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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 391-395, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.2002-0164PS

Perspective

Genetic Basis of Remitting Sarcoidosis

Triumph of the Trimolecular Complex?

David R. Moller and Edward S. Chen

The Johns Hopkins University School of Medicine, Baltimore, Maryland

Address correspondence to: David R. Moller, M.D., 5501 Hopkins Bayview Circle, The Johns Hopkins University School of Medicine, Baltimore, MD 21224. E-mail: dmoller{at}mail.jhmi.edu

Abbreviations: bronchoalveolar lavage, BAL • Fc-receptor, Fc-R • major histocompatibility complex, MHC • human leukocyte antigen, HLA • tumor necrosis factor, TNF • T cell receptor, TCR • T helper, Th • interferon, IFN • interleukin, IL


   Introduction
Top
 Introduction
Role of Human Leukocyte...
 Association of HLA Region...
 Immune Basis of the...
 Genetic Basis of Remitting...
 HLA Association in Sarcoidosis:...
 References
 
The belief that a genetic susceptibility to the development of sarcoidosis exists was initially derived from observations of familial clustering of sarcoidosis cases and racial differences in disease prevalence. Consistent with these prior studies, the recently completed, multicenter case-control etiological study of sarcoidosis from the United States found an ~ 5-fold increase in the relative risk of developing sarcoidosis in first degree relatives (1). Complex inheritance patterns in sarcoidosis argue against a single gene playing a dominant role in this disease (2). Although the search for a genetic basis of sarcoidosis was started decades ago, recent studies have confirmed that genes of the major histocompatibility complex (MHC) locus play an important role in determining the risk and clinical course of sarcoidosis.


   Role of Human Leukocyte Antigen Genes in the Adaptive Immune Response
Top
 Introduction
 Role of Human Leukocyte...
Association of HLA Region...
 Immune Basis of the...
 Genetic Basis of Remitting...
 HLA Association in Sarcoidosis:...
 References
 
The genes of the MHC region are clustered in the ~ 5-million base-pair stretch of the short arm of chromosome 6 that encompasses the human leukocyte antigen (HLA) domain (3). The MHC region includes many non-HLA genes that have critical roles in the regulation of inflammatory responses, including the transporter associated with antigen processing proteins, tumor necrosis factor (TNF)-{alpha}, and lymphotoxin-{alpha}.

HLA molecules bind antigenic peptides within a groove formed by two {alpha}-helices and a floor of antiparallel ß-strands to form a complex that is recognized by {alpha}/ß+ T-cell receptor (TCR)-expressing T cells (Figure 1) (4). Class I molecules (HLA-A, -B, and -C) usually display peptides of 8–10 amino acid length for analysis by CD8+ T cells; HLA Class II molecules (HLA-DP, -DQ, and -DR) bind longer peptides that overhang the binding groove of the molecule for analysis by CD4+ T cells (5). These peptides are largely derived from antigenic proteins that have been phagocytosed or internalized by receptor-mediated endocytosis by antigen-presenting cells such as dendritic cells or macrophages. The resulting antigen-bearing phagosomes or endosomes are fused with lysosomes, and the proteins are degraded into peptides that are loaded onto HLA Class II molecules with the assistance of HLA-DM molecules (6–8). These MHC–peptide complexes are transported to the cell surface on antigen-presenting cells (9). An effective interaction of the trimolecular complex (MHC/peptide/TCR) provides the first activation signal for antigen-specific T cells (10). When a second signal for T cell activation is provided by costimulatory molecules, T cells are stimulated to produce cytokines that orchestrate immune responses including granuloma formation (11).



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  		Figure 1. Model of the MHC-peptide-T cell receptor trimolecular complex. Antigenic proteins (Ag) are internalized by antigen presenting cells (APCs) and digested into peptide fragments that are loaded onto the peptide-binding groove of MHC molecules. Class II MHC-peptide complexes traffic to the cell surface for display and analysis by CD4+ T cells (Class I MHC molecules present peptides to CD8+ T cells). The trimolecular complex (MHC/peptide/TCR) is the basic unit of recognition for antigen-specific T cell responses. An effective interaction provides the first signal for T cell activation.

