toxicity in a single dose. Uses Local dental anesthesia, peripheral nerve block, caudal anesthesia, epidural anesthesia, spinal anesthesia, surgical anesthesia. Contraindications See also Amide Local Anesthetic Agents. Special Concerns Elderly, large doses of lidocaine in patients with myasthenia gravis.

Factors Of Acute Rejection Of The Transplanted Heart

The importance of stress proteins or heat shock proteins (Hsp) has been established in various conditions such as inflammation, infection, autoimmune disease, and tumor immunity. The role of stress proteins and their correlation with the degree of cellular rejection of the transplanted human heart was first documented by Moliterno et al.21 During rejection, increased Hsp expression is a part of the stress response. Hsp expression increases in three stress stages The first is a physiological stress secondary to the trauma of the transplant procedure and ischemia reperfusion injury (Hsp60, Hsp72). The second is associated with infiltration of lymphocytes in the allograft. Finally, during the third stage, the stress response to the inflammatory processes associated with rejection leads to increased expression of Hsp, including lower molecular weight proteins, which may represent proteolytic degradation of Hsp (Duquesnoy5).

Discharge And Home Healthcare Guidelines

646 Myasthenia Gravis Myasthenia Gravis yasthenia gravis (MG) is an autoimmune disease that produces fatigue and voluntary muscle weakness, both of which become worse with exercise and improve with rest. The muscles that are frequently involved include those for eye and eyelid movement, chewing and swallowing, breathing, and movement of the distal muscles of the extremities. This weakness progressively worsens during the day or at times of stress, so the greatest fatigue is likely to occur at the end of the day. MG frequently accompanies disorders of the immune system or the thyroid gland. MG, thought to be an autoimmune disorder, is caused by a loss of acetylcholine (ACh) receptors in the postsynaptic neurons at the neuromuscular junction. About 80 of all MG patients have elevated titers for ACh receptor antibodies, which can prevent the ACh molecule from binding to these receptor sites or can cause damage to them. MG is often associated with thymic tumors. There appears to be...

Primary Nursing Diagnosis

Assist the patient in working through any feelings of depression that can occur because of MG's profound effect on lifestyle, roles, and responsibilities. Depression can also result from the disbelief by others of the MG diagnosis because the patient may appear to have suspiciously fluctuating symptoms. Provide encouragement to these patients to live full, productive lives. Educate the family and significant others on the fluctuation of MG, and place them in contact with support groups and the Myasthenia Gravis Foundation.

Induction Of Eam In Mice By Adoptive Transfer Of Cardiac Myosinstimulated T Cells

It may be experimentally useful to induce EAM in mice in the absence of endogenous cell-mediated immunity or exogenous adjuvants. EAM can be induced by the transfer of cardiac myosin-stimulated T cells from immunized congenic C.B-17 donors into immu-nodeficient SCID (Severe Combined Immunodeficient) recipients. The SCID mice have no functional T or B cells and are an excellent model system to study the role of specific cellular effectors on the induction and pathogenesis of EAM moreover, although recipient irradiation is often required for successful adoptive transfer of autoimmune diseases in mice, use of SCID recipients makes this unnecessary in this procedure. EAM has been successfully induced by adoptive transfer in BALB c mice without recipient irradiation, using lipopolysaccharide to stimulate the recipients prior to transfer of stimulated T cells (see Bachmaier, 1999). The donor C.B-17 mice are immunized with purified cardiac myosin, as in Basic Protocol 1, and splenic T cells...

Experimental New Topical Therapeutic Agents

Another very promising development in topical dermatotherapy are the calcineurin inhibitors. Tacrolimus and pimecrolimus are prototypes of a class of immunosuppressive agents with a great potential in the treatment of inflammatory skin diseases, atopic dermatitis above all, but also in cutaneous autoimmune diseases. These pharmaceuticals have been shown to act at a point in activation of T lymphocytes that lies between T-cell receptor ligation and the transcription of early genes. Therefore, besides atopic dermatitis, all T-cell-mediated skin diseases, such as lichen planus, represent a potential area of use. Animal studies have demonstrated a beneficial effect of systemic tacrolimus in murine SLE (Furukawa et al. 1995). Similarly, systemic application of tacrolimus was used successfully in patients with SLE whose active disease had been poorly controlled by conventional treatments (Ruzicka et al. 1999). Consequently, topical calcineurin inhibitors were applied to treat the malar rash...

Induction Of Mercury Disease In Bn Rats

Mercury-induced autoimmune disease is produced by subcutaneous injections of HgCl2 (100 g 100g body weight) three times a week over the course of 1 month. It has also been reported that injecting rats for 10 days is sufficient to induce the disease as well as the regulatory phase (Aten et al., 1988).

Measurement Of Antilaminin Antibody Titer In Rats

The production of anti-laminin IgG1 autoantibodies is one of the major features of HgCl2-induced autoimmune disease, since they are also present in glomerular Ig deposits of diseased rats. An increase in anti-laminin antibody titer is found from day 7 after the first injection of HgCl2, with a peak at day 14, and returns to normal after 1 month. The ELISA described in this protocol uses laminin-coated plates to detect anti-laminin antibodies in serum samples from such rats. For more details of the design and optimization of ELISA assays, if needed, see unit 2.1.

