Autoimmune Diseases Causes and Possible Treatments

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! Continue reading...

Autoimmune Paleo Cookbook Overview

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Cellular Autoimmunity

Many immunopathogenic diseases are associated with specific MHC haplotypes.87,88 Often, the disease susceptibility can be linked to specific subtypes of MHC molecules, even to a particular mutation at a specific location of an MHC allele. Several studies suggested that individuals with particular class II MHC haplotypes, including HLA-DR4 1, HLA-DQ beta 1 (histadine at position 36), and HLA-DQ5, have increased susceptibility to myocarditis or dilated cardiomyopathy or both.89,90 In a more recent study, production of humanized mice (transgenic mice expressing the human CD4 and HLA-DQ6 genes) allowed induction of heart disease through immunization with cardiac myosin.91 This last report provides strong evidence that an MHC class II allele known to be implicated in myocarditis actually induces autoimmunity to a heart protein long suspected of being a major autoantigen in this disease. Figure 3-4 (see color plate 3) demonstrates several hypothetical mechanisms by which myocarditis can be...

Immunoglobulin in myasthenia gravis is yet to be determined Chapter References

Intravenous immune globulin in myasthenia gravis. Clinical and Experimental Immunology, 97 (Supplement 1), 49-51. Grob, D., et al. (1995). Treatment of myasthenia gravis by immunoadsorption of plasma. Neurology, 45, 338-44. Myasthenia Gravis Clinical Study Group (1993). A randomised clinical trial comparing prednisone and azathioprine in myasthenia gravis. Results of the second interim analysis. Journal of Neurology, Neurosurgery and Psychiatry, 56, 1157-63. Pascuzzi, R.M., Coslett, H.B., and Johns, T.R. (1984). Long-term corticosteroid treatment of myasthenia gravis report of 116 patients. Annals of Neurology, 15, 291-8. Yim, A.P.C., Kay, R.L.C., and Ho, J.K.S. (1995). Video-assisted thoracoscopic thymectomy for myasthenia gravis. Chest, 108, 1440-3.

Protective Autoimmunity

Autoreactive T cells and autoantibodies directed against components of the CNS are part of the normal immune repertoire. Since MBP-specific T cells can also be activated by viral bacterial peptides, and because the response to such peptides might be as high, or even higher than the response to MBP (Wucherpfennig and Strominger, 1995), it seems fair to assume that the risk to develop autoimmune diseases is the price to pay for an efficient and fast immune response against pathogens. Moreover, inflammation should not always be considered an undesirable reaction. In fact, research in animal models of traumatic or excitotoxic brain lesions convincingly demonstrated that inflammatory T cells may serve beneficial functions by limiting tissue injury and stimulating tissue repair, an observation that even led to the concept of protective autoimmunity (Moalem et al, 1999). Protective autoimmunity is not only a feature of self-antigen-specific T cells it is also observed with autoantibodies....

The Role Of Tlrs In Autoimmunity

It is clear that the TLRs are required for an effective immune response to infections. What then happens when this response goes awry It is likely that TLRs may play a role in a variety of inflammatory diseases including autoimmunity. A hallmark of autoimmune disease is the production of autoantibodies, including rheumatoid factor (RF), an autoantibody that binds to normal antibodies, as well as antinuclear antibodies, and antibodies to DNA. It has long been a mystery as to how B cells are induced to produce large amounts of autoantibodies like rheumatoid factor. Most efforts in understanding this process have focused on the adaptive immune system. However, a recent report suggests that, after tolerance is broken, the amplification of the autoreactive B cells and the secretion of autoantibodies occur in a T-cell independent manner, and that this is mediated via TLR9 80 . These authors found that immune complexes containing self-DNA activate RF-specific B cells via two signals first,...

Myocarditis Due To Postinfectious Autoimmunity

The etiology of lymphocytic myocarditis in humans in developed countries is not clearly established. However, a good deal of circumstantial evidence points toward autoimmunity after viral infection as the major cause. Most cases of clinically suspected or biopsy-documented myocarditis in the United States fit into this category. Symptoms usually develop a few weeks after a viral infection. In the US Myocarditis Treatment Trial,16 89 of enrollees had had signs or symptoms of a possible viral prodrome.

Orbital Involvement in Autoimmune Disorders Graves Disease

Autoimmune disorder with orbital involvement frequently associated with thyroid dysfunction. Histologic examination reveals inflammatory infiltration of the orbital cavity. Etiology The precise etiology of this autoimmune disorder is not clear. Histologic examination reveals lymphocytic infiltration of the orbital cavity. The ocular muscles are particularly severely affected. Fibrosis develops after the acute phase.

Disrupted B Cell Signaling Pathways in Human Autoimmunity

As discussed above, experimentally induced modification of receptor expression or alteration of signaling pathways may have a significant impact on B cell tolerance to self. In humans too, there are indications that abnormal B cell signaling may contribute to autoimmune disease. In lupus, stimulation of circulating B cells through their sIgM produced significantly higher Ca2+ fluxes compared with similarly induced responses of B cells from patients with other systemic rheumatic diseases (Liossis et al., 1996). The overall level of sIgM-initiated protein tyrosyl phosphorylation also was significantly enhanced, and correlated with the augmented BcR-mediated free Ca2+ responses. This aberrant BcR-mediated signaling process was not associated with disease activity, medications used, or specific clinical manifestations. It was disease-specific, suggesting a possible intrinsic SLE B cell defect that may have pathogenic implications. In further studies, the content of lupus B cells in Lyn,...

IFNg in SLE and Other Autoimmune Diseases

Several lines of evidence implicate IFNy in inflammatory autoimmune disease (Billiau, 1996 Schwarting et al., 1998). First, signaling through the IFNy receptor is essential for the initiation and progression of lupus nephritis in lupus-prone, MRL-lprfas mice (Schwarting et al., 1998). Second, the IFNy-related transcription factor T-bet has been shown to regulate IgG2a class switching and induction of pathogenic autoantibodies in murine lupus (Peng et al., 2002). Third, during the course of SLE, the increased level and the expression of IFNy was accompanied by an increase in IgG2a and IgG3 levels (Reininger et al., 1996). Fourth, in the absence of IFNy gene, the levels of anti-dsDNA and ss-DNA autoantibodies, and immune complex-mediated glomerulonephritis are decreased in murine models of SLE (Carvalho-Pinto et al., 2002). Fifth, blocking IFNy by the administration of plasmids with cDNA encoding the IFNy-receptor Fc into MRL-lpr mice (at preclinical or advanced stages of lupus)...

The Critical Role of B Cells in Autoimmunity

The main immunological event in the pathogenesis of SLE is B cell hyperactivity, and several lines of evidence demonstrate that B cells are essential for development of autoimmunity and disease expression (Lu and Cyster, 2002 Zouali, 2005). Transfer of cultured pre-B cells derived from (NZB x NZW) F1 fetal liver into SCID mice is sufficient to generate a lupus-like syndrome (Reininger et al., 1992). Since T cells do not develop from these donor cells, it appears that B-lineage-intrinsic defects play a primary role in the pathogenesis of the autoimmune disorder. It is also clear that, before disease development, (NZB x NZW) F1 mice have large numbers of B cells spontaneously producing low-affinity, IgM anti-DNA antibodies (Steward and Hay, 1976). In human lupus, the number of B cells that secrete Igs spontaneously is dramatically increased (Zouali et al., 1991). Characterization of autoantibody genes shows that pathogenic, high-affinity IgG anti-DNA antibody (Ab) result from an...

T Cell Signaling Abnormalities in Systemic Autoimmune Disease

The critical contribution of T cells to the generation and perpetuation of systemic autoimmune disease is beyond question. In experimental models they can transfer disease, and genetically engineered antigen-specific autoreactive T cells can promote sustained autoimmunity. In addition, treatment modalities that interfere with T or B cell function ameliorate disease. The discovery by two independent groups (Fields et al., 1996 Li et al., 1996) of the role of the route leading to transcription factor AP-1, as a pivotal mechanism responsible for the maintenance of T cell tolerance, illustrates the importance of postreceptor cell signaling in immune homeostasis. Recent work, showing bidirectional signaling, triggered by the interaction of cells responsible for innate and adaptive immunity, adds a new perspective to the understanding of the interplay between the environment and genes, a subject fundamental to the pathogenesis of autoimmune diseases. Thus, a full understanding of signaling...

Reactive Protein as a Regulator of Autoimmune Disease

Crp Synthesis

C-reactive protein (CRP) is a phylogenetically ancient, highly conserved component of the innate immune system. The pentraxin family, which includes CRP and serum amyloid P (SAP) component, is represented in all vertebrate species studied as well as in several invertebrates. Throughout evolution, pentraxins have retained similar amino acid sequence, structure, and calcium-dependent ligand-binding sites. CRP was identified and named for its ability to precipitate the C-polysaccharide of Streptococcus pneumoniae (Tillett and Francis, 1930) to which it binds through phosphocholine (PC) residues (Volanakis and Kaplan, 1971). CRP and SAP bind to microbial determinants, as well as to potential autoantigens, and interact with the adaptive immune system through the complement system and Fcy receptors (FcyR). The general properties of CRP have been reviewed recently (Du Clos, 2000 Volanakis, 2001 Du Clos and Mold, 2003) and will only be described briefly here. The focus of the current review...

