Autoimmune Diseases Treatment News

The Autoimmune Bible System

The Autoimmune Bible system was developed by Mark Steve, who was suffering from an autoimmune disease that is not treatable. He tried other medicine and did not work, but after turning to the Bible, he was able to get the best healing for the disease. The product discusses in detail the Bible recipes and also the ingredients which come with it, which can be used to fight the diseases. God has provided the people with healing through the readily available things which can be found in the grocery, and it only needs one to follow them strictly, and you will get healed. The Bible has specific herbs, which it has mentioned, which could be used to heal the various disease which we are suffering which include the autoimmune disease and diabetes which continue to be a problem to many. The program can be accessed through the e-book, and some bonuses come with the program and maximum benefits from the program. You don't need any technical skills or other intermediate skills to use the product since it entails using the Bible. Read more here...

The Autoimmune Bible System Summary


4.7 stars out of 12 votes

Contents: Ebooks
Author: Mark Steve
Official Website:
Price: $47.00

Access Now

My The Autoimmune Bible System Review

Highly Recommended

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

I personally recommend to buy this ebook. The quality is excellent and for this low price and 100% Money back guarantee, you have nothing to lose.

Autoimmunity and Autoimmune Disease

The term autoimmunity signifies the presence of specific memory-type immune reactions that are directed against one or more self-epitopes. Under most conditions, autoimmunity is determined in terms of immunoglobulins that react with either unknown or well-defined human antigens. Today it is supposed that the production of these autoantibodies requires prior activation of potentially autoreactive B cells by memory T cells. These T cells must not only recognize a closely related peptide structure. Importantly, these T cells can stimulate B cells only when primed by activated antigen presenting cells. Autoimmunity is a relatively frequent event. Most likely, any individual raises immune reactions against numerous self antigens. This autoimmunity leads only very rarely to overt autoimmune disease. Therefore, the development of autoimmune disease requires trespassing of a large number of additional security levels, beyond autoimmune reactivity (Schwartz 1998). This is illustrated by two...

Environmental Factors That Contribute to Autoimmunity 519

22.1 Relation Between Genetic and Environmental Factors in Autoimmunity 519 22.2 Environmental Factors in Autoimmunity 520 22.3.1 Drug-related Autoimmune Diseases Syndromes 520 22.4 Microbial Agents in Autoimmunity 525 22.5 Hormones in Autoimmunity 526 22.7 Acceleration and Aggravation of Autoimmunity by Environmental Agents 528 22.7.1 Acceleration of Spontaneous Autoimmune Diseases by Hg 528 22.7.2 Acceleration of Spontaneous Autoimmune Diseases by Cadmium and Lead 529 22.8 Comments on the Accelerating Effect of Metals on Autoimmunity 529 22.8.1 Mechanisms for Induction of Autoimmunity by Environmental Agents 530 22.8.3 Lessons from Metal-induced Autoimmunity 531

Th1 versus Th2 Cytokines in Humoral Autoimmunity

During immune responses, all helper CD4+ T (Th) cells produce interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), but differences in environmental stimulation skews them broadly towards two subtypes bearing distinct patterns of cytokine production (1) Th1 cells, which produce predominantly IL-2, interferon-y (IFN-y), lymphotoxin (LT), and tumor necrosis factor-a (TNF-a) and (2) Th2 cells, which produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 75-77 . This dichotomy has become less clear as recent studies have further detailed the increasingly complex environments of natural immune responses 78, 79 , but nevertheless it has remained of great utility because Th1 cytokines have consistently been associated with cellular immune functions, such as delayed-type hypersensitivity and macrophage activation, while Th2 cy-tokines have been associated with B cell-dependent antibody responses, such as allergy 76, 80 . As such, humoral autoimmune diseases were...

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.

Other organspecific autoimmune diseases of the skin

In this condition there is a loss of pigment as a result of antibodies developing against melanocytes in the skin in a limited area. However, the areas affected tend to gradually increase. There may be other autoimmune diseases in the same patient, causing, for example, pernicious anaemia, and thyroid disease.

Muscular Dystrophy and Myasthenia Gravis

Famous People With Myasthenia Gravis

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...

Autoantibodies in Experimental Models of Autoimmunity

Research into mechanisms of autoimmunity and the antigenic specificity, and possible pathogenic role, of autoantibodies has been significantly advanced by the availability of animal models. Four different types of models have been used (Table 1.4). Specific antigen immunization models are produced by direct injection of purified antigen into animals to elicit autoantibody. Direct immunization has proven most useful when the autoantigen is extracellular or on the cell membrane. In such examples the elicited autoantibody response can produce pathological consequences such as the myasthenia gravis-like disease produced in rodents following immunization with purified acetylcholine receptor 56 . The animals used in this type of model are most often healthy, normal individuals with fully functional immune systems and are able to downregulate the autoimmune response produced by the immunization of autoantigen. As a result, direct immunization models often produce transient autoimmune...

Autoimmune disease and the skin by DJ Grawkrodger

There is always the risk that the well developed human immune system may react against the body's own tissues, with a failure to distinguish between self' and non-self'. An immune response develops which may be specific for a particular organ, such as the thyroid gland, or react against a number of different organs, as in connective tissue diseases. The skin can manifest both types of autoimumme response. The results of such reactions can be destruction of the cells concerned and the production of inflammation. There is an inherited tendency to autoimmune disease, marked by specific HLA (human lymphocyte antigen) in some cases.

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

Defective Clearance of Apoptotic Cells and Autoimmunity

The role of impaired phagocytosis of apoptotic cells in the development of autoantibodies in systemic autoimmunity has attracted considerable attention in recent years. Under normal circumstances, apoptotic bodies are recognized and engulfed by phagocytic cells. Professional phagocytic cells such as macrophages and DCs clear apoptotic cells swiftly, whereas nonprofessional phagocytes appear to take up apoptotic cells when they reach the later stages of the dying process 163 . This clearance process is facilitated by the presence of eat me signals exposed in apoptotic cells (e.g., phosphatidylserine), apoptotic cell recognition receptors in phagocytic cells (e.g., phosphatidylserine receptor, 52-glycopro-tein 1 receptor, vitronectin receptor, complement receptors, and tyrosine kinase Mer receptor), and serum proteins (e.g., complement cascade components such as C1q, C-reactive protein (CRP), and serum amyloid protein) 164 . It is widely accepted that the efficient clearance of...

Autoimmune Diseases of the Thyroid

Autoimmunity to thyroid antigens is the most common cause of thyroid diseases including Hashimoto's thyroiditis (HT), Graves' disease (GD), and primary myxedema (PM). Different autoimmune diseases of the thyroid share similar GD, the most prevalent of the TSHR-mediated autoimmune diseases, is mediated by anti-TSHR autoantibodies that can act as TSH agonists and cause hyperthyroidism. However, if the anti-TSHR antibodies act as TSH antagonists, they can result in primary myxedema (PM), which is characterized by hypothyr-oidism.

Autoimmune Disease

Autoimmunity is a prerequisite for autoimmune disease. However, the events that lead from autoimmunity to an overt inflammatory disease are still unclear. Production and release of TNF seems to be important for this step, but the exact role of this cytokine is far from being elucidated (Green and Flavell 2000). Without any doubt, autoreactive T cells are not only associated with autoimmune diseases but can directly cause the disease. Analysis from mice with non obese diabetes (NOD) revealed that both, CD4+ and CD8+ T cells are required for the induction of both, autoimmune inflammation and autoimmune disease (Bendelac et al. 1987). Similarly, transfer of MBP-reactive T cells (Mokhtarian et al. 1984) and even more precisely, MBP-reactive CD4+ T cells of the Th1 phenotype alone are capable of inducing severe autoimmune encephalitis, when transferred into naive mice (Racke et al. 1994).

