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N R Rose

Publications and source records attributed to N R Rose.

At least 37 records · Page 2Linked to original sources
PubMed2000

There is only one immune system! The view from immunopathology.

The generators of B and T cell diversity produce specificities for both autochthonous and exogenous paratopes. A wide variety of positive and negative, central and peripheral mechanisms has evolved to regulate the immune response. All potential immunogens are recognized by the system using the same set of 'rules', without discrimination between 'self' and 'nonself' or between the 'toxic' and the 'benign'. In every response, whether positive or negative, the factors mobilized and the balance between protection and damage depend upon the quality, quantity, location, and timing of immunogen presentation, as well as upon properties of the host.

B-Lymphocytes↗
PubMed2000

Molecular mimicry: a critical look at exemplary instances in human diseases.

Molecular mimicry, the concept that antigenic determinants of microorganisms resemble antigenic determinants of the host, is frequently cited as a plausible mechanism to account for the association of infection and autoimmune disease. Based on analogous sequences of amino acids or on cross-reactions of monoclonal antibodies, numerous examples of such mimicry have been reported. There are, however, no clear examples of a human disease caused by molecular mimicry.

Animals↗
PubMed2000

Newer insights into the pathogenesis of experimental autoimmune thyroiditis.

Experimental autoimmune thyroiditis (EAT), produced in the mouse by immunization with murine thyroglobulin plus complete Freund's adjuvant, represents a valuable model for studying the pathogenesis of human chronic (Hashimoto's) thyroiditis. A major issue requiring clarification is the difference between benign autoimmunity, characterized solely by production of autoantibodies to thyroglobulin, and pathogenic autoimmunity where injury occurs to the thyroid cells. In this article, we describe the role of two key cytokines, IL12 and IFNgamma, in modifying the pathogenic immune response. EAT, defined by cellular infiltration of the thyroid and the development of thyroglobulin-specific autoantibodies, is a dynamic process. Consequently, a cytokine may exert a different effect at different times during the disease process. For purposes of discussion, we propose that there are three stages in the development of EAT: priming; initiation; and progression. Administration of anti-IL12 during the priming stage and initiation dramatically decreases disease and lowers autoantibody levels. In contrast, injection of recombinant IL12 after disease was established significantly decreases the severity of disease and reduces autoantibody levels. Unlike IL-12, IFNgamma was not essential for the priming of EAT. However, the severity of disease in the anti-IFNgamma-treated initiation- and progression-treated animals was higher than in controls, implying a regulatory role for IFNgamma. These findings emphasize that EAT involves a complex array of pathogenic mechanisms. The balance of cytokines produced during the early phase of the autoimmune reaction probably determines the progression from a harmless autoimmune response to autoimmune disease.

Animals↗
PubMed1999

Peptides of human thyroglobulin reactive with sera of patients with autoimmune thyroid disease.

Autoantibodies to thyroglobulin (Tg) are a prominent feature of the two autoimmune thyroid diseases, chronic lymphocytic (Hashimoto's) thyroiditis and Graves' disease. Similar autoantibodies are found in the serum of many normal individuals without evidence of thyroid disease. Previous studies have indicated that patients with autoimmune thyroid disease recognize epitopes of Tg which are not usually recognized by normal individuals. The goal of this investigation was to identify peptide fragments of Tg bearing these disease-associated epitopes. For this purpose, we utilized a panel of mAbs that bind to different epitopes of the Tg molecule. One of these mAbs (137C1) reacted with an epitope that was also recognized by the sera of patients with autoimmune thyroiditis. In the present study, we show that two peptides (15 and 23 kDa) that reacted with mAb 137C1 are located in different parts of the Tg molecule. Each peptide inhibited the binding of mAb 137C1 to the other peptide and to the intact Tg, indicating that the same epitope was represented on the two peptides. Loops and helices of the secondary structure of the two peptides might be involved in the conformational epitope recognized by mAb 137C1. A striking finding of this study is that two apparently unrelated fragments of the Tg molecule bind to the same mAb. These findings may have important ramifications with regard to epitope spread and the progression of the autoimmune response to disease.

Amino Acid Sequence↗
PubMed1999

Mouse thyroid primary culture.

Technological advances have drastically decreased the number of cells required to analyze expression of the genes and functions of the encoded proteins, making even a small organ like a mouse thyroid amenable to study in vitro. We have established primary cultures of mouse thyroids that showed, for up to 14 days after seeding, strong cytoplasmic staining for thyroglobulin. The staining then gradually decreased and was present in only 5-10% of thyrocytes at day 28. Furthermore, cultured thyrocytes expressed the thyroperoxidase and thyrotropin-receptor genes, and, although at lower levels, the sodium-iodide symporter gene. Finally, cultured thyrocytes could be transiently transfected by lipofection, using FuGENE 6. Thus, we report that it is possible to cultivate functional primary mouse thyrocytes that can be used for a variety of biological studies. This system is appealing because it permits the use of the ever-increasing number of transgenic, knock-out and knock-in mouse strains in studying thyroid pathophysiology.

