**1. Introduction**

The importance of the immune system in the pathogenesis of a large number of diseases is being increasingly accepted. Although its contribution toward organic disease is easily appreciated, the realization that the immune system is also capable of contributing to the pathogenesis of mental health disorders has only recently become more recognized as the effects of inflammation on the central nervous system function have been discovered [1]. Furthermore, research has identified significant pleiotropy between the immune system and mental health disorders [2]. However, the impact of inflammation toward the development and maintenance of anorexia nervosa has not been elucidated at this time. Anorexia nervosa, a mental illness characterized by extreme weight loss due to restricted intake resulting from an extreme fear of weight gain, ultimately impacts every organ system and has a very high recidivism rate due to the lack of efficacious treatment options. If indeed anorexia nervosa is associated with a pro-inflammatory state, as this paper will attempt to argue, weight restoration, an essential component of treatment, then becomes that much more difficult due to the hunger suppressing and weight loss effects associated with the pro-inflammatory cytokines. This paper will attempt to argue for this pro-inflammatory state by summarizing the research findings of the immune system in anorexia nervosa and how they compare to the findings in primary malnutrition. However, much of the current research on this topic is of lower quality, and this paper is not meant to serve as a systematic review. With that said, a review of the majority of the publications on the immune system in anorexia nervosa has been attempted.

One first becomes intrigued by the possibility of a dysregulated immune system in anorexia nervosa when examining the frequency of infection in patients with anorexia nervosa. Although anorexia nervosa is a subtype of malnutrition, individuals with anorexia nervosa curiously may not suffer the same increased incidence of infection as found in other types of malnutrition [3]. A pro-inflammatory state is suggested when comparing the immunologic findings in anorexia nervosa, a state of starvation secondary to a primary mental health disease, to those present in primary malnutrition (that are related to inadequate energy intake and not secondary to another condition such as cancer, infection, malabsorption, etc.).

Genome wide association studies, which are non-biased studies examining the entire genome for genetic variations occurring more frequently in a certain population, provide additional evidence for a dysregulated immune system that is potentially involved in the pathogenesis of anorexia nervosa. One locus found to be significantly affiliated with anorexia nervosa is associated with multiple autoimmune disorders [4]. Research has indeed found an increased association between anorexia nervosa and various autoimmune diseases, with a bidirectional relationship [5–7]. In addition, individuals with auto-inflammatory disease (when the innate immune system attacks various host tissues) are at a higher risk for the development of an eating disorder [6]. Curiously, there is a case report of an individual with long-standing juvenile idiopathic arthritis and anorexia nervosa who exhibited improvement in body weight and appetite after treatment with infliximab (anti-TNF therapy) [8]. There is another case report of an individual with a 12-year history of anorexia nervosa pre-dating by many years a diagnosis of Crohn's disease, who experienced significant weight gain and no further relapse in psychopathology several months after beginning immunosuppressive therapy [9].

Another genetic finding approaching significance in anorexia nervosa involves a locus containing early B cell factor 1, which encodes a transcription factor important for immune system development, regulation of adipocyte/osteoblast differentiation and possible interaction with leptin signaling [10]. A region on chromosome 7, which includes various taste receptor genes, but also a gene important for cell–cell adhesion, apoptosis, and the immune response to pathogens, was also found to approach significance in the anorexia nervosa population [11].

After comparing the immunologic findings in primary malnutrition to those found in anorexia nervosa, suspicion arises as to why these differences exist. Potential contributors to these immunologic differences between primary malnutrition and anorexia nervosa will then briefly be discussed. First, a brief review of the immune system is warranted [12,13].
