Current Pharmaceutical Design - Volume 21, Issue 18, 2015

Autoimmune diseases are a group of disorders mediated by self-reactive T cells and/or autoantibodies. Mice, as the most widely used animal for modeling autoimmune disorders, have been extensively used in the investigation of disease pathogenesis as well as in the search for novel therapeutics. Since the first mouse model of multiple sclerosis was established more than 60 years ago, hundreds of mouse models have been established for tens of autoimmune diseases. These mouse models can be divided into three categories based on the approaches used for disease induction. The first one represents the induced models in which autoimmunity is initiated in mice by immunization, adoptive transfer or environmental factors. The second group is formed by the spontaneous models where mice develop autoimmune disorders without further induction. The third group refers to the humanized models in which mice bearing humanized cells, tissues, or genes, develop autoimmune diseases either spontaneously or by induction. This article reviews the history and highlights the milestones of the mouse models of autoimmune diseases.

This article reviews the commonly used murine strains for studying lupus and lupus nephritis, including strains that develop lupus spontaneously, congenic strains, induced models of lupus, as well as genetically engineered mouse models of lupus bearing transgenes or knockouts. The review then summarizes the main cellular and molecular pathways that lead to the pathogenesis of this autoimmune disease, including autoantibodies. Finally, it concludes with therapeutic insights gained from using mouse models of lupus. To sum, much of what we have learned about lupus has arisen from studying mouse models of the disease, and the laboratory mouse continues to be one of the best tools for studying human SLE.

Sjogren’s syndrome (SjS) is a chronic autoimmune disorder characterized by immune cell infiltration and progressive injury to the salivary and lacrimal glands. As a consequence, patients with SjS develop xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). SjS is the third most common rheumatic autoimmune disorder, affecting 4 million Americans with over 90% of patients being female. Current diagnostic criteria for SjS frequently utilize histological examinations of minor salivary glands for immune cell foci, serology for autoantibodies, and dry eye evaluation by corneal or conjunctival staining. SjS can be classified as primary or secondary SjS, depending on whether it occurs alone or in association with other systemic rheumatic conditions, respectively. Clinical manifestations typically become apparent when the disease is relatively advanced in SjS patients, which poses a challenge for early diagnosis and treatment of SjS. Therefore, SjS mouse models, because of their close resemblance to the human SjS, have been extremely valuable to identify early disease markers and to investigate underlying biological and immunological dysregulations. However, it is important to bear in mind that no single mouse model has duplicated all aspects of SjS pathogenesis and clinical features, mainly due to the multifactorial etiology of SjS that includes numerous susceptibility genes and environmental factors. As such, various mouse models have been developed in the field to try to recapitulate SjS. In this review, we focus on recent mouse models of primary SjS xerostomia and describe them under three categories of spontaneous, genetically engineered, and experimentally induced models. In addition, we discuss future perspectives highlighting pros and cons of utilizing mouse models and current demands for improved models.

Systemic sclerosis is a systemic connective tissue disorder characterized by the fibrosis of the skin and certain visceral organs, vasculopathy, and immunological abnormalities. Several genetic and inducible animal models of SSc have been developed and are available for research studies. The purpose of this review is to summarize the various animal models of systemic sclerosis and describe the various contributions of these models in terms of understanding the pathophysiology of the condition and searching for new therapeutic strategies for this incurable disease.

Inflammation of blood vessels (vasculitis) results from many pathological processes and is found in many different diseases. However, in most situations, the pathological processes inducing vasculitis are unknown. The discovery of anti-neutrophil cytoplasmic autoantibodies (ANCAs) in the 1980s opened the door for studies that eventually led to the description of a new previously undescribed disease, ANCA-associated vasculitis (AAV). Unravelling the immunopathogenesis of this new disease resulted largely from the development of animal models. The major breakthroughs were the description of ANCA, its association with small vessel vasculitis and the discovery of its target autoantigens (myeloperoxidase and Proteinase 3). Three major disease syndromes comprise the AAVs, microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA). Recent human studies suggest that proteinase 3 and myeloperoxidase associated vasculitis are two separate but related diseases. The ability to induce murine autoimmunity to myeloperoxidase including ANCA (with the same immune staining patterns as human ANCA) and the capacity of this anti-myeloperoxidase autoimmunity to induce disease with many of the characteristic features of human AAV are well developed. However, the development of animal models of anti-proteinase 3 ANCA and EGPA is much less well developed. Animal models are important in understanding the human disease and in particular in defining potential therapeutic targets and in early stage therapeutic testing of potential drugs. Clearly the relevance of animal models depends on how closely they mimic human diseases. The current status of animal models of vasculitis will be described in detail with reference to these criteria.

