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The Evolution of Immunotoxicology*

Michael I. Luster

1.1 Introduction

The origins of immunotoxicology surprisingly date back to the seventeenth century when Bernardino Ramazzini, an Italian medical professor, described lung disease associated with various occupations including baking, grain handling, and mining [1]. It was not until the early 1900s, however, that the immune system was implicated and the causative agents first identified. Since then various pharmaceutical, occupational, and environmental agents have been shown to potentially influence many facets of immune-mediated diseases including allergy, immunosuppression, autoimmunity, and chronic inflammation. The following is a brief historical perspective of what we now refer to as immunotoxicology.

1.2 Immune-Mediated Environmental Lung Diseases

The most studied environmentally induced lung disease is occupational asthma, which was first described by Henry Slater in 1866 as “hyperresponsiveness provoked by exposure to chemical and mechanical irritants, as well as to particular atmospheres” [2]. It was Ehrlich, however, who described the presence of eosinophils in the sputum of workers, which is now considered a hallmark of immune-mediated asthma (reviewed by Hirsch et al. [3]). In the mid-twentieth century, it was shown that occupational asthma can be caused by two distinct groups of agents. The first group consists of proteins such as alanase, an enzyme found in soap detergent, latex, and flour, the cause of baker's asthma [4]. The second group represents small molecular weight, highly reactive chemicals that behave as haptens, such as various anhydrides and isocyanates [5]. Our understanding of how allergic responses can occur from low molecular weight chemicals originated from the pioneering studies of Landsteiner and Jacobs [6] who showed that when these chemicals covalently bind to host proteins they become antigenic (i.e., act as haptens). Late in the twentieth century, based initially on epidemiological observations of increasing asthma rates in industrialized cities and shortly after on experimental animal studies, it was shown that many common air pollutants do not cause allergic asthma but can exacerbate existing asthma by acting as adjuvants [7]. This seminal finding was followed by epidemiological studies suggesting that co-exposure to bacterial endotoxins early in life leads to a reduced likelihood of developing asthma, often referred to as the hygiene hypothesis [8] and suggested that early stimulus of the immune system is important for its normal maturation.

Immune-mediated environmental lung diseases also exist that are not Type 1 (IgE) reactions. For example, chronic beryllium disease (CBD), first described by Sterner and Eisenbud in 1951 [9], is a granulomatous lung disease representing a Type 4 immune reaction. CBD occurs most often in beryllium workers who possess the HLA DPB1 genotype with glutamic acid at amino acid position 69 [10]. This was an important observation as genetic testing is now often conducted in workers in industries that use beryllium to help identify those individuals that may be at high risk of developing the disease. Hypersensitivity pneumonitis, caused by microbes, animal and plant proteins, and low molecular weight chemicals, leads to Type 3 and 4 immune reactions involving immune complexes and complement. First identified in the 1930s [11], it produces noncaseating lung granulomas and is the cause of pigeon breeder's lung, among others.

A number of immune-mediated lung diseases have been described in which innate immunity, rather than adaptive immunity, is primarily responsible for pathology. Byssinosis (aka brown lung disease) is believed to be caused by exposure to the endotoxin in cotton dust and often occurs in inadequately ventilated working environments [12]. The severe inflammatory response that occurs, if exposure persists, can result in narrowing of the airways and scarring of the lung. Chronic inflammatory lung disease can also be induced by inhalation of various amphiboles and silica resulting in asbestosis and silicosis, respectively. Both of these fibers can interact with the nucleotide-binding domain leucine-rich repeat containing (NLR) inflammasome, causing it to function abnormally [13]. The pathology that results is caused by long-term interplay between free radicals and expression of cytokines and growth factors, which ultimately leads to the release and deposition of collagen and other extracellular matrix components by mesenchymal cells [14]. While asbestosis was observed in early mine workers in ancient Egypt, it was not until the 1920s that studies from the United Kingdom unequivocally demonstrated a link between asbestos miners and asbestosis and demonstrated a high prevalence (>25%) of the disease among workers [15, 16].

