A CRITICAL EVALUATION OF WOMEN AND RURAL DEVELOPMENT

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CHAPTER ONE

1.0  INTRODUCTION

1.1  BACKGROUND TO THE STDUY

Epidemiological studies provide increasing evidence for the rise in prevalence of immune- related disorders including autoimmune and allergic diseases in Western countries [1–3]. It is predicted that the incidence of chronic inflammatory disorders, particularly autoimmune diseases, such as type 1 diabetes, Crohn’s disease, rheumatoid arthritis and multiple sclerosis, will grow even more rapidly during the next several decades [1,4,5]. Moreover, chronic inflammation is being recognized as an important trigger and contributor to the development and progression of various other human complex diseases, such as certain cancers, atherosclerosis, strokes and ischemic heart diseases, and even psychiatric disorders (schizophrenia and post-traumatic stress disorder) [6–10].Therefore, understanding the molecular mechanisms underlying the development of inflammatory disorders will have significant impact on public health.

Autoimmune diseases(AI) are characterized by dysfunction of the immune system leading to loss of immune tolerance against self-tissues, by the presence of autoreactive T and B cells, and by a complex pathogenesis of multifactorial etiology, whereas genetics and environmental factors together are responsible for disease onset [11,12].There are more than 80 such condi- tions affecting susceptible human subjects [13]. Autoimmune conditions may be systemic (tar- geting multiple organs and tissues), as is the case of lupus, or tissue specific, as is the case of multiple sclerosis (against myelin) or type 1 diabetes (against pancreatic beta cells). The simul- taneous presence of several autoimmune diseases is observed in some cases, pointing at the possibility of a shared origin and/or mechanisms [14]. Autoinflammatory diseases (AIF) are a relatively new and expanding group of self-directed inflammatory disorders, clinically described as periodic fever syndromes but also with epi- sodes of acute inexplicable inflammation involving the innate immune system [15,16]. They are characterized by inflammatory episodes at disease-prone sites, in the absence of autoreac- tive T cells and high autoantibody titers [17,18]. Despite the differences in primary players, they share common characteristics with AI diseases, such as self-tissue directed inflammation in the absence of an obvious infectious trigger or injury. While in AIFs the innate immune sys- tem directly causes tissue inflammation, in AIs the innate immune system activates the adap- tive system and this later activates the inflammatory process [15]. The autoinflammatory syndromes include a subset of hereditary conditions characterized by recurrent episodes of fever and self-resolving attacks of systemic inflammation without microbial infection or auto- immunity. There are several AIF associated with genetic mutations affecting the innate immune system, the primary defense system against foreign antigens [19]. Such genetic mutations have been identified affecting genes encoding for the tumor necrosis factor receptor (TNFR1) as is the case for the autosomal dominant TNF receptor associated syndrome (TRAPS) [20] or the gene encoding for mevalonate kinase (MVK) responsible for the HIDS syndrome. Mutations of the MVK gene are responsible for an increase of mevalonic acid concentrations, elevated levels of IgD in the serum and also an increased secretion of IL-1β [21,22]. Similarly several autoinflammatory syndromes are related with the gene encoding for pyrin [22]. The PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a dominantly inherited autoinflammatory condition is associated with mutations in the gene encoding for proline serine threonine phosphatase-interacting protein (PSTPIP1) that inter- acts with pyrin [23]. Pyrin and PSTPIP1 proteins are associated with the cytoskeleton in mye- loid/monocytes and their interaction contributes to increased IL-1β production, NFkB activation and apoptosis [24]. Finally the connection between pyrin and autoinflammation is observed in the Cryopyrin-Associated Periodic Syndromes (CAPS) in which mutations of genes encoding for the components of the proteins involved in the inflammasome (NLRP3) are implicated [25–27].The phenotypic heterogeneity characteristic of AI and AIF diseases, does not necessarily reflect fundamental genetic or mechanistic differences between these groups. Indeed, while some gene variants and SNPs are specific to a particular disease [11,28].