Curing Your Autoimmune Diseases Forever

Autoimmune Paleo Cookbook

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

Autoimmune Paleo Cookbook Summary

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Highly Recommended

This is one of the best books I have read on this field. The writing style was simple and engaging. Content included was worth reading spending my precious time.

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

Pemphigus Vulgaris An Autoimmune Disease

The immune system normally produces defensive antibodies that selectively attack foreign substances and leave the normal tissues of our bodies alone. But in a family of disorders called autoimmune diseases, antibodies fail to distinguish our own cells and tissues from foreign ones. Such misguided antibodies, called autoantibodies, thus launch destructive attacks on our own bodies. (Autoimmune diseases are discussed in more detail in chapter 21.) One such disease is pemphigus vulgaris28 (PEM-fih-gus vul-GAIR-iss), a disorder in which autoantibodies attack the proteins of the desmosomes in the skin and mucous membranes. This breaks down the attachments between epithelial cells and causes widespread blistering of the skin and oral mucosa, loss of tissue fluid, and sometimes death. The condition can be controlled with drugs that suppress the immune system, but such drugs reduce the patient's immune defenses against other diseases.

Is there a connection between virus infection and autoimmune disease

A comment about the relationship of virus infection to autoimmune disease in general is warranted. Infectious mononucleosis occurs only when adolescents or young adults are infected with the EBV. The symptoms of infectious mononucleosis (and other autoimmune phenomena) occur as a result of the immune reaction to the viral infection. Dr. Gertrude Henle, who discovered the relationship between EBV and infectious mononucleosis, studied a possible link between MS and this virus it was concluded that there was none. Research continues because of consistently high antibody titers to EBV in many patients with MS. HSV-6 and HSV-7 are very closely related families of viruses. Indeed, their structure (EBV, HSV-6, and HSV-7) is two thirds identical, which has made

Measurement of Cytokines in Autoimmune Disease

Systemic autoimmune diseases are characterized by extensive alterations in immune system function, with cytokines and autoantibodies contributing to impaired immunoregulation and tissue damage. Characterization of the expression and function of cytokines is important for elucidation of pathogenic mechanisms and for identification of therapeutic targets and strategies. We reviewed the utility of assays that reflect individual variability in cytokine gene sequence, expression of messenger ribonucleic acid (mRNA) or protein, as well as measurement of expression of target genes regulated by cytokines. Real-time reverse transcriptase polymerase chain reaction and intracellular staining for cytokine expression are two sensitive and quantitative approaches for analysis of cytokine mRNA and protein, respectively. Detailed methods are provided for these assays. Key Words Assay autoimmunity cytokine interferon interleukin. The immune system alterations that characterize systemic autoimmune...

Immunogenetic Factors in Autoimmunity

Other Factors Causing Tolerance Breakdown Genetic Regions Associated with Autoimmune Disease Many genetic loci are likely to contribute to the genetic susceptibility to autoimmune diseases. To date, however, only three genes gene regions have been consistently associated with multiple autoimmune diseases, namely the human leukocyte antigen class II region on chromosome 6p21, the cytotoxic T-lymphocyte-associated antigen-4 gene on chromosome 2q33, and the PTPN22 encoding lymphoid tyrosine phosphatase on chromosome 1p13. Further genes have been identified that contribute specifically to a particular disease, and many putative genes are awaiting replication in further data sets. Identification of susceptibility loci is confounded by the involvement of environmental factors in many of these conditions and by their complex polygenic nature requiring large data sets to detect genes of small effect. To identify genes that may increase susceptibility to these diseases, it is necessary to...

Muscular Dystrophy and Myasthenia Gravis

Myasthenia Gravis Eye Muscles

Myasthenia gravis17 (MY-ass-THEE-nee-uh GRAV-is) (MG) usually occurs in women between the ages of 20 and 40. It is an autoimmune disease in which antibodies attack the neuromuscular junctions and bind ACh receptors together in clusters. The muscle fiber then removes the clusters from the sarcolemma by endocytosis. As a result, the muscle fibers become less and less sensitive to ACh. The effects often appear first in the facial muscle (fig. 11.25) and commonly include drooping eyelids and double vision (due to weakness of the eye muscles). The initial symptoms are often followed by difficulty in swallowing, weakness of the limbs, and poor physical endurance. Some people with MG die Figure 11.25 Myasthenia Gravis. This disorder especially affects the muscles of the head. It is characterized by drooping of the eyelids, weakness of the muscles of eye movement, and double vision resulting from the divergence (strabismus) of the eyes. Figure 11.25 Myasthenia Gravis. This disorder especially...

Fc Receptor Structure and the Design of Antiinflammatories New Therapeutics for Autoimmune Disease

Introduction - Inflammation caused by immune complexes in the blood vessels (vasculitis), the kidney (glomerulonephritis) and in the joints (arthritis) is a major cause of morbidity in autoimmune diseases. It is also one of the major mechanisms of tissue destruction in diseases including rheumatoid arthritis especially in the extra articular disease, immune thrombocytopenia (ITP), systemic lupus erythematosus (SLE) and Wegner's granulomatosis. Whilst clear that in autoimmune diseases the likely initiation of the autoimmune process is a corruption of T cell regulation, the tissue damage and the perpetuation of disease are due to immune complexes. In the last decade, the role of Fc receptors as major initiators of inflammation caused by immune complexes has become more precisely defined with the use of recombinant Fc receptor (FcR) and gene knock-out or transgenic mice (1-8). Fc receptors are cell surface glycoproteins of inflammatory leukocytes and lymphocytes that specifically bind...

Leptin and the hygieneaffluence hypothesis in autoimmunity

Insulin Resistance Images

Fewer infections and more autoimmunity, observed in affluent countries, lead us to postulate the so-called leptin hypothesis to explain this phenomenon (42). During the past century, in the industrialized world, the incidence of infections has diminished greatly because of improved hygienic conditions, better nutrition, vaccination, and the use of antibiotics (42). Interestingly, in affluent and more-developed societies, epidemio-logical studies have revealed a parallel increase in the incidence of autoimmune diseases, whereas these diseases have become less common in less-developed nations. Thus, susceptibility to infection and autoimmunity appear to be inversely related (42). Several factors other than nutrition might contribute to this relationship, such as the environment, genetic background, other hormones, stress, and exposure to specific pathogens (Fig. 1). Nevertheless, changes in diet and calorie intake and, subsequently, serum leptin concentrations should be taken into...

Basic Mechanisms in Autoimmunity

Escape of Self-Reactive T Cells from the Thymus Genetic Effects on Autoimmunity Molecular Mimicry Autoimmunity Provoked Activation of self-reactive T cells is a critical step in the pathogenesis of autoimmune diseases. The mechanisms underpinning this remain elusive and difficult to prove in the complex human system. The most intriguing hypotheses and the mechanisms that control T-cell activation and regulation, which have been studied in vitro and in experimental animal models, will be discussed in this chapter together with their relevance to human diseases. Key Words Autoimmune diseases, molecular mimicry, disease mechanisms, T cells, cryptic epitopes, T-cell activation, T-cell tolerance, animal models. The underlying basic mechanisms of autoimmune reactivity have been puzzling immunologists for decades. What makes the immune system, which has evolved over the millennia to combat the assaults of invading microorganisms, turn against the organism itself It now seems clear that...

What is autoimmunity

Autoimmunity is an immune reaction against self. Autoimmune disease implies that tissue damage is a result of an autoimmune (autoallergic) reaction. This may be the result of antibody production or as a result of lymphocytes (CD4+) causing damage directly or in concert with macrophages. There is a third type of immunologic reaction, an antibody-mediated tissue damage in which different lymphocytes (CD8+) cause additional damage. All three types of reactions are Autoimmunity

Autoimmune disorders

SLE is a chronic relapse and remitting autoimmune disease that affects multiple organ systems including the skin, joints, kidneys and nervous system. It initially manifests as fever, malaise, joint pains, myalgias and fatigue, and is virtually always accompanied by the presence of a diverse but characteristic set of autoantibodies 38 . In addition to organ-specific damage mediated by IC-triggered macrophage and neutrophil activation, Syk can potentially affect SLE pathophysiology in several other ways. The genetic contributions to disease susceptibility and severity are complex and involve multiple traits that implicate abnormalities of both the innate and adaptive immune systems 38 . Microarray studies with peripheral blood leukocytes from SLE patients have helped identify ''gene signatures'' typically found as a result of the action of type I interferons (IFNs) 39,40 . Interestingly, ICs containing nucleic acids, which are commonly found in SLE affected blood, were shown to be...

General considerations

There has been much debate about the importance of the different T cell subsets, as there is conflicting evidence about the numbers of CD4+ and CD8+ T cells and their ratio in the histopathology of active MS lesions (Babbe et al., 2000 Sobel, 1989 Traugott et al., 1983a Wucherpfennig et al., 1992). Influenced by the genetic association of MHC class II genes and MS (Haines et al., 1996), and by the animal model for the human disease, CD4+ T cells have been in the spotlight for many years. There is compelling evidence that CD4+ T cells recognizing antigenic epitopes from the myelin sheath can, in many species, initiate a relapsing-remitting disease course that mimics the human disease both clinically and histologically. Findings in this and other autoimmune disease models led to the hypothesis that autoimmune disorders arise if autoaggressive immune responses generate self-recognizing T cells that attack the target organ. This concept traditionally centered around the hypothesis of self...