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

Myasthenia gravis MG

An autoimmune disease of the neuromuscular junction involving the postjunctional acetylcholine receptors. Specific autoantibodies have been identified and microscopic changes in the membrane demonstrated. Not only is there a reduction in the number of acetylcholine receptors at the postjunctional membrane, so

Myasthenia gravis

Generalized myasthenia gravis, key features. A Ptosis B Attempted gaze to the right. Only right eye abducts incompletely. C Demonstrates proximal weakness upon attempt to raise the arms. D Holding the arms and fingers extended the extensor muscles weaken and finger drop occurs Anatomical-functional Myasthenia gravis (MG) is an autoimmune disease. Autoantibodies to acetyl-relations choline receptor epitopes block neuromuscular transmission. Long duration


An autoimmune response is an attack by the immune system on the host itself. In healthy individuals the immune system is tolerant of its host ( self ) but attacks foreign ( non-self') constituents such as bacteria and viruses. The ability to distinguish self from non-self is considered to be the determining factor in whether the immune system responds to a suspected challenge. Although it may appear obvious, there is actually considerable debate over what constitutes self and non-self and what cellular molecular mechanisms are involved. A fascinating historical perspective on self non-self recognition has been written by Alan Baxter (see Chapter 3) and includes the often-forgotten point that Mac-farlane Burnet used the phrase self and not-self' when he first introduced the concept. Possible discriminators between self' and non(not)-self include recognition of infection 1 or identification of danger signals 2 . The outcome of the debate on self non-self discrimination not withstanding,...

Peripheral Tcell Tolerance

It is generally believed that many T cells escape central tolerance, especially those with the capacity to react with self-antigens not expressed in the thymus. This view is consistent with the relative ease of inducing organ-specific autoimmunity by deliberate immunization with peripheral antigens. While tissue-specific, self-reactive T cells generally ignore their target antigen because it is inaccessible or not presented in an immunogenic form, organ-specific autoimmune diseases are common 49 . In order to minimize autoimmunity mediated by self-reactive T cells in the periphery, the immune system has apparently developed various peripheral tolerance mechanisms that can restrain, quell, or kill such cells. Peripheral tolerance is much more than a backup mechanism to prevent autoimmunity - it is an active process that is probably invoked to limit T-cell response to all antigens.

Conclusion A Model of Antigen Selection During Cell Death

The clustering and concentration of autoantigens at the surface of apoptotic cells, in combination with the striking tolerance-inducing function of apoptotic cells, have focused attention on abnormalities in apoptotic cell execution and clearance as potential susceptibility and initiating factors in systemic autoimmu-nity. The susceptibility of the majority of autoantigens across the spectrum of human autoimmune diseases to cleavage by aspartic acid-specific apoptotic proteases is a major unifying feature of this apparently unrelated group of molecules. We propose that caspase-cleaved autoantigens are the major form of the molecule tolerized during development and homeostasis, and that where apop-totic cell clearance is normal, tolerance to such fragments is fully established. Abnormalities in clearance of apoptotic cells and tolerance induction may allow autoreactive T cells recognizing caspase-cleaved antigens to persist and potentially to be activated by a large load of apoptotic...

Autoantigen Proteolysis During Granzyme Bmediated Cytotoxicity

More recently, Rosen and colleagues demonstrated that the majority of autoantigens targeted in human systemic autoimmune diseases are efficiently cleaved by granzyme B in vitro and during CTL-induced cell death, generating unique fragments not observed during apoptosis 145, 146 . Interestingly, GrB cleaved several autoantigens previously reported as not susceptible to cleavage during In a recent study, Rosen's group demonstrated that the nucleolar autoantigen B23 was efficiently cleaved by GrB in vitro but was highly resistant to cleavage by GrB during CTL-induced cell death of many different types, with the exception of differentiated vascular smooth muscle cells, suggesting that the cleavage of this autoantigen is dependent upon cell type 147 . Given that B23 is associated with pulmonary vascular phenotype in scleroderma, it was concluded that GrB-mediated proteolytic modification of autoantigens may occur selectively in the target tissue and may play a role in shaping the...

Proteolytic Cleavage of Autoantigens During Apoptosis

Since caspase-mediated cleavages typify this form of tolerance-inducing cell death, it is likely but still unproven that caspase fragments of autoantigens are actively tolerized. Consequently, abnormalities in the processes regulating clearance of, and tolerance induction by, apoptotic cells may play important roles in rendering individuals susceptible to initiation of systemic autoimmunity. The phenomenon of decreased apoptotic clearance associated with systemic autoim-munity is seen in both human disease (as in patients with C1q deficiency) and in animal models 61-63 . In addition to abnormalities in processes regulating clearance and tolerance induction by apoptotic cells, recent studies have stressed the possibility that certain forms of apoptotic death may be pro-immune, particularly those occurring occur during virus infection or killing of transformed cells. The associations among (1) viral infection and initiation and flare-ups of autoimmune diseases (2) cancer and...

Novel Conformation of Phenotypespecific Autoantigens

In spite of the fact that many autoantigens in systemic autoimmune diseases are ubiquitously expressed, there is nevertheless a striking association of specific antibody responses with unique clinical phenotypes. One potential explanation for this observation is that changes in autoantigen structure may be limited to the relevant disease microenvironment and may contribute to initiation of an autoimmune response. As several autoantigens that are targeted in systemic autoimmune diseases can also be targeted in patients with hepatocellular carcinoma (HCC), we have sought to define microenvironment-specific changes in autoantigens in liver tissue of patients with HCC as a model system in which to investigate the link between autoantigen expression and cancer. Interestingly, the nucleolar HCC autoantigen B23 (nucleophosmin) exists in a truncated form in HCC liver, lacking six amino acids at the N-terminus. While full-length B23 (expressed in all other tissues) is very resistant to...

Comparison of Multiplexed Assays

Many hundreds of different autoantibodies have been identified in the literature, but only a small percentage of them have proven to be clinically useful. Sometimes an autoantibody profile in a person can help a doctor determine whether the person has an autoimmune disease or not, and which one they have 53 . The autoantibody profiles for people with systemic rheumatic diseases show that certain sets of autoantibodies are associated with SLE, SS, SSc, RA, and PM (Fig. 8.4). It is clearly useful to measure all autoantibodies associated with rheumatic diseases at one time, but would it be an advantage to the doctor to detect all of the clinically useful autoantibodies to all autoimmune diseases in a single test The majority of the clinically useful autoantibody tests have been cleared by the FDA for in vitro use to help diagnose autoimmune diseases. These include those to help diagnose connective tissue diseases such as RA, SLE, SS, SSc, and PM DM gastrointestinal diseases such as...

The Role of Genetic Factors

The etiology of autoimmune thyroid disease (AITD) is unclear. Similar to other autoimmune diseases, genetic, environmental, and other endogenous factors contribute to the initiation of the disease. Increased incidence of GD among members of a family and a higher degree of disease concordance among identical twins indicate that genetic factors may play an important role in determining susceptibility to GD 15-17 . As in most other autoimmune diseases, the strongest bias in developing GD is gender women are 5-10 times more likely than men to develop the disease. Two recent reviews on genetic susceptibility to GD have summarized and discussed the implications of a large number of stud

The Role of Environmental Factors

Like other autoimmune diseases, environmental factors have long been suspected in the etiology of the disease. For example, excess iodine intake is a risk factor for developing autoimmune thyroid diseases in both humans and animal models of AITD 33, 34 . Stress, drugs, and smoking can also contribute to the development of the disease. The common mode of action of all these factors is that they place stress on the thyroid 35 . It is possible that these environmental stresses can lead to thyroid injury, which may in turn release thyroid autoantigens or alter the immunogenicity of the thyroid antigens. Another set of environmental factors linked to AITD 36 and host immune responses is microbial infections, which can cause overexpression (e.g., heat shock proteins, MHC class II molecules, costimulatory molecules, etc.) and or altered expression of certain self-proteins (altered self). Presentation of these antigens by professional APCs could provide the necessary strength of signal or be...