Autoimmune hepatitis is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. Although the major targets of this autoimmune-mediated disease have been identified more than two decades ago, the current treatment of autoimmune hepatitis is still based on traditional therapies including a glucocorticoid treatment. One reason for this impasse is the limited availability of reliable animal models that reflect the clinical features of autoimmune hepatitis and allow for the identification of critical factors driving the autoimmune destruction and the evaluation of innovative therapies. However, the status of the liver as an immune privileged organ harbouring many immunosuppressing mechanisms hampers the development of such models. Here we will review the past and present attempts to develop a consistent animal model for autoimmune hepatitis.

Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic liver disease of unknown etiopathogenesis that mainly affects middle-aged women. Patients show non-suppurative cholangitis with damage and destruction of small- and medium-sized intrahepatic bile ducts. Characteristically, the disease is strongly associated with autoimmune phenomena such as the appearance of serum antimitochondrial autoantibodies (AMA) and portal infiltrates with autoreactive T cells which recognize the inner lipoyl domain of the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Here we review the major characteristics of a series of inducible and genetically modified animal models of PBC and analyze their similarities and differences with PBC features in humans.

Autoimmune thyroid disease is the most common organ-specific autoimmune disorder which consists of two opposing clinical syndromes, Hashimoto’s thyroiditis and Graves’ (hyperthyroidism) disease. Graves’ disease is characterized by goiter, hyperthyroidism, and the orbital complication known as Graves’ orbitopathy (GO), or thyroid eye disease. The hyperthyroidism in Graves’ disease is caused by stimulation of function of thyrotropin hormone receptor (TSHR), resulting from the production of agonist antibodies to the receptor. A variety of induced mouse models of Graves’ disease have been developed over the past two decades, with some reproducible models leading to high disease incidence of autoimmune hyperthyroidism. However, none of the models show any signs of the orbital manifestation of GO. We have recently developed an experimental mouse model of GO induced by immunization of the plasmid encoded ligand binding domain of human TSHR cDNA by close field electroporation that recapitulates the orbital pathology in GO. As in human GO patients, immune mice with hyperthyroid or hypothyroid disease induced by anti-TSHR antibodies exhibited orbital pathology and chemosis, characterized by inflammation of orbital muscles and extensive adipogenesis leading to expansion of the orbital retrobulbar space. Magnetic resonance imaging of the head region in immune mice showed a significant expansion of the orbital space, concurrent with proptosis. This review discusses the different strategies for developing mouse models in Graves’ disease, with a particular focus on GO. Furthermore, it outlines how this new model will facilitate molecular investigations into pathophysiology of the orbital disease and evaluation of new therapeutic interventions.

Autoimmune bullous dermatoses (AIBD), such as pemphigus, bullous pemphigoid or epidermolysis bullosa acquisita, are prototypical organ-specific autoimmune diseases. Clinically they are characterized by widespread mucocutaneous blistering, which is often difficult to treat. Patients with AIBD suffer from a significant morbidity and an increased mortality. In AIBD blistering is caused by autoantibodies targeting structural proteins of the skin. During the past decades animal models of AIBD have been developed. These animal models have greatly contributed to our current understanding of AIBD pathogenesis. Most of these insights, however, still await their translation into clinical use. Recently, AIBD animal models have been used to test the efficacy of known and novel drugs. Hence, these models are now not only employed to unravel the pathogenesis of AIBD, but also to assess therapeutic approaches to address the so far unmet high medical need for new treatments. We here review animal model of AIBD: In addition to spontaneously arising AIBD in animals, AIBD can be induced, mostly in mice, by (i) transfer of (auto)-antibodies, (ii) transfer of (auto)-antigen specific lymphocytes, (iii) immunization or (iv) by genetic modifications leading to spontaneous blistering. In combined use, these models allow dissecting all aspects of AIBD pathogenesis, i.e. loss of tolerance, autoantibody production and blistering. Overall we aim to foster a broader use of AIBD animal models, especially in translational biomedical research, to deepen our understanding of AIBD pathogenesis and to develop novel treatments for patients.

Multiple sclerosis (MS) is a chronic neurological disorder of the central nervous system (CNS) leading to progressive accumulation of neurological deficits arising from recurrent episodes of inflammation, demyelination and neuronal degeneration. While the aetiology of the disease is unknown MS is widely considered to be the result of aberrant T cell and antibody responses to CNS antigens giving rise to the common concept that MS is an autoimmune disease or that there is an autoimmune component in the pathogenesis. This idea has lead to the development of experimental autoimmune encephalomyelitis (EAE) mouse models of MS in which immunisation with CNS antigens induces neurological and pathological signs of disease in mice. In addition to EAE models, injection with neurotropic viruses has been used to examine how infections are implicated in the disease process and how they may generate autoimmune responses in the CNS. Viral models are also crucial to investigate the impact of blocking trafficking of immune responses into the CNS since an emerging side-effect of current immunotherapeutic approaches in MS is the reactivation of viruses within the CNS. To investigate myelin damage and repair in the absence of the adaptive immune response, toxin-induced demyelination using cuprizone, ethidium bromide and lysolecithin, which rapidly leads to remyelination when the toxins are withdrawn, is also reviewed. Mice also lend themselves to the vast array of transgenic technologies to probe specific pathways as well as the use of humanised transgenic mice to examine the impact of human molecules. Despite the vast array of mouse models EAE is the most frequently exploited paradigm used to develop therapeutic approaches. However, despite over one thousand compounds used in the treatment of EAE few have become licenced for treatment of MS so far. Thus, this review also debates the reasons for these failures in mouse models as well as discusses how mouse models can be better utilised to provide more powerful preclinical tools to develop rational therapies for multiple sclerosis.