Animals↗
PubMed1999

Evidence for genetic transmission of thyroid peroxidase autoantibody epitopic "fingerprints".

Autoimmune thyroid disease is characterized by the tendency to cluster in families and by IgG class autoantibodies to antigens such as thyroid peroxidase (TPO). The epitopes recognized by polyclonal serum autoantibodies can be quantitatively fingerprinted using four recombinant human TPO autoantibodies (expressed as Fab) that define A and B domain epitopes in an immunodominant region. To determine whether these fingerprints are genetically transmitted, we analyzed fingerprints of 63 members of 7 multiplex Old Order Amish families and 17 individuals from 4 Hashimoto thyroiditis families. Inhibition of serum autoantibody binding to [125I]TPO by the recombinant Fab was used to assess recognition of the TPO immunodominant region (4 Fab combined) and recognition of domain A or B (individual Fab). Complex segregation analysis was performed using a unified model (POINTER). For the 4 Fab combined inhibition phenotype, the no transmission model was rejected (chi2(4) = 20.67; P < 0.0032), and the most parsimonious model includes a major gene effect. More importantly, evidence for genetic transmission was obtained for the phenotype defined by the ratio of inhibition by subdomain Fab B1:B2. Thus, for this ratio (reflecting recognition of the B domain), the no transmission model was rejected chi2(4) = 63.59; P < 0.000008). Moreover, the polygenic hypothesis could be rejected, but not the major locus hypothesis, suggesting that major genes might be involved in familial transmission of this trait. In conclusion, our findings suggest that autoantibody recognition of the TPO immunodominant region and the TPO B domain is genetically transmitted. These data may open the way to the identification by candidate analysis or positional cloning of at least one gene responsible for the development of Hashimoto's thyroiditis.

Autoantibodies↗
PubMed1999

Linking iodine with autoimmune thyroiditis.

A great deal of circumstantial evidence has linked iodine with the rising incidence of autoimmune thyroiditis in the United States. In our investigations, we have shown directly that T cells from humans with chronic lymphocytic thyroiditis proliferate in the presence of iodinated but not in the presence of noniodinated human thyroglobulin. Moreover, the proliferative response is restored when the thyroglobulin is iodinated artificially in vitro. Using a panel of monoclonal antibodies, we found evidence that the presence of iodine induces a number of stereochemical changes in the conformation of the molecule, resulting in the loss of some antigenic determinants and the appearance of others. One prominent determinant was associated with the iodine-containing amino acid thyroxine. Both the number and position of the iodine substituents determine the precise specificity of this epitope. A new model for the study of the role of iodine in inducing thyroid autoimmunity has become available in the form of the nonobese diabetic (NOD)-H2(h4) mouse. This animal develops autoimmune thyroiditis spontaneously but in relatively low prevalence. However, if iodine is added to the drinking water, the prevalence and severity of the thyroid lesions increase markedly. The immune response is specific for thyroglobulin, both in terms of the antibody response and T-cell proliferation. In fact, the appearance of lesions can be predicted by the presence of thyroglobulin-specific IgG2b antibody. The disease, moreover, can be transferred adoptively, using spleen cells from iodine-fed donors treated in vitro with iodinated thyroglobulin. The effects of iodine feeding are greater in conventional animals compared with those maintained under specific pathogen-free conditions. Based on T-cell proliferation, it appears that the NOD-H2(h4) strain of mice has innately a greater response to murine thyroglobulin than do other mouse strains and that the proliferation is increased even more by feeding iodine. We suggest, therefore, that the presence of iodine increases the autoantigenic potency of thyroglobulin, a major pathogenic antigen in the induction of autoimmune thyroiditis. This animal model provides a unique opportunity for investigating in detail the mechanisms by which an environmental agent can trigger a pathogenic autoimmune response in a susceptible host.

Animals↗
PubMed1999

Characterization of murine autoimmune myocarditis induced by self and foreign cardiac myosin.