Peptides Containing Natural Modifications and Structural Motifs

Natural modifications of peptides have been shown in certain instances to be necessary to maintain their recognition by autoantibodies. It is unclear whether this means that, in vivo, such post-translational modifications do occur in the cognate proteins and are directly involved in the breakdown of tolerance and initiation of the autoimmune response. However, this possibility and its many potential implications in the etiology of autoimmune diseases are actively being explored 156-158 .

Selected Examples of Epitope Mapping with Synthetic Peptides

Fig. 9.3 Schematic representation oflinear epitopes recognized by autoantibodies from patients and mice with systemic autoimmune diseases. Adapted from the original references indicated on the right. The data generated from studies using experimental animals immunized with autoantigens are not reported. In proteinase-3 (A), residues H44, D91, and S176 form the catalytic triad there are two glycosylation sites in residues N102 and N146 ( ) and four disulfide bridges. In calreticulin (B), distinct sequences were recognized by IgA antibodies from patients with PBC, autoimmune hepatitis, or celiac disease 219 . They are not Fig. 9.3 Schematic representation oflinear epitopes recognized by autoantibodies from patients and mice with systemic autoimmune diseases. Adapted from the original references indicated on the right. The data generated from studies using experimental animals immunized with autoantigens are not reported. In proteinase-3 (A), residues H44, D91, and S176 form the...

Mechanistic Events in Apoptosis

Once activated, initiator caspases cleave and process the executioner caspases, which in turn cleave a limited number of proteins, including specific nuclear and cytoplasmic autoantigens targeted in systemic autoimmune diseases 31, 51-53, 64 . The effector caspases disrupt the normal cellular architecture and impair virtually all pathways of macromolecular synthesis through cleavage of key proteins after specific aspartic acid residues. These cleavages constitute the pivotal event of apoptosis, leading to the characteristic morphology associated with this cell-death process. It was reported that the effector caspases, particularly caspase-3, cleave more than 280 different cellular proteins and that the great majority of these cleavages either inactivate the function of the substrate protein or generate active cleavage fragments that are required to amplify the apoptotic

GrBinduced Cleavage of Tissuespecific Autoantigens

Structural changes of autoantigens induced by post-translational modification can alter the processing of self-antigens and influence the ability to generate an immune response against self. For example, recent studies have shown that the neuronal glutamate receptor subunit 3 is an autoantigen in patients with a severe form of pediatric epilepsy, Rasmussen's encephalitis 95 . Autoantibodies tend to be of low affinity, and many recognize a well-defined extracellular epi-tope residing in the receptor-activating epitope that is aligned on the surface of the folded protein 96 . Of note, the GrB cleavage site contains an asparagine that is normally N-glycosylated and is found within a major epitope that is recognized by autoantibodies in Rasmussen's encephalitis 80 . Interestingly, Ghar-ing and colleagues showed that deglycosylated GluR3 is susceptible to cleavage by GrB, whereas the glycosylated form of this receptor is poorly cleaved, possibly because the N-linked sugar sterically...

Autoantibodies and Autoantigens Associated with Autoimmune Hepatitis Type

AIH type 3 is characterized by autoantibodies against soluble liver and pancreas antigen (SLA LP), which are directed towards UGA-suppressor transfer RNA (tRNA)-associated protein 58-61 . Recent studies have shown that anti-SLA and the independently described anti-LP are identical 50, 62 . The exact function of this protein and its role in autoimmunity remain unclear. Anti-SLA LP were initially detected in a patient with ANA-negative AIH. However, 74 of patients with SLA LP autoantibodies also have other serological markers of autoimmunity, including SMAs and AMAs 58, 61, 63 . In ANA-positive patients, SLA autoantibodies appear in 11 of cases.

Development of Islet Autoantibodies in Early Life

A number of large-scale prospective studies have been established with the intention of following the natural history of autoantibody responses to islet-cell autoantigens in early life. These studies have also tried to identify factors important for the initiation of islet autoimmunity and to estimate the risk for later development of diabetes of individuals in whom islet autoantibodies are detected. Three major studies are established. The BABYDIAB Study 121 was started in 1989 and is a multi-center study in Germany following offspring of diabetic parents from birth. In the US, the Diabetes Autoimmunity Study in the Young (DAISY) based in Denver 122 has, since 1993, followed young (

Tolerance Due to Negative Tcell Selection

Surprisingly, there is little direct support for the view that clonal deletion prevents autoimmunity. In fact, in most cases where the impact of negative selection was tested, there was little effect on autoimmunity. Instead, when negative selection was prevented or inhibited, potentially autoreactive cells appeared that were profoundly non-responsive. This was shown in a chimeric system in which viral superantigen-mediated deletion of T cells bearing the V6 element of the TCR 5-chain was reduced by irradiation 17-19 however, the V 56-bearing T cells that were positively selected were non-responsive to superantigen 18 . In another system, irradiated Fx mice reconstituted with bone marrow cells from one of the parents showed partial deletion of V 511+ T cells that normally occurs due to contact with I-E in the thymus, but V 511+ thymocytes that developed in these chimeric mice were tolerant to host-type H-2 antigens based on mixed lymphocyte reaction and failure to reject skin grafts...

Airedriven Peripheral Antigen Expression in Medullary Thymic Epithelial Cells

While it is likely that thymocytes will be killed if a high-affinity antigen is presented on mTECs, it is not clear that this process is efficient enough or necessary to prevent autoimmunity. Aire - mice that failed to delete HEL-specific T cells were not reported to develop T-cell infiltration of the HEL+ pancreas or other signs of autoimmunity 31 , despite other studies using the same transgenic system that found that failure to delete HEL-specific T cells in non-obese diabetic (NOD) mice resulted in autoimmunity targeting 5-cells that transgeni-cally expressed HEL in the pancreas 32 . T cells developing on the NOD background are autoreactive for unknown reasons, while the same type of transgenic T cells developing in Aire - mice in a non-autoimmune-prone background such as B10.BR are tolerant T-cell deletion efficiency does not distinguish these strains. Also, wild-type mice that were grafted with a thymus from mice incapable of producing the liver-specific protein serum amyloid P...

Selftolerance Due to Thymusderived Regulatory T Cells Natural Regulatory T Cells

The past half-decade has seen a large upsurge of information on T cells that suppress the function of effector T cells. While such regulatory T cells (TR) have come to be identified in different ways, a population of CD4+ T cells that consti-tutively express CD25 (interleukin-2 receptor) initially described by Sakaguchi and coworkers (reviewed in 37, 38 ) remains the most thoroughly studied. In a lymphopenic host these cells are necessary to prevent spontaneous autoimmunity to certain organs including testis, prostrate, ovaries, thyroid, pancreas, and stomach, depending on the mouse strain. CD4+CD25+ TR comprise 5-10 of the peripheral T-cell pool and suppress the activation of CD4+ and CD8+ effector T cells by a process that requires cell-to-cell contact at a suppressor effector cell ratio of 1 1 39 . It is also possible that CD4+CD25+ TR act on APCs to suppress T-cell activation, but inhibitory cytokines do not seem to be involved 37, 38 . Of particular relevance to central T-cell...

Islet Autoantibodies and Diabetes Prediction

Subjects participating in prospective studies of islet autoimmunity early in life (e.g., BABYDIAB, DAISY, DIPP) have also been followed for subsequent development of diabetes, and these studies provide an indication of the value of auto-antibodies as markers for diabetes development. The vast majority of subjects who developed diabetes at an early age in these studies possessed multiple islet autoantibodies months or years before disease onset 121, 126 . The cumulative risk of developing diabetes within five years of developing one or more islet au-toantibodies was estimated to be between 40 and 50 for individuals with multiple antibodies, but only 3 for those positive for only a single antibody specificity (IAA, GADA, or IA-2A). In these prospective studies of autoimmunity in early childhood, follow-up to disease is necessarily restricted to a narrow time window in the first few years of life, but the vast majority of patients who develop diabetes will do so at an older age....

