The diagnosis of metal hypersensitivity has not been fully established. Contact hypersensitivity to metal is a delayed type (Type IV) hypersensitivity reaction. Metal ions work as haptens. A hapten-carrier complex (antigen) is taken up by Langerhans cells (antigen-presenting cells: APCs) and then encountered by T cells [
14]. T cells and, in particular, CD4-positive Th cells are responsible for shaping the immune response. Th cells are specific for antigens presented by major histocompatibility complex II (MHC II) molecules on the surface of APCs, while CD8-positive Tc cells are specific for the class I MHC molecules on non-body-own proteins. Tc cells can cause tissue damage and to a certain extent influence the local response [
15,
16].
Testing for metal hypersensitivity has been historically conducted in vivo using skin patch testing. The patch test is considered the reference method for diagnosing contact allergy. The proportion of positive tests has increased significantly over time, especially in the last 20 years [
17]. Thomas et al. [
18] showed that, in 16 patients with revised metal-on-metal arthroplasty, patch test reactions were seen in 11/16 patients (69 %, 7/16 to cobalt, 7/16 to chromium, 4/16 to nickel); 10 of 16 patients (62 %) showed enhanced lymphocyte transformation test reactivity to metals (7/16 to nickel, 7/16 to cobalt, 5/16 to chromium). Nickel has long been identified as a cause of allergic dermatitis, affecting more than 10 % of patients. Cobalt sensitivity has been observed in approximately 1 % of the same population, with a significant degree of cross-reactivity between the two metals. In a European surveillance system for contact allergy in 2007–2008, the prevalence of nickel sensitivity was 12–27 %, with cobalt sensitivity in 5–14 % [
19]. The patch test for metal hypersensitivity after arthroplasty is unreliable, because skin is an excellent barrier, sealing the immune system from direct environmental contact. A better surface for allergy testing would be a mucous membrane such as the oral cavity, but placement and maintenance of oral tests would be difficult, and would still not have the same environment of a joint. The inability to implant test material on the joint surface has led to the use of the in vitro lymphocyte stimulation test [
17,
20,
21]. The lymphocyte stimulation test has been used to investigate metal sensitivity related to implant failure [
9,
12,
22]. T cells play a crucial role in metal hypersensitivity reactions. In four patients with positive lymphocyte stimulation tests and dominant T cell infiltration, the cause of ARMD could be suggested to be type IV hypersensitivity. Nickel has been reported to be an offending metal for metal hypersensitivity [
20,
21]. However, one might wonder if nickel exposure is relevant, since there is only a small percentage of nickel in cobalt chromium alloys [
20]. Since B lymphocyte infiltration is not characteristic of a type IV hypersensitivity reaction [
23], the major cause of ARMD could not be type IV hypersensitivity in the remaining nine patients. Kwon et al. [
9] demonstrated that lymphocyte reactivity to cobalt, chromium, and nickel did not significantly differ in patients with pseudotumors compared to patients without pseudotumors. A T-lymphocyte-mediated type IV hypersensitivity reaction may not be the dominant biological reaction involved in the occurrence of pseudotumors.
Lymphoid structures are classified as primary lymphoid organs (thymus and bone marrow), secondary lymphoid organs that arise during embryonic development (lymph nodes, spleen, tonsil, Peyer’s patches), and tertiary lymphoid organs that arise in chronically inflamed adult tissue. Tertiary lymphoid organs are synthesized with microbial infections and autoimmune diseases, such as rheumatoid arthritis and Sjögren’s syndrome. Features associated with tertiary lymphoid organs are centrally placed B cell aggregates, loosely surrounded by T cells [
24]. The B and T cell-containing aggregates seen in ARMD bear a remarkable resemblance to tertiary lymphoid organs that arise in chronically inflamed adult tissue. In addition to the well-described T cell-mediated type IV hypersensitivity response, an under-recognized immunological reaction to metal wear debris involving B cells and the formation of tertiary lymphoid organs could occur in a distinct subset of patients with ARMD [
25]. The presence and importance of B cells have been largely underestimated in the cellular reaction to metal wear debris. The significance of B cells and tertiary lymphoid organ formation and their correlations with outcome require further evaluation. Further studies to elucidate the association between tertiary lymphoid organ formation and autoimmunity to metal hapten-carrier complexes and/or T cell-mediated inflammatory responses are needed to develop novel therapies to overcome ARMD [
25].
This study has some limitations. First, a small number of patients were studied, and all patients but one were female. Second, the cause for revision was ARMD in all patients after metal-on-metal THA. No patients were revised because of dislocation and infection, and this study had no control group of tissues without ARMD. Immunohistochemical evaluations are warranted to compare the results between the patients with ARMD after metal-on-metal THA and without ARMD including the patients after non-metal-on-metal THA as a control group [
26]. Third, the presence or absence of a metal hypersensitivity reaction has no implications regarding treatment. Further studies are needed to develop strategies for prevention and future treatment for ARMD.