Critical Examination Of Autoimmunity And Inflammation

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], others predispose an individual to the development of multiple disorders, which indicates that shared mutations may affect genes or pathways implicated in the pathogeneses of several dis- eases [29,30]. Moreover, while the mechanisms and causes of development may differ in vari- ous diseases, the downstream effects occurring after the disease onset may be similar. This similarity can potentially underlie responsiveness of different types of diseases to the same type of treatment (e.g. glucocorticoids) [31–33] indicating the presence of shared drug targets.

However, the global picture of molecular mechanisms underlying the similarities and specifici- ties of chronic inflammatory disorders is not completely understood and is addressed in this study, using gene expression data to compare activation patterns of selected pathways in a sub- set of AI and AIF diseases.

Luckily, the advances in high-throughput biological data measurements, explosive growth of data in various public repositories and development of new bioinformatics algorithms for data analysis, already provide an opportunity to address the above mentioned issues from a systems biology viewpoint. Previously, we had developed a bioinformatics pipeline for path- way perturbation based analysis and similarity/specificity assessment of disease groups, and have applied it to a number of lung diseases [34]. The obtained results had confirmed the validity of our methodology, as well as had led us to draw new conclusions on pathological characteristics of lung diseases. In the present work, we have used our approach for global assessment of similarities and specificities of downstream molecular events of chronic inflammation through evaluation of pathway activity changes in autoimmune and autoinflammatory disorders.

1.2 Statement Of Problem

Our goal was to include as many conditions as possible, while in the meantime minimizing heterogeneity of microarray platforms and source tissue used for transcriptome measurement. These criteria left us with four monogenic autoinflammatory, four polygenic autoinflammatory disorders sharing characteristics with autoinflammation and autoimmunity, and four polygenic autoimmune conditions (Table 1). Monogenic autoimmune disorders were not included in our study, as to our knowledge, respective transcriptome data meeting our selec- tion criteria were not available. Even though the apparent heterogeneity of the disorders selected in our study presented a challenge for identification of common mechanisms, the existing similarities and, in particular, the common inflammatory component of these disor- ders, remained intriguing and encouraged us to undertake a comparative gene expression analysis of a large set of existing transcriptome data.

Our study offers a systems biology approach for comparative analysis of gene expression data from cohorts carrying apparent divergent diseases with common immune related manifestations. Despite the limitations discussed below, such studies may contribute to identification of common pathways in autoimmunity and autoinflammation, and have the potential to facilitate development of new experimental strategies for understanding the molecular mechanisms underlying the interplay between those processes.

1.3 Purpose Of The Study

The main aim of this study is to critically examine autoimmunity and inflammation. This study has combined several publicly available datasets for autoimmune and autoinflammatory diseases in an attempt to uncover their common and specific pathobiological features.