Human Autoimmunity An Abnormality of B Cell Function

The original concept of autoimmunity was based on the presence of antibodies to self B cell autoreactivity (Landsteiner, 1904). One hundred years later, there is a broad body of evidence for abnormalities of B cell function in a wide Molecular Autoimmunity In commemoration of the 100th anniversary of the first description of human autoimmune disease, edited by Moncef Zouali. Springer Science+Business Media, Inc., New York, 2005. range of human autoimmune diseases. Although T cell responses to autoantigens are documented in a number of murine models of autoimmunity (Busser et al., 2003), evidence for T cell autoreactivities that might be responsible for production of autoantibodies such as rheumatoid factors and antibodies to a range of nuclear antigens in the human is limited. It has often proved difficult to differentiate consistently between T cell responses in autoimmune subjects and normal individuals. Recent studies on removal of regulatory T cell populations further confirm that...

Autoimmune Diseases

The seeding of these bacteria can also result in the initiation of autoimmune diseases in some people. Such diseases are characterized by the immune system attacking the native tissues of the body. Just as the poorly broken-down food particles can provoke an immune response, the bacteria themselves, along with their metabolic byproducts, can also provoke the immune system into attacking normal body tissues. This happens when the immune system reacts against the body's own tissues that have been altered enough by the presence of the bacteria for the immune system to no longer recognize that tissue as being part of the body. The result is an autoimmune disease.

Myasthenia Gravis

Myasthenia gravis is a disease where nerve impulses don't reach the nerves in muscle endings (myoneural junction) because of an inadequate secretion of or loss of acetylcholine due to action of acetylcholinesterase, an enzyme that destroys acetylcholine at the myoneural junction.

Autoimmunity

Autoimmune diseases involve the development of antibody or cell-mediated immune responses directed against self antigens ( 88,92). In many autoimmune diseases, an individual's risk is affected by his or her HLA genes (2,3 and 4,93,94). There are several possible scenarios under which such undesirable responses might be initiated.

The Natural Immune System

Macrophages are central in orchestrating the innate immune response to infection, which is not a trivial task they must be able to discriminate microbes from self, and then initiate a proper response. The discovery of the Toll-like receptor (TLR) family of pattern-recognition receptors has provided insight into this kind of recognition. TLRs are expressed on macrophages and other innate immune cells, where they collaborate to read the molecular fingerprint of different microbes and initiate inflammatory signalling pathways. The TLR family is important in infectious diseases, and there is also evidence that they may play a role in autoimmunity and degenerative diseases in the central nervous system 46 ,

Immune System Communication with the Nervous System Hormones

Cytokines released after infection produce many effects on behavior, including decreased feeding, sexual activity, and pleasure seeking behaviors. In addition, sleep is increased and cognitive function is impaired (Banks, Farr, and Morley 2002). Several mechanisms have been proposed by which blood-borne cytokines convey information to the CNS (Dinarello 2004). These include cytokine acting at the circumventricular organ (CVO), acting at afferent nerves including the vagal, or altering the permeability of the blood-brain barrier (BBB) to immune cells or another substance. In addition to these indirect mechanisms of effects on cytokines on the brain, cytokine transport across the BBB has also been described. The list of cytokine transporters includes IL-1, IL-6, tumor necrosis factor-a, and the IL-1 receptor antagonist (Banks et al. 2002). The cytokine transporters are usually distinguishable from cytokine receptors and interestingly show differences in regional uptake in the brain...

Host Defense Mechanisms

To understand how autoimmunity occurs, one first needs to review the basic processes of immune response and immune regulation. Host defense mechanisms can be broadly defined as 2 types innate and adaptive (or antigen-specific) immunity.1'2 Although adaptive immunity is usually the most effective mechanism for eliminating invading organisms, this response is relatively slow, taking up to 7 to 10 days for effective primary immune responses and 2 to 3 days for anamnestic or memory responses. During this time, rapidly proliferating infectious agents could produce significant tissue injury and possibly death of the organism if left uncontrolled. For this reason, broadly reactive host responses, which are constantly maintained or can be rapidly induced, are essential in containing infections until the adaptive immune response kicks in.

The Central Role of the Tryptophan Metabolic Pathway in Tolerance and Immunity to Fungi

The inflammatory anti-inflammatory state of DC is strictly controlled by the metabolic pathway involved in tryptophan catabolism and mediated by the enzyme IDO. IDO has a complex role in immunoregulation in infection, pregnancy, autoimmunity, transplantation, and neoplasia (Mellor & Munn, 2004). IDO-expressing DC are regarded as regulatory DC specialized to cause antigen-specific deletional tolerance or otherwise negatively regulating responding T cells. In experimental fungal infections IDO blockade greatly exacerbated infections, the associated inflammatory pathology and swept away resistance to reinfection, as a result of deregulated innate and adaptive immune responses caused by the impaired activation and functioning of suppressor CD4+ CD25+ Treg cells producing IL-10 (Bozza et al., 2005 Montagnoli et al., 2006). The results provide novel mechanistic insights into complex events that, occurring at the fungus-pathogen interface, relate to the dynamics of host adaptation by...

Autoreactive Repertoire

Self-reactive T-cell clones should be deleted in the thymus during ontogeny (central tolerance) or inactivated peripherally through anergy by inappropriate antigen presentation (peripheral tolerance). High-affinity interactions of self-reactive T cells in the thymus with self-epitope-loaded MHC molecules on thymic epithelium or medullary dendritic cells result in clonal deletion of the autoreactive clones (negative selection). Interactions between T cells and self-MHC with nonspecific epitopes are not of high enough avidity to cause apoptosis of the developing T cell but provide sufficient signal to retain the lymphocyte in the thymus (positive selection) for further differentiation. The problem with this form of tolerance is that it depends on self-antigens being present in the thymus during T-cell ontogeny. This could be true for common cellular molecules present in all cells, but would not necessarily be true for specialized or sequestered antigens, such as thyroglobulin, cardiac...

Autoimmune Tcell Activation

Antigenic mimicry is one mechanism for infectious diseases to trigger autoimmunity. Antigenic mimicry is defined as a cross-reactivity between the epitopes of an infectious organism and one or more self-antigens.51,52 The self-antigens themselves are incapable of inducing an immune response because they are sequestered, are presented by APC in the absence of appropriate accessory molecules or sufficient cytokines required for adequate immune stimulation, or induce autoimmune T cells having low avidity TCR, which cannot maintain contact with the MHC-peptide in the immune synapse for the 20 hours required to initiate cell proliferation. Infections induce such potent immunity to the invading organism, and the infection usually results in tissue damage with accompanying release of cellular molecules, that self-proteins may be taken up by professional APCs and presented to the low-avidity autoreactive T cell under conditions favoring their activation. Also, infection will have a stronger...

Current Hypothesis Of Ms

Autoimmune Hypothesis The nature of MS lesion pathology involves inflammatory demyelination with relative sparing of axons. This supports the hypothesis that MS is an autoimmune disease targeting CNS myelin. Even in severe destructive lesions in the spinal cord of OS-MS, Schwann cells remyelinate the remaining axons, suggesting that CNS not peripheral nervous system (PNS) myelin is the target of the autoimmune attack. Myelin protein-autoreactive T-cell lines and clones have been established from peripheral blood lymphocytes taken from MS patients and from healthy subjects. Autoreactive T cells from MS patients were

Failure To Regulate The Autoimmune Response

Immune responses are usually strictly controlled. One control mechanism is the elimination of stimulated T or B lymphocytes by apoptosis once the antigen has been cleared. In this way, total lymphocyte numbers in the body are restricted, which conserves resources. Memory cells, however, are readily available to expand the antigen-specific clone if the pathogen is encountered again. Individuals with defective apoptotic pathways (such as the Fas-deficient Ipr lpr mouse)56 can develop autoimmunity as part of generalized lymph-adenopathy because their autoreactive T cells are never eliminated. A second mechanism of losing control is through epitope spread. Prolonged in situ inflammatory responses may give rise to sequential autoimmune responses directed toward different self-antigens. Epitope spreading as a component of autoimmunity has been shown in both experimental allergic and Theiler virus-induced encephalomyelitis.32'57'58 Finally, chronic infections, such as might occur with...

Reclassifying Diabetes How to Differentiate Between Type 1 and Type 2 Diabetes

From 1985 and onwards several clinical studies 14 as well as practical clinical experience demonstrated that a large proportion of patients characterised as non-insulin dependent would subsequently need insulin to maintain acceptable metabolic control. This often led to confusion with respect to classification of the individual patient, and increasingly patients were re-classified from NIDDM to IDDM. This clinical observation combined with a wish to establish a classification based on a combination of clinical stages and aetiological types 15 led WHO to abandon the terms IDDM and NIDDM and to reintroduce the terms Type 1 and Type 2 diabetes. This development was helped by the identification of several markers of autoimmunity linked to the destruction of beta cells such as islet cell antibodies (ICA), insulin auto- antibodies (IAA) and auto-antibodies to glutamic acid decarboxylase (anti-GAD). Consequently, the revised classification included as the two main groups Type 1...

