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Holistic Approach To Myasthenia Gravis And Autoimmune Diseases

The Power Of Self-healing Is Within You. Empower Yourself With Information To Heal Yourself Of Any Autoimmune Disease, Including Myasthenia Gravis. This 132-page E-book Is Based On The Author's Own Experience Of Autoimmunity, And His Journey Of Recovery. This book is a result of years of research on holistic self-healing for autoimmune diseases. This book has everything you need to know not only about how to cure myasthenia gravis but also about how to achieve total health for healing, happiness, and wisdom. This book is about the art of living healthily. This book is comprehensive and its coverage is extensive. Go to The Book Outline to look at its detailed outline, chapter by chapter, and you will see how every aspect of health is covered in detail.

Holistic Approach To Myasthenia Gravis And Autoimmune Diseases Overview

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Cancer And Autoimmunity

Many reports exist regarding the association of autoimmune diseases and neoplasms. Autoimmune phe-notype and various autoantibodies have been found in patients with diverse malignancies. For example antinuclear antibodies have been described in a prevalence of 19 31 by different authors (reviewed in Reference 39 ). Unlike the autoantibodies found in prototypic autoimmune diseases (i.e., SLE), autoantibodies in various malignancies exhibit a more restricted pattern of reactivity. Similarly, rheumatoid factor has also been detected in higher prevalence in patients with malignancies in comparison with control subjects (between 11 and 85 in different reports). The presence of RF was found to correlate with a poorer prognosis in malignancies such as transitional cell carcinoma, melanoma and gastrointestinal malignancies. Malignant transformation is an important process occurring in patients with autoimmune diseases. The reasons for the increased tendency to malignancies is not always...

Evolution Of The Autoimmunity Concept

Paul Ehrlich was the first to coin the term autoimmunity 11 with regard to the harmful aspects of immunity, namely the emergence of autoantibodies directed against the organism's own antigens. However, the expression used ('horror autotoxicus') has served to denote a mechanism avoiding autoimmunization, exemplified in goat models (producing alloantibodies but not autoantibodies). The revolutionary ideas expressed by Ehrlich were subsequently abandoned for a century although anecdotal works confirming his notions were sporadically reported. The turning point, leading to the general acceptance of the autoimmunity concept was the experiments by Witebski & Rose (reviewed in Reference 12 ) showing that rabbits immunized with rabbit thy-roglobulin developed thyroiditis following production of anti-thyroglobulin autoantibodies. These observations were supported by the models of autoimmune hemolytic anemia and thrombocytopenia in which anti-red blood cell antibodies were detected and had...

Hydralazine and procainamideinduced autoimmunity

Methylation of deoxycytosine residues of gene promoters takes place during cell ontogeny and silences genes through fixation of methylcytosin binding proteins and changes in chromatin structures (developed in 64 ) this pattern is maintained through subsequent mitoses by methyltransferases. It was shown that antigen specific T-cell clones, incubated with inhibitors of these enzymes, overexpressed LFA-1 and became able to proliferate in the presence of autologous antigen presenting cells, even in the absence of the nominal antigen. Autoreactivity is probably the consequence of the increase in LFA-1 expression since antigen specific T-cells transfected with LFA-1 also became autoreactive 63 . The injection of T-cells rendered autoreactive by incubation with procainamide 65 or with hydralazine 66 or of T-cells transfected with LFA-1 63 into a non-irradiated syngeneic normal recipient triggers an autoimmune disease 66 . This disease is marked by anti-DNA antibody production,...

The Autoimmune Response In Lung Cancer Is Similar To That In The Systemic Autoimmune Diseases

A parallel can be drawn between the systemic autoimmune diseases and cancer in relation to the antinuclear antibodies observed in both conditions. In both, cellular proteins become antigenic targets of a humoral response. By far the most common autoantibodies found in the systemic autoimmune diseases are those directed against nuclear antigens 8, 23-26, 56 . Attempts to show nuclear reactivity in patients with cancer using characterized antigens known to be involved in the immune response in the systemic autoimmune diseases have been unrewarding 14, 57 . The failure of cancer sera to recognize those antigens may merely reflect the presence of different specificities related to the cancer itself. A characteristic profile of autoantibodies is found in each of the systemic autoimmune diseases. These autoantibodies are helpful in establishing a correct diagnosis and prognosis and frequently facilitate the follow-up and treatment of these patients. The value of these antibodies in the...

Treatment Of Chronic Viral Hepatitis In Patients With Preexisting Autoimmune Disorders

The role of IFN therapy in patients with chronic viral hepatitis and a pre-existing autoimmune disorder raises separate issues What is the course of the autoimmune disorders during IFN therapy What is the virologic response to IFN in such patients In addition, does the mere presence of circulating autoantibodies define the existence of an autoimmune disorder, and does the presence of such antibodies affect the response to IFN The following discussion, therefore, focuses on both the role of IFN in the patient with autoantibodies, but without autoim mune disorders, and the effect of IFN in the patient with a well-defined autoimmune disease.

Positive Autoantibodies but Without Symptoms of Autoimmune Disorders

The presence of serum autoantibodies is essential for the diagnosis of an autoimmune disorder, but no one marker is pathognomonic for a certain autoimmune condition. In addition, many healthy persons carry silent autoantibodies, and they remain asymptomatic throughout their lives. These autoantibodies may represent a subclinical autoimmune dysregulation state, which may become manifest when a trigger, such as HCV or IFN, affects the subject. The presence of these autoantibodies ultimately does not compromise the host's immunologic response to pathogens, compared to the general population, and the literature suggests that these individuals have an acceptable response to IFN therapy. Nevertheless, these patients appear to be at a higher risk for the development of autoimmune complications during IFN therapy.

Autoimmune Disease Process

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology. SLE is characterized by the involvement of multiple organ systems and the production of autoantibodies directed against nuclear components, including ssDNA, ds-DNA and histones 1-2 , The hallmark of autoimmunity is the activation and proliferation of lymphocytes directed against self-antigen. Abnormalities in lymphoid cell function include (i) changes in the ratio of T-cell subset population (ii) increased T-helper and decreased T-suppressor functions (iii) restricted usage of T-cell receptor genes (iv) defect in programmed T-cell death mechanisms, (v) increased population of active T cells (vi) increased expansion of B cells leading to the production of autoantibodies and (vii) abnormalities in the signal transduction pathway in lymphocytes. Defect in the signal transduction cascade mechanisms in lymphocytes from SLE patients have been shown to result in the aberrant expression of many genes and...

Induction Of Autoimmunity By

In some experimental models, T-cells recognizing stress protein epitopes, especially from HSP 60, can induce autoimmune disease 9, 73 . Stress protein HSP 60 is a dominant epitope in T-cell responses to certain pathogens, for example mycobacteria 7478 . Since stress proteins are highly conserved with sequence homologies between bacterial and human members of stress protein families, it has been discussed that bacterial infections can trigger autoimmune disease 9, 10, 73, 79 . Recent experimental observations however show that the T-cell response to bacterial heat shock proteins, especially HSP 60, is suppressive for the development of autoimmune disease 11, 80 . So far there is no experimental evidence that stress proteins expressed on tumors cells can trigger an autoimmune response, even in case of an aberrant surface expression. Furthermore, from numerous experiments where HSP 70, 90 and gp96 stress protein preparations from syngenic tumors and normal liver were injected into inbred...

Neonatal Exposure to Physiological Ovary Derived Ag Induces Tolerance and Neonatal Immunization with Selfpeptide

In a gain of function experiment, when male mice were engrafted with neonatal ovaries as neonates, their response to pZP3 as adults was reduced to the level of female mice (Pramoonjago et al., unpublished data). In contrast, in studies involving neonatal injection of Ag (usually of foreign origin), the neonates develop a Th2-biased response rather than tolerance (Singh et al. 1996 Garza et al. 1997 Adkins 2000). On the other hand, we have found that neonatal response to the self-peptide frequently led to autoimmune response and autoimmune disease. Indeed, neonatal mice mounted autoimmune responses and elicited autoimmune memory in situations where adult mice would be resistant (Tung et al. 2001). Thus, the nature of neonatal immune response can vary greatly depending on the nature of the antigenic stimulus.

Neonatal Immunization Induces Autoimmune Disease Besides Autoimmune Ovarian Disease

The studies on murine AOD and other autoimmune models indicate that neonatal mice are more sensitive than adults to disease induction, and this is in turn influenced by factors including endogenous Ag expression, resistance to apoptosis, and environmental factors. We next describe the response of neonatal mice to ZP3 immune complex that results in a new intergenerational autoimmune disease known as neonatal AOD (nAOD). The nAOD model has permitted more precise dissection of the underlying mechanisms because of this and the relevance of the model to autoimmunity of the d3tx mice, it will be described in more detail.

