Is FCRL3 a new general autoimmunity gene?

Autoimmunity is a multistep pathogenic process, which arises in genetically predisposing individuals as a result of the harmful influence of environmental factors causing the breakdown of immune tolerance and induction of self-reactive immune response. Recent findings resolved common pathogenic mechanisms shared between different autoimmune diseases and suggested for the existence of genetic loci that could be involved in general autoimmunity and hence contribute to susceptibility of several autoimmune diseases. To date, several loci responsible for general autoimmunity have been identified. The Fc receptor-like 3 (FCRL3) gene is one of those loci for which a significant association with a number of autoimmune diseases such as rheumatoid arthritis (RA), autoimmune thyroid disease, and systemic lupus erythematosus (SLE) has been recently shown in Japanese. However, studies in Caucasians failed to confirm a strong association of this gene with RA and SLE and therefore made questionable the putative role of FCRL3 in general autoimmunity. In this review, we discuss whether the FCRL3 gene is a newly discovered gene contributing to shared susceptibility between autoimmune diseases.     

Balancing susceptibility to infection and autoimmunity: a role for leptin?

The immune responses to many infections have long been known to share features with autoimmune responses. In particular, both types of response are typified by the enhanced reactivity of T helper 1 cells - with high levels of interleukin-2, interferon gamma and tumor necrosis factor alpha - and are accompanied often by organ-specific and/or systemic damage and the production of IgG. Paradoxically, the geographical distributions of incidence of infectious diseases and autoimmunity are complementary, rather than coincident. In less-developed societies, an epidemiological association between susceptibility to infection and malnutrition has been observed, whereas in affluent countries, an increased incidence of autoimmune diseases has been described. We suggest that these observations can be explained partly by taking into consideration the immune effects of the adipocyte-derived hormone leptin, which has been shown recently to act as a link between nutritional status and the immune response.     

CTLA-4 gene polymorphisms and their influence on predisposition to autoimmune thyroid diseases (Graves’ disease and Hashimoto's thyroiditis)

Introduction

Autoimmune thyroid disease (AITD) is associated with both genetic and environmental factors which lead to the overactivity of immune system. Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) gene polymorphisms belong to the main genetic factors determining the susceptibility to AITD (Hashimoto''s thyroiditis, HT and Graves'' disease, GD) development. The aim of the study was to evaluate the relationship between CTLA-4 polymorphisms (A49G, 1822 C/T and CT60 A/G) and HT and/or GD in Polish patients.

Material and methods

Molecular analysis involved AITD group, consisting of HT (n=28) and GD (n=14) patients, and a control group of healthy persons (n=20). Genomic DNA was isolated from peripheral blood and CTLA-4 polymorphisms were assessed by polymerase chain reaction-restriction fragment length polymorphism method, using three restriction enzymes: Fnu4HI (A49G), BsmAI (1822 C/T) and BsaAI (CT60 A/G).

Results

Statistical analysis (χ² test) confirmed significant differences between the studied groups concerning CTLA-4 A49G genotypes. CTLA-4 A/G genotype was significantly more frequent in AITD group and OR analysis suggested that it might increase the susceptibility to HT. In GD patients, OR analysis revealed statistically significant relationship with the presence of G allele. In controls, CTLA-4 A/A genotype frequency was significantly increased suggesting a protective effect. There were no statistically significant differences regarding frequencies of other genotypes and polymorphic alleles of the CTLA-4 gene (1822 C/T and CT60 A/G) between the studied groups.

Conclusions

CTLA-4 A49G polymorphism seems to be an important genetic determinant of the risk of HT and GD in Polish patients.     

Molecular mimicry in the MHC: Hidden clues to autoimmunity?

The term ‘molecular mimicry’ has been used to describe a spectrum of antigenic crossreactivities thought to underlie autoimmune disease. For T cell crossreactivities to occur appropriate T cell clone must be available. Here Harold Baum, Huw Davies and Mark Peakman speculate that an important source of self-peptides that govern thymic selection of such clones are MHC molecular themselves.     