Selftolerance Associated with Positive Tcell Selection

Useless even without subsequent deletion by the negative selection machinery because it would be unlikely that any peptide exists that could overcome such a high activation threshold. While this phenomenon has not yet been formally demonstrated, and other tolerance mechanisms could be acting, failure to develop frank autoimmunity when negative selection was disrupted 17-23, 31 is consistent with the concept of a strong link between positive selection and central T-cell tolerance.

The Antiphospholipid Syndrome

The Antiphospholipid Syndrome (APS), also called Hughes syndrome, is a multi-system thrombophilic disorder associated with circulating AABs directed against negatively charged phospholipids (PL) and PL-binding proteins 54, 55 . APS may occur as an isolated disease entity (primary APS) or in combination with another autoimmune disease, especially systemic lupus erythematosus (secondary APS). The clinical features of APS are caused by venous and or arterial thrombosis and or pregnancy morbidity. According to the localization and severity of thrombosis, the clinical picture is extremely variable, and the complications arising from the disease may be minimal to life-threatening. International clinical and laboratory criteria have provided consensus on the typical features of the syndrome 54 . Several manifestations are relatively common in APS patients (deep vein occlusions affecting the lower limbs, stroke, large vessel occlusions, fetal loss, thrombocytopenia, livedo reticularis)....

AntiRoSSA and AntiLaSSB

The function of the Ro SSA particle is not well understood. Recent evidence suggests that the Ro SSA particle might be involved in quality control of mis-folded small RNAs and in preventing cellular damage induced by ultraviolet light 103, 104 . It is remarkable in this context that a murine knockout for 60-kDa Ro SSA is susceptible to UV damage 105 . There is evidence that Ro SSA plays a role in telomerase function 106 . Other data suggest that Ro SSA modulates the immune response to other proteins, for example, calreticulin, thereby influencing autoimmunity 87 . Mice lacking the 60-kDa Ro SSA protein develop signs of autoimmunity resembling human SLE. They exhibit anti-ribosome and anti-chromatin antibodies, photosensitivity, and glomerulonephritis 105 .

Racial Ethnic Variations in Frequency Epitope Recognition and Clinical Relevance of Diseaserelated Autoantibodies

Many studies have shown differences in the clinical as well as autoimmunologic presentation of systemic autoimmune diseases by race or ethnicity. This could be explained in part by different distributions of major histocompatibility complex (MHC) class II alleles as well as polymorphisms of genes coding for immunoglobulins, immune mediators, and regulators or genes coding for the appropriate autoantigen(s) itself. The distribution of many of the SLE-, SSc-, and myositis-related AABs differs among patients of various ethnic backgrounds. For example, Caucasian SSc patients have the highest frequency of anti-centromere antibodies (ACA), whereas American blacks have a higher frequency of anti-topoisomerase, anti-fibrillarin, and anti-fibrillin 1 antibodies 7, 8 . Anti-Sm antibodies were significantly more frequently seen in American black, Afro-Caribbean, and black South African SLE patients than in Caucasians 9, 10 . Besides such different AAB frequencies, striking ethnic differences in...

Relationship of Islet Autoantibodies to Tcell Responses in Type 1 Diabetes

The analysis of islet autoantibodies provides a means by which individuals may be identified at early stages of pancreatic autoimmunity and gives an indication of the risk of development of type 1 diabetes. T cells are likely to be more directly related to diabetes development than are antibodies, but it is unclear to what extent autoantibody secretion reflects a pathogenic T-cell response. Measures of disease-related T-cell responses in diabetes and an understanding of the relationships of these to autoantibodies are essential for further advances in our understanding of the etiology of type 1 diabetes and to provide an accurate assessment of autoimmune status. Indicators of T-cell autoimmunity will become particularly valuable for monitoring signs of disease recurrence following immune intervention and islet transplantation.

Characteristics Heterogeneity and Subsets of Systemic Sclerosis

Systemic sclerosis (SSc), also called scleroderma, is a generalized autoimmune disorder characterized by vascular damage and fibrosis within the skin and visceral organs, notably the gut, lung, heart, kidney, joints, and muscles. With regard to the extent of skin and internal organ involvement, the pace of disease progression and, consequently, the prognosis, patients with SSc present a high degree of variability. According to the preliminary ACR criteria for the classification of SSc, the presence of either the major criterion (symmetric skin sclerosis proximal to the MCP and or MTP joints) or two or more of the minor criteria (sclerodactyly, digital pitting scars, bibasilar lung fibrosis) classify a condition as SSc with 97 sensitivity and 98 specificity 33 . If used for the diagnosis in the single patient, these criteria may be quite misleading, because they do not allow the diagnosis of early SSc or sclerosis sine scleroderma, a disorder with primary organ involvement in the...

Glutamic Acid Decarboxylase

Glutamic acid decarboxylase (GAD) was first detected as an autoantigen in stiff-person syndrome 61 , a neurological disorder characterized by rigidity of the musculature often accompanied by muscle spasms. The syndrome is the result of impairment of inhibitory neuronal systems operating through the neurotransmitter y-amino butyric acid (GABA), and symptoms can be alleviated by drugs that enhance GABA-ergic neurotransmission. It was noted that a proportion of patients with stiff-person syndrome have other autoimmune disorders and that these patients have antibodies in both the serum and cerebrospinal fluid that are reactive on brain sections to regions rich in GABA-ergic neurons. The target antigen for these antibodies was shown to be the enzyme that catalyzes synthesis of GABA in these neurons, GAD 61 . There are further differences in the pattern of reactivity of GADA in stiff-person syndrome compared with those in type 1 diabetes. Titers of GADA are considerably higher in...

Cytotoxic Lymphocyte Granuleinduced Death Pathways

The most abundant cytotoxic granule components are perforin (a pore-forming protein) and a family of serine proteases termed granzymes 68 . Perforin has long been considered crucial for the entry of granzymes into the target cell, but the mechanisms underlying its activity still remain controversial 69 . Following release into the cytosol with the help of perforin, granzyme B (GrB), a rapidly acting apoptotic enzyme, catalyzes the cleavage and activation of several downstream substrates, inducing apoptotic changes in the target cell (Fig. 7.1). Prominent among the upstream mediators of the GrB effect are Bid and several procaspases, which are directly cleaved by GrB to generate their active forms. Thus, through the early cleavage and activation of Bid, GrB rapidly recruits the mitochondrial amplification loop of caspase activation 70, 71 . GrB similarly cleaves and activates effector caspases that further amplify the apoptotic proteolytic cascade, resulting in cleavage of multiple...

Autoantigen Proteolysis During Apoptosis

In the early 1990s the Rosens and colleagues elegantly demonstrated that specific SLE-associated autoantigens relocalize to surface blebs in cultured cells induced to die by apoptosis upon exposure to UV irradiation 131 . Following this observation, these investigators reported that the nuclear autoantigens PARP and U1-70kDa (70-kDa protein of the U1 ribonucleoprotein particle) were proteolytically cleaved by caspases during apoptosis 132, 133 . These observations led to the hypothesis that apoptotic cells are reservoirs of structurally modified forms of autoantigens that could initiate autoantibody responses in patients with systemic autoimmune diseases such as SLE and scleroderma. The development of this hypothesis triggered a search for modified forms of autoantigen that are generated in different types of cell death. Autoantigen modifications found to be associated with cell death included, but were not limited to, proteolysis, changes in the phosphoryla-tion state, and...

