The etiology of paraneoplastic autoimmunity

Although they may sometimes appear similar, paraneoplastic autoimmunity has a unique pathogenesis, different from the classical autoimmune diseases not associated with cancer. When distinguished clinically, paraneoplastic autoimmunity is more severe and often presents with a broader range of clinical signs and symptoms. Management of these patients is difficult and is usually centered in part on treatment of the underlying malignancy. Self-antigens recognized in the setting of paraneoplastic autoimmunity can be diverse, and the number of determinants recognized within a single antigen can be numerous. This review uses prototypic examples of paraneoplastic immune-mediated diseases and their associated malignancies to describe the mechanisms by which immune dysregulation can occur in the setting of cancer. Specific diseases covered include paraneoplastic pemphigus, Sweet’s syndrome, pyoderma gangrenosum, thymoma-associated multiorgan autoimmunity, myasthenia gravis, autoimmune hemolytic anemia, immune thrombocytopenia, and the paraneoplastic neurological syndromes. The malignancies discussed include thymoma, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia, among others. The mechanisms by which cancers induce autoimmunity are broken down into the following categories: disruption of central tolerance, peripheral immune dysregulation, and alteration of self-antigens. For each category, examples of paraneoplastic autoimmune diseases and their associated malignancies are discussed. Finally, mechanisms by which cancer treatment can lead to autoimmunity and examples of polymorphisms that are linked to both cancer and autoimmunity are discussed.     

The role of iodine in thyroid autoimmunity: from chickens to humans: a review.

Evidence has been presented to support the idea that iodine plays an important role in autoimmune thyroiditis. Excessive amounts induce thyroiditis in genetically susceptible animal strains, while intrathyroidal depletion of iodine prevents disease in strains susceptible to severe thyroiditis. While the mechanisms by which iodine promotes thyroiditis is unknown, several hypotheses have been proposed. (1) T and/or B cells may react specifically to iodinated portions of thyroglobulin (Tg) so that severe iodine depletion renders Tg non-immunogenic. (2) A defect in the iodine processing machinery in thyroid epithelial cells of a susceptible person or animal may, in the presence of iodine, result in elevated levels of oxygen or iodine radicals, which could damage membrane lipids or proteins. (3) Defective iodine processing may result in the iodination of lipid or proteins (other than Tg) which could act either as immunogens or polyclonal activators.     

Microorganisms associated to thyroid autoimmunity

Autoimmune thyroid diseases are a group of diseases characterized by a dysfunction of the immune system concerning the thyroid gland, associated with hypothyroidism or hyperthyroidism. The thyroid gland autoimmunity has been recognized as multifactorial. It has been reported that microorganisms may play a role on the pathogenesis of Hashimoto's thyroiditis and Graves´ disease. These could explain the high incidence of the autoimmune thyroid diseases.Helicobacter Pylori (H. pylori) and Hepatitis C virus (HCV) are the microorganisms in which the association with autoimmune thyroid diseases is clearer. The pathophysiologic mechanisms are still not well defined. For H. pylori, molecular mimicry has been the most accepted mechanism. It has been proposed Hepatitis C virus as the trigger of the thyroid autoimmunity by exacerbating the production of thyroid auto-antibodies, while some mention that the real factor that triggers the thyroid autoimmunity is the treatment with Interferon alpha (IFN-alpha) by upregulating MHC class I and inducing ligation of CD40+ cells to thyrocytes. Other microorganisms such as Toxoplasma gondii, Human Immunodeficiency virus, Herpes virus and others have reported information about their association with thyroid autoimmune diseases There are no proposals on how these last microorganisms induce thyroid autoimmunity.There is still a lack of evidence on this topic. Further research must be done to determine the interaction of these microorganisms and the best way to manage these patients.     

The epidemiology and etiology of influenza-like illness in Chinese children from 2008 to 2010

Influenza-like illness can be caused by a wide range of respiratory viruses. In order to investigate the epidemiology of viral pathogens related to influenza-like illness in children of Wuhan, the largest city in central China, throat swab samples were collected from 1,472 young patients, from July 2008 to June 2010, before and after the occurrence of the 2009 pandemic influenza A (H1N1) virus (pH1N1). It was found that 923 patients (62.7%) were positive for at least 1 virus and 90 patients (9.8%) were detected for multiple (≥2) respiratory viruses by real-time PCR detection of 16 viruses. Seasonal influenza A virus was the predominant pathogen among all the 16 viruses with a positive rate of 13.3% (196/1,472), which was followed by pH1N1 (159/1,472). It was also noted that the viral distribution pattern in Wuhan changed upon the introduction of the pH1N1 virus.     