Autoimmune Diseases Associated With Thymoma

The various autoimmune diseases that occur in patients with thymoma include mainly myasthenia gravis (MG), pemphigus, systemic lupus erythematosus (SLE), pure red cell aplasia (PRCA), and other conditions that seldom appear concomitantly with this tumor. 2.1. Myasthenia Gravis MG is an autoimmune disease resulting from the production of antibodies against the acetylcholine receptor of the muscular endplate 4 , Only about one-third of the patients with thymoma have MG, while 10-15 of myasthenic patients have a thymoma. MG patients with thymoma are usually older than 40 years of age, have high antibodies titer and a poor clinical response to thymectomy, whereas MG patients with thymic hyperplasia (which is more frequently found in MG than thymoma) can be either older than 40 years of age with low titer of antibodies and poor response to thymectomy, or younger than 40 years of age, with moderate antibodies titer and a good response to thymectomy. In addition, there is an increased...

Autoimmune Diseases In Benign And Malignant Thymoma

We recently discussed the difference between the association of autoimmune diseases with benign and invasive thymomas, as we have reported about 6 patients with autoimmune diseases and malignant thymoma 23 . They included 5 patients with type I malignant thymoma and 1 patient with type II malignant thymoma, and also the first reported cases of Graves' disease with thymoma and of Sjogren's syndrome with thymic carcinoma 23 . With respect to the association of malignant thymoma with autoimmune diseases, there is a significant difference between types II and I. Malignant thymoma type I (invasive thymoma) was often described in some case series to occur in patients with MG, the autoimmune disease most frequently found in thymomatous patients (summarized in 24 ). In addition, pemphigus, SLE and PRCA were also reported in patients with type I malignant thymoma. As opposed to malignant thymoma type I, there are only few case reports of autoimmune diseases with thymic carcinoma (malignant...

Suppression of Autoimmune Disease by Regulatory Cells from Donors with or Without the Relevant SelfAg

Taken together, the in vivo studies in d3tx mice support Ag-specific suppression of autoimmune diseases by CD4+CD25+ T cells, though the findings do not rule out additional suppression by nonspecific means. Our study on Ag specificity further emphasizes the dynamic nature of immune suppression by the CD4+CD25+ T cells

Role of CD137CD137L Interaction in the Pathogenesis of Autoimmune Diseases

CD137 CD137L pathway is involved in the generation of a fully competent T cell response (Blazar et al., 2001 DeBenedette et al., 1999 Tan et al., 1999, 2000). Absence of CD137 CD137L interactions prevent the development of certain autoimmune diseases (Seo et al., 2003, 2004). Elevated serum levels of soluble forms of receptor and ligand were detected in patients with various autoimmune diseases (Jung et al., 2004 Michel et al., 1998 Sharief, 2002). These studies suggest CD137 CD137L interactions may play a role in the pathogenesis of autoimmune disease.

Cigarettesmoking Transition From Immunity To Autoimmunity

The breakdown of immune surveillance is considered as the initiator of autoimmunity development. The exact mechanisms contributing to this process have not been defined, yet it appears that they are not limited to a single arm of the immune system. Polyclonal T-cell activation has been suggested to play an important role in occurrence of autoimmune disease 32 , Accordingly, cancer patients treated with high doses of IL-2, a T-cell stimulator, are more prone to the development of autoimmune thyroiditis or anti-red blood cell autoantibodies 33 . By analogy, thymectomized mice develop autoimmune disease following stimula An important mechanism thought to initiate autoimmunity is the polyclonal B-cell activation. It stems from in-vitro observations demonstrating production of rheumatoid factor and anti-DNA antibodies as well as an exacerbated clinical picture in autoimmunity-prone animals following stimulation with B-cell mitogens 32 . The evidence for B-cell mitogenicity of TGP 28...

The Effect Of Thymectomy On Autoimmune Diseases

Bone-marrow transplantation has recently been suggested as an optional treatment for severe autoimmune diseases 25 , As there is a strong association between thymic pathology and autoimmunity, it is not surprising that thymectomy also might have a beneficial effect on the course of autoimmune diseases. 4.1. The Rationale Behind Thymectomy for the Treatment of Autoimmune Diseases Since MG is the autoimmune disease most commonly found in patients with thymoma, literature reports focus on the pathogenesis of this disease in thymo-matous patients. Alterations in the thymus are found in about 80 of MG patients. When MG is associated with thymitis, the acetylcholine receptors on the my-oid cells trigger a classical antigen-driven immune reaction and the intrathymic production of acetylcholine receptor-specific autoantibodies 26 . Thymus cells from 82 out of 109 MG patients with serum acetylcholine receptor-specific autoantibodies secreted these antibodies in vitro 27 . On the other hand, in...

The Case Of Acquired Resistance To Autoimmune Disease

Among the various systems of experimentally induced autoimmune disease (AID), EAE (Experimental Allergic Encephalomyelitis) is a prime example for this discussion. Some strains of rats and mice, if immunized with myelin basic protein (MBP), one of myelin proteins, in Complete Freunds Adjuvant, develop a severe disease caused by inflammation in the central nervous system, consequent to the activation of CD4 T cells. Disease can be induced also by transfer of Beyond that demonstration of dominant tolerance in physiology, the reason to review this particular experimental system in the context of cancer immunity, is the well-established set of observations demonstrating that tolerance can readily be re-inforced and boosted by immunization. This was first suspected from the natural course of EAE, that spontaneously remits if the animal survives acute phase 9 , Moreover, new repeated attempts to re-induce another course of disease symptoms by secondary immunization systematically fail 10 ....

Pathogenesis and Spectrum of Autoimmunity

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

Mechanisms Involved in CD137 Agonistmediated Inhibition of Autoimmune Diseases

Compelling data have been shown that agonistic anti-CD137 monoclonal antibodies displayed potent immunomodulatory function in various autoimmune disease models including CD4+ T cell-mediated and both CD4+ T cell and B cell-involved, organ-specific and systemic autoimmune diseases. Multiple mechanisms are involved in CD137 engagement-induced inhibition of autimmunity, which includes (1) increase of T lymphocyte apoptosis, (2) generation of CD8+ regulatory T cells, (3) CD4+ T cell anergy, (4) autoreactive B cell apoptosis. INF-y plays an important role in various events.

Autoimmunity and Tumor Immunity

Removal of CD25+CD4+ TR cells may elicit autoimmunity in addition to provoking tumor immunity. This raises the issue of how tumor immunity can be evoked without autoimmunity by manipulating natural TR cells. It is of note in this regard that the intensity and the range of autoimmune responses (i.e., the severity, the incidence, and the spectrum of autoimmune diseases) elicited by removal of TR cells depend on the degree and duration of depleting CD25+CD4+ TR cells, and, more importantly, the genetic background of the hosts (Sakaguchi et al. 1995,1996). For example, in genetically autoimmune-prone BALB c mice, generation of effective tumor immunity can be achieved without deleterious autoimmunity by limiting the period of depleting CD25+CD4+ TR cells, whereas, in genetically autoimmune-resistant C57BL 6 mice, complete depletion of CD25+CD4+ TR cells leads to tumor rejection without producing autoimmune disease (S. Yamazaki et al., unpublished results). Thus, autoimmunity and tumor...

Pathogenesis of Autoimmunity in CLL

The most obvious explanation for autoimmune disease in CLL would be that the autoantibodies were the product of the tumor. I am constantly surprised by the many eminent immunologists who believe this to be so. The CLL cell does secrete immunoglobulin. Stevenson et al. (59) demonstrated secretion of small amounts of idiotypic IgM by CLL cells using a highly sensitive radioimmunoassay. The immunoglobulin secreted by CLL cells is often autoreactive. Stimulation by phorbol ester induced the CLL cells from 12 14 patients to secrete IgM that reacted with a variety of autoantigens, including the Fc portion of IgG, both single- and double-stranded DNA, histones, cardiolipin, and cytoskeletal proteins (60). Similar polyreactive antibodies have been described by Sthoeger et al. (61), who demonstrated that the antibodies were of the same light chain types as the surface IgM of the CLL cells and therefore not the product of contaminating normal B-cells. They also...

Antitumor Immunity And Autoimmune Disease

With distinct types of tumors, provided some insight into the increasingly blurred boundary between antitumor immunity and autoimmunity 100 , Paraneoplastic syndromes are triggered when antigens, normally restricted to the nervous system, are aberrantly expressed in a cancer. The immune system recognizes the antigen expressed by the tumor cells and mounts an immune response. This immune response, which was found to effectuate retardation of the growth of the tumor in some cases, would also attack those portions of the nervous system that express the onconeural antigen. The result is that the tumor remains small but patients may suffer severe neurological disorders 101, 102 , Further evidence to the coexistence of antitumor immunity and autoreactivity was brought about through observations by Rosenberg and coworkers that in patients with metastatic melanoma who were treated with high-dose interleukin-(IL)-2 immunotherapy, vitiligo, which is a manifestation of normal melanocyte...