Ignorance of Lymphocytes to Target Antigen

Autoreactive Lymphcyte

Many self-reactive B and T cells may exist indefinitely in the peripheral immune system in a naive functional state. For B cells this ignorance condition is due to lack of T-cell help and or access to sufficient antigen T-cell ignorance refers to failure to encounter cognate antigen on professional antigen-presenting cells. With autoreactive lymphocytes recognizing organ- or tissue-specific antigens, ignorance is probably a common way for cells to avoid becoming activated because lymphocytes reside mainly in secondary lymphoid organs. However, autoreactive lymphocytes that can recognize systemic (non-organ-specific) antigens may be harder to hide. In addition, antigen can be readily presented remotely as a result of the transport of dendritic cells from an inflammatory site to the spleen or draining lymph node, where the antigen can be delivered to waiting, autoreactive lymphocytes in a process called indirect antigen presentation. For these reasons and because the immune system must...

Immunostimulatory Properties of Dying Cells

In contrast to these findings, several studies have shown that, like necrotic cells, apoptotic cells are also capable of inducing maturation of DCs and stimulating immune responses in vivo 140, 141, 177 . Furthermore, it was demonstrated that DC uptake of apoptotic or necrotic cells alone does not shift the immune response from tolerance to autoimmunity in systemic autoimmune conditions 178 . Moreover, a recent report indicated that phagocytosis of apoptotic or necrotic cells by macrophages does not lead to induction of expression of proinflammatory cytokines in the macrophages clearing the dying cells 179 . However, these investigators also found that the clearance of necrotic cells (primary or secondary) is significantly less efficient than the clearance of apoptotic cells, which could lead to macrophages remaining at the injury site longer, thus increasing the likelihood of a proinflammatory state to develop. They also suggested that the proinflammatory environment produced by...

Introduction and Historical Perspective

Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease that can involve almost any organ of the human body. The diverse clinical manifestations of SLE are accompanied by a huge number of autoantibodies. The number of antibodies associated with SLE was recently reported to be 116 1 . No other autoimmune disease is similar to SLE with regard to the vast number of autoantibodies linked with it. SLE autoantibodies can react with nuclear, cytoplasmic, and surface cellular antigens as well as with complement components and coagulation system factors.

Activationinduced Cell Death

A remarkable feature of the T-cell response to antigen occurs after activation and clonal expansion. The bulk of these cells die by apoptosis due to cytokine depletion or to engagement by FasL of the death receptor Fas (APO-1 or CD95), a process called clonal contraction. Cytokine depletion after T-cell activation triggers the release of cytochrome c from the mitochondria, resulting in passive or programmed cell death, and may represent a failure to thrive rather than an active tolerance mechanism. However, Fas engagement by FasL, particularly on CD8 cells and on the Th1 subtype of T-helper cells, or engagement of the type I tumor necrosis factor receptor by TNF-a initiates the extrinsic pathway to apoptosis. These cell-surface molecules are upregulated upon T-cell activation, and their engagement leads to cell death through a complex series of signaling molecules and new gene transcription in a process called activation-induced cell death (AICD). While it is widely believed that AICD...

Autoantibodies in Sjogrens Syndrome

SjS is a chronic inflammatory autoimmune disease of unknown origin characterized by lymphocytic infiltration into exocrine glands. Its primary symptoms are keratoconjunctivitis sicca and xerostomia, but several extraglandular manifestations may occur. There are two types of SjS primary SjS and secondary SjS, which is associated with another underlying autoimmune disease. Ro SS-A and La SS-B antibodies are included in the classification criteria for SjS 29 and are detectable in 60-75 and 30-50 of patients, respectively. Anti-La SS-B antibodies are mostly found in SjS and SLE patients. Therefore, La SS-B antibodies in the absence of SLE-specific AABs are highly specific for SjS. If negative for Ro La AAB, a-fodrin antibodies may be determined. The sensitivity and specificity of these AABs for SjS are lower than described earlier, however 30 . Some rarely detectable AABs (Coilin-p80, NuMA, Golgi apparatus antibodies) have no relevance for the diagnosis of SjS. AABs reacting with the M3...

Learning to Ignore the Self Immunologic Dominance and Crypticity

Is there any evidence that such altered processing may contribute to the development of autoimmunity to previously non-tolerized epitopes in vivo Indeed, several experimental systems have demonstrated that immunization with cryptic epitopes can lead to the activation of autoreactive T cells. For example, immunization of mice with unprocessed mouse cytochrome c fails to induce an immune response. However, immunization with non-immunodominant peptides derived from mouse cytochrome c activates T cells specific for these epitopes 9 , thereby establishing that challenging with cryptic peptides not generated during the natural processing of cytochrome c can activate specific T-cell responses directed against the cryptic sequence. Similar findings have been made using snRNPs as model antigens, where an immune response against previously tolerized intact molecules could be initiated by immunizing mice with cryptic peptides derived from these molecules. Once the initial peptide-specific immune...

Comparison of Antigens Conjugates and Cutoff Values

The most egregious approach occurs when normal blood donors are used as the control group and a value of two or three standard deviations above the mean is chosen as the cutoff. In this case, both the control group and the statistical analysis are inappropriate. Very rarely is the blood from a healthy person, such as the average blood donor, sent to a clinical laboratory for autoantibody tests. Usually the person is sick. Thus, the correct control group should consist of people with autoimmune diseases who are expected to be negative for the au-toantibody in question and people with infectious diseases with symptoms similar to those of an autoimmune disease. Very often these latter groups have higher antibody levels, and higher binding on ELISA, than normal blood donors. The average and standard deviation are useful statistical tools only when the distribution of values in a population yields a normal, or bell-shaped, curve. In an ELISA, the distribution of values in the negative...

Development of Autoantibodies Against TSHR

Given the right circumstances, a breakdown in tolerance precipitated by thyroid injury (e.g., environmental stress factors) could lead to thyroid autoimmunity. At the site of injury and inflammation, thyroid antigens could be processed by professional antigen-presenting cells (APCs). The APCs will carry the antigen to the draining lymph nodes and present the thyroid antigen in the context of the right MHC class II to an appropriate CD4+ T helper cell, leading to its activation. In the same context, an autoreactive B cell could also acquire the thyroid antigen by binding to it with its IgM receptor and present it to the appropriate T cells. This interaction between T cells and B cells with a common antigen specificity (linked recognition), and in the presence of sufficient amounts of the thyroid antigen, could result in the formation of germinal centers where B-cell differentiation could take place with T-cell help. A continued antigenic stimulation would lead to B-cell isotype...

Antinucleolar and AntiRNA Polymerase Antibodies

Anti-RNA polymerase antibodies target RNA polymerases (RNAPs) of the RNAP multiprotein complexes consisting of 8-14 proteins weighing 10-220 kDa. There are three classes of RNAPs (RNAPs I, II, III). Whereas only RNAP-I is localized in the nucleolus, RNAPs II and III are localized in the nucleoplasm. Since the different types of RNAP antibodies often occur in combination, it is hardly possible to make a differential assessment of the clinical relevance of the individual specificities. RNAP-I antibodies are observed in 4-11 of patients with systemic sclerosis (scleroderma) but are rarely detected in other autoimmune diseases. They are associated with severe, diffuse forms of scleroderma. These patients have a poor prognosis because they tend to have a higher frequency of cardiac, hepatic, and renal involvement. RNAP-III antibodies are detected in 12-23 of patients with systemic sclerosis and are frequently associated with RNAP-I and RNAP-II antibodies. RNAP-III antibodies seem to be...

Negative Selection of B Cells

Bezeichnung Zahnrad

B cells and 20 in mature, peripheral B cells, suggesting that most of the discrepancy between B-cell production in the bone marrow and B-cell immigrants in the periphery is due to negative selection of autoreactive cells. Nevertheless, the importance of this process in maintaining self-tolerance is unclear because it has not yet been shown that failure of or deficiency in negative selection of B cells results in autoimmunity.


