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The effect of infection in initiating autoimmune disease has been debated for many years. There are, even now, few instances of a human autoimmune disease clearly caused by prior infection, probably due to the frequent separation in time and space from the clinical outcomes. As our understanding of the immunologic consequences of the infectious process has deepened, we can re-think some of the issues by focusing attention on the varied adjuvant effects of microbial products. We are now able to distinguish some of the critical steps in progression from virus infection to benign autoimmunity to autoimmune disease in an experimental model of myocarditis. Immune regulators, such as cytokines and costimulatory molecules, serve as signposts in the process. The lessons learned may be broadly applicable to autoimmune disorders. [ABSTRACT FROM AUTHOR]

This article focuses on the genetic lesions of autoimmunity. For many years, the prevailing dogma to explain self-non-self discrimination rested on the theory of clonal deletion. According to this view, potential autoimmune clones of lymphocytes are extinguished during early foetal development. An increasing body of evidence suggests that the deletionist view does not satisfy all the requirements of self-non-self distinction. A good deal of new information about the safeguards preventing autoimmune destruction has come from studies of spontaneously occurring models of autoimmune disease in experimental animals.

Two inbred strains of mice, BSVS and BRVR, are similar in their antibody response to thyroglobulin but differ significantly with respect to thyroid gland damage. F1 hybrids, like BSVS mice, respond well to thyroglobulin, exhibiting extensive thyroid lesions, whereas BRVR mice show minimal thyroid damage. H-2 typing of the two strains showed that BSVS mice have a type similar to H-2th, with the H-2D-end of H-2d and the H-2K-end of H-2s whereas BRVR mice are H-2k. The cellular response to thyroglobulin appears to be influenced by a specific immune response gene located near the K-end of the H-2 complex. [ABSTRACT FROM AUTHOR]

Human thyroglobulin (Tg) was treated with trypsin at different concentrations of trypsin/Tg for various incubation times at 37°C using non-reducing conditions. A ratio of trypsin to Tg of 1:100 (w/w) was optimal to release small peptides that were reactive to murine MoAbs to human Tg. Most peptides were released after only 1 h incubation with trypsin, but these peptides were further degraded at longer incubation times. However, a few small peptides, the largest of which with an apparent molecular weight (MWap) of 40 kD, resisted tryptic digestion up to at least 12 h of incubation. These resistant peptides were further degraded by trypsin at 18-24 h of incubation. Tryptic peptides of Tg, released at I h and 4 h of incubation, were analysed for their immuno-reactivity to 16 well characterized anti-Tg MoAbs by Western immunoblot. Patterns of peptide recognition of these MoAbs were generally unique. Eight, MoAbs reacted with peptides of MWap of 10-28 kD and above. Four reacted with peptides of MWap > 43 kD. Nine of these MoAbs failed to recognize peptides after reduction, suggesting that the MoAbs bind conformation-dependent epitopes. The above information will promote the development of models relating the structure of Tg to the autoimmune process, and may provide an understanding of those regions of Tg responsible for the induction of autoimmune thyroiditis. [ABSTRACT FROM AUTHOR]

Tryptic peptides of human thyroglobulin (Tg) were analysed by Western immunoblot for their reactivity to circulating autoantibodies from patients with Hashimoto's thyroiditis (HT), Graves' disease (GD) and thyroid carcinoma, and from normal human controls. Low molecular weight peptides were released after 4h incubation of Tg with trypsin. The sera of thyroid disease patients reacted with several peptides. but predominantly bound three peptides with apparent molecular weights (MWap) of 25kD, 20kD, and 15kD; the sera of normal individuals did not bind these fragments of Tg. The pattern of tryptic peptides recognized by the majority of sera from GD patients differed from that recognized by sera from most patients with HT. Autoantibodies from both groups of patients recognized a 15-kD peptide with a high frequency, but the sera from 26/43 (60%) GD patients also recognized a peptide with MWap of 25 kD, whereas the sera from 22/35 (63%) of HT patients recognized a 20-kD peptide. A few sera from patients with thyroid carcinoma reacted with peptides with MWap of 15 and 20-kD, and none bound the 25-kD peptide. The immunoreactivity of autoantibodies in HT sera to the 20-kD peptide paralleled the competitive inhibition of the MoAb 137Cl by these sera. In addition. MoAb 137Cl and Hashimoto's sera showed the same Western immunoblot-binding pattern to Tg tryptic peptides, suggesting that a Hashimoto-associated epitope and the 137Cl-binding site are found on the same peptide. These findings suggest that distinct peptides are recognized by Tg autoantibodies from patients with different thyroid diseases. [ABSTRACT FROM AUTHOR]

A.SW and B10.S mice share the same major histocompatibility complex (MHC) haplotype (H-2s). However, A.SW mice are susceptible to experimental autoimmune myocarditis (EAM) and develop severe disease after immunization with myosin, whereas B10.S mice are resistant. We found that naive A.SW mice have intrinsically increased total CD4+ T cell counts and increased proportions of CD4+ T cells in their spleens compared to B10.S mice. Among total CD4+ T cells, naive A.SW mice have a lower relative frequency of forkhead box protein 3 (FoxP3+)CD25+ regulatory T cells (Tregs). A.SW mice also had a higher proportion of CD4+ T cells and a lower proportion of Tregs in their hearts and spleen during EAM, with greater T cell activation and proliferation, compared to B10.S mice. These differences in the T cell compartment were not antigen-specific, as ovalbumin/complete Freund's adjuvant (OVA/CFA) or CFA immunization elicited the same differences in CD4+ T cells and Tregs between A.SW and B10.S mice. Moreover, A.SW mice had more T helper type 17 (Th17) cells and B10.S had more Th1 cells in their hearts. The higher percentage of CD4+ T cells and their enhanced potential to differentiate towards the Th17 pathway was also observed in naive A.SW mice. Interleukin (IL)-6 is required for Th17 induction. Interestingly, IL-6Rα expression was greater on naive A.SW CD4+ T cells, compared to B10.S CD4+ T cells, indicating that this intrinsic difference, together with a relatively lower Treg proportion of CD4+ T cells, might lead to heightened Th17 responses and greater susceptibility to autoimmunity in A.SW mice. [ABSTRACT FROM AUTHOR]