Systemic Inflammatory Disorders

Several systemic cutaneous disorders may lead to diffuse esophageal involvement. Epidermolysis bullosa comprises several rare disorders in which blister formation occurs after minor trauma. Dysphagia, pain, and bleeding may result (111). Pemphigus vulgaris is an autoimmune disorder in which large bullae form spontaneously, commonly affecting the esophagus. Esophageal bleeding is less common yet possible in bullous pemphigoid, a chronic disease characterized by bulla formation and circulating autoantibodies to the basement membrane. Corticoster-oids are used in the management of all these disorders. Stricturing is possible, and dilation may be necessary (111,112).

Differential Diagnosis

The most frequent admission diagnoses of infants later found to have IB include sepsis, viral syndrome, dehydration, cerebrovascular accident, failure to thrive, myasthenia gravis, poliomyelitis, Guillain-Barre syndrome, encephalitis, and meningitis. Several hereditary-endocrine or metabolic disorders considered are amino acid metabolism disorder, Werdnig-Hoffmann disease, and drug or toxin ingestion. Diagnoses less frequently considered include subdural effusion, infectious mononucleosis, brain stem encephalitis, animal bite or sting, organopho-sphate poisoning, carbon monoxide intoxication, methemoglobinemia, myoglobinuria, glycogen or lipid storage diseases, benign congenital hypotonia, congenital muscular dystrophy, myotonic dystrophy, congenital myopathy, anterior horn cell syndrome, atonic cerebral palsy, and diffuse cerebral degenerative disease.

TCell Receptor Signaling

From Methods in Molecular Medicine, Vol. 102 Autoimmunity Methods and Protocols Edited by A. Perl Humana Press Inc., Totowa, NJ Basically, in addition to the complete investigation of the expression of various signaling molecules, T-lymphocyte signaling is analyzed at four stages to compare the signaling (1) early (1, 2, and 3 min) tyrosine phosphorylation of the cellular proteins, (2) intracellular calcium response, (3) expression of cytokines, and (4) cell proliferation. In normal T cells, the intensity of the T-cell signaling directly correlates with the level of expression of the critical T-cell signaling molecule, such as TCR -chain. TCR -chain is the limiting factor in T-cell receptor assembly, transport, and surface expression and receptor function (5,6). However, in autoimmune disorders, the cell signaling remains abnormal and appears to correlate inversely with the level of TCR -chain. The exact nature of the mechanism that triggers the inverse correlation has become a topic...

Future Avenues Of Investigation

Understanding the relationship of the immune system and autoimmune diseases to androgens. Although not discussed in the text, an important aspect of sexual dimorphism is that females are much more likely to develop autoimmune diseases than men. Further investigation is required to understand the role of physiological concentrations of androgens in the normal function of the immune system and possible protection against the development of autoimmune disorders (see ref. 71).

And Jos Santos Alvarez

Adipose tissue is no longer considered as a mere energy store, but an important endocrine organ that produces many signals in a tightly regulated manner. Leptin is one of the most important hormones secreted by the adipocyte, with a variety of physiological roles related with the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. Leptin's modulation of the immune system is exerted at the development, proliferation, anti-apoptotic, maturation, and activation levels. The role of leptin in regulating the immune response has been assessed in vitro as well as in clinical studies. Both the innate and adaptive immune responses are regulated by leptin. Every cell type involved in immunity can be modulated by leptin. In fact, leptin receptors have been found in neutrophils, monocytes, and lymphocytes, and the leptin receptor belongs to the family of class I cytokine receptors. Moreover, leptin activates...

Regulatory Th cells as key players in the control of chronic neuroinflammation

Immune tolerance is needed to preserve immune homeostasis and to prevent autoimmunity while ensuring effective host defense. Active mechanisms of immune regulation have been largely attributed to specialized T cell subsets termed Treg, which can be roughly divided into thymus derived and acquired Treg. Thymus derived ''naturally occurring'' CD4+CD25+ T cells (nTreg) are generated in the process of T cell maturation, and express the distinct lineage marker and transcription factor FoxP3. CD4+CD25+FoxP3+ T cells have proved crucial for self-tolerance since targeted gene deletion leads to early fatal multiorgan lymphoproliferative autoimmune disease (Fontenot et al., 2005). In EAE, nTreg have been associated with protection and recovery from clinical symptoms. Anderton and colleagues showed that IL-10 producing CD4+CD25+FoxP3+ T cell accumulation in the CNS was associated with, and necessary for, clinical remission, which corresponded to a high in vitro regulatory potency of Treg...

Leptin and pathophysiology of the immune system

Recent data also suggest the possible role of leptin in the pathophysiology of some autoimmune diseases. This has already been demonstrated in some animal models, such as the experimental autoimmune encephalomyelitis, antigen-induced arthritis, models of type 1 diabetes, autoimmune colitis, and experimental hepatitis, as well as some clinical studies (15,17,72-74). However, this is the subject of other chapters in this book, and we are not reviewing the possible role of leptin in the pathophysiology of immune diseases.

B cells and antibodymediated immune responses in chronic neuroinflammation

With low-level presence of B cells in chronic autoimmunity in the CNS (Esiri, 1977 Magliozzi et al., 2004). These findings lead us to hypothesize that intrathecal antibody synthesis in classic MS reflects a nonspecific recruitment of antibody-secreting cells into the CNS by inflammatory cues released in the process of T cell-mediated autoimmune inflammation. In situ, the provision of survival factors for plasma cells leads to long-term antibody production in the CNS. Indeed, myeloablative therapy in MS followed by successful autologous hematopoietic stem cell transplantation left OCB presence in the CSF unchanged, most likely resulting from the resistance of long-lived plasma cells to irradiation, cytostatics, and depletion by an anti-CD20 antibody (Rituximab, see below Saiz et al., 2001).

Leptin in liver and kidney immunemediated disorders

Most recently, protection from autoimmunity in ob ob mice has been observed in experimentally induced glomerulonephritis (EIG) (32). In this immune-complex-mediated inflammatory disease induced by the injection of sheep antibodies specific for mouse glomerular basement membrane into mice preimmunized against sheep IgG, the authors observed renal protection of ob ob mice associated with reduced glomerular-crescent formation, reduced macrophage infiltration, and glomerular thrombosis. These protective effects were associated with concomitant defects of both adaptive and innate immune response (testified by reduced in vitro proliferation of splenic T-cells and reduced humoral responses to sheep IgG, respectively). In spite of this trend, in one experiment, ob ob mice developed histological injury, but they were still protected from disease, indicating that defects in effector responses were present in ob ob mice, in line with in vitro experiments that have indicated defective...

Pulmonary Pathophysiology

Pulmonary fibrosis affects 5 million people worldwide and 200,000 in the United States. Pulmonary fibrosis is caused by a thickening or scarring of pulmonary membrane. The result is that the alveoli are gradually replaced by fibrotic tissue becoming thicker, with a decreased compliance (increased stiffness) and a decrease in diffusing capacity. Symptoms of pulmonary fibrosis include a shortness of breath, chronic dry, hacking cough, fatigue and weakness, chest discomfort, loss of appetite, and rapid weight loss. Traditionally, it was thought that pulmonary fibrosis might be an autoimmune disorder or the result of a viral infection. There is growing evidence that there is a genetic link to pulmonary fibrosis.

Inflammation and Immune Effector Heterogeneity in MS 231 T and B Lymphocytes

Structures suggestive of lymphoid B cell follicles have appeared in the meninges of patients in the late progressive disease phase, suggesting that ectopic lymphoid follicle formation maintains humoral autoimmunity and contributes to disease severity and progression in chronic MS 89 . Clonally expanded populations of Ig variable gene-mutated B cells appear in the CNS of MS patients, supporting the occurrence of a germinal center-like reaction 23 . Furthermore, the CSF of MS patients is enriched with centroblasts and B cells with a memory phenotype compared to peripheral blood. In the same individuals, antibody-secreting cells are detected in the CSF and appear to correlate with CNS inflammation. These B cell subsets are the output of a germinal center reaction thought to occur in the CNS. Recent findings suggest that the inflamed brain becomes a favorable niche for B cell survival and proliferation and, under some circumstances, sustains the formation of ectopic lymphoid structures. B...

New therapeutic concepts

Current research on new therapeutic regimens focuses on precise target mechanisms rather than unspecific immunosuppression, as applied to patients with autoimmune diseases in the past. However, it should be taken into account that highly specific treatment approaches, such as selected altered autoantigens or selected T cell receptor peptides, have so far not resulted in clinical therapies (Bielekova et al., 2000). As in a number of autoimmune diseases, several autoantigens seem to be responsible. Furthermore, epitope spreading and promiscuous recognition by the T cell receptor may (among other factors) explain the lack of an antigen HLA T cell receptor-specific therapy despite extensive research. Another important issue is the establishment of effective therapies that can be given orally since most of the currently established therapeutic agents must be administered intramuscularly, subcutaneously, or intravenously. Other therapeutic developments in MS aim to directly prevent the...

Alternative Indications For Dpp4 Inhibitors

Affect the function of other proteins that associate with CD26, specifically the PTPase activity of CD45 98 . Compound 45 is also known as talabostat or PT-100 and is in clinical trials for hematological malignancies and hematopoiesis 99 . The efficacy of 45 in these therapeutic indications may be derived from the compound's inhibition of FAP 100 . Numerous other reports have focused on the involvement of DPP4 and or use of DPP4 inhibitors in various inflammatory and autoimmune diseases and pathologies, such as Crohn's disease, 92 and organ transplantation 101 .