Aberrant T Cell DNA Methylation Gene Expression and Cellular Function in Idiopathic Lupus

Pathway inhibitors (Deng et al., 2001). Since hydralazine and MEK inhibitors decrease Dnmt1 and Dnmt3a expression, demethylate DNA, and because T cells treated with these drugs induce autoimmunity (Deng et al., 2003), decreased T cell ERK pathway signaling may contribute to DNA hypomethylation and autoimmunity in idiopathic lupus by similar mechanisms.

Direct Viral Injury Hypothesis

Horwitz et al.24 used a transgenic nonobese diabetic (NOD) mouse myocarditis model to study the mechanism behind virus-induced autoimmunity. In these mice, pancreatic islet cells express interferon (IFN)-gamma under the influence of the insulin promoter. Pancreatic expression of IFN-gamma protects mice from lethal infection by a diabetogenic coxsackievirus CB4. Transgenic expression of IFN-gamma by pancreatic beta cells protected mice from lethal infection with CB3, decreased the amount of the virus in the heart, and prevented myocarditis. Nontransgenic NOD littermates, on the other hand, all died promptly. Although autoantibodies against cardiac myosin were present in the transgenic CB3-infected NOD mice as well as in the nontransgenic infected NOD mice, the authors concluded that molecular mimicry was not likely to be a mechanism, because cardiac damage induced by CB3 was required to initiate disease, probably by exposing heart antigens. They favored the hypothesis of virus-mediated...

Diversities of Complement Components C4A and C4B in Human Populations

The C4 gene is located at the class III region of the major histocompatibility complex (MHC). There may be one, two, three, or four copies of C4 genes in an MHC and two to seven copies of C4 genes with different combinations of long and short C4A and C4B genes have been found in diploid genomes from different subjects (Yang et al., 1999 Blanchong et al., 2000 Chung et al., 2002a). In about half of the Caucasian populations, there are four copies of C4 genes in an individual's diploid genome (gene dosage). Approximately 40 of normal Caucasians have a heterozygous deficiency of either C4A or C4B. In contrast, about one third of Caucasians have five or six C4 genes. This increase in gene dosage results in increased plasma protein levels of C4A, C4B, or both (Yang et al., 2003). Such genetic diversity of human C4A and C4B genes is one of the major determinants for the quantitative and qualitative variations of the C4A and C4B proteins that may be the...

Headache Specific Causes

Giant cell arteritis, an autoimmune disease of unknown cause, presents with headache in the elderly. This is severe and throbbing in nature and overlies the involved vessel - usually the superficial temporal artery, although the condition may affect any extra-or intracranial vessel.

Dampening Inflammation and Allergy to Fungi A Job for Treg Cells

The inflammatory response to fungi may serve to limit infection but may also contribute to pathogenicity, as documented by the occurrence of severe fungal infections in patients with immunoreconstitution disease (Cheng et al., 2000). These patients may experience intractable fungal infections despite recovery from neutropenia and the occurrence of adaptive immune responses. The above considerations imply that immunoregulation may be essential in fine-tuning inflammation and adaptive Th reactivity to fungi and fungal diseases. This imposes a new job upon the immune system. In addition to efficient control of pathogens, tight regulatory mechanisms are required in order to balance protective immunity and immunopathology. To limit the pathologic consequences of an excessive inflammatory cell-mediated reaction, the immune system resorts to a number of protective mechanisms. CD4+ T cells making immunoregulatory cytokines such as IL-10, transforming growth factor (TGF)-P and IL-4 have long...

Use With Cholinesterase Inhibitors

During reversal of competitive neuromuscular blockade with neostigmine or other anticholinesterase agents and in the management of myasthenia gravis with cholinesterase inhibitors, atropine or another mus-carinic antagonist should be given to prevent the stimulation of muscarinic receptors that accompanies excessive inhibition of AChE. However, extra care must be exercised because the prevention of muscarinic receptor stimulation eliminates an important early sign of cholinergic crisis (see Chapter 12).

Types Of Muscle Tissue

Myasthenia gravis is a major disorder of the skeletal muscle system. Muscle weakness and excessive fatigue characterize it. In myasthenia gravis, the muscular system is marked by progressive paralysis of the muscles, which is caused by an abnormal condition at the neuromuscular junction due to a lack of acetylcholine or an excess of cholinesterase. If there is either too little acetylcholine or an excess of cholinesterase, a contraction will not occur.

Contraindications

Because of its anticholinergic properties, disopyra-mide should not be used in patients with glaucoma. Urinary retention and benign prostatic hypertrophy are also relative contraindications to disopyramide therapy. Patients with myasthenia gravis may have a myasthenic crisis after disopyramide administration as a result of the drug's local anesthetic action at the neuromuscular junction. The elderly patient may exhibit increased sensitivity to the anticholinergic actions of disopyramide.

Preface to the Third Edition

Mucosal immunology has grown in the last decade from a discipline of perhaps peripheral interest to the mainstream immunologist into a major subspecialty with implications for the physiology of the entire immune system. An enormous and highly variable load of foreign substances, which includes indigenous mucosal microbiota as well as environmental and food antigens encountered mainly at the vast surface areas of mucosal membranes, has resulted during evolution in a strategic distribution of specialized cells involved in the uptake, processing, and presentation of antigens, the production of antibodies, and cell-mediated immunity at the front line of host defense. Furthermore, the great majority of infectious diseases and potential agents of bioter-rorism directly afflicts or is acquired through the mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tracts. In addition to the induction of protective responses to infectious agents, the unique immunoregulatory...

Thyroid Follicular Hyperplasia And Neoplasia

The pathophysiology of nodule formation remains poorly understood. The aetiology of this disorder has long remained elusive, since the goitres do not appear to be TSH-dependent (9). The work of Studer suggests that the initial proliferation is a polyclonal one involving cells that are intrinsically more rapidly growing than their neighbours (7,10,11). While the stimulus for growth is not certain, high levels of circulating thyroid growth-stimulating immunoglobulins (TGI) and defects in T suppressor cell function have been documented in patients with sporadic nodular goitre (12,13), implicating autoimmunity in the pathogenesis of this disease. Drexhage and colleagues (12) compared immunoglobulin preparations of patients who have goitrous Graves' disease with those of patients who have sporadic nodular goitre and have found that the former are approximately 10-fold more potent in inducing growth than the latter. It has been postulated that the weaker stimuli result in proliferation of...

Autoreactive T Lymphocytes in Pemphigus

Current concepts strongly suggest that autoreactive T cells play a crucial role in the initiation and perpetuation of both Ab- and cell-mediated autoimmune diseases. Autoreactive T cells may provide critical help for B cells to continuously produce pathogenic autoAbs in PV Involvement of CD4+ T lymphocytes in the pathogenesis of PV has been suggested by the aforementioned strong association of PV with HLA-DRB1*0402 and HLA-DQB1*0503 (Sinha et al, 1988 Ahmed et al, 1990 Hertl and Riechers, 1999). Using an ELISPOT assay, anti-Dsg3 autoAbs secreted by autoreactve B cells were detected upon in vitro stimulation of peripheral lymphocytes from PV patients with Dsg3 (Nishifuji et al., 2000). In contrast, activation of autoreactive B cells was virtually absent upon depletion of the peripheral lymphocytes from CD4+ T cells (Nishifuji et al., 2000). In addition, adoptive in vivo transfer of splenocytes from Dsg3- - mice immunized with Dsg3 into Dsg3+ + Rag2- - mice led to the induction of...

Regulatory T Lymphocytes in Pemphigus

In a recent study, we assessed whether the presence or absence of Dsg3-specific Tr1 cells in Dsg3-responsive healthy donors and PV patients, respectively, may account for the development of tolerance versus autoimmunity against Dsg3. In fact, Dsg3-reactive IL-10-secreting Tr1 cells were identified in 80 of healthy carriers of PV-associated HLA class II alleles and in only 17 of PV patients whose cells suppressed the proliferative response of Dsg3-reactive Th cells. The Dsg3-specific Tr1 cells secreted IL-10, TGF-P, and IL-5 upon Ag stimulation, proliferated in response to IL-2, but not to Dsg3 or mitogenic stimuli, and inhibited the proliferative response of Dsg3- and TT-responsive Th clones in both Ag-specific (Dsg3) and cell number-dependent manners. Moreover, their inhibitory effect was blocked by Ab against IL-10, TGF-P, and by paraformaldehyde fixation. These observations strongly suggest that (a) Dsg3-responsive Tr1 cells predominate in healthy individuals, (b) their growth...

The Synapse And Neurotransmitters

Major excitatory transmitters include substance E, acetylcholine, and excitatory amino acids major inhibitory transmitters include GABA, enkephalin, and glycine. Disruption of neurotransmitter function can lead to different diseases of the nervous system. One such example involves the role of acetylcholine at the neuromuscular junction. When antibodies are formed against the acetylcholine receptor at the neuromuscular junction, transmission is disrupted and the autoimmune disease called myasthenia gravis occurs. This disorder includes symptoms such as weakness and fatigue of the muscles.

