Vitiligo is a disease where the epidermal pigment cells [melanocytes], the main defense mechanism against UV mediated damage, are lost randomly.The disappearance of melanocytes shows ugly appearance of skin with varying degree of white maculae. As such, vitiligo is neither life threatening nor a debilitating disease as compared to other well known autoimmune diseases such as lupus, rheumatoid arthritis, autoimmune diabetes etc. Further, despite the demonstration of the presence of mild inflammatory infiltrate in the skin paralleling the loss of melanocytes, vitiligo can not be categorized as an inflammatory dermatoses. Interestingly, the disease is often associated with the presence of classical autoimmune disease symptoms in the same patient.
Various types of theories on the etiology of vitiligo are often being discussed and debated endlessly among the investigators. Since last decade, however, the autoimmune mechanism is being advocated by the investigators. Indeed, our own work meticulously demonstrate that the loss of melanocytes in “a certain type of generalized viriligo” is caused by autoreactive meanocyte specificT cells. In addition, in some patients auto-antibodies against melanocytes can also be demonstrated. Nevertheless, vitiligo as such is not always perceived in the category of the classically known autoimmune disease.
Since the autoimmune pathology, though remains obscure, it is believed that the perturbation of homeostatic immune physiology of host, (which is maintained via the interacting antigen presenting cells [APC]-T cells and B cells), leads to the precipitation of any autoimmune disease including vitiligo. Such perturbation immune homeostasis can be illustrated clearly in vitiligo pathology. One bonus point for studying vitiligo as a model autoimmune disease is that the therapeutics for melanoma, a deadly skin cancer, can possibly be designed, by studying vitiligo. Against the above scenario, this presentation will argue the necessity for undertaking vitiligo research within the umbrella of both autoimmunity and cancer. For further reading the followings could be referred for further reading.
11:20 – 12:00 Inflammatory mediators and lupus autoimmunity
Professor Rizgar A Mageed, William Harvey Research Institute,
St Barts and the Royal London, UK It is established that the immune and inflammatory responses cross-regulate each other. In this study we show that manipulation of the immune system in murine lupus by administration of recombinant TNFa, or blocking endogenous TNFa with antibody profoundly influences lupus autoimmunity. The studies have also shown that in this setting TNFa/anti-TNFa act directly on T and B-lymphocytes and profoundly affect their proliferation, cytokine production and a number of other vital functions with consequent effects on autoimmunity. We explore the pathways through which these responses are effected. Further, the relevance of the studies to human diseases will be discussed.
12: 00 – 12:05 Speakers photo
12:05 – 13:00 Lunch
13:00 – 13:40 Animal models for autoimmune diabetes
Dr Lucienne Chatenoud, Hôpital Necker, France
13:40 – 15:20 What knockout mice have taught us about the pathogenesis of lupus
Professor Marina Botto, Imperial College, London, UK
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by the production of an extraordinary array of autoantibodies reactive with nuclear antigens. Interaction of these autoantibodies with their cognate antigens leads to widespread inflammatory injury and underlies the pathogenesis of SLE. The aetiology of SLE in unknown, as well as the factors that influence the severity of disease manifestations. In mice and humans, expression of autoimmunity is under complex genetic control. A strategy to analyse the contribution of individual alleles to a multigenic trait has been the development of animals carrying genetic manipulations of specific genes implicated in the pathogenesis of SLE. This approach allows an in vivo assessment of the impact on the immune system of severe modifications in the expression (deficiency or overproduction) of genes suspected to play a role in the development of an autoimmune response. Genetically manipulated models have proved to be very useful to dissect effector mechanisms involved in disease pathogenesis and/or to delineate genetic mechanisms that may lead to systemic autoimmunity. Several important observations have emerged from the genetically engineered models. First, whether a particular gene or mutation causes a disease depends on the host: both disease susceptibility and the disease phenotype that result from the alteration of a single gene depend on other genes. Second, some genetic defects may share common pathogenic pathways. As a result, one could reasonably predict the possibility of developing common therapeutic strategies to treat this multifactorial complex condition. Finally, the development of genetically manipulated animals has led to the discovery of new roles for genes with known immune functions. The complement deficient animals that will be presented in more details are a typical example of this. There is overwhelming evidence that deficiency of classical pathway complement proteins causes the development of SLE in humans and mice. Complement is implicated in the pathogenesis of SLE in several ways and may act as both friend and foe. Recently it has been suggested that one of the main activities of the classical pathway is to promote the resolution of inflammation by enhancing the clearance and uptake of dying cells by macrophages. We have developed a series of murine models of complement deficiency and SLE and found that these mice develop a lupus-like disease and have an impaired clearance of apoptotic cells. We have observed a similar phagocytic defect in macrophages derived from C1q-deficient humans cultured in autologous serum. This defect was rectifiable with purified human C1q. Consistent with these findings, we have data showing that macrophages from two lupus-prone murine strains have an impaired phagocytosis of apoptotic cells when compared with two non-autoimmune strains. Collectively these data strongly support the hypothesis that deficiency in complement predisposes to the development of lupus through inefficient removal of potentially pathogenic apoptotic cell debris. However, impaired clearance of such cells is, on its own, insufficient to produce autoimmunity. The data available from knockout mice emphasize that susceptibility to an autoimmune disease might depend on many factors in addition to the defective removal of dying cells. In summary it is clear that the traditional view of the role of complement in autoimmunity needs revision. Complement activation in lupus has been viewed as a major cause of tissue injury. Instead, evidence is emerging that complement may play a protective role rather than an exclusively pro-inflammatory role in tissue injury.
15:20 - 16:00 Pre-clinical models of autoimmune connective tissue diseases
Professor David Abraham, University College London ¸UK
Connective tissue diseases have complex pathogenic mechanisms encompassing host genetics, vascular manifestations, aberrant inflammation and autoimmunity leading to enhanced tissue repair resulting in scarring and replacement fibrosis. Contemporary approaches use reporter transgenesis to track and target pathogenic cells and knock-in and -out technologies to manipulate the cells and key molecular events involved. These are utilised within existing naturally occurring disease models and those induced by modulating the environment. Developing useful systems to model and study human disease processes in vivo represents a major biomedical challenge, as does their interpretation and utility as pre-clinical models to reliably access novel therapeutics
16:00 – 16:30 Selected Abstracts
16:30 – 17:00 Chairman’s summing up.