Uveitis is a sight threatening intraocular inflammation accounting for approximately 10% of blindness worldwide. On the basis of aetiology, disease can be classified as infectious or non-infectious; and by anatomical localization of inflammation as anterior, posterior and panuveitis. Non-infectious uveitis is believed to be autoimmune in nature with Th1 and Th17 cells being identified as the prominent effector cell types. Numerous animal models of autoimmune uveitis were developed contributing to our understanding of this inflammatory condition. The classical peptide-induced experimental autoimmune uveoretinitis (EAU) model resembles human posterior uveitis due to the recurrent/relapsing nature of the disease; while the intraocular inflammation triggered by administration of bacterial lipopolisaccharide (endotoxin-induced uveitis, EIU) mimics closely anterior uveitis. The clinical need for novel, more targeted forms of anti-inflammatory therapy has emerged as currently available therapeutic strategies are associated with a number of adverse effects and intolerance in patients. This review summarises knowledge about existing mouse models of uveitis, discusses mechanisms driving intraocular inflammation and describes possible customised translational treatment strategies that can be potentially used in the clinic to prevent blindness in patients.

Myasthenia gravis is a muscle weakness disease characterized by autoantibodies that target components of the neuromuscular junction, impairing synaptic transmission. The most common form of myasthenia gravis involves antibodies that bind the nicotinic acetylcholine receptors in the postsynaptic membrane. Many of the remaining cases are due to antibodies against muscle specific tyrosine kinase (MuSK). Recently, autoantibodies against LRP4 (another component of the MuSK signaling complex in the postsynaptic membrane) were identified as the likely cause of myasthenia gravis in some patients. Fatiguing weakness is the common symptom in all forms of myasthenia gravis, but muscles of the body are differentially affected, for reasons that are not fully understood. Much of what we have learnt about the immunological and neurobiological aspects of the pathogenesis derives from mouse models. The most widely used mouse models involve either passive transfer of autoantibodies, or active immunization of the mouse with acetylcholine receptors or MuSK protein. These models can provide a robust replication of many of the features of the human disease. Depending upon the protocol, acute fatiguing weakness develops 2 - 14 days after the start of autoantibody injections (passive transfer) or might require repeated immunizations over several weeks (active models). Here we review mouse models of myasthenia gravis, including what they have contributed to current understanding of the pathogenic mechanisms and their current application to the testing of therapeutics.

Immune thrombocytopenia or ITP is a debilitating and life-threatening disorder affecting more than 4 in every 10, 000 adults annually. Following a basic understanding of the immunopathology underlying ITP, namely that production of anti-platelet antibodies results in accelerated platelet clearance and thrombocytopenia, animal models of ITP were quickly developed. Rodent models that develop ITP spontaneously or by passive transfer of anti-platelet sera or antibodies have become instrumental in investigating the mechanisms responsible for the breakdown of tolerance in human ITP, understanding the immunopathology that underlies the progression of platelet destruction, elucidating the mechanism(s) of therapeutic amelioration of the ITP, and driving the development of new therapeutic modalities. This review aims to capture the development history and methodology of currently available ITP disease models, and review their advantages and limitations in the study of various aspects of ITP. We also review how closely the various ITP models reflect the pathobiology of human ITP and their usefulness in advancing the development of new therapeutics, which are particularly needed to address the unmet need of patients who are refractory to the currently available repertoire of interventions.

Cardiovascular diseases are the leading cause of death in industrialized nations worldwide. Of all deaths resulting from cardiovascular diseases, 2% are caused by inflammatory heart disease; specifically, myocarditis. The etiology causing myocarditis still remains unclear. Both infectious and non-infectious factors are capable of triggering myocarditis. Acute myocarditis manifests itself in a variety of ways ranging from subclinical disease to sudden heart failure, as well as the occurrence of chest pain, palpitations, and syncope. Myocarditis can lead to dilated cardiomyopathy, this being the most frequent cause for heart transplantation. Since the underlying mechanism and the pathways behind the disease initiation and progression still need to be elucidated, the need for mouse models simulating the human disease is evident. Various mouse models are frequently used to study myocarditis. Inflammation of the myocardium as a result of infectious agents can be investigated with a widely used animal model where mice are infected with coxsackievirus B3. For autoimmune (non-viral) myocarditis, several mouse models (including induction with myosin or troponin I) have been established to better understand the role of autoantibodies and their influence on disease progression. With these different models, various phases of the disease can be investigated and these findings are used to develop more specific therapies that can be translated into the clinic as a "bench-to-bedside" approach.