Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis

Molecular mimicry of viral antigens with self determinants has been proposed as one of the pathogenic mechanisms in autoimmune disease. Evidence of viral mimicry in animal models of autoimmunity is accumulating. Murine adenovirus, Semliki forest virus, lactate dehydrogenase-elevating virus, herpes simplex virus type-1, hepatitis B virus, encephalomyocarditis virus, Theiler's murine encephalomyelitis virus, Coxsackievirus and cytomegalovirus have been found to mimic physiologically important host proteins. However, epitope homology of a viral and self determinant is not in itself strong evidence for mimicry as a pathogenic mechanism. The mimicking determinant must also be capable of inducing disease in the absence of replicative virus. Animal models provide evaluation of the viral trigger, and development and therapy for autoimmune diseases. Identification of host proteins that can induce disease together with the knowledge of immune system dysregulation, genetic association and environmental factors may lead to improved immunotherapeutic strategies for human autoimmune diseases.     

Kinetics of the appearance of HLA-DR antigens on human alloactivated T lymphocytes and the demonstration of new antigenic determinants

By studying serologically the appearance of HLA-DR determinants on T lymphocytes activated by a mixed lymphocyte culture, we have been able to demonstrate the existence of a new class of antigenic determinants distinct from classical HLA-DR antigens. Indeed, some monospecific anti-DR sera were cytotoxic from some alloactivated T cells, though not directed against their HLA-DR specificity. The absorption of these anti-sera on B lymphocytes bearing the HLA-DR antigen against which they were directed, did not remove their reactivity on alloactivated T lymphocytes. The absorption of the same anti-sera on activated T lymphocytes did not affect their anti-DR reactivity. This study shows the existence of new antigenic determinants expressed by T lymphocytes during their activation: alloactivated T lymphocyte antigens (AATL).     

Antigenic correlation between rat brain synaptic vesicles and rat bone marrow B lymphocytes.

Rabbit anti-rat brain synaptic vesicle serum reacted with thymocytes and B lymphocytes in cytotoxicity and immunofluorescence assays. Quantitative absorption analysis revealed that this antiserum contained antibodies specific for antigenic determinants on the surface membrane of a subpopulation of rat bone marrow B lymphocytes.     

Antigenic correlation between rat brain synaptic vesicles and rat bone marrow B lymphocytes

Summary Rabbit anti-rat brain synaptic vesicle serum reacted with thymocytes and B lymphocytes in cytotoxicity and immunofluorescence assays. Quantitative absorption analysis revealed that this antiserum contained antibodies specific for antigenic determinants on the surface membrane of a subpopulation of rat bone marrow B lymphocytes.This work was supported by the Republic of Serbia Research Fund, Belgrade.     

Molecular mimicry in neurological disease: what is the evidence?

Autoimmune diseases are a leading cause of disability and are increasing in incidence in industrialized countries. How people develop autoimmune diseases is not completely understood, but is related to an interaction between genetic background, environmental agents, autoantigens and the immune response. Molecular mimicry continues to be an important hypothesis that explains how an infection with an environmental agent results in autoimmune disease of the nervous system and other target organs. Although molecular mimicry has yet to be unequivocally proven, in the past several years there has been a sharpening of its definition with better experimental data implicating it as a cause of neurological disease in humans. Received 9 July 2007; received after revision 15 November 2007; accepted 27 November 2007     

Heat shock proteins in immune response to cancer: The Fourth Paradigm

The involvement of heat shock proteins in immune response is categorized into four distinct paradigms. In the First Paradigm, HSP derived from foreign organisms act as classical foreign antigens, and they elicit immune response to the non-conserved HSP epitopes. The Second Paradigm refers to instances where the host responds to self HSP to which there is no central or peripheral tolerance. The Third Paradigm involves molecular mimicry, where cross-reactivity between an HSP and another protein leads to an immune response to the latter under conditions which elicit an immune response to the former, such as infection with a bacterium whose immunodominant antigen is an HSP. The Fourth Paradigm refers to situations where an HSP-antigen complex elicits an effective response to the antigen andnot to the HSP. Thus the HSP acts as a carrier for the antigenic peptide. The role of HSP in recognition by γδ T cells may also fall into this paradigm. In this article, the Fourth Paradigm is considered as a crucial element in the development of vaccines against cancers and infectious diseases, and is analyzed through the prism of the observed association of hsp70 species with antigenic peptides.     

