A comprehensive summary of disease variants implicated in metal allergy

Abstract

Allergic disease represents one of the most prominent global public health crises of the 21^st century. Although many different substances are known to produce hypersensitivity responses, metals constitute one of the major classes of allergens responsible for a disproportionately large segment of the total burden of disease associated with allergy. Some of the most prevalent forms of metal allergy - including allergic contact dermatitis - are well-recognized; however, to our knowledge, a comprehensive review of the many unique disease variants implicated in human cases of metal allergy is not available within the current scientific literature. Consequently, the main goal in composing this review was to (1) generate an up-to-date reference document containing this information to assist in the efforts of lab researchers, clinicians, regulatory toxicologists, industrial hygienists, and other scientists concerned with metal allergy and (2) identify knowledge gaps related to disease. Accordingly, an extensive review of the scientific literature was performed - from which, hundreds of publications describing cases of metal-specific allergic responses in human patients were identified, collected, and analyzed. The information obtained from these articles was then used to compile an exhaustive list of distinctive dermal/ocular, respiratory, gastrointestinal, and systemic hypersensitivity responses associated with metal allergy. Each of these disease variants is discussed briefly within this review, wherein specific metals implicated in each response type are identified, underlying immunological mechanisms are summarized, and major clinical presentations of each reaction are described.Abbreviations: ACD: allergic contact dermatitis, AHR: airway hyperreactivity, ASIA: autoimmune/ autoinflammatory syndrome induced by adjuvants, BAL: bronchoalveolar lavage, CBD: chronic beryllium disease, CTCL: cutaneous T-cell lymphoma, CTL: cytotoxic T-Lymphocyte, DRESS: drug reaction with eosinophilia and systemic symptoms, GERD: gastro-esophageal reflux disease, GI: gastrointestinal, GIP: giant cell interstitial pneumonia, GM-CSF: granulocyte macrophage-colony stimulating factor, HMLD: hard metal lung disease, HMW: high molecular weight, IBS: irritable bowel syndrome, Ig: immunoglobulin, IL: interleukin, LMW: low molecular weight, PAP: pulmonary alveolar proteinosis, PPE: personal protective equipment, PRR: pathogen recognition receptor, SLE: systemic lupus erythematosus, SNAS: systemic nickel allergy syndrome, Th: helper T-cell, UC: ulcerative colitis, UV: ultraviolet.

Keywords: Metal allergy; dermatitis; immunotoxicity; occupational health; respiratory hypersensitivity.

Figure 1.

The different types of hypersensitivity responses based on the Gell and Coombs classification scheme. Type I hypersensitivity reactions are mediated by antigen-specific IgE molecules that facilitate degranulation of mast cells following antigen exposure. Type II hypersensitivity reactions are mediated by antigen-specific IgG/M molecules that recognize cell-associated antigens, causing destruction of the target cell (type IIa) or alterations in target cell functionality (type IIb). Type III hypersensitivity responses involve soluble antigen recognition by IgG/M molecules. This leads to the formation of antigen/immune complexes that can deposit in various tissues of the body, activate complement, and cause local tissue damage. Type IV hypersensitivity reactions involve the effector functions of various subsets of T-lymphocytes. Type IVa responses are mediated by CD4+ Th1 cells and result in activation of macrophages. Type IVb reactions involve the actions of CD4+ Th2 cells, which promote eosinophilic inflammation. Type IVc responses implicate CD8+ CTLs, which exert direct cytotoxic effects on target cells. Finally, type IVd reactions are mediated by various subsets of T-cells that facilitate the development of neutrophilic inflammation.