Interferon And Autoimmunity

Given the possible effects of interferons on the immune system it is perhaps not surprising that autoimmune disorders have been reported as a consequence of interferon-a therapy. For example, autoimmune haemolytic anaemia, autoimmune thyroid disorders and thrombocytopenic purpura have all been described 18 . Interferon-a therapy is also associated with autoantibody production including antibodies to nuclear antigens 19 , thyroid antigens and epithelial cells. Ronnblom et al. 20 described a patient with a malignant carcinoid tumour who developed SLE during interferon-a therapy. Interestingly, this patient had a further course of interferon-a therapy which resulted in the recurrence of anti-DNA antibodies and clinical evidence of active lupus. This report stimulated the authors to prospectively study 135 patients with malignant carcinoid tumours treated with interferon-a and they found 25 patients who developed clinical evidence of autoimmune disorders 18 . This included 18 patients...

Evaluation of Autoimmunity to Transaldolase in Multiple Sclerosis

Transaldolase is a target of autoimmunity mediated by T cells and antibody (Ab) in patients with multiple sclerosis. Functional T-cell assays, T- and B-cell epitope mapping, and detection of transaldolase-specific antibodies in patients with multiple sclerosis are described. Recombinant transaldolase was produced in a prokaryotic expression vector for use in Western blot analysis of sera of these patients. Overlapping transaldolase peptides 15 amino acids (aa) long were synthesized onto cellulose membranes to map immunodominant B-cell epitopes. Amino acid sequence homologies between viral peptides and immunodominant B-cell epitopes of transaldolase were identified using a computer-based algorithm. Direct assessment of molecular mimicry between transaldolase B-cell epitopes and related viral peptides is also shown. T-cell epitopes are mapped in a T-cell proliferation assay using multiple sclerosis patient and control donor cells. Autoantigen-specific T cells are identified by...

Treatment of Autoimmunity in CLL

Triggered the autoimmunity has to be weighed against the prospect that treating the disease will eliminate the complication. 2.5.4. Management of Post-Fludarabine Autoimmunity A special risk is the retriggering of autoimmunity by re-exposure to purine analogs and even chlorambucil may retrigger the complication (135). However it is possible to reintroduce fludarabine while the patient is maintained on cyclosporin (120). Whether it is safe to use purine analogs in patients with a positive Coombs' test or evidence of pre-existing AIHA is difficult to answer. Some patients have had an exacerbation of their hemolysis or thrombocytopenia when

Autoimmunity To Cenpf In Cancer

Although the clinical significance of anti-CENP-F autoantibodies still needs to be further investigated, the available evidence indicates that autoimmunity to this protein is likely to be associated with the presence of a malignant tumor. An evaluation of the clinical histories of 26 patients producing anti-CENP-F IgG antibodies revealed that 14 (54 ) of these patients had cancers of various types 20 , Some of the non-cancer patients had conditions associated with ab- normal or increased cell proliferation such as hepatitis B and C-associated chronic liver disease. Interestingly, the average IIF titer of the anti-CENP-F antibodies in the patients with cancer, 1 10,103, was significantly higher than the average titer in the noncancer patients, 1 3,200 (p 0.008), indicative of a vigorous immune response to CENP-F in the antibody-positive cancer patients. A more recent study extended the characterization of the 26 anti-CENP-F positive sera and added an additional group of 10 CENP-F...

In Vivo Antiidiotypic Therapy In Autoimmune Diseases

Anti-idiotypic therapy has not been tried in human autoimmune diseases directly. One study used the approach of passage of plasma over an anti-idiotype column which removes antibodies bearing the common idiotype 51 , In this study, an anti-3I Id column was used to remove anti-ds DNA antibodies bearing the 31 Id from patients with SLE. There were no significant side effects. The recent development of 'humanized' murine or rat monoclonal antibodies opens the way for direct injection of Id-bearing or anti-idiotypic antibodies into patients. Intravenous immune globulin (IVIG) exhibits a number of immunomodulatory properties that are mediated by the Fc portion of IgG and by the spectrum of variable (V) regions contained in the immune globulin preparations. Significant progress has been made in understanding the mechanisms by which IVIG exert immunomodulatory effects in the treatment of autoimmune diseases 52, 53 (see Table 3). Much attention has been given in recent years to the...

Measurement of Cytokines in Autoimmune Disease

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

Ms As An Autoimmune Disease Unresolved Issues

Although current opinion favors MS to be an autoimmune disease in humans that is similar to EAE in animals, evidence of autoimmunity in MS is not without controversy.*9,10 If MS is truly an autoimmune disease, it should be possible to identify the neural antigens that are responsible for the autoimmune process. In EAE, the encephalitogenic neural antigens capable of inducing disease are well defined. In contrast, the encephalitogenic antigen (s) in MS remain unknown. Some MS patients, but not all, do show an increase in the number of circulating T cells that recognize different MBP peptides.(7,11,12) However, similar reactivity to MBP is seen in healthy volunteers. Attempts to show the reactivity of lymphocytes present in the cerebrospinal fluid (CSF) to MBP in MS patients has met with mixed results. Numerous attempts to show the presence of MBP-reactive T lymphocytes in brain tissue from MS patients have been equally unrewarding. Thus, the consistent identification in MS of reactive...

Myasthenia Gravis And Thymoma

Myasthenia gravis is a condition in which the patient develops progressive muscle weakness secondary to acetylcholine receptor antibodies. Medications used to treat myasthenia gravis include anti-cholinesterase medications which block the cholinesterase-mediated removal of the acetylcholine from its receptor. The classifications of myasthenia gravis include ocular and generalized. In the ocular group, there is involvement of ocular muscles only with ptosis and diplopia. This is a very mild form of myasthenia gravis with no mortality. The generalized type of myasthenia gravis may be mild or progress to severe disease. In the more severe forms, the response to drug therapy is poor and the prognosis is poor. Ninety percent of patients with myasthenia gravis have adult onset disease. It affects women twice as often as men. Ten percent of patients with myasthenia gravis have thymomas. One-third to one-half of patients with thymomas have myasthenia gravis. Myasthenia patients are not...

Mechanism Of CpneumoniaeMediated Accentuation Of Autoimmune Disease

In experimental allergic encephalitis (EAE), an animal model of MS. EAE was recently used to evaluate a possible association of EAE with C.pneumoniae infection. Intraperitoneal inoculation of mice with C. pneumoniae, following immunization with neural antigens, increased the severity of EAE. Accentuation of EAE required live infectious C. pneumoniae, and the severity of the disease could be attenuated with antiinfective therapy. Following immunization with neural antigens, systemic infection with C. pneumoniae led to the dissemination of the organism into the CNS in mice, which then caused accentuated EAE. In contrast, inoculation with C. trachomatis did not worsen EAE, and infectious organisms were not seen in the CNS. This study demonstrates the potential effect of a C. pneumoniae infection in the CNS on the amplification of autoimmune disease following immunization with three different neural antigens (MSCH, MBP, and MOG). A causal association between C. pneumoniae infection and...

Autoimmune Disease

Evolution of an autoimmune disease from a state of autoimmunity may require the participation of diverse elements consisting of environmental, hormonal, immunological and genetic effects. These factors may act in concert or each one a part, to render an individual prone to autoimmune disease following an inciting 'triggering event'. It is probably the combined action of these factors, rather than the existence of each, that results in an autoimmune disease. 9. CONCLUDING REMARKS-THE MOSAIC OF AUTOIMMUNITY an immune mediated inflammatory process to damage self-structures. Thus, incriminated predisposing factors include hormonal, environmental, immunologic and genetic elements (Figure 2), which collectively constitute a milieu which enable a seemingly innocent triggering event to activate a vicious cascade resulting in autoimmune disease. Thus, for example, two members of the same family (first degree relatives) indeed 'inherit' the same preponderance to develop autoimmunity...

Natural Autoimmunity

The existence of B and T-cells harboring self-reactivity complicates the concept of autoimmunity, since it goes to show that this property is not necessarily associated with disease states 18 . Moreover, the abundant existence of anti-self reactivity implies that representation of self within the immune system might even have teleological roles in terms of protection or immune modulation. As such, it has been initially proposed by Grabar 19 that natural autoantibodies (NAA) could act as transporters of catabolic products serving to clear the organism of harmful self as well as foreign substrates. This view has later been extended by suggesting that by low affinity binding to autoantigens, natural autoantobodies could function as filters preventing the induction of autoimmunity 20 , An elaborate description of the biological roles of NAA is provided in Table 4. Another relevant finding is the increased occurrence of NAA with ageing, which may seem paradoxical, owing to the well...