Active Animal Model of Pemphigus Vulgaris

Amagai et al. (2000a) have taken advantage of the availability of Dsg3- -mice to establish an active in vivo model of PV Dsg3- - mice immunized with recombinant mouse Dsg3 produced anti-Dsg3 Abs. Their splenocytes were then transferred into immunodeficient Rag- - mice that expressed Dsg3. The recipient mice produced anti-Dsg3 autoAbs and developed erosions of the mucous membranes with typical histological findings of PV In addition, the mice showed tel-ogen hair loss, as seen in Dsg3- - mice. This first active in vivo model of pemphigus will be useful for understanding how autoimmunity develops in PV and for evaluating therapeutic strategies aimed at specifically interfering with the T cell-dependent autoAb production by autoreactive B cells.

Myocarditogenic Antigens Of

Various experimental models of autoimmune myocarditis have been reported during the last 4 decades (Table 8-1). Initially, outbred animals were immunized with heart tissue homogenates. Prevalence and severity of myocarditis were inconsistent in those models. The development of organ-specific autoimmune disease varies with antigens and animal strains. Subsequently, specific antigens, such as cardiac myosin, membranous protein, and sarcoplasmic reticulum protein, which were purified from heart tissue, were challenged in inbred strains of animals. From this initial work, 2 models of EAM were established by immunizing mice or rats with cardiac myosin.6'7 The clinical and pathologic severity of EAM in mice or rats is consistent. The models are characterized by increased cardiac size, macroscopic abnormalities, or histologic evidence of myocarditis. Rat EAM has several unique characteristics. The prevalence of histologic myocarditis is 100 in Lewis rats. Pathologically, rat EAM is...

Causes of Pancreatic Fibrosis

Metabolic disorders, hereditary diseases such as cystic fibrosis, obstruction of pancreatic ducts, autoimmune diseases, and idiopathic disorders such as retroperitoneal fibrosis. It was recentlyproposed that chronic pancreatitis and fibrosis may be caused by many factors, according to the TIGAR-O theory 1 , short for Toxic and metabolic pathway, Idiopathic pathway, Genetic pathway, Autoimmune pathway, Recurrent and severe acute pancreatitis pathway, and Obstructive pathway. Other hypotheses, such as the primary duct hypothesis and sentinel acute pancreatitis event (SAPE) hypothesis, have also been developed. Many pathways or hypotheses of pancreatic inflammation or fibrogene-sis support the concepts of multifaceted regulation of chronic pancreatitis and fibrosis.

Healing And Recurrence

One of the unique characteristics of rat EAM is the recurrence of the disease by resen-sitization with the same antigen.40 Animals cured of autoimmune disease acquire tolerance to the same antigen in other organ-specific autoimmune disease models. On the other hand, EAM may be induced in Lewis rats that were cured of actively induced EAM, at 2 months from the initial immunization. Until 2 months, rats are refractory to reinduction of EAM. The refractory period to recurrence may be explained by the Th1 Th2 balance. The mechanism of the progression from myocarditis to dilated cardiomyopathy is probably related to the above-mentioned persistent or recurrent myocarditis.

Relevance To Dilated Cardiomyopathy

Acute myocarditis shows a monophasic clinical course in human cases and in animal models. Left ventricular function improves after healing of the myocarditis. The mechanisms of how healed myocarditis progresses into dilated cardiomyopathy have been investigated extensively for a long time. Chronic myocarditis, either persistent or recurrent, is considered to be one of the mechanisms of the process (Fig. 8-11). Persistent viral infection, inappropriate antiviral immunity, and autoimmunity are proposed as the causes of

The effects of the antiacetylcholine receptor antibody

Eighty to eighty-five per cent of patients with myasthenia gravis have an identifiable and quantifiable antibody found in the IgG fraction of plasma which is responsible for the changes which take place at the neuromuscular junction. This is called the anti-acetylcholine receptor antibody and has the following effects.

The role of the thymus gland

The removal of the thymus gland frequently improves the clinical state of patients with myasthenia gravis. The reason for this is not clear. Cells in the thymus gland have been shown to produce anti-acetylcholine receptor antibody. However, the amount of antibody produced is small, and most is produced in the periphery outside the thymus gland. Acetylcholine-receptor-like tissue has been identified in thymic tissue and may act as an antigenic stimulus for antibody production. The thymus gland may be a source of lymphocytes which stimulate antibody production elsewhere in the body. The removal of the thymus gland is followed by a decrease in antibody level in those patients with a thymus which appears histologically active. The precise trigger for the onset of myasthenia gravis is not known.

Clinical grading of disability

Several methods of staging disability in myasthenia gravis have been used in the past. The best known is that of O S m n laDd lGenkiDS l 19Z1) which divides myasthenics into four classes (Table ). More useful clinical scoring systems have been devised based on the patient's ability to perform a few simple tasks ( Besinger etal 1983) (Table. ). These are clinically relevant as they reflect the response to treatment. Table 1 Classification of myasthenia gravis Table 2 Clinical scores for patients with myasthenia gravis

Antiacetylcholine receptor antibody

An immunoprecipitation assay is available for the anti-acetylcholine receptor antibody. An assay value greater than 2 * 10 -10 mmol l is diagnostic of myasthenia gravis. There is no close relationship between antibody level and severity of illness in a population of individuals. However, in a particular individual there is a direct relationship between antibody level and clinical weakness. Fifteen to twenty per cent of patients with myasthenia gravis have no detectable anti-acetylcholine receptor

Chapter References

Besinger, U.A., Toyka, K.V., Homberg, M., Heininger, K., Hohlfeld, R., and Fateh-Moghadam, A. (1983). Myasthenia gravis long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with changes in disease severity. Neurology, 33, 1316-21. Lennon, V.A., et al. (1995). Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. New England Journal of Medicine, 332, 1467-74. Osserman, K.E. and Genkins, G. (1971). Studies on myasthenia gravis. Review of a twenty-year experience in over 1200 patients. Mount Sinai Journal of Medicine, 38, 497-573. Soliven, B.C., et al. (1988). Seronegative myasthenia gravis. Neurology, 38, 514-17.

Anticholinesterase drugs

Pyridostigmine is probably the anticholinesterase of choice in the majority of patients with myasthenia gravis. The half-life of the drug is reasonably long (90 min) but it does not accumulate easily. It can be given orally as a tablet or elixir and has relatively mild cholinergic side-effects. It is frequently used to improve muscle strength, but only produces symptomatic improvement and does not correct the basic pathophysiological problem. If given in too large a dosage, anticholinesterase drugs produce cholinergic neuromuscular blockade and increase muscle weakness. In the longer term, these drugs can damage the neuromuscular junction itself. Anticholinesterase drugs can produce cholinergic side-effects such as excessive salivation, abdominal cramps and diarrhea, sweating, and bradycardia. An average dose of pyridostigmine would be 30 to 60 mg four or five times daily.

Inhibition Of Activation By Self Recognition

In intravenous immunoglobulin (IVIg). IVIg inhibited in vitro growth of the J4.1 and JIg3.1 variants obtained while enhancing Jurkat growth. The variants bound more monoclonal antibodies against activation-associated molecules including CD25, CD 134, and CD45RA which rises transiently about 1 day after T cell activation. Binding of anti-CD45RB and anti-pan CD45 were increased with anti-CD45RO binding unchanged or slightly decreased. Immunoblotting revealed more of the higher molecular weight isoforms of CD45. Binding was decreased for antibodies against CD69, CD 122, CD3 and FAS. Thus, similar to the findings from the murine model, markers which are increased about 1 day after activation, particularly the asialo forms, are likely targets of normal IgG and IgM. This further supports the idea that natural IgG and IgM directly regulate T cells during an early, possibly transient stage of normal activation likely critical for inflammation, autoimmunity and early neoplastic development 120...

Tigaro Theory and the New Hypotheses

Autoimmune chronic pancreatitis (AIP) is a rare condition. The entity known as non-alcoholic duct-destructive chronic pancreatitis may actually represent AIP. AIP may be associated with other autoimmune diseases, such as Sjogren's syndrome, primary sclerosing cholangitis, and inflammatory bowel disease. Recently, a characteristic high concentration of serum IgG4 was found in patients with sclerosing pancreatitis. Histology reveals lymphoplasmacytic infiltration in periductal non-occlusive fibrosis in the pancreatic tissue, and

Myelin Basic Proteins

Injection of MBP or peptides containing portions of MBP sequence gives rise to the autoimmune disease experimental allergic encephalomyelitis (EAE), a model for MS (28) (see Chapter 6). The use of defined, overlapping peptides has allowed epitope mapping of this immune response, with variations in encephalitogenic potency of a given peptide between species and even between different strains of rats or mice. Many aspects of this disease mimic characteristics of MS, especially with regard to the immune-mediated demyelination that occurs. Induction of EAE is not exclusive to MBP. Injection of PLP, myelin oligodendrocytic glycoprotein (MOG), and several other myelin proteins also give rise to EAE, but MBP has been the most studied model. The use of MBP to induce EAE and the ability of some pep-tides to suppress disease provided the basis for exploring the use of a random sequence of basic amino acids to suppress disease, first in animal models and then, with some success, in MS (29) (see...