Dynamin 2 gene is a novel susceptibility gene for late-onset Alzheimer disease in non-APOE-ε4 carriers

Alzheimer disease (AD) is characterized by progressive cognitive decline caused by synaptic dysfunction and neurodegeneration in the brain, and late-onset AD (LOAD), genetically classified as a polygenetic disease, is the major form of dementia in the elderly. It has been shown that β amyloid, deposited in the AD brain, interacts with dynamin 1 and that the dynamin 2 (DNM2) gene homologous to the dynamin 1 gene is encoded at chromosome 19p13.2 where a susceptibility locus has been detected by linkage analysis. To test the genetic association of LOAD with the DNM2 gene, we performed a case–control study of 429 patients with LOAD and 438 sex- and age-matched control subjects in a Japanese population. We found a significant association of LOAD with single nucleotide polymorphism markers of the DNM2 gene, especially in non-carriers of the apolipoprotein E-ε4 allele. Even though subjects with the genotype homozygous for the risk allele at rs892086 showed no mutation in exons of the DNM2 gene, expression of DNM2 mRNA in the hippocampus was decreased in the patients compared to non-demented controls. We propose that the DNM2 gene is a novel susceptibility gene for LOAD. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Accelerated thymocyte maturation in IL-12Rβ2-deficient mice contributes to increased susceptibility to autoimmune inflammatory demyelination

IL-12Rβ2^−/− mice, which are unresponsive to IL-12, develop severe experimental autoimmune encephalomyelitis (EAE). The mechanisms for enhanced autoimmunity are incompletely understood. We report that in IL-12Rβ2^−/− mice, thymocytes undergo markedly accelerated maturation. This occurs at the transition from a double positive (DP) to a single positive (SP) phenotype, resulting in higher numbers of CD4 and CD8 SP cells, and to a lesser extent at the transition from double negative (DN) to DP cells. Accelerated maturation is observed in mice injected with anti-CD3 to mimic pre-T-cell receptor stimulation, and also in mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide to induce EAE.     

How can the innate immune system influence autoimmunity in type 1 diabetes and other autoimmune disorders?

The environment is important in determining the onset of autoimmune diseases such as type 1 diabetes. Genetic susceptibility factors interact with the environment to trigger and modulate a series of immune responses that ultimately lead to destruction of the insulin-producing beta cells of the pancreas. Although T lymphocytes are thought to play a major pathogenic role in the pathogenesis of diabetes, undoubtedly other components of the immune system also contribute to this process. How the environment may alter the course of disease is unknown, although viruses have been implicated in triggering and/or exacerbating the disease process. In this review, we will focus on how infection, particularly with viruses, may influence the onset of type 1 diabetes and other autoimmune diseases. Mechanisms such as molecular mimicry, bystander activation, and uncontrolled polyclonal activation of the immune system may contribute to the immune pathogenesis. We will also explore the interaction of the innate immune system with adaptive immune responses in predisposing individuals to the development of autoimmunity.     

FCεRI gene promoter polymorphisms and total IgE levels in susceptibility to atopic dermatitis in Korea

IgE-dependent activation of mast cells and basophils through the high-affinity IgE receptor (FcεRI) is involved in the pathogenesis of allergen-induced immune responsiveness in atopic diseases like atopic dermatitis (AD). We sought to determine FcεRI gene polymorphisms are associated with AD in Korean patients, and analyzed the relevance of FcεRI gene polymorphisms and serum IgE levels. We conducted a case-control association analysis (175 patients and 56 controls) of Korean subjects. Genotyping was performed using the TaqMan fluorogenic 5' nuclease assay, and serum levels of IgE were measured using a fluorescence enzyme immunoassay. We found that there were no significant relationships between FcεRI and AD, although there were trends towards an association between the 66T>C (rs2251746) polymorphism and total serum IgE levels in the Korean AD patients. In conclusion, while the 66T>C (rs2251746) of the FcεRIα polymorphism may be linked to AD and higher serum IgE levels, polymorphisms in the FcεRIβ gene did not confer susceptibility to AD in our patient sample.     

Molecular mimicry to Borrelia burgdorferi: pathway to autoimmunity?

Lyme borreliosis is due to infection with the tick-borne spirochete Borrelia burgdorferi, and is associated with persistent infection unless treated with antibiotics. The persistent nature of infection by B. burgdorferi can lead to development of chronic disease, as found in patients infected before recognition of the effectiveness of antibiotic therapy. Much speculation has surrounded the possibility that autoimmune mechanisms are involved in chronic symptoms. In most cases, involvement of autoimmunity in Lyme disease has not received experimental support. The exception is in a small group of patients with chronic arthritis whose abnormal joint symptoms persist after apparent elimination of the bacteria. In this review, the evidence supporting autoimmune mechanisms in Lyme disease will be discussed.     

