Elsevier

Clinics in Chest Medicine

Volume 18, Issue 4, 1 December 1997, Pages 719-739
Clinics in Chest Medicine

IMMUNOLOGY OF SARCOIDOSIS

https://doi.org/10.1016/S0272-5231(05)70415-9Get rights and content

Sarcoidosis, a multisystem granulomatous disease, was first described by Sir Jonathan Hutchinson in 1878.63 Other early investigators described a variety of eponym-bearing syndromes without realizing their common origin. In 1899, Cesar Boeck6 identified the unifying attribute for those conditions when he determined that noncaseating granulomatous inflammation was the pathologic hallmark of sarcoidosis. He found no microorganisms, and postulated that the cause of the disease was defective blood formation or autointoxication. In 1916, he observed the lack of cutaneous reaction to old tuberculin in sarcoid patients, and a lack of mycobacteria in guinea pigs inoculated with sarcoidal tissue.7 That celebrated work launched the science of sarcoid immunology. Since then, our understanding of sarcoid immunopathogenesis has undergone major conceptual advances. The evidence of depressed cellular immunity reflected by cutaneous anergy was found to be accompanied by hypergammaglobulinemia, suggestive of active humoral immunity.9, 76, 82 Only since 1976, however, have we become aware that cellular immunity in sarcoidosis is hyperactive rather than depressed.56, 61, 75, 77, 79 Those and other landmarks in the evolution of sarcoid immunology are listed in Table 1 . The evolution of sarcoid immunology has provided a rational basis for treatment and has fostered the search for the causative agent.

In this article, we examine studies of peripheral blood lymphocytes, humoral immunity, cellular immunity and its role in sarcoid granuloma formation, cutaneous anergy with a proposed mechanism, the immunology of the Kveim-Siltzbach (K-S) skin test in relation to etiopathogenesis, and future perspectives. The human leukocyte antigen system is discussed by others in this issue.

Section snippets

IN VITRO STUDIES OF PERIPHERAL BLOOD LYMPHOCYTES

The early studies on lymphocytes were directed toward defining the mechanism of cutaneous anergy in sarcoidosis. Interestingly, those studies proved to elucidate the immunopathogenesis of sarcoidosis. The studies performed on peripheral blood lymphocytes in sarcoidosis fall into four groups—(1) proliferative responses of lymphocytes to stimulation with mitogens and recall antigens; (2) lymphocyte proliferation in mixed lymphocyte cultures; (3) spontaneous lymphoblastic transformation and

PHYTOHEMAGGLUTININ SKIN TEST

As with various recall antigens, mitogens such as PHA and concanavalin-A also activate peripheral blood T lymphocytes and cause them to release soluble lymphokines, which then attract monocytes to the site injected with antigen or mitogen. The PHA skin test has been used to explore the state of cellular immunity in a variety of disorders. Defective in vivo response has been found in lymphoproliferative diseases162 or with congenital defects of cellular immunity, including thymic dysplasia,

Hypergammaglobulinemia

Polyclonal hypergammaglobulinemia is common in sarcoidosis. We reported elevated levels of serum immunoglobulin G (IgG) and IgM in 7 of 14 untreated patients. One of the patients also had elevated serum IgA levels.76 In 10 treated patients, hypergammaglobulinemia was less frequent: IgG and IgM were each elevated in only one patient and IgA was elevated in two patients. Subsequently, we extended our observations to 211 patients and found that 68% (81% of blacks and 55% of whites) had

CELLULAR IMMUNITY AND THE MECHANISM OF SARCOID GRANULOMA FORMATION

The mechanisms of hypersensitivity granuloma formation by infectious (e.g., tuberculosis) and noninfectious (e.g., berylliosis) agents have striking similarities and provide a framework for comparative analysis with the immunopathology of sarcoidosis. Insights into the mechanisms come from studies of peripheral blood, BAL, and in vitro-cultured intact sarcoidal skin granulomas.75 Fiberoptic bronchoscopy revolutionized the clinical diagnosis and research of sarcoidosis because it provided a

CUTANEOUS ANERGY

In Boeck's time, a cutaneous response to tuberculin was commonplace in the general population.7 Negative tuberculin reactions in sarcoidosis patients did not imply absence of prior tuberculous infection.51 Indeed, the observation that the finding was caused by suppression of previously existing tuberculin sensitivity was based on direct observations in patients with known positive tuberculin reactions prior to the onset of sarcoidosis.51 Evidence of previous tuberculous infection was also

ROLE OF IMMUNOLOGY IN DEFINING THE CAUSES OF SARCOIDOSIS

The previously described hypothetical model of granuloma immunopathogenesis in sarcoidosis is based on extensive, albeit indirect, evidence that antigen presentation is the initiating stimulus for granuloma formation. A nagging question is whether the resultant hyperactive cellular arm of the immune system in sarcoidosis is the result of a specific antigenic stimulus or the result of a nonspecific polyclonal phenomenon, analogous to the hypergammaglobulinemia of the humoral arm. Investigation

FUTURE DIRECTIONS

The demonstration of granulomagenic activity in autologous sarcoid alveolar macrophages and monocytes serves as a beacon for further pursuit of the initiating antigenic events of sarcoid granuloma formation. Because of its association with lysosomes and cell membranes, it is likely that the granulomagenic factor is a ligand of MHC-class 2 molecules, providing an opportunity for its isolation by monoclonal immunopurification of those molecules. Once isolated, the antigen could be further studied

SUMMARY

Because of its association with cutaneous anergy, sarcoidosis was originally viewed as a defect of cellular immunity. Supporting that misperception were early studies of peripheral blood lymphocytes that found lymphopenia and impaired lymphocyte responses to mitogens and recall antigens. The clue to a vast underlying network of complex hyperactive cellular immune functions was discovered in the paradoxical finding of in vitro spontaneous lymphoblastic transformation and lymphokine production.

ACKNOWLEDGMENT

The authors thank Nick Shukla and Wei Li for their dedicated technical assistance, and H. Kim Park for her expertise in dermatopathology.

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    Address reprint requests to Yash P. Kataria, MD Section of Pulmonary and Critical Care Medicine Department of Medicine East Carolina University School of Medicine 3 East 149 Brody Building Greenville, NC 27858

    This work was supported by grants from the American Lung Association of North Carolina.

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