Autoimmunity

Immunopathology of Autoimmune Disorders Autoreactive Antibodies 296 Immunopathology of Autoimmune Disorders Cell-mediated Immunity 299 Immunotherapy of Autoimmune Disease Immunotherapy of Autoimmune Disorders Cytokine Modulation 306 The autoimmune disorders are readily understood from discussions on the development and induction of antigen specific immunity (both B- and T-cell immunity). As noted in earlier chapters, the developing immune system produces populations of cells with an infinite array of recognition receptors, which do not recognize self components as foreign. Where such cells do develop, a back-up system must be in place to suppress their function. This avoids any functional consequences from AUTOimmune reactivity. A failure at these stages results in disease. The reader will find our discussion subdivided into consideration of diseases where immunopathology results from autoantibodies (and or complement activation), and those where cell-mediated immunity is the primary...

Cd And Autoimmunity

Although the pathogenic mechanism of CD is not yet fully elucidated, there is no doubt about the involvement of immune factors in the development of the disease. Many features present in CD fulfil the criteria generally accepted to define autoimmune disease and suggest that CD belongs to this group of diseases 1,11 (2) Associated autoimmune diseases It has been reported that insulin-dependent diabetes mellitus (IDDM) occurs in 1-10 of adult coeliac patients and the prevalence of CD in patients with IDDM has been 2-7 . Similarly, 2-4 of coeliacs suffer from autoimmune thyroid disease and serological screening for CD in patients with autoimmune thyroid disease gives a coeliac prevalence of approximately 4 . The association between Sjogren's syndrome and CD was recently shown 3-5 of adult coeliac patients had Sjdgren's syndrome and 14 of patients with Sjogren's syndrome had CD 1,13 . (4) Presence of specific autoantibodies Characteristically increased levels of IgA and IgG antigliadin...

Causes Of Cancers In

Treatment of neoplastic diseases immunomodulat-ing agents may result in a state of autoimmunity. SLE and other autoimmune diseases may develop following therapy with interferon 57, 58 , Several case of patients with myeloproliferative disorders including chronic myelogenous leukemia (CML) and essential thrombocytosis (ET) developed SLE following treatment with a- and y-interferons 57, 58 , Twenty percent of 137 patients with CGL or ET developed rheumatic symptoms 58 after interferon therapy. During interferon therapy, 18 (72 ) of 25 patients with CGL had ANA positivity. Of these, 15 reported symptoms related to rheumatic diseases and 3 patients fulfilled the classification criteria for SLE. In another study, 19 of 135 patients with malignant carcinoid, developed autoimmune diseases including autoimmune thyroid disease, SLE, pernicious anemia and vasculitis 59 , The data indicate that interferon therapy may trigger the development of autoimmunity and should not be used in patients with...

Mapping the Systemic Lupus Erythematosus Susceptibility Genes

From Methods in Molecular Medicine, Vol. 102 Autoimmunity Methods and Protocols Edited by A. Perl Humana Press Inc., Totowa, NJ Often, lupus shows familial cosegregation with other autoimmune diseases, like rheumatoid arthritis, Sjogren's syndrome, or antiphospholipid antibody syndrome. In fact, studies show that 10-20 of lupus probands have at least one first or second-degree relative afflicted with other autoimmune diseases. In a classic study, Bias et al. (8) defined an autoimmune phenotype in lupus pedigrees based on the presence of an autoimmune disease or high titers of autoantibodies (e.g., rheumatoid factors, anti-smooth muscle antibodies, anti-acetylcholin-esterase antibodies, thyroid insufficiency). Bias and coworkers found that the most parsimonious model for the mode of inheritance of this new phenotype was autosomal dominant with variable penetrance (92 and 49 for women and men, respectively). This led to the hypothesis that a single gene confers susceptibility to...

Historical Perspective

The association between SS and lymphoma has been known since 1951, when Rothman et al. 6 described the first case of this association. Some years later, in 1964, Talal and Bunim 7 reported the first study on the incidence of lymphoma in a cohort of 58 patients with SS followed-up over 4 years and observed 3 cases of reticulosarcoma and 1 of IgM macroglobulinemia. In 1966, Hornbakeret al. 8 described the association of SS and nodular reticulum cell sarcoma in a patient dying due to a severe hemolytic crisis. One year later, Miller 9 studied the presence of autoimmune diseases in 264 patients with lymphoma and found 14 cases of autoimmune disorders, one was a patient who developed a reticulum cell sarcoma 4 years after the diagnosis of SS.

TCR Chain Abnormalities in Human Systemic Lupus Erythematosus

A growing number of studies have revealed that the expression of many genes is abnormal in T lymphocytes of patients with systemic lupus erythematosus (SLE). Although aberrant expression of signaling molecules may arise intrinsically or in response to the environment, these abnormalities play a significant role in the pathogenesis of this autoimmune disease. Modern research on lymphocyte signaling abnormalities in SLE has been directed toward identifying defective expression of various signaling molecules, understanding the molecular basis of the deficiency, and dissecting the T-cell signaling abnormalities that result from abnormal gene expression. The developments suggest that interplay of abnormal transcriptional factor, aberrant messenger RNA processing editing, ubiquitination, proteolysis, oxidative stress, and changes in chromatin structure invariably contribute to the abnormal expression of numerous signaling molecules in SLE T cells. The contribution of each of these...

Paraneoplastic Syndromes Of The Nervous System

The best current hypothesis that explains the peculiar phenomenon of nervous system degeneration in these syndromes is autoimmunity. Most investigations suggest that antigens normally restricted to the nervous system are aberrantly expressed by the tumor. The immune system recognizes the ectopic foreign antigen and responds by antibody production thus damaging all neurons expressing this onconeural antigen 24 , The histopathological picture of these syndromes differs according to the individual syndrome and although sometimes no pathological lesion can be identified in light microscopy, the usual picture is that of neuronal degeneration and inflammatory infiltrates 25 ,

Other Tissue Autoantibodies

Tion between neoplasia and autoimmunity results from increased incidence of both conditions in senescence. In our preliminary investigation 61 we studies 139 patients (55 of whom were aged 60 years and younger, and 84 were older than 60 years) suffering from a variety of malignant tumors for ANA, RF and antiery-throcyte antibodies (Coomb's test). There was no significant difference between the incidences of ANA and RF in the young patients and in the young controls and similarly, there was no significant difference between the incidences of ANA and RF in the elderly cancer patients and in the elderly controls. Our results suggest that the reported high incidence of ANA and RF in malignancies is a result of the old age of these patients rather than the tumor itself. However, the incidence of antierythrocyte antibodies was significantly higher in the patients than in the controls. This study was later extended to test a large battery of autoantibodies and the malignancies were grouped...

Diagnosis 71 Detection of MIgs

Cryoglobulins have been observed in a wide variety of diseases, including malignancies, infections and systemic autoimmune diseases 173 . Since the first report of cryoglobulinemia in a patient with S S 174 , some studies on the prevalence and clinical significance of cryoglobulins in primary SS patients have been performed. The prevalence of cryoglobulinemia in primary SS has ranged from 5 to 61 104, 154, 175-179 , Further characterization of the cryoprecipitates demonstrated a IgMk monoclonal RF in most of the cryoglobulins that presented the SS patients 27, 175, 179 , We have found 179 that the presence of leukocytoclastic cutaneous vasculitis, hypocomplementemia and HCV infection are independently associated with the presence of cryoglobulins in the sera of patients with SS.

Autoantibodies Against Oncoproteins

Proteins encoded by oncogenes and tumor suppressor genes are involved in the control of cell growth and differentiation and, if inappropriately expressed or mutated, in the genesis of tumors. Recently, AAb against oncoproteins and the tumor suppressor p53 have been reported in patients with malignant tumors. Such immune responses may be of special interest in the early diagnosis and therapy of cancer. There are a growing number of reports regarding p53 AAb, but only a few data about autoimmunity against oncogene products in tumor patients (summarized in Table 2) are available to date 7, 16-23 . AAb to the HER-

Summary And Perspectives

CENP-F is a novel proliferation-associated and cell cycle-regulated nuclear protein whose unique subcellular distribution is indicative of an important role in mitosis. The observation that CENP-F is the target of a vigorous IgG autoantibody response in some cancer patients points to this protein as a potential cancer-associated autoantigen. It should be cautioned, however, that since autoantibodies to CENP-F appear to be rare in unselected cancer populations, one can not rule out the possibility that autoimmunity to this protein might be associated with yet to be identified clinical- or therapy-associated conditions shared by CENP-F antibody-positive patients. Multicenter studies on the clinical associations of anti-CENP-F autoantibodies, involving a significant number of CENP-F antibody-positive patients, will be essential to fully understand the significance of the high frequency of malignancy currently observed in patients producing these antibodies. Assessment of the expression,...