Keratoconjunctivitis Sicca

Keratoconjunctivitis sicca is a dry eye syndrome commonly associated with an underlying systemic autoimmune disorder such as Sjogren's syndrome, rheumatoid arthritis, or HIV infection. However, it must be included in the differential of ocular allergy, especially in perimenopausal and postmenopausal women. Tear production decreases with age 60 fewer than at the age of 18. The eye produces approx 400 drops of tears per day. It is characterized by an insidious and progressive lymphocytic infiltration into the main and accessory lacrimal glands. Patients initially complain of a mildly injected eye with excessive mucus production. Symptoms include a gritty, sandy feeling in the eyes compared to the itching and burning feeling many patients complain of with histamine release into the eye. As the cornea becomes involved, a more scratchy and painful sensation as well as photophobia may appear. The corneal epithelial injury can be detected with punctuate staining with fluorescein. The...

Skin Anomalies Pathological Noninfective

Vitiligo is thought to be an autoimmune disease in which the melanocytes at the border of the dermis and epidermis are destroyed. It tends to occur around orifices, and genital skin involvement sometimes occurs before involvement of other parts of the body. It is characterised by patches of sharply demarcated milk white skin with no signs of texture change.

Clinical Box 21 Graft Versus Host Disease

A main reason for the shortage of transplant organs is the fact that the tissues of the donor and the recipient need to match for successful transplantation. Tissues are matched when they have a similar pattern of cell surface proteins. Cell surface proteins are in fact glycoproteins due to the carbohydrates (sugars) attached to their surface. The carbohydrate acts as a flag designating the cell as belonging to the individual. The cellular gly-coprotein pattern may specify an individual within a species or specify a species. If a particular sugar is missing from the surface of a cell, the immune system may recognize this cell as foreign and try to kill it. An attack on self tissue may lead to autoimmune diseases, where the autoimmune reaction can be directed against a specific tissue such as the brain in multiple sclerosis or the digestive tube in Crohn disease. In other cases, the overly active immune system may attack many cells and tissues so that various organs are affected such...

Expanding regulatory T cells

This approach preferentially stimulated and expanded regulatory CD4+CD25+ T cells, proposing a beneficial effect for autoimmune disease, in this case MS (Rodriguez-Palmero et al., 1999). Subsequently, it was shown that a CD28 superagonist can be an effective treatment for EAE by enhancing and promoting Treg function. However, when the humanized version of the antibody (TGN1412) was tested recently in a Phase I study, it led to extremely severe adverse events. Shortly after the first administration of the drug serum, virtually all cytokines shot up to immense levels in all six of the volunteers that received TGN1412. This cytokine storm was followed by severe lymphocyte and monocyte depletion, leaving the patients with multiorgan failure and permanent damage (Suntharalingam et al., 2006). So far, the detailed mechanisms underlying this event remain unclear, leaving us with a stark reminder of the caution with which immunologic research data from animal models must be translated, and...

Key advances in preclinical validation

Studies of pre-clinical models of other autoimmune diseases have also been reported recently. In a model of systemic lupus erythematosus, CCR2_ _ mice exhibited prolonged survival and reduced renal disease relative to their WT counterparts 20 . Importantly, reduced macrophage and T-cell accumulation in the renal lesion sites was noted. Overall, these data are consistent with other recent studies on genetic deletion of MCP-1 21 or administration of a peptide antagonist of CCR2 22 in models of lupus. The recent data with experimental autoimmune encephalomyelitis (EAE, a rodent model of human multiple sclerosis) are more complex, in that different outcomes were observed depending on the system studied. Administration of a small molecule antagonist blunted EAE disease progression in C57BL 6 mice 15 . Likewise, genetic deletion of CCR2 in the C57BL 6 background also reduced EAE disease score, particularly in the early stages of disease 23 . However, CCR2_ _ mice on a Balb C background...

Self Antigens as a Source of MHC Class II Epitopes After Macroautophagy

The influence of macroautophagy on the MHC class II self-ligandome has been investigated in an elegant study (Dengjel et al. 2005). Indeed, upon starvation-induced macroautophagy, mass spectrometric analysis of natural HLA-DR ligands from a human B lymphoblastoid cell line showed a significant change in the amount of presented peptides derived from cytosolic and nuclear proteins, while MHC class II presentation of membrane and secretory proteins was unchanged. Interestingly, the presentations of four proteins were particularly elevated (HSP70, RAD23, elongation factor-1a and cathepsin D). As we discussed above, two of these, HSP70 and RAD23, are proteins with long half-lives and are therefore good candidates for macroautophagy substrates. Further studies are needed to investigate the possible implications of self-protein presentation as the basis for autoantigen recognition during autoimmune diseases or for allogeneic transplant rejections where upregulated macroautophagy could...

Is Maturation Required For Migration Of Dcs

On their way, also in the steady state, antigen processing has to occur, followed by loading of MHC II and I molecules and their transport to the surface together with costimulatory molecules. For antigen processing and tolerogenic cross-presentation of apoptotic material, at least some maturation of DCs seems to be required (44,49). We have shown that TNF-a is inducing an incomplete maturation of DCs, and that such semi-mature DCs could still act in tolerogenic manner, as they were able to protect mice from autoimmunity (47,50). Similarly, pulmonary DCs pulsed with antigen for tolerance induction are mature DCs after reaching the draining lymph node (46). Thus, tolerance induction by migrating DCs in mice requires at least partial maturation.

Biological Roles for Surface Carbohydrates and Potential Uses

Because polysaccharides represent the predominant structures on the bacterial cell surface, they are important in the interaction between the pathogen, host, and environment. To summarize the reports described in Subheadings 2.-4., C. jejuni carbohydrates are involved in many cellular functions, including assembly of the flagellar filament (73), which we now realize is a type III-like secretory apparatus necessary for the release of invasion colonization proteins (14,15), motility (73), assembly of the TFSS that affects DNA uptake and natural transformation (79), adherence and invasion in vitro (41,54,76), colonization, and disease in vivo (41,64,68,76-78), molecular mimicry of gangliosides (82), autoimmunity leading to GBS (48), maintenance of cell surface charge (41), serum resistance (41,53), antigenic (53,60,83) and phase variation (41,54,57,83,84). Considering the importance of glycoconjugates in C. jejuni biology and based on the hypothesis that glycoconjugates have evolved in...

Mode of action of FTY720

Immunosuppressants are clinically important for organ transplantation and the treatment of autoimmune diseases. Currently approved immunosuppressive drugs have a low therapeutic index and require careful drug monitoring. In particular, the use of calcineurin inhibitors such as cyclosporine A or tacrolimus (FK506), which specifically block T-cell activation, is limited by mechanism-based side effects. These adverse side effects are currently partially reduced by combining calcineurin inhibitors with antiproliferative agents such as IMPDH inhibitors (e.g. mycophenolic acid) or mTOR inhibitors, however, significant medical need remains for novel mechanisms of action in the field of immune modulation. In the early 1990s, Fujita et al. showed that the palmitoyltransferase inhibitor, Myriocin, isolated from the fermentation broth of Isaria sinclairii, exhibited in vitro and in vivo immunosuppressive activity with an IC50 3 nM in the mouse allogeneic mixed lymphocyte reaction (MLR). Myriocin...

Major Histocompatibility Complex and Multiple Sclerosis

The only genomic region consistently shown to have a large effect on multiple sclerosis susceptibility across studies is the major histocompatibility complex (MHC human leukocyte antigen HLA in humans), which spans about 3.5 Mb on chromosome 6p21.3. The HLA contains a large array of highly polymorphic genes involved in immune response and self-recognition 78 . The major classes of the HLA genes are the class I and class II genes, located telomerically and centromeri-cally, respectively (Fig. 1). In an immune response, the cell surface HLA proteins present fragmented antigen proteins to T cells. The highly polymorphic regions of the class I and class II HLA genes correspond to the peptide-binding grove of the protein, which indicates that the polymorphisms likely developed to battle varying pathogenic challenges throughout evolution. Because of its role in antigen recognition, including self-antigens, the HLA system has been extensively studied in autoimmunity.

Fas Mutations and Various Disorders in Experimental Animals and Humans

Concerning the relationship between Fas gene mutations and various disorders, it is notable that Fas gene mutations showing a 2-bp insertion in intron 2 and a missense point mutation in the intracytoplasmic region were found in lpr and lprcg mice, which were experimental models of autoimmune disease. These mice have characteristic features of hypergammaglobulinemia, autoantibodies, rheumatoid factor, circulating immune complexes, lymphadenopathy, and splenomegaly (A2, N3, W1). All of these clinical features are probably due to the failure to eliminate self-reactive T cells with defective Fas owing to the mutation of the Fas gene, resulting in the accumulation and expansion of a large number of nonneoplastic polyclonal T cells in the lymph node, peripheral blood, and spleen.

PDE74 dual inhibitors

Recently, IBFB-211913 (structure unavailable) was claimed as a new PDE4 7 inhibitor. It is reported under development for the treatment of asthma, autoimmune diseases and psoriasis 51 . Future data related to this compound will be helpful to assess and understand the intrinsic contribution of the PDE7 inhibition toward efficacy and side effects. In relation to this topic, several patents claimed the use of dual inhibitors (PDE7 PDE4) to synergize pharmacological effects and to increase the therapeutic index 32,33 . A series of phthalazinones have been disclosed as dual

The evolution of cell killing when a target cell became invited to choose how to die

The core of vertebrate immunity system is clonal amplification, and all cells belonging to a given class (i.e., B or T lymphocytes) are distinct in their capacity to react with different antigens. This amplification is mediated by unique receptors encoded in gene segments that needs somatic rearrangement and can recognize a large variety of different epitopes presented by specialized antigen-presenting cells. As a consequence, this receptor able to recognize the cellular structures in details is considered imperfect because the selection for the above-mentioned discrimination is at single cell level. Although the mechanism of diversity generation offers an immense repertoire for the recognition of antigens, it can also determine the presence of autoreactive clones that can be responsible for the onset of autoimmune disease. This can be considered as a sort of price to pay to the increased complexity and sophistication of the immune responses. Therefore, behind somatic rearrangement,...