Are SCN1A gene mutations responsible for genetic susceptibility to subacute sclerosing panencephalitis?

Dravet syndrome, characterized predominantly by myoclonus, has a striking clinical resemblance to subacute sclerosing panencephalitis (SSPE). Patients with Dravet syndrome develop significant mental decline with advancing age of affected child like in SSPE. It is well established that SCN1A gene mutations are associated with Dravet syndrome. Even periodic EEG complexes have been described in Dravet syndrome. In addition to Dravet syndrome, several other types of acute and subacute encephalopathic syndromes having clinical and electroencephalographic resemblance to SSPE are associated with SCN1A gene mutations.SSPE is a devastating progressive inflammatory disorder of the central nervous system. It is caused by persistent infection of the brain by an aberrant measles virus. Only a few of a vast number of measles infected pediatric population develop SSPE. There are several reports describing presence of SSPE is close relatives and it has been described previously in sibling and twin pairs. A genetic susceptibility for development of SSPE is likely. In fact, a variety of genetic abnormalities have already been described in patients with SSPE. It can also be argued that because of striking clinical resemblance between Dravet and various epileptic and encephalopathic syndromes associated with SCN1A gene mutations and SSPE, SCN1A gene abnormalities may also be responsible for susceptibility to SSPE in measles infected children.     

Animal models of endocrine/organ-specific autoimmune diseases: do they really help us to understand human autoimmunity?

Organ-specific or endocrine autoimmune diseases are complex, polygenic afflictions the penetrance of which is heavily dependent on various environmental influences. Important target tissues are the thyroid, the islets of Langerhans, gastric parietal cells and steroid-producing cells in the adrenal and ovary. The etiology of these diseases remains to be clarified. The pathogenesis is strongly associated with autoimmune phenomena. None of the current treatment approaches provides a cure; rather they represent replacement therapy. An important objective in the treatment of endocrine/organ-specific autoimmune diseases is the detection of individuals at risk for the development of such diseases and the development of interventions to prevent an outbreak of the diseases. This requires an exquisite knowledge of the early etio-pathogenic stages of these diseases. This review concentrates on the usefulness of animal models for a precise understanding of these very early stages. It must be emphasized that studying animal models cannot answer all the problems presented by endocrine/organ-specific autoimmune diseases as seen in the clinic. It must be expected – considering the different etiologies in the different animal models (see below) – that the causes of the diseases in the human and the involvement of various genes and environmental factors may also vary. Yet, particularly in the study of the pre-autoimmune phases of the diseases, there is hardly any alternative to the study of animal models. Only limited series of experiments can be carried out in human subjects at risk to develop such diseases. Moreover, a general semblance (blueprint) of the etio-pathogenesis found in the animal models can lead the way for human studies. Efforts to understand the patho-physiology of the early stages of endocrine/organ-specific autoimmune diseases have mainly involved animal models that ”spontaneously” develop such diseases. Of these the bio-breeding diabetes-prone (BB-DP) rat and the non-obese diabetes (NOD) mouse are the most well studied, yet many studies have also been carried out in the obese strain (OS) chicken. Apart from these spontaneous models there are animal models that are induced by environmental perturbations (viruses, toxic substances), by thymectomy procedures or by genetic manipulations, e.g., the RIP-LCMV model and the BDC 2.5 TCR mouse model. A general blueprint has emerged from the studies into the early stages of the pathogenesis of endocrine/organ-specific autoimmune diseases in these animal models: animals at risk to develop endocrine/organ-specific autoimmune diseases show various pre-autoimmune aberrancies in their target glands, T cells, macrophages (Mφ) and dendritic cells (DC). The presumably aberrant target cells, T cells, DC and Mφ need to interact abnormally before autoimmune disease can fully develop. In this abnormal interaction additional aberrancies in other regulatory systems may play a role in a further exacerbation of the self-directed immune response, such as defects in the hypothalamus pituitary adrenal (HPA) axis system. The various aberrancies are partly genetically determined by a variety of separate genes, particularly MHC-related genes, but they may also be environmentally induced (e.g., via viruses, high iodine diet, and other experimental manipulations). Recently evidence has been gathered for pre-autoimmune aberrancies similar to the animal models in the DC/ Mφ compartment and the HPA axis in humans at risk to develop endocrine/organ-specific autoimmune diseases. However, analogous pre-autoimmune abnormalities in human target glands or in T cell function have not yet been found with certainty. We believe that animal models of endocrine/organ-specific autoimmune disease still hold immense promise for the discovery of pathways, genes and environmental factors that determine the development of endocrine/organ-specific autoimmune diseases. Animals affected by such diseases provide a unique opportunity to uncover disease-associated pathways, which are complicated to define in man. Acknowledgments. Work in our departments is supported by grants from the Dutch Diabetic Foundation, the Dutch Organization for Scientific Research Now – Health Sciences, the European Community and the American Diabetic Association. Correspondence to: H.A. Drexhage     

Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?