Lymphoid Malignancies

Complications With Autoimmunity 45 than in the normal controls. Full-blown autoimmune diseases, such as multiple sclerosis, Grave's disease, RA, SLE and pernicious anemia have also been recorded in the family members of these patients, again suggesting that a common genetic factors predispose to B-cell proliferation and antiself reactivity. Conversely, levels of serum IgG, IgM and IgA have been reported to be abnormally high in 25,17 and 50 of RA patients and 10, 23 and 8 of their relatives 4. CD5+B CELLS CROSSROADS OF LYMPHOID MALIGNANCY AND AUTOIMMUNITY CD5-positive B lymphocytes represent such a unique physiological subset that they act as the source of natural autoantibodies, are involved in setting up the idiotypic network as well as the repertoire of the immune system, and in addition play some role in antigen presentation and tolerance induction 47 . These cells are located at the crossroads of systemic diseases and B-cell lymphoproliferative disorders. Thus, higher...

Monoclonal Gammopathies

In patients with MGUS, myeloma or Waldenstrom's macroglobulinaemia, the monoclonal protein may demonstrate unusual specificities e.g., antistreptolysin, antinuclear, dsDNA, apolipoprotein or even anticardiolipin activity 94 , Up to 10 of MGUS sera demonstrate autoantibody activity without autoimmune disease. aPL in patients with MGUS were studied by Stern et al. 95 in 1994. In MGUS sera it was found that they manifested a significantly higher (p < 0.01) incidence of aPL than did normal controls.

The Autoreactive Repertoire Is An Important Component Of The Normal Bcell Repertoire

In 1956, Witebsky and Rose 9 induced for the first time, an experimental autoimmune disease mediated by autoantibodies autoimmune thyroiditis. They succeeded in inducing the disease by injecting thyroglob-ulin in the presence of Freund's adjuvant. Since they were able to produce autoantibodies, the precursor B cells producing these should exist. More recently, considerable data have accumulated raising doubts concerning the clonal deletion theory as an unique explanation for tolerance since (1) autoimmune diseases can be induced by injecting organ extracts 9 (2) numerous autoantibodies have been demonstrated under normal conditions 10-12 and (3) autoantibodies have been induced from normal B lymphocytes upon mitogenic stimulation 13, 14 , Thus, we have evolved from Ehrlich and Morgen-roth's 3,4 horror autotoxicus notion, to Burnet and Fenner's 7 forbidden clones hypothesis, to now reach the view that autoimmunity is a normal physiological phenomenon. But, how can we reconcile the...

Nonhodgkin Lymphoma Eatl Enteropathyassociated Tcell Lymphoma

Coeliac patients have a higher incidence of non-Hodgkin's lymphoma than that of the general population 7, 34-39 , Malignancy develops in 8-13 of patients. EATL is slightly more frequent in males and has its peak in the sixth decade of life. An interesting recent finding shows that the incidence of lymphoma in CD diagnosed in elderly patients (over 60 years) was much higher (23 ) than that in younger population (8 ). Moreover, other autoimmune diseases, dermatitis herpetiformis and autoimmune thyroiditis, were common in this group of patients 10 . The relationship between EATL and CD is underlined by the finding of the CD associated DQA1 0501, DQB1 0201 phenotype in EATL patients.

Hcv Infection And Malignancy

Silvestri et al. 108 found a striking high prevalence of HCV genotype 2ac among patients with B cell NHL and suggested that this genotype might be involved in the pathogenesis of lymphoproliferative and autoimmune disorders. Recent studies revealed a link between HCV infection and NHLs outside the setting of cryoglobulinemia. A high frequency of HCV-infected patients without cryoglobulinemia have been found to have clonal immunoglobulin gene rearrangements in their peripheral blood 119 . De Vita et al. 120 recently reported detailed information on 35 consecutive patients with overt B cell NHL of recent onset and HCV infection. Control groups included 122 consecutive HCV negative patients with B cell NHL and 464 consecutive histopathologic cases of B-cell NHL referred to the same center, as well as 127 consecutive patients with HCV infection and without lymphoma referred to a different center in the same geographical area. B-cell NHLs in HCV infected patients frequently presented at...

Functional Significance Of

OVEREXPRESSION OF ERGB FLI1 GENE IN AUTOIMMUNE DISEASE Lymphocytes are important components and regulators of immune response. We and have shown that the ETS family of proteins are involved in lymphoid cell development, differentiation, maturation and activation and therefore, they are important regulators of lymphoid gene expression. Inappropriate expression of ETS family of genes may have a detrimental effect on lymphoid cell differentiation, activation and function. T cells in autoimmune diseases are in activated state because they have been shown to express In normal T cells, both ETS1 and ERGB genes are expressed at high levels in quiescent state and their expression level decreases to low levels after activation. ETS2 gene expression is induced only after T-cell activation. High expression of ETS2 genes in SLE patients with active disease could thus be contributed by the activated lymphocytes. High levels of ERGB FLI1 expression observed in lymphoid cells from autoimmune...

The Influence Of Cigarette Smoke On The Effectors Of The Immune System

Ulates the proliferation of peripheral T lymphocytes in murine models and in humans 24 . TGP (in contrast to the classical T-cell mitogens PHA and con-A that provoke significant proliferation of the T cells) activates only approximately 3 of the T cells and therefore exerts an antigenic rather than a mitogenic effect 24 , These effects of TGP, an inherent component of cigarette smoke may aid in understanding the link to autoimmunity which will later be explained.

The Role Of Mhc Class Ii Molecules In Antigen Presentation

Presentation of antigens to TCRs requires complexing of antigenic peptide fragments derived from processed antigen with either MHC class I or class II molecules 21 . Class I molecules are loaded in the endoplasmic reticulum with peptides that are usually derived from antigens synthesized within the cells and processed by the proteozome in the cytosol 22 . Exogenous fragments, processed by professional antigen presenting cells (APCs) arrive to the endozome and interact with MHC class II molecules 23, 24 , Nascent MHC class II molecules in the endoplastic reticulum are protected from binding to peptides due to their association with the invariant chain (li) 25 . Following fusion of MHC class II-containing vesicles to endozome, the Ii chains are actively removed with the aid of the non-classical HLA-DM 26 , and MHC class II molecules can then associate with degraded antigenic peptides 27 . It has been suggested that Ii provide a mechanism, which prevents MHC class II molecules from...

TCell Signaling Abnormalities in Human Systemic Lupus Erythematosus

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

Clinical Trials With Modified Dendritic Cells

Tolerance as well where they are involved in the induction of anergy or deletion of mature T cells in lymphoid organs. Kurts et al. 98, 99 showed, that MHC class I-restricted cross-presentation of exogenous self-antigens by bone marrow-derived APC can induce tolerance by peripheral deletion of autoreactive CTL through CD95-signalling. There is also evidence that cross-presentation, a mechanism describing MHC class I-restricted presentation of exogenous antigens, is involved in CD8+ T cell depletion 100 . This means that 'professional' APC may induce au-totolerance by presenting self-proteins, derived from the normal turn-over of somatic cells, in a MHC class I-restricted manner to T cells. In animal models, Clare-Salzler et al. 101 observed a significant protection from diabetes when DC isolated from pancreatic lymph nodes of nonobese diabetic (NOD) mice were transferred into pre-diabetic NOD mice. A further illustration of the ability of DC to prevent the development of autoimmunity...

Ivig In Cancer Treatment

Autoimmunity and malignancy co-exist frequently, and share etiological and pathological mechanisms. Since the two diseases are similarly treated, we studied the efficacy of i.v. with melanoma or sarcoma cells induced a statistically significant inhibition or metastatic lung foci and prolongation of survival time. Similar results were seen with SCID mice inoculated with SK-28 human melanoma cells. In a different model, melanoma was induced in the foot pad, followed by

Selection Of Target Antigens For Antitumor Vaccination

T cells reactive with particular tumor antigens would bear great relevance to the in vivo immunogenic-ity of such antigen. A second criterion concerns the prevalence and heterogeneity of antigen expression by tumor cells, since identifying target antigens that are expressed by a majority of cancers from different individuals would assist in developing antigen-based therapeutic strategies that could be broadly applied. Moreover, the uniformity of antigen expression in the tumor cell population could also influence the efficacy of the vaccine as the outgrowth of tumor antigen loss variants has been observed in both animal models and clinical studies following initially successful immunomodulatory therapy 68-71 , In situ immunophenotyping studies of tumor sections from melanoma patients have demonstrated homogenous staining of MART-l MelanA but heterogenous staining, with as few as 20 of cells staining positive, for gplOO and gp75 72, 73 , These results suggest that antigen-based...