Detection Of Renal Immunoglobulin Deposits In HgCl2Treated Rats

The kidney is the main target organ of HgCl2-induced autoimmunity in BN rats. Kidneys appear normal under light microscopy. Beginning at day 14 after treatment, rats develop proteinuria, which is associated with linear IgG deposits along the glomerular capillary wall. Tubular basement membranes are also linearly stained. Later (after 1 month), the pattern of immunofluorescence is modified by granular IgG deposits in glomeruli and in arteriolar walls. Both patterns of fluorescence are due to the presence of kidney-bound anti-laminin antibodies. Renal samples may be addressed to pathologists for staining with fluoresceinated anti-rat IgG, or processed in the laboratory as described below.

Measurement Of Il4 mRna Expression In Bn Rat Spleen Cells Exposed In Vitro Or In Vivo To HgCl2

HgCl2 induces in vitro mRNA IL-4 gene expression in normal BN T cells but not in LEW T cells. IL-4 gene expression is probably a crucial factor for susceptibility to the development of autoimmunity and it may condition the development of autoreactive T cells into pathogenic TH2 cells. This support protocol may be used to test for this condition. Total cellular RNA is obtained from spleen or lymph node cells of rats rendered autoimmune by HgCl2 treatment (see Basic Protocol 1) or, alternatively, from cells of untreated rats and then treated with HgCl2 in vivo. Synthesis of the cDNA by reverse transcriptase follows, and the cDNAs are then amplified by PCR using primers that are specific for IL-4. PCR products are visualized on an ethidium bromide-stained agarose gel and the IL-4 RNA levels are measured as arbitrary densitometric units as the ratio of the band intensity for IL-4 to that for p actin run on the same gel.

Autoimmune Ovarian Disease Induced by Immunization with Zona Pellucida ZP3 Peptide

Unlike other autoimmune models, the target organ in experimental ovarian autoimmune disease can easily be removed by surgery without jeopardizing the animal's life. For example, by eliminating ZP3 with bilateral ovariectomy at any age, the requirement of endogenous antigen in tolerance and pathogenic T cell activation can be investigated. By comparing the changes in the two ovaries of the same mice, one can obtain information on the progression of autoimmune disease in the same animal. In addition, a syngeneic ovarian graft in the ovariectomized female or male mice can be used to monitor pathogenic autoimmune responses in mice without endogenous ZP3. This autoimmune model has several versatile features that have been successfully exploited in investigating some fundamental issues of self tolerance and autoimmune disease mechanisms (Tung et al., 1997). This unit describes the immunologic properties of the ZP3 peptides (Table 15.17.1), the method of active autoimmune oophoritis...

Neonatal Ovariectomy In Mice

Murine ZP3 is first detected at birth. Therefore, neonatal oophorectomy prevents exposure of the developing immune system to endogenous ZP3. This approach can be used to investigate the physiologically expressed endogenous antigen on the acquisition of self tolerance or the induction of autoimmune disease during the neonatal period (Garza et al., 1997). In these mice, a subsequent ovarian graft can be used to monitor the pathologic response of the target organ (see Support Protocol 4). The technique for neonatal ovariectomy can be applied to mice during the first week of life.

Choice of SLE Animal Models

SLE animal models are often used to test the effects on systemic autoimmune disease of therapeutic interventions (e.g., drugs, monoclonal antibodies, or environmental or nutritional conditions). They have also been useful in assessing the role of certain genes on autoimmunity for example, many investigators have bred cytokine gene-deleted mice to the autoimmune strains, or have examined effects of receptor knockouts or of enforced transgene expression on disease. The most commonly used SLE mouse strains are listed in appendix 1E. For straightforward drug or monoclonal antibody administration, the NZB NZW hybrids or the very similar NZB SWR mice are probably the best. Their disease resembles human SLE and is not complicated by the extreme lymphadenopathy observed in MRL lpr mice. The MRL lpr strain shows more rapidly developing disease and may be preferable if vasculitis is important in the model. For breeding of other genes to autoimmune strains, B6 lpr or B6 gld should be considered....

Pcr Based Genotyping Of The faslpr AND fasLgld Mutations

Mice bearing the faslprmutation of Fas or the fasLgldmutation of its ligand FasL have been extensively studied as spontaneous models of lupus-like systemic autoimmunity (for further discussion see Background Information Zhou et al., 1991 Weintraub et al., 1998 Seo et al., 2002). The subsequent discovery of the pleiotropic function of Fas and FasL in other aspects of normal cell biology has extended their popularity beyond this narrow area of use (Griffith et al., 1995 O'Connell et al., 1996). The generation of Fas- or FasL deficient mice on different strain backgrounds or in combination with other genes has proven to be informative in elucidating the many roles of this receptor-ligand pair. For example, Roark et al. (1995) demonstrated that an Ig heavy chain transgene from an anti-dsDNA hybridoma produces anti-DNA auto antibody when combined with the faslpr mutation, yet does not generate anti-DNA in normal mice (Roark et al., 1995). The need to generate Fas and FasL mutant mice...