Supplemental Reading

Vincent A, Palace J, and Hilton-Jones D. Myasthenia gravis. Lancet 2001 357 2122-2128. Wittbrodt ET. Drugs and myasthenia gravis An update. Arch Intern Med 1997 157 399-408. Answer The patient shows classic signs of myasthenia gravis, an autoimmune disease that results from antibody attack against the end plate receptors of skeletal muscle and leads to muscle weakness. The disease may be triggered by disorders of the thymus, which contains a protein antigenically related to skeletal muscle receptors. The train-of-four stimulation is used to differentiate between a prejunctional cause of weakness (such as Lambert-Eaton myasthenic syndrome, which normally shows facilitation in the action potentials) and a postjunctional cause (such as myasthenia gravis). Use of a short-acting nondepolarizing neuromuscular blocker (mivacurium) followed by a short-acting acetylcholinesterase inhibitor (edrophonium) is an almost conclusive test for myas-thenia gravis. In many instances, edrophonium alone...

Autoimmune Pancreatitis

It has recently been elucidated that there is a group of patients with duct-narrowing pancreatitis in whom steroid therapy is very effective 17, 18 . Since this group of patients often has other autoimmune diseases such as Sj gren syndrome, and their serum 7-globulin, IgG, or particularly, IgG4, often shows a high value, the autoimmune mechanism has been suggested as the cause of this particular form of chronic pancreatitis, and it was named autoimmune pancreatitis 19-21 . In autoimmune pancreatitis, narrowing of the pancreatic ducts due to dense lymphoplasmacytic infiltration is seen 22, 23 (fig. 3a). These inflammatory cells are distributed especially within and around the pancreatic ducts, and often include a significant number of IgG4-positive plasma cells (fig. 3b). This contrasts with other types of chronic pancreatitis in which only mild infiltrations of inflammatory cells are usually seen, and IgG4-positive plasma cells are, if any, usually not so many. Inter- and intralobular...

Major Histocompatibility Complex Class II Gene Control of Susceptibility

The recognition of genetic linkage of susceptibility in EAT to the MHC H2 gene complex has pioneered more than 3 decades of research into many autoimmune diseases in humans and in other species. Induction of EAT with the self-antigen, mTg, was compared in multiple inbred mouse strains of different H2 haplotypes, and susceptibility was distinguished from resistance by the marked infiltration of mononuclear cells (Vladutiu and Rose, 1971). Subsequent availability of intra-H2-recombinant strains enabled the identification of class II I-A gene as the locus encoding susceptibility or resistance alleles (Beisel et al., 1982). A strong HLA class II association with autoimmune thyroid disease, including Hashimoto's thyroiditis and Graves' disease, has been more difficult to gain widespread acceptance, despite implications from patient studies, due to the poly-genic nature of the human class II genes as well as ethnic differences. Firm association of autoimmunity with specific HLA class II...

CD25 Expression on CD4 Regulatory T Cells in Induced Resistance

BALB c background) blocks the development of several autoimmune diseases including thyroiditis, which can arise by the transfer of CD4+CD25- T cells alone (Sakaguchi et al., 1995). In vivo depletion of CD4+CD25+ T cells enabled the induction of autoimmune gastritis in otherwise resistant mice (McHugh and Shevach, 2002). We examined the participation of these cells in dmTg-induced resistance to EAT induction (Morris et al., 2003). After the establishment of tolerance, mice were depleted of CD4+CD25+ T cells with CD25 mAb, their peripheral blood leukocytes verified for depletion, and challenged with mTg and LPS. Depletion of CD4+CD25+ T cells led to the loss of tolerance in most animals, whereas dmTg-pretreated mice given rat IgG remained tolerant. Thus, the CD4+ regulatory T cells mediating EAT tolerance also carry the CD25 marker.

Pathogen Recognition by Tolllike Receptors

Macrophages are central in orchestrating the innate immune response to infection, representing both the janitor and the security guard. While performing their normal scavenging functions in various tissues they will, at the same time, survey the tissues for pathogenic intruders. This is not a trivial task They must be able to discriminate microbes from self, and then initiate a proper response. The discovery of the Toll-like receptor (TLR) family of pattern-recognition receptors has provided a better understanding of how this can be done. TLRs are expressed on macrophages and other innate immune cells, where they collaborate to read the molecular fingerprint of different microbes and initiate inflammatory signalling pathways. It is becoming clear that the TLR family is important in infectious diseases, and there is also evidence that they may play a role in autoimmunity and degenerative diseases in the central nervous system. In this review we will give an overview of the current...

The Multiple Facets of Multiple Sclerosis

Evidence for T Cell-Mediated Autoimmunity Since MS is an inflammatory demyelinating disease, which is, at least in northern Europe, often associated with the expression of the MHC class II antigen HLA-DR2, the search for autoimmunity was mainly a search for myelin antigens possibly recognized by brain-infiltrating CD4+, MHC class II-restricted T cells. And indeed, T cells specifically recognizing myelin basic protein (MBP), prote-olipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG) (Pette et al., 1990 Kerlero de Rosbo et al., 1997) could be readily isolated from the blood of MS patients. However, such cells can be isolated from the blood of healthy individuals just as well, indicating that they are normal components of the immune system (Wekerle, 1998). Then, the search was on for quantitative differences (Olsson et al., 1990b) in the antimyelin response of T lymphocytes found in the blood of MS patients and healthy controls. Here, simple assays such as testing for...

The Triggers for Autoimmune Reactions in MS Patients

Ciated with an increased risk to develop other autoimmune diseases (Henderson et al., 2000). What triggers autoimmune reactions in MS patients different situations in the termination of acute disease episodes or in the global control of autoimmunity. can induce autoimmune reactions against components of the CNS tissue, which may be involved in the propagation of chronic disease, possibly by antigen or determinant spreading (Croxford et al., 2002). This implicates a contribution of autoimmune T cells to the chronicity of the inflammatory reaction and to the induction of tissue injury. Since the virus is not completely eliminated from the CNS of the experimental animals, it remains unclear whether virus-induced autoimmunity alone, in the absence of viral persistence in the CNS, could maintain a long-lasting chronic inflammatory demyelinating disease.

Applications of ISH examples

In spite of the development of a large and still growing number of highly specific reagents, immunohistology may fail to provide information about the cellular source of a protein. This is a particular problem with secreted proteins. Thus, RNA ISH has been successfully employed to study the cellular origin of different extracellular matrix components and spatial and temporal expression patterns of collagen RNA transcripts, e.g. in liver fibrosis (Milani et al., 1995). Similarly, the identification of cytokine- or chemokine-producing cells may be difficult because these polypeptides may be secreted by one cell and bound by receptors on another cell, leading to false negative or false positive results, respectively. RNA ISH has proved useful in this context. Thus, Hodgkin and Reed-Sternberg (HRS) cells were demonstrated to produce a number of cytokines, e.g. IL-6 and IL-10, using this technique (Beck et al., 2001 Herbst et al., 1996, 1997). Similarly, expression of chemokines has been...

Cell Receptor Mediated Signaling Checkpoints

Throughout B cell development, lymphocyte survival and selection are determined by the specificity of the hetero-oligomeric BcR, a module that interacts with coreceptors, protein tyrosine kinases (PTKs) and phosphatases (PTPs), adapters, and other proteins to propagate signaling cascades (Reth and Wienands, 1997 Benschop and Cambier, 1999). Since the BcR is responsible for Ag recognition, the transduction events that occur after its ligation mediate interpretation of the magnitude and duration of BcR signaling. In addition to orchestrating the efficient development and subsequent activation of B lymphocytes at several discrete stages during B lineage differentiation, the BcR plays a central role in self-tolerance. During B lymphocyte development, potentially aggressive autore-active B cells must be tolerized at various checkpoints. While studies over the past few years have provided a wealth of new information regarding the selection processes, systemic autoimmune disease is often...

Critical Regulators of B Cell Receptor Signaling

While Lyn is not required to initiate BcR signaling, it is an essential inhibitor of transduction pathways. B cells from mice homozygous for a disruption at the Lyn locus had a delayed, but increased, Ca2+ flux and an exaggerated negative selection response to Ag, and a spontaneous hyperactivity (Hibbs et al., 1995 Nishizumi et al., 1995). The deficient mice also had circulating autoreactive Abs and severe GN caused by the deposition of ICs in the kidney, a pathology reminiscent of SLE. The role of Lyn in BcR-mediated signaling and in establishing B cell tolerance to self-Ags also stems from the phenotype of Lyn deficiency on a C57BL 6 background. The mutant mice are more susceptible to myelin oligodendrocyte glycoprotein-induced experimental allergic encephalo-myelitis (Du and Sriram, 2002). This strain dependence suggests that Lyn may represent a genetic susceptibility factor for autoimmune disease. The key role of Lyn in establishing and maintaining peripheral tolerance also comes...