Autoimmune Manifestations Following autoBMT

Show any measurable GVL effects 43 , However, in principle, antitumor responses may be elicited even against weakly immunogenic tumor cells, similarly to antiself-reactivity in autoimmune diseases. Since GVHD correlates with GVL following alloBMT, it remains to be seen whether the untoward autoimmune-like GVHD observed after autologous or syngeneic BMT can be translated to beneficial GVL effects. In this regards, our data suggest that it is not the GVHD per se that induces GVL, but rather donor T cells that can recognize residual tumor cells in the host as alloantigens can be effective in inducing GVL.

Alloimmune Or Autoimmunelike Manifestations Following alloBMT

Several new approaches are currently in the pipelines for down-regulation of donor antihost responses by selective elimination of effector T-cell subsets, regulation of antihost reactivity by veto of alloreactive T cells or using genetically engineered T cells that harbor a suicide gene that can be used to limit their life span 44 , In addition, we have recently developed a new regimen for alloBMT based on the use of nonmyeloablative stem-cell transplantation (NST) 29 . Such a modality, which focuses on elimination of host lymphocytes to prevent rejection, rather on myeloablative therapy, may provide a safer protocol for patients with autoimmune diseases that may be candidates for alloBMT.

Autoimmune Manifestations Following alloBMT

The pathogenesis of autoimmune manifestations post-alloBMT may be related to transfer of abnormal Band T-cell clones from the donor or to dysregulation of the newly developing immune system of donor origin in the host across minor or major histoin-compatibility barriers, frequently further perturbed by immunosuppressive agents administered to prevent or treat GVHD. The general immune imbalance seen during the first period following alloBMT, which may last several years, may contribute to an acceleration of autoimmune manifestation including organ specific autoimmune dysfunction. In addition cytomegalovirus (CMV) or possible other viral infections have been suggested to be possible important etiologies that may be associated with certain autoimmune phenomena post-alloBMT 45 . CMV disease is associated with various autoimmune manifestations including autoimmune hemolytic anemia, autoimmune granulocytopenia and the formation of autoantibodies 46 . It was found that CMV induces a...

Conclusions And Future Directions

The use of alloBMT and autoBMT for the treatment of otherwise resistant hematologic malignancies and and certain chemotherapy sensitive solid tumors, respectively, is well established. Our recent observations suggest that GVL and possibly GVT effects may be amplified with alloCT mediated by donor alloreactive lymphocytes which could be further activated with rIL-2. Furthermore, we suggest that equally effective GVL and possibly GVT effects may be induced with a safer alloBMT procedure following nonmye-loablative conditioning, which could open new and safer therapeutic options for patients in need of alloBMT at all age groups. Furthermore, we suggest that many of the benefits that can be accomplished with autoBMT and alloBMT may be applicable for patients with life-threatening autoimmune disorders. Experiments carried out in animal models of human autoimmune disorders suggests that disease manifestations and immunological processes leading to the development of autoimmunity may be...

Combination Chemotherapy

There are many possible reasons for the development of autoimmune disease following chemotherapy, not least of which is the remote possibility that the lymphoma was a disease manifestation that preceded the appearance of the CTD. The coincidental appearance of the two conditions also cannot be excluded. However, there are more cogent possible explanations. In recent years there has been a change in chemotherapy regimens for malignancies with ever more toxic combinations in the search for effective remission inducing regimens. Taken together, the description of 46 patients with postchemotherapy rheumatism and the development of defined CTD following chemotherapy for lymphoma or leukaemia suggests that combination chemotherapy may capable of disturbing the immune system profoundly enough to alter the normal balance of self-tolerance, possibly by altering thymic function, leading to autoimmunity.

Genetic Polymorphisms That Contribute to Altered Cytokine Production

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

Assays of Cytokine Expression

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

And Autoimmune Thyroiditis

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

Diabetes Prevention in the NOD Mouse

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

Peptide Vaccine Induced Anaphylaxis in the NOD Mouse

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

Conclusions The Selection of Murine Lupus Models

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

Anti Islet Autoantibody Assays

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

Role Of Ets In Cancer And Disease

New Zealand Black (NZB) New Zealand White (NZW) provides a good model system because F1 hybrids of NZB with NZW develop autoimmune disease having characteristic phenotypes similar to that seen in human SLE. We studied ETS1, ETS2, ERGB FLI 1 gene expression in thymocytes, splenic B and T cells from NZW, FI hybrids (NZB xNZW), as well as

Molecular Analyses for BCell Clonality

Few studies have focused on the T-cell repertoire of patients with SS in the course of B-cell lymphopro-liferation 190-192 , T-cell expansion may be in turn sustained by chronic antigenic triggering in the local microenvironment, as demonstrated in the model of H. py ori-associated B-cell lymphoproliferation in the stomach 78, 193 . Thus, the study of T-cell clonal expansion is of great importance in investigating the stages of B-cell lymphoproliferation (fully benign, pseudolymphoma or definitely malignant) which may be still T-cell- and antigen-dependent. Two different, although complementary, approaches are currently employed for the assessment of TCR expression, i.e., reverse transcriptase (RT)-PCR-based molecular analyses and cytofluorometry and or immunohisto-chemistry studies using monoclonal antibodies 194, 195 . Concerning T-cell expansion in autoimmune diseases predisposing to B-cell malignancies, conflicting results have been obtained in RA 196-198 and few studies have...

Suggestions On Strategies To Break Dominant Tolerance To Cancer Cells

How can we then achieve effective anti-tumor immunity, while avoiding the risk of emergence of autoimmune diseases The experimental protocols, which make normal animals suffer from autoimmune disease, seem to give us a clue to approach the problem. It has been shown that treatment of normal adult animals with cyclophosphamide (Cy) or sublethal y-irradiation, if coupled with thymectomy, results in development of various organ-specific autoimmune disease, whereas each treatment alone does not induce any disease 28, 29 , It has been suggested that this drastic effect of Cy and y-irradiation is due to elimination of regulatory T cell pool from the periphery. Obviously, if the animals are not thymectomized, the pool is eventually restored by thymic emigrants and consequently the animals are free of any autoimmune disease 1,2, 28, 29 . In addition, it is also shown that repetitive infusion of anti-CD25 monoclonal antibody to normal mice lead to emergence of organ-specific autoimmune disease...

P53 Autoantibodies and Cancer Speciiicity Diagnosis and Monitoring

The presence of p53AAb is generally indicative of malignancy. Nevertheless, rare exceptions become known. In autoimmune diseases (AID), p53AAb can be detected in patients with systemic lupus erythematosus (SLE) 57, 58 , Sjogren's syndrome and systemic sclerosis (scleroderma) 57 , Additionally, we found seropositive individuals among patients with Graves' disease, Wegener's granulomatosis, and other vasculitis 58 , The role of p53AAb in AID is yet unknown. Furthermore, is there an association between p53AAb generation and p53 protein accumulation in patients with AID Recently, extensive apoptosis was demonstrated in most of the epidermis of cutaneous lupus erythematosus lesional skin showed a marked increase in p53 protein-positive keratinocytes 59 . Skin samples from 44 patients with scleroderma, however, revealed no abnormal expression of p53 59 although Kovacs et al. 57 found a p53AAb-positive patient.

The Use Of alloBmt For The Treatment Of Cancer

The marked therapeutic benefits of alloCT induced by DLI always carry the risk of GVHD, with an incidence and severity that are unpredictable. As such, GVHD is in fact an iatrogenic autoimmune disease which may attack in principle any organ or tissue. New approaches to limit the life span of donor-derived T cells in case of uncontrolled GVHD are currently under development. The most promising modality for controlling GVHD, and its incidence after discontinuation of anti-GVHD prophylaxis, is the use of donor T cells transduced with the herpes simplex virus thymidine kinase gene 81 . Genetically modified T cells of donor origin still retain their GVL capacity. Hence, in the event of uncontrolled GVHD these antitumor effector cells can be successfully eliminated by administration of conventional doses of ganciclovir 81 . The feasibility to eliminate safely and consistently GVHD induced intentionally by donor lymphocytes to enhance GVL effects may pave the way for using DLI to treat...

Lupus Prone Mice With Defined Mutations

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

Detection Of A Malignant Disease

From all the reports on p53 autoantibodies it seems to come up that p53 autoantibodies are in general associated with a malignant disease, whereas, healthy blood donors are rarely positive for p53 autoantibodies. Two individuals were found to express p53 autoantibodies although no tumor was detected. Both individuals were heavy smokers and diagnosed for chronic cough or a benign obstructive tracheal tumor. Both developed lung cancer within 5 or 15 months, respectively 27 . In a study of patients with prostate carcinoma, a healthy control patient was also positive for p53 autoantibodies 28 , Later, it turned out that this patient died from an undetected lung cancer. Thus, these studies might indicate that p53 autoantibodies may be early markers for malignancy and that this type of analysis allows for the detection of an unknown cancerous malignancies. However, there are also reports that p53 autoantibodies were found in patients with nontumorous diseases such as autoimmune diseases....