Cytokines in thyroid autoimmunity

The role of cytokines in the pathogenesis of autoimmune thyroid disease (ATD) has been extensively investigated over the past years. In patients with ATD, these molecules can be found in both the thyroid and sites of extrathyroidal complications of the disease. Cytokines can affect the autoimmune process through a number of mechanisms including recruitment of inflammatory cells and upregulation of molecules essential for perpetuation of the inflammatory response in the affected site. In addition, cytokines can interfere with thyroid hormone synthesis, implicating them directly in thyroid dysfunction found in ATD patients. Also, these molecules can modulate the function of cells in orbital tissue, which results in localised oedema, indicating a central role for cytokines in the development of proptosis, the cardinal feature of thyroid associated ophthalmopathy.     

The SCID-hu mouse and thyroid autoimmunity: characterization of human thyroid autoantibody secretion

Severe combined immunodeficient (SCID) mice were injected with peripheral blood mononuclear cells (PBMC) from normal individuals and 14 out of 18 had detectable serum human (h) IgG (maximum levels providing a mean +/- SEM 934 +/- 213 micrograms/ml) and IgM (253 +/- 93 micrograms/ml) at 3-6 weeks after transplantation. Serum human immunoglobulin levels were maximum 6-12 weeks after transplantation and declined to low levels over the subsequent 5 months. Human B cells constituted up to 10% and human T cells up to 40% of cells in the peripheral circulation and spleens of these animals 2-3 weeks after transplantation, PBMC, or intrathyroidal (IT) lymphocytes, from 6 patients with Graves' disease and high serum levels of thyroid autoantibodies were transplanted into 30 SCID mice (Graves' SCID-hu). Although serum human immunoglobulins were observed in only low amounts in the animals receiving IT lymphocytes (n = 4), increased levels of hIgG or hIgM were more easily detectable in 19 Graves' SCID-hu mice that received PBMC. The Graves' SCID-hu mice had significantly lower mean levels of hIgG and hIgM than those observed following transplantation of normal PBMC (mean maximum 328 +/- 113 and 32 +/- 21 micrograms/ml, respectively). Six of these 19 mice had detectable human autoantibody to thyroid peroxidase (TPO, as microsomal antigen) between 3 and 8 weeks after transplantation, with titers ranging from 0.05 to 0.39 (normal SCID-hu serum less than 0.02 ELISA Index). No abnormal thyroid hormone (T4 and T3) levels or thyroiditis was seen when compared to normal SCID-hu mice. Immunization of reconstituted SCID mice with recombinant immunoactive human TPO antigen failed to initiate anti-TPO in normal PBMC-treated mice nor did it increase the titer of human anti-TPO in the anti-TPO positive animals. In conclusion we successfully established human thyroid autoantibody secretion in the SCID-hu mouse and characterized the transient nature of the model. Further studies will be required to achieve successful antigen presentation in this system.     

The cryptic self in thyroid autoimmunity: the paradigm of thyroglobulin

Recent studies have increased the number of known thyroiditogenic sites in thyroglobulin (Tg) to thirteen. These sites contain T-cell epitopes and are scattered throughout Tg, with nine of them localized toward the carboxyl terminal third of the molecule. So far, no pathogenic determinant has been found to be dominant, i.e. to be readily and consistently generated in extrathyroidal antigen-presenting cells (APC) following processing of intact Tg in vivo and in vitro. However, certain conditions, such as internalization of Tg-antibody complexes or enhanced iodination of Tg, have been described to promote generation of cryptic pathogenic peptides in APC, in vitro. These findings support the view that post-translational events can "unmask the cryptic self' and suggest mechanisms that may contribute to the pathogenesis of thyroiditis.     

Susceptibility genes in thyroid autoimmunity

The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely, these loci interact and their interactions may influence disease phenotype and severity.     