Genetic Polymorphisms That Contribute to Altered Cytokine Production

The production of cytokines is a function of the activating and inhibiting signals delivered to the cell surface of immune and inflammatory cells by their ligands. However, the degree of expression of individual cytokines is also regulated based on individual genetic differences that translate into variable efficiency in cytokine production. The extent of genetic polymorphisms that contribute to SLE has not been fully characterized. However, variable sequences in the promoter region of tumor necrosis factor (TNF) may contribute to other autoimmune diseases, including juvenile dermatomyositis, and IL-6 polymorphisms have been associated with SLE (38-40). Genetic variability can be localized to regulatory regions of genes, potentially modifying the level of expression, or can be in coding sequences, sometimes resulting in an altered amino acid sequence and modified conformational structure. More complete study of the genetic variants associated with disease activity and clinical disease...

Assays of Cytokine Expression

In our experience, real-time PCR of cells assayed both immediately ex vivo and after in vitro culture with activating stimuli has proved useful for determining relative quantity of cytokine mRNA in cells from patients with SLE and control subjects (see Subheadings 4.2. and 4.3.). Parallel studies of intra-cellular cytokine expression confirm the PCR data and provide an indication of the cellular source of the cytokine. We are also measuring mRNA specific for cytokine target genes in peripheral blood cells studied immediately ex vivo to support an important functional role for the cytokine in immune system function. It is this redundant approach using complementary assays that is most likely to generate accurate and interpretable data leading to new understanding and treatments of the altered immune function of patients with autoimmune disease.

What are genes What genes cause MS

(Figure 7) at a point on the short arm of the chromosome at location number 21. You have probably heard of these in relationship to organ transplantation but the majority of genes that play a role in immune function and autoimmunity are located in this location. There are 4 of these important gene loci (locations), A, B, C, and D. The A locus is a gene that codes for the MHC class I protein and it is the actual immune response gene for antibody production. The DR gene (at the D locus) is another immune response gene that codes for the so-called MHC class II protein that plays a central role in cell-mediated immunity. These reactions principally involve monocytes and CD4 lymphocytes. Although, the B locus is near the D locus, its role is obscure. There are many additional genes in this region of chromosome 6 that are involved in immune reactions.

Microarray Analysis of Apoptosis

Apoptotic cell death is a genetically regulated process and the balance between death and survival signals determines the fate of a cell. Apoptosis is important in development and in a number of pathological conditions including cancer and autoimmune diseases. Many transcription factors have been shown to regulate apoptosis in a range of biological systems. However, the downstream target genes and the mechanism of their action have not been clearly defined. The recent advent of gene microarray technology will allow the expression patterns of a large number of genes to be analyzed. Changes in transcription in response to an apoptotic stimulus can be identified and novel pathways defined.

Rheumatoid Arthritis309

Rheumatoid arthritis is a chronic autoimmune disease in which the immune system attacks the synovial tissue, the membrane that lines the joints. It is the second most common form of arthritis and usually appears between ages 20 and 40. Although the cause of rheumatoid arthritis is unknown, there is a genetic component if a close relative is affected, you are more likely to develop the disease. There is no known cure.

Possible Mechanism for Loss of AT in Acquired Lipodystrophies

As mentioned before, some varieties of AGL are associated with autoimmune diseases, suggesting autoimmune destruction of AT. Some autoimmune diseases show a strong association with the HLA complex, but because of the rarity of these patients, HLA typing in AGL has not been explored. Fat loss in APL is believed to involve complement-mediated lysis of adipocytes, which might be initiated by viral infections (46). There is evidence to suggest the presence of circulating autoantibodies, some of which may be directed against adipocytes in some patients with AGL and in many with APL (46,85). The adipocyte-specific antigens against which these autoantibodies are directed remain to be identified.

Microarray Studies from Blood

The first microarray study in MS using blood was reported by Ramanathan et al. 99 . They compared the peripheral blood mononuclear cell (PBMC) gene expression of 15 RRMS patients to 15 healthy controls using a 4,000-gene array. Thirty-four genes were differentially expressed, and 13 of these were immune response-related. To determine the gene expression similarities between normal immune response and autoimmune diseases, Maas et al. 77 compared the expression levels of more than 4,000 genes in PBMCs from nine healthy controls, pre- and post-flu vaccination, with individuals having four different autoimmune diseases including four individuals with MS. The results indicated that the gene expression patterns of individuals with different autoimmune diseases were similar but differed from the expression patterns of the immunized individuals. The major classes of genes that were upregulated in the autoimmune group were receptors, inflammatory mediators, signaling second messenger...

And Autoimmune Thyroiditis

This chapter describes four murine models of autoimmune diseases two related to autoimmune myocarditis and two related to autoimmune thyroiditis. The first model, Coxsackie virus B3 (CB3)-induced myocarditis, results in the development of acute myocarditis in susceptible as well as resistant mouse strains, whereas chronic myocarditis develops only in genetically susceptible mice. CB3-induced myocarditis closely resembles the course of human myocarditis, which is believed to be initiated by viral infection. Mouse cardiac myosin heavy chain has been identified as the major antigen associated with the late chronic phase of viral myocarditis. The second model is cardiac myosin-induced experimental autoimmune myocarditis (EAM) and, in a modification, cardiac a-myosin heavy chain peptide-induced myocarditis. In the EAM model, cardiac myosin or the relevant peptide in Freund's complete adjuvant (FCA)is injected subcutaneously into mice. The immune response, the histological changes, and the...

Oxidative Stress in Autism

Oxidative stress is known to be associated with premature aging of cells and can lead to inflammation, damaged cell membranes, autoimmunity, and cell death. The brain is highly vulnerable to oxidative stress due to its limited antioxidant capacity, higher energy requirement, and high amounts of unsaturated lipids and iron (Juurlink and Peterson, 1998). The brain makes up about 2 of body mass but consumes 20 of metabolic oxygen. The vast majority of energy is used by the neurons (Shulman et al., 2004). Glutathione (GSH) is the most important antioxidant for detoxification

Lipid Rafts in immune Cell Signaling

Introduction - The cells of the immune system express a variety of receptors that allow the system to recognize and respond to the universe of foreign pathogenic organisms including viruses, bacteria and parasites. An important class of immune receptors are the multi-chain immune recognition receptors or MIRRs that include the antigen receptors on the two major classes of lymphocytes, namely, B cells (the B cell receptor or BCR) and T cells (the T cell receptor or TCR) (1). Another important MIRR family member, the high affinity receptor for IgE, or FceR1, is expressed on mast cells and basophils and plays a key role in allergic immune responses. The engagement of the MIRRs by their multivalent ligands, either soluble antigens for the BCR, peptide fragments of antigens bound to Major Histocompatibility Complex (MHC) molecules for the TCR and complexes of antigen bound to IgE antibodies for the FcsRI, leads to the initiation of tyrosine-kinase based signaling cascades that ultimately...

Rafts As Potential Targets Of Therapies

The observations that lipid rafts play an important role in immune cell signaling suggests that they may provide new targets for treatment of autoimmune diseases and allergy and to block organ rejection in transplantation. To provide such opportunities the molecular mechanisms by which rafts function to facilitate MIRR signaling will need to be delineated in detail. Nonetheless, even in the absence of Glucocorticoids (GCs) are a class of cholesterol-derived steroids produced by the hypothalamic-pituitary-adrenal axis that have significant immunosuppressive and anti-inflammatory effects on the immune system (69). GCs inhibit T cell responses and consequently, GCs have been widely prescribed in the treatment of autoimmunity, allergy and inflammatory disease and in the prevention of graft rejection. The primary targets for the action of GCs appear to be intracellular receptors that alter nuclear gene transcription. However, recent evidence indicates that GCs alter both the lipid...

Pathogenesis of Paraneoplastic Nervous System Syndromes

Several criteria have to be fulfilled for an autoimmune disorder to be regarded as antibody mediated demonstration of a specific antigen the reproduction of disease in recipient animals on transferral of antibodies the induction of autoimmune disease by active immunization with antigen and clinical improvement or stabilization of the symptoms when antibodies are removed by immunotherapy or plasmapheresis 114 . Most antibodies found in PNS only satisfy the first criterion. However, there are some exceptions. The prime example is LEMS, where the VGCC antibodies interacting with presynaptic calcium channels are pathogenic. However, these antibodies are not markers of a paraneoplastic background for LEMS 180 . Another example is the recoverin antibody that is present in some patients with CAR. This antibody is incorporated into rod photoreceptor cells and is pathogenic in vitro as well as in vivo 181 . Antibodies to mGluR1 that are found in some patients with Hodgkin's disease and...