Intracellular adhesion molecule-1 (ICAM-1) expression on the thyroid follicular cells of non-obese diabetic (NOD).H2h4 mice is enhanced by iodide treatment, which correlates with autoimmune thyroid disease in genetically susceptible NOD.H2h4 mice. The current study examines the mechanism of iodine-enhanced up-regulation of ICAM-1 on the surface of thyroid cells. We hypothesized that the up-regulation of ICAM-1 is due to a transient increase in production of reactive oxygen species (ROS). ROS may initiate signalling of the ICAM-1 gene promoter, enhancing up-regulated ICAM-1 protein on the cell surface. Single-cell suspensions of thyroid follicular cells from thyroiditis-susceptible NOD.H2h4 or non-susceptible BALB/c mice were treated in vitro with sodium iodide. Extracellular and intracellular ROS were assessed by luminol-derived chemiluminescence and flow cytometry assays respectively. Our results demonstrate that thyroid follicular cells of NOD.H2h4 generate higher levels of ROS compared with cells from non-susceptible strains of mice. Expression of a subunit protein of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, p67 phox, was analysed by Western blot immunoassay. A constitutive expression of the p67 phox subunit protein was observed in NOD.H2h4 mice prior to iodine treatment. No such expression was found in BALB/c mice. Treatment of NOD.H2h4 thyroid cells with diphenyleneiodium, an inhibitor of NADPH oxidase, reduced generation of ROS and of ICAM-1 protein expression. Thus, thyrocytes from NOD.H2h4 mice produce enhanced levels of ROS that may be mediated by NADPH oxidase. Consequently, in NOD.H2h4 mice the ROS-induced signal for ICAM-1 up-regulation may contribute to mononuclear cellular infiltration of the thyroid gland and the progression of autoimmune thyroid disease. [ABSTRACT FROM AUTHOR]

The article presents several letters discussing the 50 years of operation of the British Society for Immunology. The Society is celebrating its 50 years in the study of immunology focusing on dismantling the immune system into its component cells and molecules. According to other immunologists, the next years to come will be centered on the study of autoimmunity as an acceleration to the progress in immunotherapy.

Autoimmune thyroiditis in humans has been linked to excess iodine intake. A causative relationship between dietary iodine and thyroiditis has been clearly established in animal models of thyroiditis, including the NOD.H2h4 mouse strain, which develops enhanced thyroiditis spontaneously after supplementation of drinking water with sodium iodide. To assess the mechanisms by which iodine may contribute to disease pathogenesis, we have purified hypoiodinated thyroglobulin (Lo-I Tg) from the thyroids of mice fed methimazole and potassium perchlorate. This preparation contained only a trace of iodine and was poorly reactive to monoclonal antibody 42C3, which has been shown previously to distinguish hypoiodinated from normal Tg. A cloned T cell line 2D11 from a diseased NOD.H2h4 mouse proliferated in response to normal Tg, but not to Lo-I Tg. Serum antibodies from NOD.H2h4 mice with thyroiditis were poorly reactive to Lo-I Tg. To determine that these changes were due specifically to iodine content, Lo-I Tg was reiodinated in vitro. Reiodination of Lo-I Tg partially re-established the reactivity of NOD.H2h4 serum antibodies. The data demonstrate that the reactivity of thyroglobulin-specific antibodies and certain T cells are dependent on the iodine content of thyroglobulin. These findings suggest that iodine contributes to autoimmune thyroiditis in the NOD.H2h4 mouse by directly enhancing the antigenicity of thyroglobulin. [ABSTRACT FROM AUTHOR]

This study was undertaken to determine if immunoglobulin G (IgG) antibodies could be eluted from the hearts of mice with Coxsackievirus B3-induced autoimmune myocarditis and to characterize the immunoreactivity of any elutable autoantibodies. Susceptible (A/J)and resistant (B10.A) mice were administered the virus or the control treatment and killed at various times after treatment. Acid eluates from pooled heart tissue from each treatment group and each time were tested for IgG reactivity with normal heart tissue by immunohistochemistry and with normal heart extracts by Western immunostaining. Eluates from infected A/J mice reacted strongly with syngeneic heart and modestly with syngeneic skeletal muscle tissue. Eluates from infected B10.A or control mice of either strain exhibited little reactivity with either tissue. Tissue reactivity was similar when allogeneic tissue was used as the substrate. Eluates from infected A/J mice recognized the heavy chain of cardiac myosin and several other cardiac antigens by Western immunostaining while eluates from the other treatment groups exhibited little or no reactivity with any normal heart constituents. These results indicate that in vivo IgG deposition occurs in the hearts of mice with post-infectious autoimmune myocarditis and that the specificity of these antibodies is similar to that reported for serum from animals with this disease. The mechanism(s) leading to myocardial IgG deposition and its possible role in pathogenesis remain lo be elucidated. [ABSTRACT FROM AUTHOR]