The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts

FOXP3 is a key gene in the development of regulatory T cells (Treg). FOXP3 expression commits naïve T cells to become Treg cells. Indeed, mutations in the FOXP3 gene cause severe systemic autoimmune diseases in humans and in mice. Therefore, we hypothesized that the FOXP3 gene may be associated with thyroid autoimmunity which is among the typical autoimmune diseases that develop in individuals with FOXP3 mutations. Moreover, the FOXP3 gene is located within an X-chromosome locus (Xp11.23) previously shown to be linked with autoimmune thyroid diseases (AITD). We tested the FOXP3 gene locus for association with AITD in two large cohorts of US Caucasians and Japanese AITD patients. We analyzed 269 Caucasian AITD patients (52 males and 217 females) and 357 Caucasian controls (159 males and 198 females), as well as 377 female Japanese AITD patients and 179 female Japanese controls. The FOXP3 gene locus was analyzed using four microsatellite polymorphisms [(GT)n; (TC)n; DXS573; DXS1208] flanking the FOXP3 gene locus. Interestingly, while no association was found between FOXP3 polymorphisms and AITD in the Japanese cohort there was a significant association in the Caucasian cohort. There was a significant association of the (TC)n polymorphism with AITD in the Caucasian male AITD patients (p = 0.011; 5 degrees of freedom [df]). Similarly, there was an association between the DXS573 microsatellite and AITD in the Caucasian female AITD patients (p = 0.00023; 4 df). These results suggest that polymorphisms of the FOXP3 gene may play a role in the genetic susceptibility to AITD in Caucasians, perhaps by altering FOXP3 function and/or expression.     

Female infertility related to thyroid autoimmunity: the ovarian follicle hypothesis

Citation
Monteleone P, Parrini D, Faviana P, Carletti E, Casarosa E, Uccelli A, Cela V, Genazzani AR, Artini PG. Female infertility related to thyroid autoimmunity: the ovarian follicle hypothesis. Am J Reprod Immunol 2011; 66: 108–114 Problem The aim of this study was to verify whether anti‐thyroid antibodies are present in the follicular milieu of euthyroid infertile women with thyroid autoimmunity undergoing in vitro fertilization (IVF) and whether IVF outcome is different in affected women with respect to negative controls. A secondary endpoint was to check whether there are changes in thyroid hormone levels during the IVF cycle. Method of study Anti‐thyroglobulin and anti‐thyroperoxidase levels were measured in both follicular fluid and serum on the day of oocyte retrieval in women with thyroid autoimmunity. Serum TSH, FT3, and FT4 levels were measured in all patients before treatment initiation, on the day of oocyte retrieval and of pregnancy test. IVF outcome parameters were recorded in all women. Results Oocyte fertilization, grade A embryos, and pregnancy rates were lower in women with thyroid autoimmunity than in negative controls, while early miscarriage rate was higher. Anti‐thyroid antibodies were measurable in follicular fluid in all affected women and were strongly correlated with serum levels. No significant changes in thyroid hormone levels were recorded in any women. Conclusion The presence of anti‐thyroid antibodies in ovarian follicles, as demonstrated for the first time in this study, may play a critical role in female infertility related to thyroid autoimmunity.     

The infectious etiology of the antiphospholipid syndrome: links between infection and autoimmunity

Like many other autoimmune diseases, the antiphospholipid syndrome (APS) is considered as of a multifactorial etiology, mainly genetic susceptibility coinciding with environmental triggers, of which infectious agents are considered most prominent. Different clinical and experimental studies of the β2 glycoprotein I (β2GPI) molecule, one of the target autoantigens in APS, have linked infection to the development of APS. Using a peptide phage library, it has been shown that target epitopes of β2GPI share similarities with common infectious pathogens. Also, circulating anti-β2GPI antibodies have been identified in the sera of patients with different infectious conditions, and have been associated with various clinical APS manifestations. Molecular mimicry as a key mechanism linking infection and APS has been demonstrated in experimental models. In these studies, APS was induced by immunization of mice to various microbial pathogens. Anti-β2GPI titers were found to be especially high following immunization with Haemophilus influenzae, Neisseria gonorrheae or tetanus toxoid. These findings contribute greatly to the understanding of APS pathogenesis, as well as create new directions for therapy modalities, namely specific peptide toleragens and antimicrobial treatment.     

The complex role of interleukin-10 in autoimmunity

Interleukin-10 (IL-10) is a cytokine that has been tested in different clinical trials based on its ability to down regulate T helper 1-type responses, namely IFN-gamma secretion and activation of monocytes/macrophages. There is also evidence in different animal models, that IL-10 could be useful in controlling Th2-mediated inflammatory processes. However, IL-10 also displays immunostimulatory properties especially on B cells and activated CD8(+)T cells. These seemingly divergent effects may explain the apparent lack of activity or adverse effects observed after IL-10 treatment in several animal models or clinical trials. Nevertheless, the ability of IL-10 to induce the differentiation of a subset of regulatory CD4(+)T cells (Tr1) and the importance of IL-10 for the in vivo function of regulatory T cells tends to support the view of IL-10 as a crucial cytokine in the control of immune responses. In different in vivo models, these cells were shown to inhibit Th1 and Th2-type inflammatory responses through the secretion of IL-10. These Tr1 cells may thus be used in specific cellular therapy in order to deliver IL-10 precisely at the site of inflammation.     