Traditional Diagnostic Methods

Also been commonly used (Romanowski et al., 1987). Both dark-field microscopy and DFA-TP, however, do not distinguish T. pallidum from the other pathogenic species of Treponema (Larsen et al., 1995). On the other hand, nontreponemal serologic tests are based on detection of antibodies to a cardiolipid-cholesterol-lecithin antigen. They include the Venereal Diseases Research Laboratory (VDRL) and the Rapid Plasma Reagin (RPR) card test. Both are modified from the original Wasser-man reaction (Larsen et al., 1989 Young, 1992). Limitations of these tests include the lack of sensitivity in early and latent stages of syphilis and the well-known possibility of biological false-positive reactions. Treponemal serologic tests are based on detection of treponemal specific antibodies to cellular component of T. pallidum. They include the serum fluorescent treponemal antibody absorption test (FTA-ABS), the microhemagglutination test (MHA-TP), and the Treponema pal-lidum particle agglutination...

Mhc Class Ii Dimeric Molecules

Despite the emphasis on CD8+ T cells in immune responses, CD4+ T cells have been shown to be as critical in inducing an effective immune response against tumors, as well as in infectious and autoimmune diseases. Until today, analysis of CD4+ T cell responses using multimeric MHC molecules is hampered by the lack of suitable reagents. It is important to remember that it took more than two years from the first study showing the use of multimeric MHC molecules for detection of antigen specific T cells in 1996 until tetrameric MHC and MHC dimers became available for the analysis of T cell responses in different settings. Different groups including ours have come to realize that the technology for making tetravalent or dimeric MHC class I constructs cannot be simply transferred to the

Anti Islet Autoantibody Assays

For NOD mice, two International Diabetes Antibody Workshops have been organized by the Immunology and Diabetes Society since 2000. The results from these two NOD antibody workshops demonstrated that IAAs measured by sensitive radio-binding assay (RBA) are a marker of autoimmunity in NOD mice disappointingly, enzyme-linked immunosorbent assays (ELISA) were discordant with the results obtained by RBA. GAAs and ICA512AAs by both RBA and ELISA were increased in NOD mice compared with control mice at diabetes onset, but GAAs and ICA512AAs frequencies varied significantly with respect to the source colony of NOD mice. Furthermore, sera with increased binding to GADs and ICA512 also had increased binding to the unrelated antigen myelin oligodendrocyte glycoprotein, and binding to GADs could not be inhibited with excess unlabeled GADs, suggesting nonspecific interactions. The above has led to questions regarding the true nature of reported GAAs and ICA512AAs in this animal model.

Diabetes Prevention in the NOD Mouse

Finally, antigen-specific therapy is under study in type 1 diabetes and other autoimmune diseases for which the autoantigens have been identified. Potential autoantigens include insulin B-chain and insulin B 9-23 peptide, GAD, and heat shock protein (p277 peptide of HSP60). Autoantigen peptide vaccination is perhaps the most specific type of immunotherapy in both humans and the mouse, but has properties of a double-edged sword although such therapy may prevent diabetes, there is also potential to accelerate or even induce disease. The precise rules in immunotherapy to modulate the immune system toward disease induction or remission are not well understood, and it is likely that dose, timing, and route of administration will be important factors in the design of peptide vaccines.

Group A streptococcal invasion

S. pyogenes is almost exclusively associated with humans and commonly causes a variety of diseases, including pharyngotonsillitis, impetigo, scarlet fever, and more severe infections, such as puerperal sepsis, myositis, necro-tizing fasciitis, and toxic shock syndrome. Among several ofthe nonsuppu-rative complications ofgroup A streptococcal infections are acute rheumatic fever and acute glomerulonephritis, which are usually preceded by infections of the throat and skin, respectively. These sequelae are thought to be due to autoimmune T- and B-cell responses induced by streptococcal products. Accumulating evidence also suggests that group A streptococcal infections may lead to other autoimmune diseases, such as obsessive compulsive disorders, or they may exacerbate others such as guttate psoriasis (reviewed by Cunningham, 2000).

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).

Peptide Vaccine Induced Anaphylaxis in the NOD Mouse

The identification of autoantigens in autoimmune diseases such as type 1 diabetes or multiple sclerosis has made peptide immunotherapy possible. In fact, peptide vaccine trials are currently underway in type 1 diabetes for an altered peptide ligand of insulin peptide B 9-23 (20), for GAD peptides, and for heat shock protein 60 (HSP60) (p277) (21). However, in mouse studies of peptide vaccination, anaphylaxis has been reported in diabetes experiments using the B 9-23 peptide (22) and GAD peptides (23) and in multiple sclerosis studies (experimental autoimmune encephalitis) using proteolipid protein (PLP) (139-151) and myelin oligodendrocyte glycoprotein (MOG) (35-55) peptides (24). Even more concerning is the report of systemic hypersensitivity reactions in humans during phase II trials with an altered peptide ligand for myelin basic protein (MBP) (83-99) (25,26), which led to the premature discontinuation of therapy in some patients. More research into peptide-induced anaphylaxis,...

Plasma membrane cholesterol and lipid rafts

Recent studies have identified differences in plasma membrane cholesterol levels between transitional and mature B lymphocytes. Furthermore, studies in which cholesterol levels were augmented in transitional B lymphocytes to levels comparable to those in mature B lymphocytes suggest that these differences are responsible for both the differential ability to stably organize BCR into lipid rafts and relative ability to maintain signaling pathways associated with PI-hydrolysis and PKCp activation (Karnell et al., 2005 Monroe, 2005). The mechanisms regulating the developmental difference in cholesterol levels are unknown but could reflect variations in cholesterol uptake and or biosynthesis by B lymphocytes. The implications of these results are profound, for they indicate that developmental-related differences in plasma membrane cholesterol levels affect the ability to organize lipid rafts and point to potential risk factors for B lymphocyte autoimmune diseases. For example, genetic or...

Reticuloendotheliosis virus strain TA

Retroviridae A family of large single-stranded RNA viruses which have a virion RNA-dependent DNA polymerase. Virions are spherical, about 80-100nm in diameter. Lipoprotein envelope encloses an icosahedral core shell within which there is a helical nucleocapsid. The envelope has glycoprotein surface projections 8 nm long. The genome is a dimer of two hydrogen-bonded positive single-stranded RNAs, each monomer 7-11kb in length. Viral RNA is transcribed by the virion transcriptase into a covalently linked circle of double-stranded DNA (provirus) which becomes integrated into the cellular DNA. Viral RNA serving as mRNA and virion RNA for progeny particles is transcribed from the integrated DNA provirus. Replication is sensitive to inhibitors of DNA synthesis during the first 6 h after infection, and to actinomycin D at any time. Maturation occurs by budding from the cytoplasmic membranes. Provirus DNA extracted from infected cells is infective. There are seven genera Alpharetrovirus,...

Data Interpretation

The pathogenesis of a number of diseases is still not very well understood. The exact mechanisms of containment of either transformed or virally infected cells have not been determined. In general, effective adaptive T-cell responses are desirable in these diseases. The flip side of the coin - in the context of cellular immune responses - is a strong T-cell response which mediates auto-immune disorders. Many parameters exist to measure disease activity in autoimmune diseases, but the magnitude of a cellular immune response is hard to assess, particularly if no molecular targets have been identified. Since TCR CDR3 analysis visualizes objectively every alteration in the TCR composition, it may be helpful to define new markers of disease activity in autoimmune diseases it may also present a potential matrix to gauge immuno-suppressive effects of novel drugs. For instance, TCR diversity has been suggested as a readout in PBL from patient suffering from SLE (39), or in the synovial fluid...

Experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis can serve as a classical example of immune-mediated demyelinating disease. It is a neurological autoimmune disease produced by an immunization with myelin basic protein. The central role of T lymphocytes can be demonstrated by transfer experiments using lymph node-derived T cells8 and by prevention of the disease by neonatal thymectomy.9 A characteristic feature of this disease is perivascular T-helper and mononuclear cell inflammation and subsequent primary demyelination of axinal tracks in the central nervous system, resulting in progressive hind-limb paralysis. In mice, the disease is a Th-1 cell-dependent autoimmune disease with macrophages as the effector cells. Several mouse models exist the most common strains are SLJ, B10.PL, and Biozzi AB H. The Biozzi AB H strain is particularly useful, because acute as well as chronic disease can be studied on one animal model. Peptide specificity of encephalitogenic T lymphocytes is dependent on...

Other screening methods

A technique called tethering, in which a library of di-sulfide containing fragments are reacted with active site cysteine-containing mutant target proteins in order to form covalent adducts, has been applied to the extremely challenging autoimmune disease target IL2 30 . Ten cysteine mutants of the IL-2 protein were screened against 7000 disulfide fragments. Aromatic acids, such as compound 13,

Rheumatoid arthritis

Rheumatoid arthritis is the single most common autoimmune disease in man. The principal manifestations are periarticular soft tissue swelling and joint stiffness and pain. Despite significant progress in our knowledge of the disease, there is still no cure for rheumatoid arthritis. For more information about the clinical aspects of this disease, see References 18 and 29. This disease is a complex one involving an IgM and IgG autoantibody (called rheumatoid factor), with subsequent tissue damage caused by immune complex deposition. Rheumatoid factor is present in the serum of most adult patients. Rheumatoid factor is in reality an autoantibody reacting with the Fc portion of human IgG. The occurrence of the rheumatoid factor is rather confusing, as it can be found not only in rheumatoid arthritis or systemic rheumatic disease, but also in hypergammaglobulinemic patients, or even in healthy persons. Three classes of rheumatoid factor can be found IgM, IgA, and IgG.20 Despite the fact...

Clinical Signs and Diagnosis

Differential diagnosis in a patient without a suggestive food ingestion history and sudden onset of neurologic symptoms includes Guillain-Barre syndrome, myasthenia gravis, cerebrovascular accident, tick paralysis, intoxications, and infectious diseases of the central nervous system.