Tolerance

The fundamental study of any autoimmune disease is initiated by attempts to characterize and define the autoantigen towards which the autoantibody is directed. Research in this field is headed by immunohis-tochemical studies of recombinant proteins obtained by screening expression libraries with autoantibodies. Examples of autoantigens detected by this method consist of myelin basic protein (MBP) in mice and acetylcholine receptors in patients with myasthenia gravis.

Damage

* Binding of the antibody to the cell surface receptor may reduce the expression of the receptors. This process of effective down-regulation of receptors results from their realignment causing their disappearance from the cell surface. The classic example of this phenomena is impairment of neuromuscular function in myasthenia gravis due to the presence of anti-acetyl choline receptors.

Solid Tumors

The association between thymoma and autoimmunity is of a great interest 53 , SLE has been associated with thymoma. SLE may develop concurrently or subsequently to thymoma. It has been reported that more than 30 of patients with thymoma develop autoimmune diseases including, myasthenia gravis, pure red cell aplasis, pemphigus and SLE. Thymectomy may result in regression of the autoimmune diseases 53 in a large number of the patients.

Pathogenesis

PSS should not be considered a paraneoplastic syndrome unlike other autoimmune diseases, such as some myositis. However, there is a close relationship between the occurrence of some malignancies and scleroderma. Indeed, lung cancers seem to be associated with lung fibrosis more often than with scleroderma. Although alveolar cell carcinoma is the most frequent cancer complicating lung fibrosis in PSS patients, other lung carcinomas, such as squamous cell carcinoma, have been observed 8 . A hypothesis possibly explaining the occurrence of alveolar cell carcinoma could be the mitogenic effect of growth factors implicated in the genesis of lung fibrosis 17 . The changes in the extracellular matrix could also affect the behavior of normal cells 18 . Abu-Shakra et al. 19 hypothesized that an altered immune response could facilitate the occurrence of malignancies. The patient's age at the time that the cancer developed in PSS could also be a factor, since patients over 50 years old at the...

Causality

In four pathological entities (i) RA in association with lymphoproliferative neoplasm (ii) SS in association with lymphoproliferative neoplasm (iii) dermato-myositis in association with solid tumors and (iv) systemic sclerosis in association with lung cancer. For the above four autoimmune disease-cancer relationships the main Bradford-Hill's postulates are satisfied strength, consistency and temporality of association, as well as plausibility, coherence and analogy. For other associations as that of SLE with solid tumor or with lymphoproliferative disorders, there is not enough evidence to establish causality. On the other hand, the absence of specificity, biological gradient, and experiment tells us that occurrence of cancer is not only conditioned by presence of the rheumatic disease. Also, there is no dose-response like gradient (e.g., more rheumatic disease vs. less rheumatic disease). Experiment on this could only be conducted in animal models.

Conclusion

There are many reports on the association between autoimmune diseases and neoplasia. Autoimmune phenomena and autoantibodies have been detected in patients with malignancies. Conversely, many autoimmune conditions are associated with increased incidence of malignant tumors. The association between autoimmune diseases and malignant tumors can be due to a common pathogenic factor inducing the diseases, due to triggering of malignant transformation by the autoimmune process or due to the treatment. Several lines of evidence demonstrate that both genetic factors and nongenetic factors associated with the autoimmune process contribute to the increased frequency of malignancies. This association supports the notion that the immune system is of prime importance in the natural defense against malignancies, and we believe that future research will lead to increased utilization of immunotherapy in malignant tumors.

Concluding Remarks

Autoimmune conditions are the result of a mosaic interplay of factors 1 , As such, it is suggested that the appearance of trigger mechanisms in individuals with predisposing immunologic, genetic and hormonal backgrounds may lead to the development of an overt autoimmune disease 1 . This chapter conveys the idea that smoking may be causally associated with the initiation of autoimmunity and its signatures (i.e., the respective autoantibodies). The mechanisms by which cigarette smoking contributes to autoimmunity are unresolved. It is, however, tempting to implicate other well characterized mechanisms such as altered self to the above model 55 . Thus, a physical damage induced by smoke on certain tissues or native substances may no longer be recognized as self and lead to the production of autoantibodies and subsequently, a full blown autoimmune reaction. A demonstrative example to this theory is the Goodpasture's syndrome where exposure of a cryptic epitope (e.g., NCI), probably by...

Animal Studies

These results prompted in part the studies and research towards a similar treatment modality in autoimmune diseases. Thus successful in vitro and in vivo manipulations of autoantibody production by anti-idiotypic (anti-Id) antibodies were described in several animal models of autoimmunity 12-19 .

Toxins

Another method by which anti-idiotypes can be employed in the treatment of autoimmune diseases is as specific carriers of toxins. Sasaki et al. 30 have developed a new way of using anti-Id antibodies by conjugating them with cytotoxic agents, NCS (Neo-carzinostatin). The conjugates killed Id-positive EBV-transformed-cell clones, resulting in the suppression of anti-DNA production. Later on, the same group demonstrated that this method is capable of manipulating the human anti-DNA system through the specific elimination of anti-DNA Id-positive cells from lymphocytes in the peripheral blood 31 . improvement in the survival rate of female NZBAV F1 mice. It also caused a retardation of development of lupus nephritis and decreased the numbers of anti-DNA reproducing cells. The suppression of anti-DNA antibody synthesis was specific and Id-mediated. These results indicate that the use of a limited number of anti-Id antibodies in combination with a cytotoxic agent may be applicable...

Immunomodulation Of

EXPERIMENTAL ANIMAL MODELS OF AUTOIMMUNITY WITH IDIOTYPE-SPECIFIC T CELLS AND ANTIBODIES THAT BIND TO T-CELL RECEPTOR (TCR) Similarly decreased numbers and activity of Ts cells in humans with SLE and other autoimmune diseases have regularly been reported. If the production of autoantibodies in SLE and other autoimmune states is related to down-regulation of Ts, the reconstitution of Ts cell numbers and activity, and especially the Ts specific to the harmful autoantibody in question, may lead to amelioration of disease manifestations. In fact, several studies have suggested this very possibility 70-72 ,

Ets2 208

Experimental allergic encephalomyelitis (EAE) 338, 339 Experimental autoimmune encephalomyelitis 366 Experimental autoimmune myasthenia gravis (EAMG) 370 Experimental autoimmune thyroiditis 373 Experimental autoimmune uveoretinitis (EAU) 370 Extramammary Paget's disease 125

Nyeso1

Response causing paraneoplastic syndromes affecting the nervous system. AAb against ONA may detect neuronal nuclear antigens ( antineuronal nuclear antibodies ANNA), cytoplasmic antigens of Purkinje cells ( anti-Purkinje cell antibodies APCA), synaptic or retinal proteins (see Table 6). In most cases of paraneoplastic syndromes the detection of specific AAb can strongly suggest the presence of a tumor. Anti-Hu positive patients with paraneoplastic encephelomyelopathies (PEM) or subacute sensory neuronopathy (SSN) most often have small cell lung cancer (SCLC) as underlying disease. Similarly, anti-Yo positive patients with paraneoplastic cerebellar degeneration (PCD) often harbor gynaecological neoplasms. Furthermore, Hu, Yo and Ri AAb can be found in lower frequency and at lower titers in SCLC or ovarian cancer patients without neurological diseases 67, 68 . Neurological syndromes associated with AAb to ion channel proteins have a lower frequency of tumors as the syndromes associated...

CD4CD25 Regulatory T Cell Selection in the Thymus

Early studies showing that CD4+CD25+ T cells possess important regulatory activities pointed to thymic processes in their formation. In these studies, thymectomy of 3-day-old neonatal mice (d3Tx) led to the development of organ-specific autoimmune diseases unless mice were given unfractionated CD4+ T cells, or just the CD4+CD25+ subset of T cells, within 2 weeks of thymectomy (Shevach 2000). Sakaguchi's group went on to show that approximately 3 -5 of CD4SP thymocytes also express CD25, and that these CD4SP CD25+ thymocytes are as suppressive as peripheral CD4+CD25+ regulatory T cells in in vitro suppression assays (Itoh et al. 1999). Furthermore, 1 week Indeed, early clues that regulatory T cells were important in preventing autoimmune disease came in studies in which mice expressing an encepha-latogenic CD4+ TCR as a transgene were protected against the development of autoimmune encephalitis when maintained on a background that permitted endogenous TCR gene rearrangement (termed T...