 

   Association of HLA Region Genes with Sarcoidosis
Top
 Introduction
 Role of Human Leukocyte...
 Association of HLA Region...
Immune Basis of the...
 Genetic Basis of Remitting...
 HLA Association in Sarcoidosis:...
 References
 
Because of the known role of HLA genes in regulating the adaptive immune response, many early studies examined the association of HLA alleles in sarcoidosis. Although some studies reported associations with Class I alleles, the HLA Class II alleles have been most frequently reported to be associated with risk of developing sarcoidosis (12). Since different, specific HLA alleles were associated with sarcoidosis risk in different populations, it remained unclear whether the HLA genes themselves or other linked genes were responsible for modifying sarcoidosis risk. Many non-HLA genes have also been studied using a candidate-gene approach, including the vitamin D receptor, angiotensin-converting enzyme, mannose-binding lectin, natural resistance-associate macrophage protein, and the interleukin (IL)-1 cluster (13–17). Importantly, a recent family study by Schurmann and colleagues, using a genome-wide search for genetic markers associated with sarcoidosis, has provided evidence that the genes most strongly associated with the risk of developing sarcoidosis lie within the MHC region (18).

Preferential associations of specific HLA alleles have been observed in many other diseases, particularly those associated with autoimmunity (19, 20). Experimental models of autoimmunity have demonstrated how MHC Class II alleles may influence the autoimmune process (21). Disease severity or susceptibility has been linked to Class II alleles by nature of their functional differences in peptide binding motifs that affect which peptides are presented during an autoimmune response, or by influencing the deletion of subsets of self-reactive T cells (22–24). Interestingly, some studies suggest that protective Class II alleles influence the shift in the balance of T helper (Th)-1/Th2 cytokine production (25, 26). Still other studies suggest that non-MHC genes are important in the development of autoimmune T cell responses by causing a breakdown in tolerance (27, 28). The fact that linkage of MHC genes to autoimmune disease is Class II allele-specific suggests that it is the peptide-binding motifs that are critical in determining the phenotypic manifestation of organ-specific autoimmunity (29). Thus, a specific MHC haplotype, which includes a Class II allele to provide specificity to the autoimmune process and non-HLA genes that influence immunoregulatory mechanisms, may be necessary for a pathogenic autoimmune response to arise.


   Immune Basis of the Pathogenesis of Sarcoidosis
Top
 Introduction
 Role of Human Leukocyte...
 Association of HLA Region...
 Immune Basis of the...
Genetic Basis of Remitting...
 HLA Association in Sarcoidosis:...
 References
 
Current models of the pathogenesis of sarcoidosis are based on data from patient studies, interpreted in the context of experimental models of immune responses (30). The initiation of granuloma formation in sarcoidosis is thought to involve deposition of poorly soluble antigenic material that forms a nidus for granuloma formation. Direct evidence that granulomatous inflammation in sarcoidosis involves conventional antigen-driven responses is based on studies of oligoclonal expansion of T cells at sites of disease (31). The best-studied example involves the remarkable expansion of AV2S3(V{alpha}2.3)+ T cells in bronchoalveolar lavage (BAL) fluid from HLA-DR17+ (now designated DR*0301) Scandinavian patients with sarcoidosis (32). Oligoclonal expansions of other specific Vß+ or V{alpha}+ T cell subsets have also been documented in the lung, skin, and blood of other patients with sarcoidosis (33–35). In all cases, the nature of the stimulating antigens remains unknown.

Experimental models have shown that immune-mediated granulomatous inflammation may be dominated by either Th1 cytokines (interferon (IFN) {gamma}, IL-2) or Th2 cytokines (IL-4, IL-5, IL-13) (36, 37). Many studies have now confirmed that sarcoidosis is characterized by highly polarized Th1 cytokine profiles with dominant expression of IFN{gamma} and the IFN{gamma}-promoting cytokines, IL-12 and IL-18 (38, 39). Characteristic of a Th1 response, most sarcoidosis BAL T cells express a functional IL-12 receptor composed of both the IL-12 receptor ß and {alpha} subunits (40). Although this Th1 dominance is characteristic during the initial years of known disease, there are no data on cytokine profiles in late sarcoidosis to indicate whether this Th1 polarization persists in advanced fibrotic disease. A critical effector of granuloma formation is TNF, produced by local T cells and mononuclear phagocytes (41). Although cytokine profiles demonstrate a polarized Th1 response in most patients with sarcoidosis, early studies have documented that sarcoidosis is characterized by the presence of circulating immune complexes, probably 100% of the time, in Löfgren's syndrome (a form of acute, spontaneously remitting disease) and other forms of acute sarcoidosis (42). A postulated role for poorly soluble immune complexes as a nidus for granuloma formation in sarcoidosis remains unverified.


