Regulation and Genetic Determination of Inflammatory Processes and Their Diagnostic Relevance

Abstract

Human responses to gram-negative infection show high interindividual variation [1]. Comparable amounts of infectious units of microbial organisms induce a wide range of severity of infectious diseases. Endotoxin, a constituent of cell walls of gram-negative bacteria, is a major inducer of in_ammatory responses in human infectious diseases. Not only exogenous gram-negative organisms invading and infecting the human organism but the vast endogenous source of gram-negative bacteria within the human gastrointestinal tract contribute to the endotoxin pool which challenges the human immune system in states of disease [2]. The immune response to endotoxin involves a complex pattern of primary, secondary and tertiary humoral and cellular responses. The genetic background of the individual in_uences the endogenous mediator response to endotoxin modifying the expression of endotoxin-induced pathophysiology. Primary responses to endotoxin challenges are mediated by proin_ammatory cytokines such as tumor necrosis factor (TNF) and interleukin 1 (IL-1) [3]. Secondary proin_ammatory mediators like interleukin 6 (IL-6) and interleukin 8 (IL-8) are induced by TNF and IL-1 [3]. Tertiary mediators comprise factors of different, even non-cytokine origin such as proteases, coagulation factors, kinins, eicosanoids, nitric oxide and others which take effects in the distal part of mediator cascades [4]. Recent evidence suggests that not only proin_ammatory mechanisms contribute to organ failure and death induced by gram-negative sepsis but that antiin_ammatory mediators have important effects on the host immune system as well [5]. Antiin_ammatory mediators are supposed to induce a state of immunosuppression in sepsis which has also been named immunoparalysis [6]. This state of decreased immunoreactivity is accompanied by high levels of antiin_ammatory cytokines such as interleukin 10 (IL-10) and interleukin-1 receptor antagonist (IL-1ra) [7]. Symptoms of immunosuppression include a decreased number of circulating monocytes expressing surface HLA class II molecules and impaired ex vivo responses of macrophages and lymphocytes to lipopolysaccharide (LPS) [8]. Proand antiin_ammatory responses contribute to the outcome of gram-negative sepsis which represents the ultimate endotoxin challenge in humans. Therefore, all genes encoding proteins involved in in_ammatory responses are candidate genes to determine the human genetic background which is responsible for interindividual differences in systemic in_ammatory responses to infection. Genetically determined capacity of cytokine production and release, heat shock protein expression, nitric oxide synthase activity or gene polymorphisms of coagulation factors and many other genes involved in in_ammation may contribute to a wide range of clinical manifestations of in_ammatory disease: a patient with peritonitis, for example, may present without symptoms of sepsis and recover within days or may suffer from fulminant septic shock resulting in death within hours. What is the bene~t of having information on the genetic background of an individual’s in_ammatory response to infectious as well as non-infectious challenges? Besides the interest of basic science concerning the role and interaction of mediators, there is a very practical and clinical point of view: which group of patients carries a high risk of developing severe sepsis and multiple organ dysfunction in the situation of a systemic in_ammatory reaction? Is there a high risk group for death? Will certain patients bene~t more than others from anti-mediator strategies because of their genetic determination to high cytokine release in the in_ammatory response? Knowledge of the role of the genetic background in the expression of human systemic in_ammation may permit more rational therapy of this lethal process.