Chemokines in autoimmunity: from pathology to therapeutics

Leukocyte recruitment, accumulation, and activation have been both a unifying and enigmatic feature of a variety of autoimmune pathologies. While these processes were not well-known for decades, recent scientific discoveries have underscored the importance of specific chemokines in the evolution of autoimmunity. This has been supported by in vivo data from clinical studies and animal model experiments. Although chemokines are an attractive target for drug development, there are hurdles that need to be cleared. Nonetheless, the quest to understand chemokine biology and develop effective therapies continues to capture the imagination of scientists in academia and pharma alike.     

Celiac disease: from gluten to autoimmunity

Celiac disease, also known as gluten-sensitive enteropathy and nontropical sprue, is a prevalent autoimmune disorder that is triggered by the ingestion of wheat gluten and related proteins of rye and barley in genetically susceptible individuals. The immune response in celiac disease involves the adaptive, as well as the innate, and is characterized by the presence of anti-gluten and anti-transglutaminase 2 antibodies, lymphocytic infiltration in the epithelial membrane and the lamina propria, and expression of multiple cytokines and other signaling proteins. The disease leads to inflammation, villous atrophy, and crypt hyperplasia in the small intestine. In addition to the intestinal symptoms, celiac disease is associated with various extra-intestinal complications, including bone and skin disease, anemia, endocrine disorders, and neurologic deficits. Gluten-free diet is currently the only effective mode of treatment for celiac disease, but better understanding of the mechanism of the disease is likely to add other choices for therapy in the future.     

Lyme borreliosis: from infection to autoimmunity

Lyme borreliosis in humans is an inflammatory disease affecting multiple organ systems, including the nervous system, cardiovascular system, joints and muscles. The causative agent, the spirochaete Borrelia burgdorferi, is transmitted to the host by a tick bite. The pathogenesis of the disease in its early stages is associated largely with the presence of viable bacteria at the site of inflammation, whereas in the later stages of disease, autoimmune features seem to contribute significantly. In addition, it has been suggested that chronic persistence of B. burgdorferi in affected tissues is of pathogenic relevance. Long-term exposure of the host immune system to spirochaetes and/or borrelial compounds may induce chronic autoimmune disease. The study of bacterium-host interactions has revealed a variety of proinflammatory and also immunomodulatory-immunosuppressive features caused by the pathogen. Therapeutic strategies using antibiotics are generally successful, but chronic disease may require immunosuppressive treatment. Effective and safe vaccines using recombinant outer surface protein A have been developed, but have not been propagated because of fears that autoimmunity might be induced. Nevertheless, new insights into the modes of transmission of B. burgdorferi to the warm-blooded host have been generated by studying the action of these vaccines.     

Genetic and epigenetic mechanisms in thyroid autoimmunity

Autoimmune thyroid diseases (AITD), including Graves’ disease and Hashimoto’s thyroiditis, are among the commonest autoimmune disorders, affecting approximately 5?% of the population. Epidemiological data support strong genetic influences on the development of AITD. Since the identification of HLA-DR3 as a major AITD susceptibility gene, there have been significant advances made in our understanding of the genetic mechanisms leading to AITD. We have shown that an amino acid substitution of alanine or glutamine with arginine at position 74 in the HLA-DR peptide binding pocket is a critical factor in the development of AITD, and we are continuing to dissect these mechanisms at the molecular level. In addition to the MHC class II genes, there are now several other confirmed gene loci associated with AITD, including immune-regulatory (CD40, CTLA-4, PTPN22, FOXP3, and CD25) and thyroid-specific genes (thyroglobulin and TSHR). Mechanistically, it is postulated that susceptibility genes interact with certain environmental triggers to induce AITD through epigenetic effects. In this review, we summarize some of the recent advances made in our laboratory dissecting the genetic–epigenetic interactions underlying AITD. As shown in our recent studies, epigenetic modifications offer an attractive mechanistic possibility that can provide further insight into the etiology of AITD.