Immunological comparison between albumins of three species of mice (genus Mus).

Three closely related species of short-tailed mice (Mus musculus musculus, M. spretoides and M. spicilegus) were tentatively discriminated using immunological techniques based on albumin cross-reactivity. Different fractionations of crude albumin antisera allowed the recovery of antibody populations specific to the M. m. musculus albumin, whereas antibody population differences do not seem to exist between M. spicilegus and M. spretoides. Moreover, immunoreactivities tested with native and S-carboxymethylated albumins revealed that species-specific antibodies correspond to antigenic determinants depending on the amino acid sequence (sequential determinants). The observed immunological differences are related to species divergence and albumin sequences.     

Studies on the modification of Escherichia coli ribosomal protein L7/L12 by succinic anhydride

Lysine modification by increasing quantities of succinic anhydride in the Escherichia coli ribosomal protein L7/L12 produces loss of its ability in reconstitution of elongation-factor-G-dependent GTP hydrolysis and polyphenylalanine synthesis activities, showing lower antigenicity and loss of antigenic determinants.     

Current cases in which epitope mimicry is considered as a component cause of autoimmune disease: immune-mediated (type 1) diabetes

Autoimmune diseases result from a combination of genetic, immunologic, hormonal, and environmental factors. Infectious agents may induce the breakdown of immunological tolerance and the appearance of autoreactivity. However, the specific relationship between infection and autoimmunity is still unclear. One of the mechanisms responsible could be molecular mimicry between the infectious agent and self. The concept of molecular mimicry is a viable hypothesis in the investigation of the etiology, pathogenesis, treatment, and prevention of autoimmune disorders. Immune-mediated (type 1) diabetes in humans and in non-obese diabetic (NOD) mice is polygenic and characterized by autoimmune destruction of insulin-producing pancreatic beta cells in islets of Langerhans. In NOD mice, a T-helper 1 (Th1)-based autoimmune response arises spontaneously against glutamate decarboxylase (GAD) concurrently with the onset of insulitis. Subsequently. this Th1-type autoreactivity spreads intra- and intermolecularly to other beta cell autoantigens, suggesting that a Th1-type response is responsible for the progression of the disease, whereas Th2 responses when experimentally induced are protective. In humans, a homology between GAD and the P2-C protein of Coxsackie B make a cause-and-effect molecular mimicry an attractive hypothesis. Evidence to support the concept of molecular mimicry in diabetes is reviewed.     

Cellular and molecular aspects of Lyme arthritis

Lyme disease is a multisystem illness initiated upon infection with the spirochete Borrelia burgdorferi. Whereas the majority of patients who develop Lyme arthritis may be successfully treated with antibiotic therapy, about 10% go on to develop arthritis which persists for months to years, despite antibiotic therapy. Development of what we have termed treatment-resistant Lyme arthritis has previously been associated with both the presence of particular major histocompatibility complex class II alleles and immunoreactivity to the spriochetal outer surface protein A (OspA). Recently, we showed that patients with treatment-resistant Lyme arthritis, but not patients with other forms of arthritis, generate synovial fluid T cell responses to an immunodominant epitope of OspA and a highly homologous region of the human-lymphocyte-function-associated antigen-1α _L chain. Identification of a bacterial antigen capable of propagating an autoimmune response against a self-antigen provides a model of molecular mimicry in the pathogenesis of treatment-resistant Lyme arthritis. Received 21 December 1999; received after revision 10 April 2000; accepted 11 April 2000     

Antigenic correlation between rat thymus and superior cervical ganglion.

By using rabbit anti-rat thymocyte and anti-rat superior cervical ganglion sera in cytotoxicity, immunofluorescence and absorption assays, it has been shown that surface membranes of rat thymocytes and cervical ganglion cells (i.e. peripheral nervous tissue cells) contain common antigenic determinants.     

Immunological comparison between albumins of three species of mice (genusMus)

Summary Three closely related species of short-tailed mice (Mus musculus musculus, M. spretoides andM. spicilegus) were tentatively discriminated using immunological techniques based on albumin cross-reactivity. Different fractionations of crude albumin antisera allowed the recovery of antibody populations specific to theM. m. musculus albumin, whereas antibody population differences do not seem to exist betweenM. spicilegus andM. spretoides. Moreover, immunoreactivities tested with native and S-carboxymethylated albumins revealed that species-specific antibodies correspond to antigenic determinants depending on the amino acid sequence (sequential determinants). The observed immunological differences are related to species divergence and albumin sequences.     