Previously we showed that autoimmune myocarditis could be induced in mice by immunization with purified murine cardiac myosin (MCM). In this study, we found that identical disease could also be induced in genetically susceptible mice by immunization with porcine cardiac myosin (PCM). The cardiac lesions induced by both antigens were characterized by extensive infiltration of the myocardium accompanied by myocyte necrosis. A novel finding was the presence of multinucleated giant cells and eosinophils in the cardiac infiltrates, in addition to a mixture of mononuclear cells and polymorphonuclear cells described previously. Immunohistochemical staining demonstrated that the mononuclear cells consisted predominantly of macrophages, CD4+ T cells and, to a lesser extent, CD8+ T cells and B cells. In addition, increased cardiac expression of adhesion molecules E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) were demonstrated in mice that developed myocarditis as compared with those that did not develop disease upon immunization with either PCM or MCM. The levels of TNFalpha detected in spleen cell culture supernatant were found to be higher in mice that developed myocarditis than in those that did not develop the disease. Mice immunized with PCM generated T cells and B cells reactive not only with PCM but also with MCM, and vice versa. In addition, the serum levels of IgG1 anti-MCM antibodies produced in mice immunized with PCM as well as MCM were found to correlate positively with the development of myocarditis. Such a detailed characterization of the murine model of autoimmune myocarditis induced by PCM or MCM allowed us to compare the disease process induced by homologous self and foreign antigens.

Animals↗
PubMed1998

The role of infection in the pathogenesis of autoimmune disease.

Autoimmune disease has long been considered a shadow following infectious diseases. Epidemiological evidence shows that rheumatic fever follows streptococcal infection and Trypanosoma cruzi infection is the instigator of Chagas' disease. There is, however, very little information of the mechanism by which such a train of events is initiated. Autoimmunity, in a form of autoantibodies, is common after many infections and may well result from the mimicking of host proteins by antigens of the infectious agent. There are, however, few if any examples in humans where molecular mimicry gives rise to autoimmune disease. The progression from benign autoimmunity to pathogenic autoimmune disease depends upon the balance of cytokines produced during the inflammatory process accompanying infection. In many autoimmune diseases, the cytokine profile favors the proinflammatory cytokines, IFN-gamma and IL-1, which support the production of disease. A searching study of cytokine profiles during infection may offer a promising approach to avoiding the harmful consequences of post-infection autoimmune responses.

Animals↗
PubMed1998

Iodination of human thyroglobulin (Tg) alters its immunoreactivity. I. Iodination alters multiple epitopes of human Tg.

Human Tg, the site of synthesis of thyroid hormones, thyroxine (T4) and triiodothyronine (T3), is one of the major autoantigens in autoimmune thyroiditis. The degree of iodination of Tg may have a major impact on its immunological properties by changing its antigenicity with respect to antibody binding. We have previously prepared a panel of MoAbs that bind to different epitopes of the Tg molecule. In the present study, we show that iodination alters the conformation of Tg molecule in such a way that it is recognized differently by different MoAbs. Monoclonal antibody 137C1 recognizes Tg regardless of its iodine content. Monoclonal antibody 42C3 recognizes Tg only if the Tg is iodinated either in vitro or in vivo. Monoclonal antibody 133B1 recognizes both in vivo iodinated Tg and non-iodinated Tg, but this MoAb did not recognize Tg following in vitro iodination. Monoclonal antibody 41A5 recognizes intact Tg and tryptic peptides of normal (in vivo) iodinated and non-iodinated Tg, but did not bind the tryptic peptides of artificially (in vitro) iodinated Tg. From the results of these experiments, we conclude that iodination of Tg by either in vivo or in vitro methods changes its conformation in such a way that some natural epitopes are 'lost' and some 'new' epitopes are generated. The generation of new epitopes may be important in the generation of autoimmune responses leading to autoimmune disease.

Antibodies, Monoclonal↗
PubMed1998

Iodination of human thyroglobulin (Tg) alters its immunoreactivity. II. Fine specificity of a monoclonal antibody that recognizes iodinated Tg.

In a previous investigation, we found that murine MoAb 42C3, raised against human Tg, recognized Tg differently depending upon its level of iodination of Tg. A possible explanation for this finding is that iodine is directly involved with the specific epitope recognized by MoAb 42C3. In the present study, we report that the binding of MoAb 42C3 to iodinated Tg is inhibited by T4, T3, reverse T3 (rT3), triiodothyroacetic acid (triac), diiodothyronine (T2), diiodotyrosine (DIT), but not by thyronine (TO) or tyrosine. The order of inhibition of these iodinated compounds is T4 > T3 > rT3 > triac > T2 > DIT. The MoAb 42C3 does not have the same specificity as the T3, T4-receptor since the order of binding of these iodinated compounds on the receptor differed from the order of their inhibition of this MoAb. Monoclonal antibody 42C3 also recognized non-iodinated Tg that was subsequently iodinated in vitro. It failed to recognize another protein, bovine serum albumin, that was iodinated in vitro by the same method. These results suggest that iodinated tyrosines and thyronines determine the binding specificity of MoAb 42C3. The inhibitory effects of these compounds on MoAb 42C3 depend on their iodine content as well as location of iodine in the aromatic ring.

Antibodies, Monoclonal↗