The stimulus for this book came from a chapter written for the second edition of R. A. Meyer's Encyclopedia of Molecular Cell Biology and Molecular Medicine. Appreciating that autoimmunity, and autoantibodies in particular, has contributed to more than just the medical sciences, that chapter approached its discussion of autoantibodies from four different directions. The conventional topics of autoimmunity and mechanisms of elicitation of autoantibodies were addressed. The contribution of autoantibodies to diagnostic markers was also discussed. In addition significant consideration was given to the important but often neglected role that au-toantibodies have played as probes in molecular and cellular biology. The last area covered focused on the different types of animal models of autoimmune disease, the autoantibody specificities associated with those models, and the relevance of animal models to human idiopathic autoimmune disease. In Chapter 2, Eng Tan summarizes a series of...


Fig. 5.1 T cell-dependent induction of autoimmune reactions in B cell-mediated autoimmune diseases. (A) Initiation of autoreactive B- and T-cell activation. Autoreactive T cells are activated when autoreactive B cells encounter antigen in the periphery, travel to lymphoid organs, and act as antigen-presenting cells (APC, 1A), or when professional APCs process and present autoantigens and or other T-cell epitopes in the T-cell zone (1B). These activated T cells can then in turn activate the same or other auto reactive B cells via costimulatory molecules such as CD154 and or CD28 (2A), or by secreting cytokines such as IFN-y and or IL-4 (2B), which promote and or augment B-cell activation and class switching. Activated autoreactive B cells then travel to the B-cell zone where they form germinal centers and undergo class switching, somatic hypermutation, and affinity maturation in the dark zone (DZ, 3). They escape apoptosis by receiving survival signals in the light zone (LZ, 4), either...

Other Cytokines

Several other T cell- or B cell-derived cytokines may also participate in the pathogenesis of humoral autoimmune diseases. For example, IL-5, produced by T cells, has been demonstrated to exacerbate autoantibodies in a murine model of AIHA 161 as well as in the (NZB x NZW) Fj murine lupus model 81 . Prior studies have implicated IL-12 which is primarily produced by macrophages but is also produced by B cells 171 - in the pathogenesis of EAT 172 , EAMG 106, 173 , (NZBxNZW) Fj, and MRL lpr lupus 111, 174 , as well as in collagen-induced arthritis 175 . But other studies have suggested that it may be protective, at least in mercury-induced autoimmunity 176 and GVHD 177, 178 . However, given the recent discovery of multiple members of the IL-12 family that share common active subunits, such as IL-23 and IL-27, these findings are likely confounded and thus require revisitation 179 . Finally, soluble forms of surface receptors, such as soluble CD154 180, 181 , have been described in these...


Understanding the influence of genes and their products not only on susceptibility but also on resistance to autoimmunity and autoantibody expression is in its infancy. But the tools to mature this field (inbred animal models of spon taneous and induced autoimmunity, molecular techniques of transgenics and gene knockout) are already available. They await the complex but potentially fruitful identification and functional analysis of candidate genes.

Cell Death

In addition to activation, T-B cell interactions may also result in cell death or apoptosis, generally of the B cell 72 . Such interactions typically involve death receptors such as CD95 (Fas), TNFR1 (TNF receptor-1), and the TRAIL receptors DR4 and DR5, whose dysfunction may lead to autoimmune manifestations, in part due to the inability to exclude autoreactive B cells from the lymphoid follicle and germinal center reaction 5, 73, 74 . However, a detailed description of cell death and apoptosis in autoimmunity is beyond the scope of this chapter, and the reader is directed to other sections of this book for further details (e.g., see Chapters 4 and 6).

Breaking Tolerance

For each putative tolerance mechanism, there have been numerous descriptions of its breakdown that could lead to autoimmunity. Genetic alterations in intra-cellular signaling pathways are prime candidates because enhanced signaling through the antigen receptor, reduced signaling through inhibitory receptors, or abnormalities in intracellular negative regulators of lymphocyte activation could readily contribute to autoreactivity (reviewed in 95 ). Also, extracellular factors that could influence tolerance and contribute to autoimmunity have been invoked, such as viral- or bacterial-derived antigens that cross-react with the BCR or TCR (reviewed in 96 ), coincidental signaling through Toll-like receptors to enhance APC function by pathogens (reviewed in 97 ), or even self-materials 98 or increased self-antigen load due to a deficiency in antigen clearance machinery 99 . However, of primary importance in the productive activation of B cells is the availability of T-cell help, because...

The Thyroid Gland

The thyroid gland produces the thyroid hormone that is required to maintain normal metabolism of the body. A highly regulated feedback loop controls thyroid function and helps maintain the euthyroid status (Fig. 14.1). Thyroid-stimulating hormone (TSH) is produced in the anterior pituitary in response to stimulation by thyroid-releasing hormone (TRH) produced in the hypothalamus. The TSH binds to the thyrotropin receptor (TSHR), which then activates adeny-lyl cyclase and phosphatidyl inositol pathways and leads to the production of thyroid hormone. Hormone production begins when tyrosine residues of the thyroglobulin (Tg) are iodinated and then coupled through the catalytic action of the thyroid peroxidase (TPO), leading to the formation of the thyroid hormone precursor T4. The T4 undergoes deiodination and results in the formation of the thyroid hormone triiodothyronine (T3). The T3 binds to its cognate receptor in cells throughout the body and forms a complex, which is translocated...

Anti Clq Antibodies

C1q (460 kDa), a highly conserved protein, is part of the first component of the complement system. The biological function of C1q is to bind immune complexes via its six globular domains and of a variety of other non-immune activators of the complement system, including CRP, DNA, fibronectin, fibrinogen, and lipopolysaccharides, by its collagen-like region (CLR). In immune complexes, C1q is normally bound to Fc regions of IgG in order to fulfill the activation function of C1q within the classical pathway 156 . For many years, C1q was therefore used in radioimmunoassays and ELISAs to detect circulating immune complexes (CIC) in numerous diseases, including SLE 157-159 . In SLE, the CIC titers determined by C1q assays correlated well with disease activity and renal involvement. However, an alternative means of binding C1q has also been described for use in cases where high-affinity autoantibodies directly recognize the CLR of C1q through the antibody F(ab) antigen-combining sites...

Bcell Anergy

Much of the description of B-cell anergy derives from a mouse model expressing transgenic heavy (u) and light chains, which together encode an anti-hen egg lysozyme (HEL) antibody. These cells can be considered autoreactive when the mice are genetically crossed with, or when anti-HEL mature B cells are adoptively transferred into mice expressing lysozyme as a transgene. In contrast to the controls that spontaneously secreted IgM anti-HEL, antibody secretion in the double-transgenic mice was profoundly silenced 89 . HEL-specific B-cell precursors were still present but had downregulated approximately 95 of their surface IgM and were largely non-responsive to stimulation with antigen plus T cells in the appropriate host 89 . It was proposed that the functional tolerance or anergy that developed when B cells encountered high-affinity, monovalent antigen in the absence of T-cell help produced a critical level of BCR occupancy to initiate an anergy program rather than activation, ensuring...

Tcell Anergy

A fundamental tenet of immunology is the requirement for dual receptor engagement of the T cell by an APC in order to achieve full activation. In addition to signaling through the TCR by peptide MHC (signal 1), simultaneous ligation at a different site (signal 2), particularly CD28 on the T-cell membrane by the B7 family of ligands (CD80 and CD86), on the APC generally must occur. If costimulation does not occur, engagement of the TCR by a high-affinity ligand produces a long-lasting state of paralysis. Upon subsequent challenge with cognate antigen by professional APCs, i.e., cells expressing costimulatory molecules, T cells in this anergic state will not transcribe certain cytokines (most notably IL-2), will not respond to other T-cell growth factors, and will not proliferate 58 . Anergic T cells are deficient in helper activity for B cells but are not dead they remain viable for an indefinite time and can be made to proliferate in vitro and provide helper activity with cognate...