1.3 Immunotoxic Drug Reactions

Many idiosyncratic drug reactions have often been shown to be allergic in nature, either producing autoallergy, in which the immune response is directed to self-tissues, or stimulating a specific immune response against a drug [17]. Much of our early understanding of human drug allergy originated from studies of β-lactam antibiotics, particularly penicillin, which can produce a Type 1 reaction [18]. These early studies helped demonstrate the importance of genetic variability in the development of an immunotoxic drug reaction and in particular genetic variants that control drug metabolism and the HLA gene region that controls epitope recognition [19]. The former is best exemplified by the gene variants that regulate N-acetyltransferase activity in the development of drug-induced lupus erythematosus [20] and the latter in abacavir-induced hypersensitivity, which is so strongly associated with HLA-B*5701 that it can be used as a prescreen for contraindication [21].

1.4 Autoimmunity

Establishing an association between autoimmune disease and immunotoxicology is challenging for a number of reasons. In addition to the fact that there are different types of autoimmune diseases with different organ targets and pathology, there are intrinsic factors (e.g., specific gene polymorphisms, sex-related hormones, and age) and extrinsic factors (e.g., lifestyle, infectious agents) that play varying roles in disease causation. The issue of whether xenobiotics induce disease or simply exacerbate preexisting disease through immunomodulation is often complicated. It is clear that agents such as strepzotocin and the rotencide, pyrinuron (removed from the US market in 1979), destroy pancreatic beta cells, resulting in type 1 diabetes but this can occur independently of the immune system. Regarding drug-induced autoimmunity, Hoffman in 1945 [22] first observed that administration of sulfadiazine often coincided with the development of systemic lupus erythematosus (SLE), and since then over 35 drugs have been implicated in the onset of autoimmune responses and autoimmune-like diseases [23–25]. Drug-induced autoimmune diseases, however, are different from the classical spontaneous counterpart as they are usually milder, there is minimal organ involvement, autoantibodies to native DNA are seldom observed in the circulation, and disease remission occurs following cessation of drug treatment.

In contrast to these pharmaceuticals, certain environmental chemicals may induce or exacerbate preexisting autoimmune diseases. Since the observation by Pernis et al. in the 1960s [26] of increased prevalence of rheumatoid factor in asbestos-exposed individuals, there has been a growing body of epidemiological and experimental evidence that exposure to fibrogenic fibers including crystalline silica and asbestos as well as to several heavy metals and solvents is associated with systemic autoimmune diseases [27, 28]. Silica-exposed workers are at an elevated risk for a number of systemic autoimmune diseases, including rheumatoid arthritis (aka Caplan's syndrome), systemic sclerosis, SLE, and antineutrophil cytoplasmic antibody (ANCA)-related vasculitis/nephritis. Epidemiological studies have also shown a higher than expected risk of systemic autoimmune disease among asbestos-exposed populations [29]. While some consider these adjuvant effects, there is increasing evidence that these diseases are under T-cell regulation, specifically Tregs [30].

Solvent exposure in workers has also been associated with autoimmune disease. For example, a meta-analysis, looking at 10 different epidemiological studies, showed a fairly modest but consistent association between solvent exposure, particularly trichloroethylene, and systemic sclerosis or connective disuse disorders that were likely autoimmune in nature [31]. Epidemiological studies, case reports, and animal studies have also suggested that exposure to mercury contributes to idiosyncratic autoimmune disease in humans. While in most cases these epidemiological studies were underpowered, they have been supportive of experimental animal studies with genetically developed autoimmune-prone rodents [28].

1.5 Immunosuppression

During the1970s, increasing numbers of studies were published demonstrating that certain agents produce immunosuppression. Initially, the majority of these studies focused on a small set of chemical classes such as heavy metals, halogenated aromatic hydrocarbons, abused drugs (e.g., tobacco smoke and alcohol), and air pollutants, in which case the focus was on the lung rather than on systemic immunity [32, 34–36]. These studies were initially limited to experimental animal models but were soon followed by epidemiological...