Review
Geoepidemiology, gender and autoimmune disease

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Abstract

Autoimmune diseases include more than 70 different disorders affecting over 5% of the population of the Western countries. They are mainly characterized by female predominance and have great impact on the quality of life of affected subjects. It is generally accepted that ADs are the result of a complex interaction between genetic and environmental factors; however the mechanisms involved in the loss of tolerance remain unknown. Studying the distribution of these conditions across various global regions and ethnic groups by means of geoepidemiology might readily provide epidemiological data and also advance our understanding of their pathogenesis. Indeed, geoepidemiology demonstrates that genetic susceptibility interacts with lifestyle and environmental factors, which include socioeconomic status, infectious agents (triggering or protective agents), environmental pollutants, and vitamin D (dependent on sunlight exposure), in determining the risk of developing autoimmunity and in the understanding of their female prevalence. To properly understand the geoepidemiology of human autoimmunity, it is important to consider the many pleiotropic factors which lead to its initiation. In most studies the focus has been on genetics and environment. However, in this review the focus is primarily on gender. Overall, autoimmune diseases are well known to have female predominance, but there is significant variation in geographic area. Further, the mechanisms that influence female predominance are relatively unknown. Hence the attempt in this review is to focus on these critical issues.

Introduction

Autoimmune diseases (ADs) are a well-known cause of morbidity and mortality affecting approximately 6% of the western population [1], [2]. The study of the distribution of these conditions and the determinants of disease gradients across different regions and populations, otherwise known as geoepidemiology, indicates that incidence and prevalence of ADs are growing worldwide. Moreover, the frequency of ADs differs from country to country and geographic aggregates have been delineated [3]. Interest in these conditions is increasing as well, and the number of scientific publications has strongly risen over the last decade [4]. The importance of geoepidemiology does not lie solely in geographically delineating the burden of each disease, but also in advancing our understanding of its etiology, the mechanisms of immune disregulation, and triggering elements, which might ultimately enhance our ability to diagnose and treat [2], [3]. In this respect, an important body of research has pointed out the necessity, for autoimmunity to occur, of the combination of a susceptible genetic background with environmental triggers. Unfortunately large, international epidemiological investigations are lacking in the majority of ADs; on the other side, epidemiological data have been recently generated in countries with no previously available information.

In order to properly understand the geoepidemiology of ADs, it is important to consider that these disorders manifest a wide variability in terms of targeted tissues, age of onset, and response to immunosuppressive treatments. The one feature that is shared by the majority of these conditions, however, is the predominance in the female sex with over 80% of patients with AD being women [5]. The unbalanced sex ratio also varies significantly across the clinical spectrum and the more conspicuous sex differences are observed in Sjogren's syndrome, systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC) [5]. Even though the female predisposition to AD has been known for over a century, the precise cause of this bias remains unknown and relatively few hypotheses have been proposed. Epidemiological studies have led to the identification of both genetic factors and environmental elements, as additional players in tolerance breakdown, to explain both ADs onset and the female predominance. Among sex-related factors that have been proposed, we note that sex hormones and reproductive history, fetal microchimerism, X chromosome inactivation; and X chromosome abnormalities have collected the most data. However, none of these hypotheses has thus far gathered enough convincing evidence and in most cases data are conflicting.

This review will critically describe geoepidemiological aspects related to the study of autoimmune conditions and its female prevalence. We will analyze the role of genetic and environmental factors in the so-called “geographical gradient”, and discuss geoepidemiological aspects about AD and its sex prevalence.

Section snippets

Geoepidemiology and autoimmunity

Analytical epidemiology deals with the concept of risk; indeed, distinguishing genetic elements from environmental injuries and identifying new potential risk factor for ADs development, is the effort of the clinical epidemiologist in autoimmunity [1]. Since incidence and prevalence of most ADs are not homogeneous, their frequency differs from country to country, and geographic aggregates have been delineated avoiding methodological errors is essential in order to compare epidemiological data

Sex prevalence

The most striking sex differences in autoimmune diseases are observed in Sjogren's syndrome, SLE, PBC, autoimmune thyroid disease (including both Hashimoto's and Graves' diseases) and scleroderma in which 80% of the patients are women. On the other hand, RA, MS and myasthenia gravis have a lower female prevalence but still 60% of the patients are women [46].

The effects of sex hormones on the immune function were first based on the reported role of estrogens in lymphocyte maturation, activation,

Concluding remarks and future directions

The field of autoimmunity is clearly showing how the findings of basic science influence routine clinical practice in terms of diagnostic procedures, clinical management and prediction of outcome. However, continuous effort should be performed and geoepidemiological studies and clustering analysis are essential tools to define the associated risk to single environmental and genetic factors. In particular, it will be important to collect additional information on the incidence and prevalence of

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