ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 6, No. 3 Copyright © 1976, Institute Cor Clinical Science Berylliosis as an Auto-Immune Disorder ANDREW L. REEVES, Ph.D. Wayne State University, School of Medicine, Department of Occupational and Environmental Health, Detroit, MI 48201 ABSTRACT Exposure to compounds of beryllium can cause dermatitis, acute pneumonitis and chronic pulmonary granulomatosis (“berylliosis”) in hu­ mans. These syndromes seem to have an allergic-immunologic component in common. Hypersensitivity to beryllium is of the delayed (cell-mediated) type and can be measured as skin reactivity to patch test; lymphocyte blast transformation; and macrophage migration inhibition. There is good corre­ lation between the results of these tests in exposed populations, but the degree of hypersensitivity is not necessarily a measure of either extent of exposure or severity of berylliosis. In animal experiment, inhalation expo­ sure has suppressed a previously established cutaneous hypersensitivity, and degree of hypersensitivity and degree of berylliosis were in significant inverse correlation. Introduction considerable mortality. It is associated Beryllium is a light metal widely used with inhalation of various, including in­ in fatigue-resistant alloys, nuclear reac­ soluble, beryllium compounds, some­ tors, space vehicle and missile parts, times in very low concentration. Occupa­ electronics and for other specialized pur­ tional as well as “neighborhood” cases poses. Exposure to compounds of beryl­ (the latter having occurred in the general lium has caused dermatitis, acute population living within about a mile pneumonitis and chronic pulmonary from a beryllium plant) are on record; granulomatosis (“berylliosis”) in hu­ they are collected in a “Beryllium Case mans. The dermatitis is of the allergic Registry.” 13 type with edematous lesions following The allergic nature of beryllium skin contact with soluble salts or with lesions was recognized by Curtis,8 who granulomatous ulceration following the developed a patch test. Concurrently, cutaneous imbedding of insoluble com­ Sterner and Eisenbud29 noted that the pounds. Acute pneumonitis followed in­ epidemiology of chronic pulmonary be­ halation of soluble salts in high concen­ rylliosis cases also suggested an allergic tration; typical attacks resolved with com­ etiology. Specifically, it was noted by plete recovery within several months. them that a dose-response relation be­ The chronic granulomatosis is an insidi­ tween exposure and incidence was em­ ous and slowly developing disease with phatically absent, with workers from the 256 BERYLLIOSIS AS AN AUTO-IMMUNE DISORDER 257 cleanest plants and neighborhood cases “tolerogenic”, including a very low dose sometimes showing the worst clinical of beryllium intraperitoneally or a high forms. Furthermore, the morphology of toxic dose intravenously. Krivanek and pulmonary granulomata caused by beryl­ Reeves18 showed that the beryllium ion lium, with considerable similarity to acted as a hapten in provoking the im­ those observed in sarcoidosis, also al­ munological reaction. Complexes where lowed the assumption of an immunologi­ the beryllium ion was unavailable (aurin- cal etiology. The lesions typically con­ tricarboxylate, citrate) could not elicit sisted of a cluster of monocytes sur­ sensitivity, whereas beryllium serum al­ rounded by a zone of lymphocytes and buminate could elicit stronger sensitivity plasma cells.36 These findings created the than the beryllium ion alone. Vasil’ eva33,34 impression that cutaneous and pulmo­ detected beryllium-nucleoprotein com­ nary beryllium lesions may be interre­ plexes which were antigenic. However, lated, and pulmonary berylliosis may be evidence was also presented that beryl­ in some way dependent on immune reac­ lium can interact with cells without prior tions in the organism. complexing to macromolecules and can in­ Search for humoral antibodies was hibit the response of allergized lympho­ made24*27,35 and some increases in serum cytes to antigen.15,16 /3- and y- globulin fractions were noted. These results strongly suggested that However, these turned out to be essen­ the pathogenesis of beryllium disease tially nonspecific. In 1959, it was pointed contained an immunologic component. out that the skin reaction to beryllium The application of this component for being delayed, the immunity is likely to purposes of diagnosis was further be cell-mediated.37 Alekseeva1 and Cirla explored by Epstein and collaborators12-14 et al6 accomplished passive transfer of who first performed lymphocyte blast hypersensitivity in guinea pigs with lym­ transformation and macrophage migra­ phoid cells, while the transfer of serum tion inhibition in preparations originat­ was