Differential diagnosis Physical disorders

A few hypochondriacal patients suffer from undetected physical disease. Consequently, it is important to exclude medical conditions that, in their early stages, may cause vague symptoms with few definite signs or laboratory abnormalities. These might include neurological conditions such as multiple sclerosis or myasthenia gravis, endocrine conditions such as thyroid or parathyroid disease, diseases that affect multiple body systems such as systemic lupus erythematosus, or occult

Cellular Immune Components

It is widely held that MS is an autoimmune disease in which immunological tolerance to one or more CNS antigens is broken down, or dysregulated (Wekerle et al., 1994). Thus, T-cells play a central role in the targeting of the immune system to the CNS, and it is thought that the immune assault is directed at myelin antigens. It is not known whether during the evolution of MS, or in experimental models of MS, the axons eventually become a specific immunological target. As tissue, including axons, degenerates, there may be epitope spreading (Tuohy et al., 1998) leading to the generation of axon antigen-specific T-cell populations. In this regard, the role of both Th1 and Th2 cells needs to be considered. Although the Th1 component of the inflammatory response is usually believed to lead to tissue damage and the Th2 component to a protective response, it is clear that Th2 cytokines have a profound influence on the macrophage phenotype (Gordon, 2003). Macrophages activated by Th1...

Diagnosis of celiac disease

Endomysial IgA antibody (EMA) reacts with the endomysium or loose connective tissue around smooth muscle bundles and is assayed by immunofluorescence using monkey esophagus or human umbilical cord as the substrate. It is now known that tissue transglutaminase (tTG) is the antigen to which EMA reacts, and ELISAs have been developed that use guinea pig or human recombinant tTG as the antigen. Human sources of tTG are superior to guinea pig as the assay substrate. The sensitivities of EMA and IgA tTG are similar and can approach 98 , although lower levels of sensitivity are reported for EMA testing. Both have lower sensitivity in the presence of lesser degrees of villous atrophy. The EMA is virtually 100 specific, while the tTG IgA specificity is about 95 with false-positive tests reported in autoimmune diseases, liver disease, inflammatory bowel disease and heart failure. The IgG tTG may have value in diagnosing celiac disease in the presence of IgA deficiency, although the literature...

Idiopathic Subglottic Laryngeal Stenosis

Idiopathic s ubglottic stenosis (ISS) is a rare, slowly progressive inflammatory disease of unknown aetiology involving mainly the region of cricoid cartilage and the first tracheal ring. The pathogenesis of the disease remains hypothetical. ISS has recently been associated with various possible causes, such as gastro-oesopha-geal reflux, autoimmune diseases and previous infections of the respiratory tract 30, 174, 369 . Maronian and co-workers suggested that the term ISS should even be replaced by reflux-induced subglottic stenosis, if there is no other clear cause of the disease 229 . ISS has a strong female predilection 73, 132, 369 . The age of females when the symptoms start to appear ranges from 15 to 75 years (average 43.5 years) 73 .

The Pathogenesis Of Htlvassociated Tcell Lymphoma And Leukemia

Development of HTLV-associated adult T-cell lymphoma leukemia (ATL) is seemingly controlled by the infected individual's genetic predisposition. If the individual can mount a strong antiviral CTL response, his or her immune system will eliminate cells as they are being transformed, putting that individual at low risk for developing ATL, but increasing the risk for autoimmune diseases that have also been associated with HTLV. Those who cannot mount such a strong CTL response to the virus will not clear transformed cells with the same efficiency, and are therefore at a much greater risk of developing ATL.

Pathologic Findings of Pancreas in Sjogrens Syndrome

Recently, autoimmune pancreatitis was proposed as a new clinical entity 11 . The disease was designated as idiopathic chronic pancreatitis with a possible etiologic factor of autoimmunity. SS overlapped with autoimmune pancreatitis in about a quarter of the cases 12 . However, in most cases with SS, no inflammation or mild inflammatory reaction is seen in the pancreas, and the case reports of pancreatitis are few. This leads to the conclusion that SS usually does not cause autoimmune pancreatitis by itself.

Complications of celiac disease

Malignancy is the most feared complication of celiac disease, but more concerning than the risk of malignancy are other, more common complications of celiac disease that can develop when celiac disease is not recognized and or treated. These include osteopenic bone disease, growth retardation in children, iron deficiency and other nutritional deficiencies. There are also issues related to fertility including increased rates of infertility, spontaneous abortions and intrauterine growth retardation that are associated with untreated celiac disease 21-24 . There is some suggestion that untreated celiac disease may be complicated by developing other autoimmune diseases at a higher rate than expected, but this may only be true in children, and even then, not all studies support this observation. Complications of the malabsorption associated with celiac disease include metabolic bone

Treatment Of Acute Exacerbation Of Ms

The Cochrane systematic review provides quantitative evidence favouring ACTH or methylprednisolone against placebo for treating acute exacerbations in patients with MS. In the various trials, benefit is seen in the form of quicker recovery and lowering of mean disability score at 1 week and 4 weeks. With respect to ACTH, it was postulated that adrenal steroids other than cortisol or possibly a direct effect of ACTH on neural tissue was responsible for a therapeutic effect. The subsequent endocrine work suggested that the cortisol response to ACTH is not consistently reproducible, may not be prompt, and endogenous steroid production may never reach the range generally recommended for autoimmune diseases. Besides, ACTH is hardly used to treat any systemic disease of presumed autoimmune etiology. The majority of neurologists use IV methylprednisolone for the treatment of a relapse of MS.

Pathophysiology of Diabetes

By a symptomless prediabetic phase whose presence can be inferred from immune markers. Pre-type-1 diabetes is a period of accelerated p cell loss, whose tempo varies from acute in those who present young to subacute or chronic in those who present later in life 17 . The differences in tempo are assumed to be under genetic control, since those who develop type-1 diabetes in childhood tend to carry more intensely responsive HLA genes than those who develop it later in life 18, 19 . p cell autoimmunity appears to start early in life, insofar as immune markers predictive of future diabetes can be present as early as at 9 months of age 20 .

T Cell in Human Lupus

Tsokos et al. studied TCR CD3-mediated signaling events to identify lupus T cell primary abnormalities (Vassilopoulos et al., 1995 Liossis et al., 1998). Using anti-human CD3 monoclonal antibody (mAb), they showed that lupus T cells exhibited significantly increased Ca2+ responses compared with the T cell responses from patients with non-SLE autoimmune disease (Vassilopoulos et al., 1995). In particular, anti-CD3 mAb enhanced Ca2+ fluxes in lupus but not in nonlupus T cell clones. Furthermore, they also demonstrated that lupus TCR CD3 signaling is defective in tyrosine phosphorylation, which is necessary for proper T cell activation (Liossis et al., 1998). Specifically, T cell stimulation in SLE patients results in significantly enhanced production of tyrosine-phosphorylated cellular proteins and consists of an early elevated response as well as a steep decrease to baseline phos-phorylation levels. In contrast, protein tyrosine phosphorylation in normal T cells gradually increases...

Does underlying process involve brain spine or motor unit

Are any family members nonambulatory Is there a family history of childhood deaths Family history helps to determine possible congenital causes (eg, glycogen storage disease, hereditary neuromyopathies, spinal muscle atrophy, Ehlers-Danlos syndrome, Tay-Sachs disease, congenital myasthenia gravis, or benign congenital hypotonia).

Viral Myocarditis

Postinfectious autoimmunity Immune suppression, cytokine suppression Autoimmunity Immune suppression, cytokine suppression Nonspecific antiviral therapies have been tested or proposed for treatment of myocarditis. Immunoglobulin therapy, studied in children7 and in adults,8 appears promising, but it is not yet proved and may act against antibody-mediated autoimmunity rather than through viral suppression. Interferons also have the potential to ameliorate ongoing cardiotropic viral infections, but at present the only approved antiviral use is of interferon-a in condyloma acuminatum and hepatitis. A common myocyte membrane receptor for coxsackievirus and adenovirus has been proposed as a target for preventing development or spread of myocardial viral infection.9 Lymphocytic myocarditis is a well-recognized complication of acquired immunodeficiency syndrome (AIDS). Its incidence varies from less than 10 to more than 50 .10-13 Its etiology is debated. Human immunodeficiency virus...

Immunosuppressive Therapy

In deciding if patients with lymphocytic myocarditis should be treated for a presumed autoimmune disorder, the first step is to rule out active viral infection. In most patients this distinction is not difficult because they present afebrile days or weeks after a virus-like illness or report no such prodrome. In a small proportion the viral symptoms are more recent and fever is present. There are no randomized studies of therapy in patients with presumed

Immunotherapy Of Multiple Sclerosis Theoretical Basis And Practical Approach

Over the last 50 years, multiple sclerosis (MS) has been considered to be an autoimmune disease. Most authors supported a concept of accelerating immune stimulation, thus explaining why most relapsing-remit-ting patients become secondary progressive. However, MS is now seen as a disease mixing elements of both an immune disease and a degenerative disease recent suggestions that the degenerative element could start very early have been appealing to many and are supported by pathologic studies showing axonal loss very early in the disease, even before the progressive phase. This author has found very appealing the most recent attempts to show how both phenomenon are linked.

Possible Scenarios Of Bioterrorism Attacks Distinguishing Victims From Perpetrators

Interpretation of a positive clinical test must take into account the health status of the person being tested. This is important for the practice of medicine and can have relevance when extended to forensic analysis. The following situations illustrate the concept. Individuals who have syphilis, a bacterial spirochetal infection, can typically have a positive FTA (fluorescent treponemal antibody) test for years. However while infected they would have a positive venereal disease research laboratory (VDRL) test. This reverts to negative with successful antibiotic therapy. There are some notable exceptions related to cross-reactive epitopes or autoimmune diseases. These are readily distinguishable by history and clinical information. Similarly individuals infected with tuberculosis will have a positive skin test (Mantoux), whereas the unin-fected healthy person will be negative. In certain instances, a sick person with a cell-mediated immune deficiency will be anergic, that is, he she...