Preface to the First Edition

It took, however, more than fourty years that some distinct organ-specific immune disorders were categorized as true autoimmune diseases. Among the first identified were autoimmune orchitis, allergic encephalomyelitis, autoimmune The rapid development of immunological research has also provided major insights in the pathogenesis of autoimmune disorders which has implications for classification, diagnosis and therapy of these disorders. Classical examples for well-characterized autoimmune disorders are myasthenia gravis, pemphigus vulgaris, and hemolytic anemia. Furthermore, the availability of recombinant forms of the major autoantigens of these disorders has provided critical tools to investigate autoimmunity versus immunological tolerance to these self proteins in affected patients and healthy individuals. I am very grateful that internationally leading experts in the field of cutaneous autoimmune disorders spontaneously agreed to provide comprehensive and well-illustrated overviews...

Arthrogryposis multiplex congenita AMC

Not a distinct entity, but rather a symptom complex, in which there is congenital but nonprogressive stiffness and deformity ofjoints, most probably associated with immobility of limbs in utero. More than 150 conditions are known to have congenital contractures (Steinberg et al 1996).The primary cause may be neurogenic, myopathic, an abnormality ofjoints or connective tissue, or restrictive, secondary to oligohydramnios. In a pathological study of 21 fatal cases, 11 were myogenic (10 congenital muscular dystrophy) in origin (Quinn et al 1991). One case occurred after the mother had received tubocurarine in the tenth week of pregnancy for the treatment of tetanus. It is suggested that those cases of neurogenic origin may be associated with degeneration of anterior horn cell columns.Those in the neurogenic group have a number of congenital abnormalities in association. Infants at birth who are ventilator dependent have a poor prognosis, unless myasthenia gravis is the basis of the

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).

Activation of Self Reactive T and B Cells

Autoimmune diseases require the presence of autoreactive T cells and, in the case of immunoglobulin mediated diseases, of autoreactive B cells. In view of the potent and large number of regulatory mechanisms that protect against autoimmune disease, activation of autoreactive T and B cells is thought to require a series of destabilizing events. One important aspect is the activation and reactivation of potentially autoreactive T cells (Rocken et al. 1992). However, induction of autoreative T cells or B cells alone does not induce or predispose for autoimmune diseases. For example, in individuals, which are genetically predisposed of developing autoimmune diabetes, the relative risk of becoming diabetes increases significantly if their T cells respond vigorously against endogenous antigens from pancreatic islet cells. In sharp contrast, individuals from the same population are largely protected against autoimmune diabetes, when they exert high immunoglobulin titers but weak T cell...

Chromosome 6 And Mhc Resources

The MHC is the most important genetic region in relation to common human diseases such as autoimmunity and infection. Because of this biomedical importance, the MHC was completely sequenced by 19994, well ahead of the human genome draft sequence. Driven by pathogen variability, the MHC is under enormous pressure to evolve and adapt quickly. Over time, it has become the most polymorphic region in the human genome with some genes such as HLA-B (which has been associated with Behcet's disease), having over 400 alleles. However, even subtle changes in the self non-self recognition pathways can lead to genetic miscommunication and result in autoimmune diseases such as Diabetes, Multiple Sclerosis and Behcet's disease. Figure 2 shows a summary of chromosome 6 including the extended MHC which is located on the short arm at 6p21.31-22.1. The high gene and SNP densities of the MHC are clearly visible.

Aidsassociated Multicentric Castlemans Disease

In non-human immunodeficiency virus (HlV)-infected individuals, MCD can be associated with other diseases such as cutaneous KS, B-cell lymphoma, Hodgkin's disease, and polyneuropathy, organomegaly, endocrinopathies, monoclonal gammopathy and skin changes (POEMS) syndrome, and autoimmune diseases.147,229 MCD was diagnosed in two homosexual men with AIDS in 1985.231 In individuals with HIV, MCD is linked with malignant transformation to NHL at 15-fold higher rate than those not diagnosed with MCD.232

Presentation and Clinical Setting

BP typically affects the elderly, with onset after 60 years of age. Its incidence has been estimated t o be 6.1 and 7 new cases per million per year in a German and a French study, respectively, and it rapidly increases with aging (Bernard et al. 1995 Jung et al. 1999). The relative risk for patients older than 90 years has been estimated to be approximately 300 fold higher than for those of 60 years of age or younger. In contrast to most autoimmune diseases, men have a higher risk of suffering from BP than women (Jung et al. 1999). Although BP is usually a disease of the elderly, it may rarely occur in children (Nemeth et al. 1991, Trueb et al. 1998). BP has been also described in patients with other autoimmune disorders, such as rheumatoid arthritis, Hashimoto's thyroiditis, dermatomyositis, lupus erythematosus, and autoimmune thrombocytopenia. Although a case-control study did not find any increased risk for autoimmune disorders in BP (Taylor et al. 1993), it is likely that these...

Materials And Methods

For immunohistochemical staining frozen sections were prepared using the alkaline phosphatase method with new fuchsin as chromogen. The applied monoclonal antibodies (MAbs) (Table 1) were directed against CD45, CD3, CD4, CD8, and CD44 isoforms, i.e. panCD44, splicing variants v3 (cytokine binding capacity), v6, v7 (exhibiting inhibitory function in different experimentally induced autoimmune diseases), and v10. Control staining was achieved on murine tongue and spleen sections.

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).

Cells and Immunoglobulins

Probably the best example for an immunoglobulin-mediated disease is pemphigus vugaris. In patients, this disease is associated with little inflammation and seems to be directly mediated by the binding of autoreactive immunoglobulins to the desmogleins that guarantee the adherence between kerati-nocytes (Amagai et al. 1991). Indeed, transfer of patient sera and monoclonal antibodies directed against desmoglein 3 into the skin of new-born mice can directly induce acanthosis (Rock et al. 1989). This critical role for a direct binding of immunoglobulins to desmoglein structures is further supported by the observation that in patients with pemphigus vugaris the disease activity correlates closely with the serum levels of the autoantibodies (Hertl 2000). Such a close association is unusual for other autoimmune diseases, including lupus erythematosus or bullous pemphigoid. For comparisons, bullous pemphigoid is of special interest. It is also an immunoglobulin mediated bullous skin disease....

Unresolved Issues and Perspectives

The etiologic factors underlying the initiation of the BP remain unclear. One of the major challenges will be the elucidation of the predisposing factors, including genetic polymorphism, leading to a break of autotolerance. It is important to better characterize the humoral and cellular immune response in the various phases of the disease and to elucidate whether findings obtained from the mouse model of BP about the pathophysiology of subepidermal blister formation can be directly applied to the situation in humans. This insight will not only further our understanding of autoimmune diseases in general, but, hopefully, also facilitate the development of diagnostic tools for the identification of patients at risk for BP. Better knowledge of the autoimmune response in BP is a crucial step towards the design of novel immunomodula-tory approaches devoid of the severe side effects of current immunosuppres-sive treatments. For example, preliminary observations indicate that the new...

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

Linda A LeeMD and Georgia B VogelsangMD

Stem cell transplantation (SCT) has rapidly advanced over the past 10 years, with a 5 fold increase in the frequency at which they are being performed. No longer restricted to the treatment of hematologic malignancies, aplastic anemia, and hemoglobinopathies, SCT has been used to eradicate solid tumors and autoimmune diseases. The use of non-myeloablative SCT has expanded the age limit, so that patients 70 years and older are now transplantation candidates. SCT is generally performed at university medical centers, although recipients frequently reside in areas distant from the academic environment. Thus, with increased numbers and survival among transplantation recipients, the likelihood that a community gastroenterologist or hepa-tologist will confront the gastrointestinal (GI) and hepatic complications of SCT will only increase in the future.

Systemic Lupus Erythematosus SLE and Chronic Discoid Lupus Erythematosus CDLE Incidence Prevalence

SLE and CDLE are quite frequently compared to other cutaneous autoimmune diseases. Incidence rates for SLE increased from 2 100,000 in the early 1960s to 4.6-7.6 100,000 in the 1970s. Prevalence rates of 17-48 100,000 population have been determined for the sixties worldwide (Siegel and Lee 1973 Fessel 1974 Hochberg 1985 Michet et al. 1985). Recent publications even point to an incidence rate of 5.56 100,000 and a prevalence rate of 130 100,000 (Uramato et al. 1999). The difference may not show a real increase for SLE but be explained by the use of different diagnostic criteria (i.e. different revisions of the ARA ACR criteria) and different surveillance methods. Nevertheless incidence rates differ for gender and race (Table 3).