ineffective. Chiappino et al4'5 were ing from beryllium-sensitive subjects. also able to inhibit all cutaneous reac­ tions to beryllium in guinea pigs by injec­ Patch Test tion of an antilymphocyte serum from rab­ The earliest diagnostic use of im­ bits. Turk and Polak31 could suppress munologic phenomena in berylliosis was reactivity by intravenous injection of be­ the Curtis patch test.8 All of the 13 beryl­ ryllium lactate. Inhalation exposure to lium dermatitis cases reacted positively beryllium sulfate could also suppress to beryllium fluoride. Eight to ten cases cutaneous reactivity.26 Among guinea also reacted positively to beryllium pigs, not all individuals responded iden­ chloride, nitrate or sulfate. Only three re­ tically to the beryllium challenge. Ability acted positively to beryllium metal pow­ to become sensitized was genetically der and none to beryllium oxide powder. controlled and transmitted as a non-sex- However, application of the test ap­ linked, dominant trait.23 peared to be itself sensitizing and eight Mode of administration and choice of out of 16 controls who have never been beryllium compound also influenced the previously exposed to beryllium com­ nature of the immunological reaction. pounds experienced spontaneous flareup V acher32 found only those forms and or eczematous reactions at the test site. In routes which were capable of producing a 1955, Sneddon28 reported that a patient complex with skin constituents as im­ with positive patch test to beryllium de­ munogenic; freely diffusible forms were veloped a sarcoid-like granuloma at the 258 REEVES test site. Even though Curtis later9 ex­ Macrophage Migration Inhibition tended his observations to 32 chronic Bloom and Bennett3 in 1966 dem­ pulmonary berylliosis cases, all of whom onstrated a soluble factor which could reacted positively to the patch test (with inhibit the free migration of macrophages 19 out of 21 control patients reacting in vitro. The factor was elaborated by negatively) it was obvious that extreme sensitized lymphocytes and appeared to caution was advisable in the application be highly antigen-specific but not cell- or of this measure.7’11’20,80,37’38 species-specific. It appeared possible to culture pure populations of lymphocytes Lymphocyte Blast Transformation from buffy coat in the presence of an an­ Lymphocyte blast transformation can tigen and then test the supernatant of be defined as the morphological en­ such a culture on guinea pig peritoneal largement of small lymphocytes to large exudate cells. Inhibition of migration of lymphoblasts in vitro.21 The transforma­ the latter cells was observed if, and only tion can be brought about by numerous if, the source of lymphocytes was a stimuli including tissue antigens, specific sensitized patient This principle was antigens, antisera and a group of very successfully employed with beryllium active stimulants referred to as “nonspe­ as antigen by Henderson et al,14 who cific” of which phytohemagglutinin demonstrated that beryllium oxide- is the prototype. In 1970, Hanifin stimulated lymphocytes from patients et al12 showed that among specific with berylliosis, but not from normal in­ antigens, beryllium compounds (includ­ dividuals, produced the inhibitory factor. ing the insoluble oxide) caused Marx and Burrell19 studied seven patients striking transformation of lymphocytes with chronic beryllium disease by means from beryllium-sensitive subjects only, of the macrophage migration inhibition while the lymphocytes from normal, non­ test and found positive results in all, sensitive subjects did not transform. while the results in six normal controls Transformation of beryllium-sensitive and two non-berylliotic pulmonary pa­ and nonsensitive lymphocytes by tients were negative. On the other hand, phytohemagglutinin was similar. In 1973, Jones-Williams17 examined seven other Deodhar et al10 reported on the exploita­ chronic berylliosis patients and found tion of this discovery for the diagnosis of positive results only in one—but the lat­ berylliosis. Among 35 patients with ter patients were on corticosteroid chronic berylliosis, 25 (71 percent) therapy at the time of testing. It thus showed at least some blast transformation seems that macrophage migration inhibi­ (with 21 patients showing strong or very tion is also a useful indicator of beryllium strong transformation), even though these hypersensitivity although it can be patients were treated at the time of the abolished by immunosuppressive treat­ test with prednisone, an inhibitor of im­ ment. mune reactions. There was also correla­ tion between the severity of the clinical Correlation of Test Results disease and the degree of blast transfor­ Krivanek and Reeves18 as well as mation. Incidence of positive results