Experimental Aspects Of Demyelination

Experiments in sheep demonstrated that naive lymphocytes infused directly into the blood could circulate through the CSF (113). Further, it was demonstrated that naive T-cells can traffic to the CNS without prior activation in MBP TCR transgenic animals. Interestingly, it was also suggested that naive MBP-specific T-cells do not trigger autoimmunity when they traffic to the CNS because they undergo tolerance induction within the brain (5). Therefore, we also have to consider that, even if nonactivated autoimmune T-cells could gain access to the brain parenchyma, they would be eliminated or functionally inhibited very rapidly in the CNS due to the absence of costimulatory molecules and major histo-compatibility antigens in the CNS (Figure 5.7). The circulation of naive, autoreactive T-cells through the CNS represents a potential hazard for autoimmunity therefore, it must be tightly controlled. However, the circulation of non-CNS specific naive T-cells through the CNS could be an...

Mechanisms of Theilers Virusinduced Demyelination

Demyelination in the TVID model is partly mediated by (a) direct viral lysis of oligodendrocytes (Roos and Wollmann, 1984) immune mechanisms including (b) autoimmunity (Welsh et al. ,1987,1989,1990 Miller et al. ,1997 Borrow et al., 1998) (c) bystander demyelination mediated by virus-specific DTH T cells (Clatch et al., 1987 Gerety et al., 1991) (d) cytotoxic T-cell reactivity (Rodriguez and Sriram, 1988) (summarized in Fig. 10.2). Susceptibility to TVID is correlated with (e) increased MHC class II expression in vitro on astrocytes (Borrow and Nash, 1992) and (f) cerebrovascular endothelial cells (Welsh et al., 1993) after treatment with IFN-y. Increased MHC class II expression on cells within the CNS may lead to increased antigen presentation and inflammation. Figure 10.2. The mechanisms of demyelination induced by TMEV. Demyelination is partly mediated by (a) direct viral lysis of oligodendrocytes immune mechanisms including (b) autoimmunity, (c) bystander demyelination mediated by...

Diagnosis of myasthenia

Edrophonium is a short acting anticholinesterase used in the diagnosis of myasthenia in patients with no previous history of myasthenia gravis. In myasthenic patients with an acute deterioration the test may distinguish a myasthenic from a cholinergic crisis. In cholinergic crisis there is a possibility of further deterioration and atropine and facilities for urgent intubation and ventilation should be available. An initial dose of 2 mg IV is given. If there are no cholinergic side-effects a further 8 mg may be given. A positive test is judged by improvement of weakness within 3 min of injection. The test may be combined with objective assessment of respiratory function by measuring the FVC response or by assessing the response to repetitive stimulation with an EMG.

Neuroprotective Pathways and Treatment Approaches

Clinically established therapeutic strategies for the treatment of MS mainly target the autoimmune response by using anti-inflammatory, immunomodulatory, and immuno-suppressive agents. Although these substances have been proven to be beneficial in terms of modifying the clinical disease course, clear neuroprotective properties have been demonstrated for none of them so far. Unfortunately, the concept of achieving neuroprotective effects as a secondary phenomenon resulting from the treatment of inflammation and autoimmunity was not confirmed by many studies. In a study using magnetic resonance spectroscopy, immunomod-ulatory treatment with interferon-P did not prevent progression of axonal injury in patients with MS with active disease course (Parry et al., 2003). Detrimental effects of anti-inflammatory treatment on the survival of neurons have been described in a rat model of MOG-induced EAE that especially reflects the neurodegenerative aspects of the disease (Diem et al., 2003b)....

Organ and systembased theories

Immunity in humans attains maximum potential during adolescence and thereafter the thymus-dependent component gradually declines following early postadolescent involution and atrophy of that organ. Also with advancing age, there are increased rates of chronic autoimmune diseases which, for example, can result in reduced thyroid capacity. Thus, functional decline in the major histocompatibility complex ( MHC) has been identified as a central component of the ageing process, with the MHC, in effect, acting as a 'supergene' system.

Pathological Effects

In autoimmune diseases, accessibility of target tissues, cells, and antigens to immune effectors is critical in determining the distribution of injury. This is all the more important for the diseases of the nervous system, because the blood-tissue barriers contribute to the immune privileged status of neural tissues. For an immune effector to cause neural injury it has to cross the respective blood tissue barrier (i.e., blood-nerve-barrier for PNS and blood-brain barrier for CNS injury). Peripheral nerve fibers are organized into individual bundles or fascicles. A fibrofatty layer, the epineurium, surrounds and holds individual fascicles in nerve bundles. Each nerve fascicle is surrounded by per-ineurium, which consists of a variable number of layers of specialized perineurial cells attached to each other by tight junctions, with each cell layer covered by basal lamina. The thickness of perineurium varies along the course of peripheral nerves the thickness diminishes in linear...

Jeremy D Pearson and Sarah E Riley

Autoimmune Diseases and Autoantibodies Autoimmune diseases are those in which clinical problems are due to dysregulation of the patient's immune system in the absence of ongoing infection, and they are characterized by the presence of autoantibodies, that is, antibodies that react with self-antigens. Autoimmune diseases arise in susceptible individuals due to variations in the ability of T and or B lymphocytes to be activated or to undergo apoptosis this variation presumably usually being genetically determined, and often involving inappropriate expression of cytokines coupled with exposure to an environmental trigger, often unknown in individual cases but including microbial antigens and drugs. Two processes are considered to be important in the generation of autoantibodies molecular mimicry and epitope spreading. The former implies that the initial antibody formation is directed at epitopes of foreign antigens that are sufficiently similar to epitopes of self-antigens that they...

Retinal Autoantigens and Mimicry Peptides

Mimicry of a sequestered, tissue-specific autoantigen and a ubiquitously expressed MHC antigen (which is an autoantigen as well) is a rather unconventional idea for the cellular pathogenesis of an autoimmune disease. However, it has been proposed that for their promotion of homeostasis and survival naive peripheral T cells in lymphoid follicles need to be tickled with low-affinity self-peptides (e.g., MHC-derived) presented on MHC molecules, but without getting activated (Goldrath and Bevan, 1999). Thus, T cells escaping thymic selection despite recognizing an equivalent of peptide B27PD might have a potential to become autoaggressive lymphocytes that cause uveitis by cross-reacting with retinal autoantigen peptide. We, and others, postulate that these HLA peptide-specific T cells could be activated peripherally, either by bystander activation or by a third cross-reactive environmental antigen (Wildner et al., 2002 Choi and Craft, 2004). Evidence for the latter possibility will be...

HLA Peptide B27PD in EAU

The mechanism of oral tolerance (Mowat, 1987) is usually effective for nutritional proteins, preventing adverse reactions that potentially lead to food allergies. When autoantigens are fed, autoimmune reactions can be suppressed as well, indicating a potential for oral tolerance as a therapeutic approach for autoimmune diseases (Weiner, 1997). Tolerance is mediated by suppressor cells specific for the respective antigen however, the exact mechanisms underlying orally induced suppression are not yet fully elucidated. It is assumed that suppressor T cells recognize the respective antigen and secrete suppressive cytokines, such as TGF-P (Miller et al, 1992), IL-10 (Rizzo et al, 1999 Slavin et al., 2001) (Th3, Tr type), or cytokines belonging to the respective antagonistic Th type of the pathogenic immune response (Weiner, 2001).

Pathology Diagnosis and Treatment

Penicilliosis due to P. marneffei in Southeast Asia is the third most common opportunistic infection, after tuberculosis and cryptococcosis, in HIV patients in northern Thailand, and it is considered an AIDS-defining illness in the region. P. marneffei infection is endemic in Southeast Asia, with a particular focus in Thailand, southern China, Hong Kong, Vietnam, northeastern India, and Taiwan (Vanittanakom et al., 2006). Penicilliosis due to P. marneffei has been also reported in HIV patients residing outside of the endemic areas. The majority of these cases correspond to patients with a history of travel to the Southeastern Asia. Infection by P. marneffei has also been noted in other groups of immunocompromised patients, such as those having Hodgkin's disease, tuberculosis, or autoimmune disease (Lupi et al., 2005).

Molecular Abnormalities in Benign Lymphoid Proliferations

The presence of a clonal B-cell population, by itself, does not establish a diagnosis of B-cell malignancy. Small B-cell clones may be detected by IGH PCR and SBA in benign lymphoid hyperplasias in the absence of other criteria for malignancy.40-42 This occurs in the setting of immune deficiencies, autoimmune diseases, and immunosuppres-sion, and reinforces the critical necessity for interpretation of these tests for B-cell clonality in conjunction with clinical, morphologic, and immunophenotypic information. Patients with immune dysfunction have an increased risk of non-Hodgkin lymphoma (NHL), in particular BCL, but many of these patients will never develop lymphomas,even without correction of the abnormal immune status.