Dass S Vinay and Byoung S Kwon

CD137 and CD137L belong to the tumor necrosis factor (TNF) superfamily, a group of cysteine-rich cell surface molecules. With a few exceptions, both CD137 and its ligand, CD137L, are activation induced. CD137 activates CD8+ T cells more strongly than CD4+ T cells, and is a potent inducer of IFN-y. Stimulation through CD137L also relays activation signals to B cells and monocytes. These signals elicit activation of NF- kB via the TRAF-NIK pathway and lead to the induction of a plethora of immune modulators that accentuate the ongoing immune reaction. CD137 and CD137L-deficient mice develop normally, have normal numbers of T and B cells and only demonstrate modest immune malfunction. However, in vivo administration of agonistic anti-CD137 mAb protects strongly against a variety of autoimmune and non-autoimmune diseases. The basis of this protection is unclear however, it seems to involve an indoleamine dioxygenase (IDO)-dependent process in which pathogenic T cells are killed suppressed...

Prognostic Indicators

A long list of prognostic indicators were reviewed by Molica in 2001 (64) and Montserrat and Rozman in 1988 (53). Some of these indicators are clinical stage, lymphocyte count (ALC), lymphocyte morphology, size, immunophenotype, molecular cytogenetics, lymphocyte doubling time, bone marrow histology, response to chemotherapy, autoimmune disease, other medical problems, and a number of serum factors. In addition to cytogenetics, CD38 expression and Ig gene sequence have emerged as potential prognostic indicators that will be clinically useful. Immunophenotyping has for the most part played a role in both establishing B-cell monoclonality and contributing significantly to the differential diagnosis of CLL. Zwiebel and Cheson in 1998 (65) noted that the usefulness of many prognostic factors remains uncertain unless they are evaluated in prospective randomized studies.

Techniques Of Discovery

Understanding of the molecular basis of immune responses has allowed the definition of mechanisms by which cellular function is altered by a legion of local hormones or autacoids in, for example, infections, cancer, autoimmune diseases, organ transplant rejection. These processes present targets for therapeutic intervention. Hence the rise of immunopharmacology

The Antigen Specificity of Naturally Arising TR

The prevailing hypothesis regarding the TCR specificity of naturally arising regulatory T cells is that they recognize self-antigen, and that this interaction is important for TR development and function to suppress autoimmunity. This model was originally prompted by two studies in the 1990s that indirectly suggested that naturally arising TR recognize tissue-specific self-antigens. Initial studies by Taguchi and colleagues suggested that the functional maintenance of CD4+ Tcellscapableofprotectionagainst prostatitisoroophoritisrequired Where does this TCR interaction with antigen occur Early reports suggested that CD25+ T cells originate in the thymus, as animals thymectomized at day 3 of life develop spontaneous autoimmunity which could be rescued by the adoptive transfer of normal CD25+ regulatory T cells (Sakaguchi et al. 1995). Thus, the development of autoreactive cells relative to TR is favored under the conditions of early thymectomy, and these observations suggested that the...

Annexinopathies

Although a mutation in an annexin has never been categorically proven to be the cause of a disease state, they have been implicated in pathologies as diverse as autoimmunity, infection, heart disease, diabetes and cancer. 'Annexinopathies' were first described by Jacob H. Rand to describe the pathological sequelae in two disease states, the overexpression of annexin 2 in a patients with a haemorrhagic form of acute promyelocytic leukaemia, and the under-expression of annexin 5 on placental trophoblasts in the antiphospholipid syndrome. In this chapter we will outline some of the more recent observations in regard to these conditions, and describe the involvement of annexins in some other major causes of human morbidity

The Paradox of Foreign Antigen Recognition by Regulatory T Cells

The above description of self-reactivity within the naturally arising regulatory T cell population fits with the original identification of regulatory T cells as a critical mechanism for the prevention of autoimmunity. However, it has become increasingly evident that TR play an important role in the regulation ofvirtually all immune responses. While initial studies focused on defining the progression of a variety of autoimmune responses in the absence or presence

Tr Appear to Have a Diverse TCR Repertoire That Is Different from the CD25 TCR Repertoire

This diversity may explain the apparent ability of the naturally arising regulatory T cell population to participate in regulation of immune responses to pathogens such as Leishmania. Although TR were shown to inhibit a sterilizing immune response in the Leishmania infection model, thereby allowing for the maintenance of functional memory T cells, these and other analogous results provide insufficient support for the idea that the naturally arising Tr population evolved to control infectious immunity. From a general perspective, the potential benefits of preserving a chronic low level infection to maintain functional memory T cells over a sterilizing immune response to pathogens are not immediately obvious. Furthermore, it is possible that TR involvement in responses to pathogens may be happenstance due to the diversity of the regulatory T cell receptor repertoire and the shared features of inflammation associated with both chronic infection and autoimmunity.

What Is the Tissue Distribution of TR Target Self Antigens

We already discussed earlier studies suggesting that regulatory T cells need to specifically recognize tissue-derived self-antigens for their survival and or functional activity in the periphery (Seddon and Mason 1999 Taguchi et al. 1994) and subsequent work supporting tissue specificity of TR-mediated protection from autoimmunity (Green et al. 2002 Walker et al. 2003a). However, the recognition of tissue-specific antigens by some TR does not exclude the recognition of ubiquitously presented self-antigens by others. Such recognition is predicted by TCR transgenic models in which regulatory T cell development is directed by a transgene driving expression of the cognate antigen in a variety of tissues (Cozzo et al. 2003). Furthermore, the development of regulatory T cells in H-2M-deficient mice, which express primarily a single peptide-MHC class II complex, CLIP I-Ab, or in mice expressing Ea peptide covalently bound to I-Ab molecules, strongly argues for the existence of Tr recognizing...

Evolutionary Significance and a Possible Handle on Treg Regulation

Caramalho and colleagues have reported the surprising finding that murine Treg express transcripts for seven of nine Toll-like receptors they have studied, and that four of these are not expressed by conventional CD4 T cells, either before or after activation (Caramalho et al. 2003). Furthermore, they have shown that Treg actually respond to pro-inflammatory agents and inflammatory conditions that are known to involve this set of innate receptors (Caramalho et al., submitted). The expression of TLRs on T cells has been extended to humans (Komai-Koma et al. 2004) and, together with the findings of Treg amplification by conventional T cell responses (Almeida et al. 2002 Caramalho et al., submitted), shed new light on the operation of Treg and the general physiological regulation of this cell subset. In addition, these findings could contain the solution for current controversies on Treg markers, on distinct cellular and molecular mechanisms of regulation, eventually, on the range of...

Apoptosis and Cell Death

Apoptosis (programmed cell death) is characterised morphologically by increased cytoplasmic granularity, cell shrinkage and nuclear condensation. The most prominent feature of apoptosis is the activation of an endogenous endonuclease that degrades nuclear DNA at linker sections to fragments. It has been suggested that a decrease in the rate of apoptosis plays a role in the pathogene-sis and age-related events such as tumorigenesis. Energy restriction increases apoptosis, which may be the mechanism for its effect in suppressing tumours, ameliorating autoimmune diseases, and prolonging life span. Programmed cell death is an endpoint for many cellular events, but it has not been examined in nutrition studies 48 .

Development Of Lmb2 For The Treatment Of Cd25 Malignancies

Containing all three of them, but with low affinity (Kd 10-8 M) to CD25 alone, also called p55 or Tac.54 In contrast, the mAb anti-Tac binds to CD25 with high affinity (Kd 10 10 M).55 CD25 is overexpressed in a variety of hematologic malignancies, including adult T-cell leukemia (ATL) and HCL, other T- and B-cell leukemias and lymphomas, and Hodgkin's disease.56-58 CD25 usually far outnumbers other subunits of the IL-2R on cells, and in some tumors is the only IL-2R subunit present. To construct an anti-CD25 recombinant immunotoxin, the variable heavy domain of anti-Tac (VH) was fused to the variable light domain via a 15-amino-acid linker to the variable light domain (VL), which in turn was fused to PE40.59 Both anti-Tac(Fv)-PE40 and the slightly shorter derivative anti-Tac(Fv)-PE38 (Figure 33.1) bound well to CD25, and were very cytotoxic to CD25+ cell lines and activated human T cells, which mediate autoimmune disease.5960 LMB-2 induced complete regression of CD25+ human xenografts...

Innate Antitumor Responses

While these innate responses may contribute to tumor suppression, their aberrant activation may also prove deleterious when normal tissues are perturbed, as during autoimmunity or chronic inflammation. In these settings, the sustained expression of NKG2D ligands leads to downregulation of NKG2D surface expression through increased endocytosis and the consequent suppression of protective responses (Oppenheim et al, 2005). As a result, there may be an onset of a kind of low-level chronic inflammation process, termed smoldering inflammation, which preserves certain characteristics that actually promote tumor progression. Thus, depending on its context, expression of stress ligands may either trigger cytotoxic antitumor reactions or contribute to conditions that can facilitate immune escape.