Subtypes of HLA-DR4 are associated with susceptibility or protection against type 1 diabetes (T1DM). We addressed whether this reflects linkage disequilibrium with the true susceptibility locus by studying broader MHC haplotypes marked by alleles of HLA-B, IKBL (adjacent to TNFA) and complement C4. The study used a largely Caucasian cohort from Western Australia. HLA-DRB1*0401 and HLA-DRB1*0405 marked susceptibility to T1DM. In Caucasians, DRB1*0401 occurs predominantly in the 44.1 ancestral haplotype (AH; HLA-A2,B44, DRB1*0401,DQB1*0301) and the 62.1AH (HLA-A2,B15(62),DRB1*0401,DQB1*0302). HLA-B15 marked susceptibility and HLA-B44 marked with resistance to T1DM in patients and controls preselected for HLA-DRB1*0401. A gene between TNFA and HLA-B on the 8.1AH (HLA-A1,B8,;DR3,DQ2) modifies the effects of the class II alleles. Here, alleles characteristic of the 62.1AH (C4B3, IKBL+446*T and HLA-A2,B15) were screened in donors preselected for HLA-DRB1*0401. C4B3 was associated with diabetes, consistent with a diabetes gene telomeric of MHC class II. However, increases in carriage of IKBL+446*T and HLA-A2,B15 were marginal, as too few control subjects were available with the diabetogenic alleles. However, with these tools, selection of HLA-DRB1*0401, DQB1*0302 donors who are positive and negative for C4B3 will allow bidirectional mapping of diabetes genes in the central MHC.     

Adenoviral vectors--how to use them in cancer gene therapy?

Gene therapy is most often described as a technique for introducing the foreign genetic material into cells with a correction of a dysfunctional gene as its final goal. Today, it is well known that cancer is one of the leading causes of mortality in the world. Besides classical methods for cancer treatment new strategies against cancer are needed. Although originally being designed as a treatment for monogenetic illness, soon after, gene therapy appeared as a potential new strategy in cancer therapy. One of the widely used vectors for cancer gene therapy is adenovirus. In this review we have described molecular biology of adenoviruses and basis for construction of adenoviral vectors. We have also described concepts for cancer gene therapy including their in vitro and in vivo application. Special attention is drawn toward retargeting of adenovirus as a new approach in vector design for cancer gene therapy, in order to restrict transgene expression in tumor tissue. This approach uses biophysical as well as genetic characteristics of tumor itself and its supporting tissue, allowing new "bypass" in cancer gene therapy.     

Coexistence of thyroid autoimmunity with other autoimmune diseases: friend or foe? Additional aspects on the mosaic of autoimmunity

Autoimmunity encompasses a wide spectrum of diseases from organ-specific diseases like Hashimoto thyroiditis, to systemic diseases such as systemic lupus erythematosus. These diseases are characterized by inflammation and the production of a wide range of autoantibodies directed against multiple autoantigens. Although their etiology is still poorly understood, genetic, immunological, hormonal, and environmental factors are major predisposing and triggering factors. These multiple factors, like pieces in a mosaic, may interplay in different forms, leading to the expression of various autoimmune manifestations and diseases. This phenomenon, which has been referred by us as the "mosaic of autoimmunity", illuminates the diversity of autoimmune manifestations among susceptible individuals. From this theoretical framework we conducted a wide search of the literature, on the prevalence of thyroid autoimmunity, the commonest of the autoimmune conditions, among other autoimmune diseases, and discuss the possible clinical significance of this association.     

Islet beta-cell death - fuel to sustain autoimmunity?

Under what context do dying beta-cells enhance the autoimmune process in type 1 diabetes? Kim et al. (2007) find that secondary necrosis of beta-cells can prime the autoimmune response via uptake by and activation of antigen-presenting cells through Toll-like receptor 2.