Stanford L Peng Summary

Murine models of systemic lupus erythematosus provide fertile research systems for the pathogenesis and therapy of systemic autoimmune disease. Their phenotypes span the broad range of clinical manifestations of human lupus and consist of both spontaneous and experimentally induced disease in both inbred and targeted mutant animals. This chapter contrasts the clinical characteristics of these various models, providing an outline for the use and analysis of these in vivo autoimmune systems. Keywords Arthritis autoantibodies autoimmune diseases glomerulonephritis hemolytic anemia lupus inbred mice knockout mice mutant mice transgenic mice.

Murphys Recombinant LargeMpJ

Murphy's recombinant large (MRL) Mp mice developed from efforts in the 1960s to develop inbred mouse strains for the study of obesity (20,99), but they were found to develop autoantibodies and end-organ disease highly reminiscent of human SLE. They currently are estimated to consist of 75 LG J, 12.6 AKR, 12.1 C3H Di, and 0.3 C57BL 6 lineages. During the 12th brother-by-sister intercross, the spontaneous lymphoproliferation (Ipr) mutation developed, associated with massive lymphadenopathy and precocious autoimmunity (100-102 see Subheading 1.6.1.). Of the available lupus-prone strains, MRL Mp and their congenic MRL Mp-lpr lpr strains develop the most systemic and severe form of autoimmunity, involving multiple autoantibody specificities, such as anti-dsDNA, ribo-nucleoprotein (including small nuclear ribonucleoproteins snRNPs , Ro, La, Su), ribosomal, and erythrocyte, as well as rheumatoid factor and cryoglobulins. End-organ disease includes not only varying and severe forms of...

Experimentally Induced Models

Few widely used, experimentally induced models exist for lupus. Graft-vs-host disease models have been sometimes studied because of the concomitant development of lupuslike autoimmunity however, given the importance of allogeneity, its physiology probably represents a mode of pathogenesis distinct from the other lupus models described here (194) (see also Chapter 14). Alternatively, when exposed to bacillus Calmette-Guerin, nonobese diabetic mice have been demonstrated to develop hemolytic anemia, autoantibodies, worsened sialadenitis, and immune complex-mediated glomerulonephritis (195), but

Lupus Prone Mice With Defined Mutations

(Canale-Smith syndrome 239-241), CD95 ligand (242), and caspase-10 (243). These syndromes share in common the development of severe lymphadenopa-thy because of CD3+CD4CD8- T cells and the high incidence of often lupuslike autoimmune disease. CD95 defects alone generally do not convey autoimmunity per se, but rather accelerate and amplify any underlying autoimmune diathesis For example, C57BL 6-lpr animals develop mild inflammatory disease consisting of lymphadenopathy, anti-single-stranded DNA (anti-ssDNA) antibodies, and mild, if any, glomerular disease MRL Mp-lpr animals develop widespread inflammation, including lymphadenopathy, autoantibodies of multiple specificities including anti-dsDNA, antiribonucleoprotein, anticardiolipin, and antiribosomal P, immune complex glomerulonephritis, as well as sialadenitis and hepatitis (see Subheading 1.2. 155-157). Thus, these mutations have often been used in murine lupus to accelerate the in vivo assay.

Conclusions The Selection of Murine Lupus Models

The diverse array of inbred and genetically altered mice provides many models for systemic lupus erythematosus, each with particular clinical manifestations and unique pathogenesis (Tables 1-4). Investigators should therefore choose models based on areas or phenomena of interest within the lupus autoimmune spectrum For instance, studies focusing on anti-dsDNA antibody responses, T-cell autoreactivity, or hemolytic anemia may find the best supporting literature and precedence in the NZ systems. In contrast, studies of diversification and diversity of autoantibody repertoires and multisystem autoimmune disease may prefer MRL models. Congenic autoimmune-prone CD95-mutant animals, like MRL Mp-lpr lpr, may provide particularly rapid assay systems, but investigators should beware of possible confounding from the concomitant, severe lymphadenopathic process. Finally, studies with interests

Concept Of Therapeutic Antibodies And Their Use In Clinical Practice

Passive immunization works where active immunization may fail or be inappropriate, either because the immune response to the agent may take too long or require a specific combination of factors to be mounted appropriately or because lack of an intact immune system. Slow growth viruses, such as rabies, are best treated using antibodies already prepared against the virus rather than waiting for the patient to develop them, which may take decades and no longer protect them from the pathogenic agent. Subjects who are immunosuppressed may also benefit from receiving passive antibodies when exposed to infections or foreign agents (27). This practice is not unusual it is standard procedure to inject gammaglobulin to children or elderly exposed to Hepatitis A, Parvovirus, pneumonia and other infectious diseases as well as to mothers who have a blood type lacking her husband's red blood cells' surface antigens (28, 29). In contrast to active immunization, using passive immunization provides...

Conclusions And Future Directions

IFN-g is crucial for immunity against viral and intracellular bacterial infections and tumor control however, aberrant IFN-g expression has been associated with a number of autoinflammatory and autoimmune diseases. During infection, the innate recognition of pathogens leads to the production of IFN-g by NK and or NKT cells, which in turn influences the generation of IFN-g-producing CD4 and CD8 T cells. In NK and NKT cells, the Ifng locus is open and accessible, allowing them to produce IFN-g rapidly, in response to signals that activate STAT4, NFkB, and AP-1.

Isoelectric Focusing of the CSF

Polyspecific Response Associated with CNS Autoimmune Diseases. The oligoclonal, intrathecally synthesized IgG contains numerous specific antibodies and autoantibodies. Antibodies are frequently found with specificities against measles, the rubella virus and the varicella-zoster virus, but seldom against the herpes simplex virus. The occurrence of one, two, or three of these antibodies is referred to as the MRZ reaction. The corresponding antigens are not present in these cases. The MRZ reaction is typical of multiple sclerosis as well as cerebral lupus erythematosus and is a chronically evolving immune process (F5, K10, S16).

Malaria And Insulin Dependent Diabetes Mellitus An Ecological Study

Malaria is the most important natural selective factor on human populations that has been discovered to date.13 In areas of high endemicity, malaria operates the genetic selection responsible for the influence on the susceptibility to autoimmune diseases.14 In Sardinia, malaria is known to have selected for some serious hereditary diseases such as 3-thalassaemia, Cool-ey's disease and favism the latter is caused by a deficiency of glucose-6-phospate dehydrogenase enzyme.10 Sardinia is therefore particularly suitable for investigating the association between insulin dependent diabetes mellitus and malaria. The incidence of insulin dependent diabetes mellitus in Sardinia is quite atypical of other Mediterranean countries. Sardinia has the second highest incidence in Europe at 33.2 per 100 000 person years Finland has the highest incidence at 40 per 100 000 person years. A study of 18-year-old military conscripts born between 1936 and 1971 showed that the risk for insulin dependent...

Osteonecrosis Avascular Necrosis or Aseptic Necrosis

Asherson Syndrome

Small vessel vasulitis or thrombotic microvasculopathy associated with aPL have been suggested as the pathogenetic mechanisms in autoimmune diseases, even in the absence of corticosteroid administration. Several autoimmune diseases have been associated with SNHL SLE, Sjogren's syndrome, RA, ulcerous colitis, PAN, polymyositis, Hashimoto's thyroiditis, scleroderma, Behcet's disease, Cogan's syndrome.

T cell trafficking to the CNS

Cell Extravasation

The CXCR3 ligands CXCL9 and CXCL10 robustly attracted IFN-g-producing T cells that were generated by murine influenza infection in the lung. On the other hand, IL-10-producing and especially IL-10 IFN-y expressing CD4+CXCR3+ T cells also strongly migrated toward their ligands in this Th1-mediated disease model (Debes et al., 2006). Extrapolating these findings to Th1-mediated autoimmune diseases, it seems that not only proinflammatory Th1 cells but also the recruitment of potential Treg subsets might depend on Th1 cell-attracting chemokines, making interference with these complex processes unpredictable, especially in the human situation. correlation of chemokine-driven migration may be variable in different inflammatory conditions. For example, IFN-g-producing CD4+ T cells migrated robustly toward the CXCR3 ligands in an ex vivo chemotaxis assay if isolated from influenza infected mice, but they responded poorly to their classic ligands if generated in parasitic infection (Debes et...

Antagonists of VLA4

Introduction - Integrins are a family of heterodimeric cell surface receptors consisting of an a and a p subunit (1). Different a and p subunits can associate to yield a family of no less than 23 members each with a distinct pattern of ligand selectivity. The integrin a4pi is also known as VLA-4 (very late antigen-4). VLA-4 is expressed on the surface of most leukocyte or related cell types including lymphocytes, eosinophils, monocytes, basophils, and mast cells (2,3). More recently, the integrin has been detected on neutrophils in certain inflammatory settings (4,5). The ligands that bind to VLA-4 include the inducible cell surface receptor vascular cell adhesion molecuie-1 (VCAM-1) (6) and the extracellular matrix molecule fibronectin via its alternatively spliced connecting segment-1 (CS-1) domain (7). The interaction of VLA-4 with VCAM-1 and or fibronectin is thought to be key to leukocyte adhesion, migration and activation. These processes are key to the normal immune response as...