General Conclusions

Sensitization of central proinflammatory cytokine expression by social stress may contribute to the dysregulation of central inflammatory responses during early infection. Because early immune responses shape the specific immune response to infection, dysregulation of this response may contribute to the failure to eliminate the pathogen and exacerbation of acute infection. We hypothesize that the establishment of a persistent infection, combined with a heightened inflammatory environment in the CNS, may contribute to the development of autoimmune diseases such as multiple sclerosis. To test this hypothesis, future research will need to examine whether social stress-induced GC resistance and central sensitization of IL-6 expression will have cascading effects that increase the severity of the demyelinating phase of disease.

Protection of Axons via Facilitation of Remyelination

The existence of pathogenic autoantibodies is well established for several peripheral neurological syndromes including myasthenia gravis, Lambert-Eaton syndrome, Guillain-Barre syndrome, and acquired neuromyotonia (Vincent et al., 1999). Involvement of pathogenic autoantibodies in a particular dis

Clinical diagnosis of neuromuscular respiratory failure

Although the decision to intubate and start artificial ventilation depends primarily on the overall clinical assessment, measurement of vital capacity provides a useful quantitative assessment of respiratory muscle strength and helps to determine when intubation is necessary. In general, a steady fall in vital capacity over several consecutive hours usually predicts the need for ventilation. Impaired clearance of secretions occurs at values below 30 ml kg and frank respiratory failure at less than 10 ml kg. In practice, mechanical ventilation is usually instituted when vital capacity is approximately 15 ml kg.3 Whilst measurement of vital capacity is a useful guide to the timing of intubation in patients with GBS, it is less so in patients with myasthenia gravis, perhaps due to the fluctuating nature of this disease.4 Respiratory rate should also be monitored closely, since the development of rapid shallow breathing indicates that the patient is likely to require intubation within the...

Liver DiseasesA Variety of Conditions

Hepatitis is mainly caused by viruses, hepatotoxic substances, and autoimmune diseases. The condition is characterized by cell necrosis and inflammation in the liver. All forms give the same alterations of the liver, including simultaneous necrosis and degeneration of hepatocytes, infiltration of mononuclear cells, degeneration of Kupffer cells, and varying degree of cholestasis.

Neuromuscular junction disorders

Respiratory failure can herald disorders of the neuromuscular junction (Table 11.2), which can be distinguished from neuropathic causes by the absence of sensory deficit and preservation of tendon reflexes. In myasthenia gravis respiratory failure usually occurs in the setting of established disease that has failed to respond to conventional treatment. Even in an acute case the diagnosis is usually evident because of ptosis, facial weakness, and bulbar palsy with muscle fatigue. The diagnosis can be confirmed by showing a decrement in the compound muscle action potentials elicited by a train of stimuli, neurophysiological tests, or detecting variable conduction block (jitter) in terminal motor nerve fibres in Myasthenia gravis nerve stimulation. It may be associated with a small cell lung carcinoma or autoimmune disease.

Humoral Immunity in Atherosclerosis

The specificities of anti-oxLDL antibodies are quite diverse. Some of them bind to oxidized lipid moieties in the LDL particles, whereas others may recognize the oxidative modifications of apoB (Thiagarajan, 2001). Cross-reactivities toward oxLDLs have been suggested for various autoantibody populations associated with systemic autoimmunity. APS patients have autoantibodies to a phos-pholipid-binding protein, 62-glycoprotein I, which can in turn bind to LDL (Horkko et al., 1997 Reddel et al., 2000). Overall, antibody specificities such as anticardiolipin, anti-62 glycoprotein I, or anti-62 glycoprotein I-cardiolipin complexes have been reported to cross-react with various epitopes of oxLDL (Mizutani et al., 1995 Horkko et al., 2001 Matsuura et al., 2002). It has also been suggested that the clinical associations of these antibodies may be different. For instance, anti-62-glycoprotein I-cardiolipin-complex antibodies are associated with both arterial and venous thrombosis in SLE,...

Granulomatous Inflammation

The specific granulomatous inflammations of the in-tra-ocular tissues can be divided into infectious and autoimmune causes. The autoimmune diseases are sarcoidosis, sympathetic ophthalmitis and lens-induced uveitis. While many of these diseases may be appropriately treated with immunosuppressive medication, the management of infectious uveitis is antimicrobial therapy. Inappropriate immunosuppressive therapy may be disastrous for patients with an infection. Chorioretinal biopsy may provide useful information for determining the diagnosis and guiding the subsequent management of patients with progressive chorioretinal lesions of unknown aetiology 69 .

Vaccination or Immunoglobulin Administration in Atherosclerosis

In addition to active immunization, passive administration of antiphospho-lipid antibodies can also improve disease in atherosclerosis-prone mice (Nicolo et al., 2003). We obtained a panel of antiphospholipid IgG monoclonal antibodies from (NZW x BXSB) F1 mice, a cross that spontaneously develops systemic autoimmunity reminiscent of lupus and APS (Monestier et al., 1996). We observed that biweekly administration of one such monoclonal antibody, FB1, prevents plaque formation in LDLR- - mice when compared to PBS- or control antibody-treated animals (Nicolo et al., 2003).

Effect of Deprivation of Cytokines on the Duration and Pattern of Sleep

A number of immunological disorders including autoimmune diseases and certain infections are associated with an increased release of proinflammatory cytokines. Deprivation of proinflammatory cytokines may be achieved by including an administration of monoclonal antibodies against the cytokine, by administration of antireceptor antibodies, soluble receptors that inhibit the activity of their cytokines and receptor antagonists. A good example for the latter is the study where the effectiveness of administration of the naturally occurring IL-1 receptor antagonist that binds to the IL-1 receptor but fails to transduce a signal was demonstrated (Dinarello 1998). Another approach is the usage of physiological down-regulators of proinflammatory cytokine production, i.e., the usage of anti-inflammatory cytokines (e.g., IL-10) in the treatment of inflammatory and autoimmune diseases (Braat, Peppelenbosch, and Hommes 2003 Asadullah, Sabat, Friedrich, Volk, and Sterry 2004 Hofstetter, Flondor,...

Early Life Stress Increases Disease Susceptibility in Adulthood

Early life stress modulates neural and neuroendocrine mechanisms in host defence and autoimmunity, thereby predisposing to adult disease susceptibility. Here, we reported on opposing effects of MD and HA on a diversity of diseases like asthma, multiple sclerosis, and periodontitis. Summarizing, MD increases, whereas HA decreases, disease susceptibility to all investigated disease models. Furthermore, HA prolongs the pain threshold, decreases anxiety-like behavior, and improves motor function and explorative behaviors, whereas MD induces more or less opposite-like effects. Denenberg and Karas (1959) summarized different experiments and stated that handled animals weighed most, learned best, and lived longest. The question is, how are these effects mediated

Molecular Basis of Disease

Immunodeficient patients are at an increased risk for developing lymphoproliferative disorders (LPD), including lymphomas. The World Health Organization (WHO) classification recognizes four clinical settings associated with the development of immunodeficiency-related LPDs (1) primary immune disorders, (2) HIV infection, (3) iatrogenic immunosuppression following solid organ or allogeneic bone marrow transplantation (posttransplant lymphoproliferative disorder PTLD ),and (4) methotrex-ate therapy, usually for an autoimmune disorder.1 These lesions are highly heterogeneous, largely due to the various underlying causes of the different immunodeficiencies however, they share several features (see Table 34-1). In most instances, the LPD are related to Epstein-Barr virus (EBV or HHV-4) infection, and thus, in situations where immunocompetence can be reestablished, these EBV-driven proliferations may regress. However, the development of secondary genetic structural alterations in oncogenes...

Antigen Induced Regulatory T cells

Vaccination with autoantigens via a tolerogenic route is thought to protect from autoimmune diseases through the induction of Tregs. Depending on the mode of vaccination, the antigen used, the timing and dosage, these Tregs variously produce regulatory cytokines such as IL-4, IL-10, and transforming growth factor (TGF)-P, and suppress autoaggressive T cells via bystander suppression. It is important to note that antigen-induced Tregs are probably distinct from another much-investigated subset of Tregs, the naturally occurring CD4+CD25+ T cells. CD4+CD25+ Tregs are generated in the thymus possibly by active positive selection on autoantigens (Shevach et al., 2001 Apostolou et al., 2002). It is clear that CD4+CD25+ T cells play an important role in normal immune homeostasis, as depletion of CD4+CD25+ T cells by thymectomy results in the spontaneous development of various autoimmune diseases (Sakaguchi et al., 1985). In vitro, CD4+CD25+ T cells can suppress the proliferation and cytokine...

Vital capacity measurement

Normal vital capacities range from 65 to 75 ml kg. Reduction occurs in a variety of conditions associated with weakness, for example cervical cord injury, myasthenia gravis, Guillain-Barr syndrome, persistence of muscle relaxants, poliomyelitis, botulism, and organophosphate poisoning. Rising Paco2 and falling Pao2 are also features of these conditions. However, normal blood gases may be maintained in the early stages of these disorders. Vital capacity recordings provide useful insights into the rate of development of weakness. Measurements of less than 10 to 15 ml kg are generally considered incompatible with spontaneous ventilation and are an indication for mechanical ventilation.

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