Antigenic correlation between rat thymus and superior cervical ganglion

Summary By using rabbit anti-rat thymocyte and anti-rat superior cervical ganglion sera in cytotoxicity, immunofluorescence and absorption assays, it has been shown that surface membranes of rat thymocytes and cervical ganglion cells (i.e. peripheral nervous tissue cells) contain common antigenic determinants.Acknowledgment. This work was supported by grants from the Republic Research Fund of Serbia, Belgrade.     

Animal deception and the content of signals

In cases of animal mimicry, the receiver of the signal learns the truth that he is either dealing with the real thing or with a mimic. Thus, despite being a prototypical example of animal deception, mimicry does not seem to qualify as deception on the traditional definition, since the receiver is not actually misled. We offer a new account of propositional content in sender-receiver games that explains how the receiver is misled (and deceived) by mimicry. We show that previous accounts of deception, and of propositional content, give incorrect results about whether certain signals are deceptive.     

Hemagglutination of neuraminidase-treated human erythrocytes by Leishmania enriettii infected guinea-pig sera.

Sera from guinea-pigs infected with the protozoan parasite Leishmania enriettii showed higher hemagglutination (HA) titres for neuraminidase treated human erythrocytes than those of normal guinea-pig sera. This HA activity was associated mostly with the 19S fraction of the immune serum and could be absorbed out with an antigenic fraction of the parasite membrane. Antigenic determinants involved in this HA reaction consisted of, at least, beta-D-galactosyl or lactosyl residues.     

Demonstration of measles virus antigens in osteoclasts in Paget's disease of bone]

The first results of histo-immunological studies on biopsies in Paget's bone disease strongly favour the presence of antigenic material of viral origin in osteoclasts. Measles virus may play a role in the etiology of Paget's bone disease.     

Presence of the H blood group antigen on a carcinoembryonic antigen (CEA). Enzymatic transformation of H to A and B specificities]

The carcinoembryonic antigen (CEA-M) was purified from a hepatic metastasis obtained from a blood group O patient with a cancer of the rectum. Using 125I-labelled-CEA and blood group antisera, H specificity was found on the CEA-M; the addition of anti-H to anti-CEA does not modify the binding of labelled-CEA-M to its antibodies (86%), this result leads us to conclude that H and CEA determinants are carried by the same molecule. However the low percentage of binding (30% with 1/10 anti-H) suggests that only a few CEA-M molecules do carry the H antigenic determinant. Finally, glycosyltransferases were used to modify the H specificity into blood group A and B specificities.     

Mechanisms underlying celiac disease and its neurologic manifestations

The extra-intestinal manifestations of celiac disease (CD), including ataxia and peripheral neuropathy, are increasingly being recognized as the presenting symptoms of this autoimmune disease. Although there is a greater understanding of the pathogenesis of the intestinal lesions in CD the mechanisms behind the neurologic manifestations of CD have not been elucidated. In this article, the authors review the cellular and molecular mechanisms behind the histopathologic changes in the intestine, discuss the presentation and characteristics of neurologic manifestations of CD, review the data on the mechanisms behind these manifestations, and discuss the diagnosis and treatment of CD. Molecular mimicry and intermolecular help may play a role in the development of neurologic complications.Received 11 March 2004; received after revision 29 October 2004; accepted 12 November 2004     

Molecular weight of human alpha2-H-ferroglobulin subunits. Comparison with molecular weight of ferritin subunits]

alpha2 H globulin, a glycoferroprotein, was first demonstrated in the sera of patients with malignant diseases. This protein was isolated from cancerous human liver, and compared with ferritin, a ferroprotein showing some identical properties (presence of iron, high molecular weight, common antigenic determinants). However, physicochemical differences were observed between these two proteins. The study of protein dissociation was performed by polyacrylamide gel electrophoresis in sodium dodecyl sulfate after reduction by mercaptoethanol. A similar molecular weight of 19 000 is obtained for subunits of these two proteins. This value agrees well with the results obtained by other authors for ferritin.