CD4 T cells play multiple roles in adaptive immunity

Th1 cells combat infection by intracellular pathogens by producing IFN-y and IL-2 to stimulate and sustain an effective cellular immune response. Th2 cells, on the other hand, produce the cytokines IL-4, IL-5, and IL-13 that promote clearance of infection by multicellular helminths. In mice, IL-4 and IL-5 secretion induces antibody (Ab) class switching in activated B cells from IgM and IgD to IgG1 and IgE and augments IgA production, respectively. IgG1 and IgA are functionally important for neutralization and targeting of extracellular pathogens for phagocytosis and killing by macrophages and neutrophils. IgE targets helminths for attack by eosinophils and triggers the activation of mast cells, thereby inducing mucus secretion, smooth muscle contraction, and vasodilatation to facilitate expulsion of helminths, while also playing a predominant role in asthma and allergy (Bischoff, 2007 Grimbaldeston et al, 2006). CD4 Th17 cells are thought to protect against...

CD8 T cells in neuroinflammation A neverending controversy

Neuroinflammation Model

FIGURE 1.2 The pathogenesis of chronic neuroinflammation. Classically chronic neuroinflammation was regarded as CD4 Thl-mediated autoimmune disease. More recent data rather point to a disregulation of two dichotomous T cell subsets the highly pathogenic CD4 Th17 cells and the recovery-mediating CD4 Treg. TGF-b, which has been associated with Treg for a long time, also promotes the differentiation of Th17 cells in the context of antigen-specific (re)activation by mature dendritic cells (mDC) secreting the proinflammatory cytokines IL-6 and IL-23. Uninhibited Th17 cells induce a massive recruitment of effector T cells and APC such as macrophages, B cells, and DC to the target organ. The release of proinflammatory cytokines such as IFN-g, TNF-a, and IL-17 promotes CNS inflammation and tissue injury either by directly targeting neurons or indirectly via APC activation, which releases neurotoxic compounds like nitric oxide (NO) and reactive oxygen species (ROS). Further effector mechanisms...

Specimens From Sterile Body Sites Fluids

The parietal pleura, a serous membrane of the thoracic cavity (see Chapter 53), lines the entire thoracic cavity. The outer surface of each lung is also covered by the visceral pleura (Figure 61-1). Pleural fluid is a collection of fluid in the pleural space, normally found between the lung and the chest wall (see Figure 61-1). The fluid usually contains few or no cells and has a consistency similar to that of serum but with a lower protein content When excess amounts of this fluid are present, it is called an effusion, or transudate, and is often the result of cardiac, hepatic, or renal disease. Pleural fluid that contains numerous white blood cells and other evidence of an inflammatory response (an exudate) is usually caused by infection, but malignancy, pulmonary infarction, or autoimmune diseases in which an antigen-antibody reaction initiates an inflammatory response may also be responsible. The material collected from the patient by needle aspiration (thoracentesis) is submitted...

Methods for Inducing Apoptosis

Apoptotic cells are sources of tolerogenic material during tissue homeostasis abnormalities in apoptosis or in the clearance of apoptotic material generate a novel source of antigens against which an autoimmune response may be initiated. In our laboratory, we study the biochemistry and cell biology of systemic autoimmune disease autoantigens during different forms of cell death. Several different methods for inducing apoptosis, and for assaying the induction of this cellular process, are routinely performed. This chapter describes methods for inducing apoptosis via ultraviolet B irradiation, small molecule drug treatments, death receptor ligation, and exposure to granule components of cytotoxic lymphocytes. Assays to confirm the induction of apoptosis by quantifying changes in mitochondrial membrane potential, phosphatidylserine membrane localization, DNA content, and autoantigen cleavage are also detailed. Key Words Apoptosis autoantigens autoimmunity caspase cytotoxic lymphocytes...

Demographics And Epidemiology

Like many other neurodegenerative disorders, symptoms usually begin insidiously in the sixth to eighth decade and gradually progress over 3-15 yr until death. Males and females are equally affected. A defining characteristic of the CBS is asymmetric limb findings, but there does not appear to be any predilection to the right or left side. A relatively high frequency of coexisting autoimmune diseases was noted in one series (12). This is a sporadic disorder, although there are rare reports of a similarly affected relative (13).

Interference with lymphocyte activation

Inhibiting T Cell cycle progression Blockade of the b-3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) by inhibitors (HMGCRI), also known as statins, results in interference with T cell cycle progression and plays a beneficial role in chronic neuroinflammation (Aktas et al., 2003 Waiczies et al., 2005). The HMGCR pathway utilizes several key enzymes to convert intermediary metabolites via a series of sequential organic reactions (rearrangements, condensation reactions, etc.) that finally lead to cholesterol synthesis. This pathway is a source of hydrophobic molecules important for a wide range of inter- and intracellular functions involving hormonal communication, protein synthesis, electron transport, protein lipid modification for membrane anchoring and intracellular signaling (via isoprenoids), and cell membrane maintenance (via cholesterol). Previous studies demonstrating the anti-inflammatory nature of statins revealed the possible benefits of employing...

Leptin in type 1 autoimmune diabetes

Leptin is involved in other autoimmune conditions (17). Leptin accelerates autoimmune diabetes in female NOD LtJ mice (18). Fluctuations in serum leptin levels have also been observed in a study performed by our group in an animal model of CD4+ T-cell-mediated autoimmune disease, such as T1D. Nonobese diabetic (NOD LtJ) female mice, spontaneously prone to the development of -cell autoimmunity, have higher serum leptin levels, as compared with NOD LtJ males and nonsusceptible strains of mice, and show a serum leptin surge preceding the appearance of hyperglycemia (19).

Paraneoplastic Nervous System Syndromes of the Neuromuscular Junction

Myasthenia gravis, LEMS, and neuromyotonia affect the neuromuscular junction. These disorders are not necessarily associated with malignancy but are sometimes associated with tumors and are regarded as PNS in these patients. Eighty-five percent of patients with myasthenia gravis have antibodies to the acetylcholine receptor 133 , but only 10-15 of patients with myasthenia gravis have a thymoma. LEMS is much more commonly associated with cancer than myasthenia gravis. LEMS affects individuals in mid to late life, begins insidiously and typically presents as proximal muscle weakness and generalized fatigue, with a sparing of the ocular and bulbar muscles. Auto-nomic dysfunction is more frequent than in myasthenia gravis, and dry mouth is a particularly common symptom. Cancer is found in about 60 , usually diagnosed within 2 years of the onset of neurological symptoms 134 . The most common malignancy is SCLC. Smokers who are HLA-B8 negative are particularly prone to harboring SCLC, but...

Leptin in multiple sclerosis

Leptin is involved in both the induction and progression of EAE in mice (11-13). Analysis of the disease susceptibility in naturally leptin-deficient ob ob mice before leptin replacement revealed resistance to both active and adoptive EAE that was reversed by leptin administration. Leptin replacement converted Th2- to Th1-type response and shifted IgG antibodies from IgG1 to IgG2a. In addition, leptin administration to susceptible wild-type C57BL 6J mice worsened the disease by increasing proinflammatory cytokine release and IgG2a production (11). In addition, it has also been recently observed that a serum leptin surge precedes the onset of EAE in susceptible strains of mice (12). This peak in serum leptin is correlated with inflammatory anorexia, weight loss, and development of a pathogenic T-cell response against myelin (12). In animals with EAE, inflammatory brain infiltrates have also been shown to be a source of leptin, attesting to an in situ leptin production in active lesions...

Recent Advances in Therapeutic Approaches to Type 2 Diabetes

Introduction - Diabetes mellitus is the only non-infectious disease designated as an epidemic by the World Health Organization (1). The prevalence of all types of diabetes is estimated to be 2.3 of the world's population, with the number of diabetics increasing by 4-5 per annum. It is projected that as many as 40-45 of persons aged 65 or older have either Type 2 diabetes or its precursor state, impaired glucose tolerance (IGT). In the US -10 of the diabetic population suffer from Type 1 diabetes, an autoimmune disease characterized by the loss of pancreatic P-ceil function and an absolute deficiency of insulin. The remainder of the diabetic population suffers from Type 2 diabetes or IGT, which, although related to the body's inability to properly respond to insulin, have a more complex etiology (2). Diabetes can be treated by a combination of lifestyle change, dietary change and medication. However, the metabolic disorder underlying diabetes also affects protein and lipid metabolism,...

Strategies to Overcome the Humoral Immune Response

Chronic immune suppression with drugs such as cyclosporine and cyclophosphamide has improved the stability of adenovirus-encoded transgene expression in animal models of liver-, lung-, and muscle-directed gene therapy 64-66 . Cyclophosphamide is a commonly used immune suppressive agent for the treatment of autoimmune diseases and prevention of rejection following allograft organ transplantation 67 . It is activated by hepatic cytochrome p450 to metabolites that exhibit toxicity primarily to dividing cells, including activated T and B cells 68 .

Tcell And Combined Disorders

In contrast to the unregulated lymphoproliferation in XLP, autoimmune lymphoproliferative syndrome (ALPS) results from defects in programmed cell death or apoptosis. As an essential feature of the immune system, apoptosis allows the negative selection of autoreactive lymphocytes and the removal of activated cells after an immune response. Apoptosis may be induced through the activation of the Fas pathway. Fas, a member of the tumor necrosis factor (TNF) receptor superfamily, is one of the main receptors used by the immune system to control the peripheral lymphocyte pool. Binding of Fas (CD95) by the Fas ligand leads to the activation of the caspase 8 and 10, triggering the caspase cascade, activation of caspase 3, 6, 7, and cell death. Patients with defects in the Fas pathway commonly present with autoimmune diseases and lymphoproliferative disorders or ALPS. The most common defect in ALPS patients results from the mutations in the intracellular domain of the Fas receptor. However,...