   Genetic Basis of Remitting Sarcoidosis
Top
 Introduction
 Role of Human Leukocyte...
 Association of HLA Region...
 Immune Basis of the...
 Genetic Basis of Remitting...
HLA Association in Sarcoidosis:...
 References
 
HLA Class II genes have also been associated with presentations of sarcoidosis with favorable clinical outcomes (acute arthritis, Löfgren's syndrome, stage I chest radiographs, or with documented recovery within 2 yr) (12). The most consistent finding has been the association of good prognosis sarcoidosis with HLA-DR3 haplotypes reported in Scandinavian, Polish, Czech, Italian, German, and Japanese patients (43–50). A recent study from Germany found a significantly greater frequency of HLA-DR3 and the TNF-A2 allele (which is in linkage disequilibrium with HLA-DR3) in patients with Löfgren's syndrome compared with non-Lofgren's patient groups (48).

The study by Sato and colleagues in this issue of AJRCMB is a further important contribution to our understanding of the genetic determinants of clinical outcomes in sarcoidosis (51). These investigators studied the relationship between 19 DQB1 alleles and disease severity and progression in white patients with sarcoidosis and control subjects from the United Kingdom and The Netherlands. Disease severity was evaluated by chest X-ray and pulmonary function tests at presentation and progression, measured by chest radiograph follow-up at 2 yr and 4 yr. They found DQB1*0201 was associated with milder disease manifestations (erythema nodosum, Löfgren's syndrome, stage 0/1 chest radiograph) and that it is strongly protective against severe sarcoidosis (uveitis, chest radiograph stage II or greater, diffusing capacity < 80% predicted). The DQB1*0201 allele was also strongly associated with reduced risk of disease progression (improved or stable stage I chest radiograph, no progression, or persistent stage II/III disease) regardless of corticosteroid treatment. In contrast, the DQB1*0602 allele was associated with more severe disease. The authors suggest the DQB1*0201 allele (or a tightly linked gene within this MHC haplotype) significantly reduces the risk of disease progression or persistent lung abnormalities in their sarcoidosis cohorts.

An important fact mentioned by the authors is that HLA-DQB1*0201 allele is in tight linkage disequilibrium with HLA-DRB1*0301 allele that has previously been associated with a good prognosis in several sarcoidosis cohorts mentioned above. The DRB1*0301/DQB1*0201 haplotype also includes non-HLA–related genes, such as the TNF gene and lymphotoxin-{alpha}, that could plausibly influence disease severity or outcome. The findings of Sato and colleagues that the DQB1*0602 allele is associated with severe disease are consistent with prior studies of Scandinavian and Japanese patients with sarcoidosis who reported an association of severe disease and DQB1*0602 or the closely linked DRB1*1501 allele (47, 52).


   HLA Association in Sarcoidosis: Peptide-binding motifs or Immunoregulation at Work?
Top
 Introduction
 Role of Human Leukocyte...
 Association of HLA Region...
 Immune Basis of the...
 Genetic Basis of Remitting...
 HLA Association in Sarcoidosis:...
References
 
The linkage between DQB1*0201/HLA-DRB1*0301 haplotypes and remitting sarcoidosis takes on special importance when viewed in a pathophysiologic context. It is the HLA-DRB1*0301 haplotype that is found in Scandinavian patients with sarcoidosis who demonstrate oligoclonal expansions of AV2S3+ T cells in the lung (53). This latter finding is of particular importance given the possibility that these AV2S3+ BAL T cells may be specific for pathogenically-relevant peptides bound by the DRB1*0301 molecule. Importantly, Grunewald and colleagues have found that higher proportions of AV2S3+ BAL T cells in Scandinavian patients with sarcoidosis are associated with an acute disease onset and a short (< 2 yr) disease duration (54). If a cardinal feature of remitting sarcoidosis is the expansion of subsets of peptide-specific T cells (exemplified by the DRB1*0301/peptide/AV2S3 TCR correlation), this would suggest that associations with specific HLA alleles in sarcoidosis are based on their peptide-binding properties.