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 .

Immunological Infertility

The autoantigenic effect is prevented from causing an autoimmune response by the Sertoli cells which form the blood-testis barrier within the testes. If this barrier is breached or incompetent then an autoimmune response will result, along with the destruction of spermatozoa (Jones, 1980 Wright, 1980). Such antibodies have been isolated in bull semen, but do not seem to have a direct correlation with breeding ability (Purswell et al., 1983). Such autoimmunity has been induced experimentally in stallions immunized with their own spermatozoa. It has, therefore, been suggested as a cause of idiopathic subfertility in stallions (Teuscher et al., 1994).

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.

Innate Immunity Autotoxicity and Degenerative Neurologies

The absence of antibodies and minimal presence of lymphocytes indicate that the elements of a classical autoimmune disease are absent in AD tissue. The neuroinflammation must then be viewed as evidence of an innate immune response which has self-damaging effects. We define this phenomenon as 'autotoxicity' in order to distinguish it from 'autoimmunity'.

Preoperative abnormalities

Muscles are fatiguable, as in myasthenia gravis, but the proximal limbs and trunk are initially affected, and the external ocular muscles tend to be spared. By contrast with myasthenia, although the patient complains of fatiguability, the muscle power may actually increase after brief exercise. Lower limb reflexes are reduced or absent, but may be enhanced by prior voluntary contraction, whereas in true myasthenia, reflexes are preserved. Neostigmine produces little or no improvement in the weakness. In a review of 50 cases (O'Neill et al 1988), the main neurological features were proximal lower limb weakness (100 ), reduced or absent tendon reflexes (92 ), post-tetanic facilitation (78 ), autonomic dysfunction, in particular dryness of the mouth

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.

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...

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.

Disease Modifying Therapy

A variety of different types of agents have been used to treat PBC. Because it is thought to be an autoimmune disease, many different immunosuppressive agents have been tried. In addition, antifibrotic and anticholestatic agents have been studied to see if they may slow down disease progression. Because of the likely need for very prolonged therapy to combat this slowly progressive disease, long-term complications of therapy are critical to consider. It is imperative to ensure that such complications are not worse than the disease itself.

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,...

Hyposecretion and Hypersecretion

Same Person Different Ages Pictures

Inadequate hormone release is called hyposecretion. It can result from tumors or lesions that destroy an endocrine gland or interfere with its ability to receive signals from another gland. For example, a fractured sphenoid bone can sever the hypothalamo-hypophyseal tract and thus prevent the transport of oxytocin and antidi-uretic hormone to the posterior pituitary. The resulting ADH hyposecretion disables the water-conserving capability of the kidneys and leads to diabetes insipidus, a condition of chronic polyuria without glucose in the urine. (Insipidus means without taste and refers to the lack of sweetness of the glucose-free urine, in contrast to the sugary urine of diabetes mellitus.) Autoimmune diseases can also lead to hormone hyposecretion when misguided antibodies (autoantibodies) attack endocrine cells. This is thought to be one of the causes of diabetes mellitus, as explained shortly. Excessive hormone release, called hypersecretion, has multiple causes. Some tumors...

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.

Myotonic Dystrophy Newborn

Neonatal Myasthenia

The face of the same infant as shown in Figure 3.117 shows the typical lack of expression and the bilateral ptosis seen in myotonic dystrophy. This should be differentiated from neonatal myasthenia gravis. About 10 to 15 of infants of myasthenic mothers are affected and signs present in the baby at or shortly after birth. The clinical picture of neonatal myasthenia gravis is dominated by general hypo-tonia, there being symmetrical involvement of the face, trunk and limbs. In severe cases there is lack of facial expression and difficulty in sucking and swallowing. Prognosis is good, with improvement within a week the infant may be symptomatic as long as 6 weeks.

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...

Type 2 T Cells and TB Cell Interactions

A large number of autoimmune diseases is immunoglobulin mediated. These 'humoral' diseases can roughly be divided into two major categories. Immu-noglobulins can induce damage through direct binding of their target-antigen. This is the situation in most other bullous autoimmune diseases of the skin, especially pemphigus vulgaris. Alternatively immunoglobulins bind to circulating antigens and cause damage through deposition along basement membranes or in vessels. The former situation is given in the case of lupus (Rubin 1997) the latter at sites of vasculitis.

Pulmonary Pathophysiology

Asthma And Fibrosis

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.

Etiology and Pathogenesis

Collagen Overlap

We now understand that EBA does not always present as a noninflammatory mechanobullous disease reminescent of DEB. Although less common, EBA may present as an inflammatory, widespread, vesiculobullous disease reminiscent of BP. Therefore, it is possible that autoantibody recognition of one or several domains of type VII collagen may invoke an inflammatory cascade which could result in proteolytic degradation of matrix components within the DEJ that are essential for epidermal-dermal adherence. Therefore, within the spectrum of EBA and autoimmunity to type VII collagen, there are several possible mechanisms for autoantibody-induced blister formation. First, because EBA often occurs with minimal clinical or histologic inflammation, it has been hypothesized that defective epidermal-dermal adherence in EBA involves autoantibodies that target and compromise functional epitopes on the NC1 domain. This then interferes with the normal interactions between NC1 and its extracellular matrix...

Clinical Box 21 Graft Versus Host Disease

Grafty Verse Host Stem Cell

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...

Definition and Classification

Lupus erythematosus (LE) is a polyclonal T and B lymphocyte autoimmune disease thought to result from a complex interplay of genetic and environmental factors. Clinical expression of LE ranges in continuum from minor cutaneous lesions to life-threatening vital organ dysfunction. Throughout this continuum skin manifestations are variable and common. In 1981 Gilliam and Sontheimer developed a classification system that divides lesions into LE specific and LE non-specific cutaneous disease. LE specific cutaneous disease includes three clinically, immunologically and genetically distinct disorders acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE) and chronic cutaneous LE (CCLE). Histopathological differentiation between especially the first two disorders can be difficult.

Myopathies associated with endocrinemetabolic disorders and carcinoma

Paraneoplatic Endocrinal

Thyrotoxicosis is associated with muscle atrophy and weakness. It may also be associated with a progressive extraocular muscle weakness, ptosis, periodic paralysis, myasthenia gravis, spastic paraparesis and bulbar palsy. Subjects may have brisk reflexes and fasciculations similar to amyotrophic lateral sclerosis.

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...

Immunological Mechanisms

Of y5+TCR lymphocytes of patients with abd38-40. These peptides show significant homology with the corresponding peptides derived from the human 60 kDa mitochondrial HSP41. In the cerebrospinal fluid of patients who had parenchymal neurological involvement an increased level of anti-HSP antibodies could be found42. On the other hand, immunoglobulin A isotype of antibodies specific for mycobacterial tuberculosis HSP-65 could cross react with certain serotypes of Streptococcus sanguis43. In general, cross reactions between microbial and human 65-kDa HSP possibly link infection with autoimmunity.

Clinical Manifestations

There is great diversity in the clinical presentation of EBA. The common denominator for patients with EBA is autoimmunity to type VII (anchoring fibrils) collagen and diminished anchoring fibrils (Woodley 1988 Woodley et al. 1988). Although the clinical spectrum of EBA is still being defined, it appears that there are at least five clinical presentations of EBA (Fig. 2)

More Products

Autoimmune Paleo Cookbook

Download Instructions for The Autoimmune Bible System

The best part is you do not have to wait for The Autoimmune Bible System to come in the mail, or drive to a store to get it. You can download it to your computer right now for only $37.00.

Download Now