Application of Linkage to SLE

Thrombocytopenia And Genetic

As discussed, SLE is a complex autoimmune disease with a definite genetic predisposition. However, the exploration of SLE genetics is in its infancy. SLE is an extremely complicated clinical illness with a wide range of manifestations. Clinical manifestations of SLE can be very diverse, with glomerulonephritis, dermatitis, thrombosis, vasculitis, seizures, arthritis, hemolytic anemia, and thrombocytopenia counted among the disease's manifestations. Consequently, the variation between patients is incredible. Indeed, it is possible to have two patients afflicted with SLE who satisfy the classification criteria three different ways with no features in common. This degree of clinical heterogeneity may be because of the involvement of multiple major and modifier genes. Thus far, the genome scans have been performed using a general SLE phenotype.

Attachment Of Pc To Filarial Molecules As A Target For Chemotherapy

Raises the possibility of rather than targetting PC as in filarial nematode infection, of actually using it for therapeutic purposes. For example, PC mimetics could perhaps be developed for use in the treatment of inflammation-associated TH-1 diseases such as rheumatoid arthritis. Additionally, they could be considered as immunomodulators to drive the TH-2 phenotype in the treatment of diseases resulting from TH-1 derived pathology such as endotoxin-shock. Whether or not this turns out to be the case the unravelling at the molecular level of the effects which PC has on lymphocytes will at least suggest new targets for therapeutic intervention. There may be scope for example, in considering phosphatases such as SHP-1 and Pac-1 as routes to manipulating lymphocyte function in autoimmune diseases.

What are the reported benefits and adverse effects of fish oil

Fish oils are used primarily in the treatment of hyperlipidemia, hypertension, and chronic inflammatory states such as rheumatoid arthritis and autoimmune disease. Fish oils contain two long-chain omega-3 fatty acids that compete with arachidonic acid in the cyclooxygenase and lipoxygenase pathways and have antiinflammatory effects, likely caused by the inhibition of leukotriene synthesis. Fish oils decrease blood viscosity and increase red blood cell deformability. The antithrombotic activity offish oils results from prostacyclin inhibition, vasodilation, reduction in platelet count and adhesiveness, and prolongation of bleeding time. Concomitant use of fish oils and anticoagulant and antiplatelet drugs previously mentioned may increase the risk of bleeding.

Acquired generalized lipodystrophy

Acquired generalized lipodystrophy (AGL) is another rare disorder and has been reported in approx 80 patients (47). It is characterized by selective loss of AT from large regions of the body occurring after birth. AT loss usually involves face, trunk, and extremities, and sometimes also spreads to the palms and soles. Intra-abdominal fat may also be lost, although retro-orbital and bone marrow fat are generally well preserved. The loss of AT may occur precipitously, within a few weeks, or may be more insidious over several months. In some patients, fat loss is preceded by the appearance of tender, inflamed subcutaneous nodules caused by panniculitis, but in others the disease is associated with autoimmune diseases such as juvenile dermatomyositis, Sjogren's syndrome, juvenile rheumatoid arthritis, chronic active hepatitis, and autoimmune hemolytic anemia. However, in more than half the reported cases of AGL, neither panniculitis nor autoimmune diseases have been reported. Although...

Macroautophagy in Epithelial Cells

The thymus is involved in the education of the T cell compartment. In this process, medullary thymic epithelial cells autoreactive T cell specificities (Klein and Kyewski 2000). They do so for both CD4+ and CD8+ T cells. In order to perform this task comprehensively, they should express and present both epithelial self-antigens and also a broad spectrum of proteins that T cells may encounter in the periphery. The importance of thymic peripheral antigen expression has been clearly demonstrated by mutations in the transcription factor Aire. In human diseases and in mouse models in which the Aire gene is mutated, a dramatic reduction in the efficiency of negative selection is responsible for the susceptibility to autoimmune disease (Mathis and Benoist 2007). Medullary thymic epithelial cells (mTECs) express a wide range of tissue-specific antigens that are dependent on Aire for expression at this site. Although the classical view of negative selection of CD4+ T cells implicates thymic...

Constitutive Gpcr Activation Disease And Inverse Agonist Utility

Studies to rule out autoimmunity, as this is generally responsible for Grave's disease, a situation where autoantibodies have been shown to act as agonists of the TSHR. Moreover, transient disease can be caused by the passage of such antibodies from the milk of mother to child. Persistent hyperthyroidism in non-autoimmune patients is one of the key findings that points to a possible TSHR mutation. The age of onset in such disorders is variable and not fully explained at present. As with LH in the Leydig cell, the Gas- and Gaq-coupled TSHR stimulates thyroid hormone production and thyroid cell growth. Several germline mutations in the TSHR have been identified that result in constitutive activation of the cAMP pathway 50,51 , and somatic mutations have been identified in hyperfunctioning thyroid adenomas whereas nearby non-adenomatous thyroid tissue contained the wild-type TSHR 52 . Interestingly, a similar phenomenon has been shown to occur in so-called hot thyroid nodules from...

New Therapies Or Therapeutic Strategies

Therapeutic efficacy than serum levels (81-83). Macrolides such as clarithromycin and azithromycin are concentrated in leukocytes and have higher concentrations in alveolar ELF tissues compared with plasma (84). Therefore, these agents are very active for pneumonias. The treatment of uncomplicated pneumonia caused by isolates with MICs as high as 4 mg mL or even 8 to 16 mg mL may be possible due to the exceptional tissue penetration of the macrolides. For now, macrolide monotherapy remains a reasonable alternative for outpatients without comorbid-ities. Continued monitoring of the clinical efficacy of the macrolides will be important as the prevalence and the magnitude of macrolide resistance continues to increase. Ketolides are generally active against MLS-resistant pneumococci due to a greater affinity for the ribosomal binding site and weaker induction of inducible erm expression. Telithromycin is also a weak inducer and poor substrate for the mefA efflux pump (85). In April 2004,...

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...

Therapeutic Antibodies

The development of mAB technology boosted the functional characterization, immunologic definition and CD clustering of surface antigens of lymphocytes and antigen presenting cells. This process coincided with the early phase of cytokine discovery. Both of these fields generated new concepts in immunology by the recognition of critical surface antigens (CD3, CD4, CD20, CD25, CD28, CD40, CD52 integrins etc) and the first interleukins (IL1-IL9, chemokines and TNF family of cytokines) via their blockade with mABs in-vitro and in mice. The straight forward approach was to test the mABs in human diseases. The best known early mABs were directed against selected inhibitory epitopes of CD25, the alpha chain of the IL2 receptor (anti-Tac), CD3 (OKT3 Orthoclone), depleting CD4 specific sites (OKT4A, B-F5, 16H5, VIT-4 etc.) and ICAM-1 (BIRR-1) (4-7) which have been shown to be effective in the treatment of acute graft rejection, graft versus host disease, and showed limited improvement in some...

Andras Perl

The immune system specifically recognizes and eliminates foreign antigens and thus protects the integrity of the host. During maturation of the immune system, tolerance mechanisms develop that prevent or inhibit potentially harmful reactivities to self-antigens. Autoreactive B and T cells that are generated during immune responses are eliminated by apoptosis in the thymus, lymph nodes, or peripheral circulation or are actively suppressed by regulatory T cells. However, autoreactive cells may survive because of failure of apoptosis or molecular mimicry, that is, presentation and recognition of cryptic epitopes of self-antigens or aberrant lymphokine production. Development of immune responses and tolerance is determined by an interplay of genetic and environmental factors. Autoimmunity is a result of the breakdown of one or more of the mechanisms of immune tolerance. Key Words Apoptosis autoantibodies autoimmunity cytokines molecular mimicry T-cell signaling. From Methods in Molecular...

History

The antiphospholipid syndrome (APS), first described in 1983 by Dr. Graham Hughes and his team at the Hammersmith Hospital, included recurrent arterial and venous thromboses, fetal losses, and thrombocytopenia in the presence of autoan-tibodies, the so-called antiphospholipid antibodies (aPL). Although a wide variety of clinical manifestations have been added over the last 5 years, these major features have stood the test of time. Many patients with APS have clinical and laboratory features common to other autoimmune diseases, particularly systemic lupus erythematosus (SLE). Such patients are defined as having secondary APS to distinguish them from patients with features of APS alone (primary APS-PAPS). There appears to be very few differences, if any, between the clinical complications associated with the primary and the secondary form of the syndrome, and the rates of arterial or venous thrombosis or fetal loss do not appear to be different. Distinguishing between PAPS and APS due...

Content Changes

I have strengthened the coverage of the following topics (indicating chapter numbers in parentheses) mitochondrial diseases (3), autoimmune diseases (5), the stages of hair growth (6), biomechanics of bone tissue (7), the enteric nervous system (15), receptive fields of sensory neurons (16), hormone-transport proteins (17), the blood-thymus barrier (21), clonal deletion and anergy (21), renal autoregulation (23), lipostats and leptin (26), and the trisomies (29).

Epidemiology

In autoimmune diseases, especially SLE, however, the prevalence is much higher. The Euro-Lupus study found a prevalence of 24 for IgG anticardiolipin antibody (aCL), 13 for IgM aCL, and 15 for lupus anticoagulant (LA), respectively, in a cohort of 1,000 patients with SLE. A recent study showed that the prevalence of antiphospholipid syndrome (APS) increases from 10 to 23 after 15-18 years in a large cohort of SLE patients.

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