There are several mechanisms by which a peptide-specific T cell subset could influence disease remission. The Stockholm group has shown that DRB1*0301 patients contain lung T cells with a tendency for diminished Th1 responses (55). Although a direct analysis of the Th1/Th2 phenotype of AV2S3+ T cells in these patients has not yet been completed, it is likely that these AV2S3+ lung T cells will also display a diminished Th1 phenotype. The fact that this T cell subset is associated with remitting disease suggests that expressing a diminished Th1 capability or possibly, an ability to produce high levels of transforming growth factor-ß as seen in some regulatory T cells, may be critical for a favorable prognosis. Müller-Quernheim and colleagues have shown that decreased production of TNF and increased release of transforming growth factor-ß from sarcoidosis BAL cells is associated with reduced risk of disease progression, suggesting that downregulation of the Th1 immune response is an important feature of patients with remitting disease (56, 57). The DQB1*0201/DRB1*0301 haplotype might influence disease outcome favorably by also including specific TNF, lymphotoxin-{alpha}, or other MHC-region alleles that nonspecifically regulate these immune responses.

Before a general downregulation of the immune response can occur in remitting sarcoidosis, it is likely that a critical component of this outcome depends on clearance of the initial pathogenic antigen(s), or control of an associated autoimmune response (Figure 2) . Although speculative, it is reasonable to hypothesize that the AV2S3+ T cells in Swedish patients are part of a cell-mediated or humoral response that promotes clearance of the pathogenic antigen(s) or tolerance of an autoimmune response. Conceivably, the unknown peptide is derived from the original inciting pathogenic antigen or relevant autoantigen. In the former instance, by shifting the Th1/Th2 balance, an effective humoral response could develop that clears pathogenic antigens by either Fc-mediated mechanisms or from removal of relevant immune complexes through complement receptor-1–mediated pathways. In this scenario, immune complexes are not the incipient cause of granuloma formation in sarcoidosis, but rather play a role in clearing pathogenic antigens in those patients that undergo remission. The recently published finding that complement receptor-1, a glycoprotein involved with immune complex clearance from circulating erythrocytes, is a candidate susceptibility gene in sarcoidosis may be relevant to this pathway despite a lack of any association with clinical phenotype in this study (58, 59). This hypothesis would be consistent with an association of circulating immune complexes with the favorable Löfgren's syndrome and would also explain why immune complexes are rarely found at sites of granulomatous inflammation in sarcoidosis tissues. In this model, the nidus for granuloma formation may be insoluble protein aggregates, possibly of microbial origins, that are initially not cleared because of an absent or ineffective humoral response within the context of a polarized and pathogenic Th1 immune response to the same antigens.



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  		Figure 2. Hypothetical model of the pathogenesis of remitting versus chronic sarcoidosis. Antigen-presenting cells (APCs) bearing favorable HLA-DQB1*0201/DRB1*0301 Class II MHC molecules present putative sarcoidosis peptides to V{alpha}2.3+ T cells, initiating a cellular and humoral response that fosters clearance of pathogenic antigen–antibody complexes through Fc-receptor (FcR)- and CR1-mediated mechanisms and disease remission. APCs bearing unfavorable HLA-DQB1*0602 Class II MHC molecules present different sarcoidosis-related peptides to Vß8+ T cells promoting a pathogenic Th1 response that is ineffective in removing pathogenic antigens, resulting in continual granuloma formation and chronic sarcoidosis.

 
Although the scenario outlined above is only one possible pathogenic pathway, if true, peptide or peptide/MHC-based therapies can be envisioned. This will, of course, depend on the identification of relevant peptides that bind preferentially to certain protective HLA molecules and that stimulate appropriate regulatory T cell subsets. Alternatively, identification of relevant peptides that bind to HLA molecules associated with chronic disease would lead to attempts to block peptide binding to these HLA molecules using peptide variants. Of course, the possibility remains that the association between known HLA alleles and remitting or chronic disease in sarcoidosis is not due to the function of HLA molecules as peptide-binding presenters, but is a result of linkage to non-HLA genes. Further mapping of linkage to the MHC region to sarcoidosis should provide more definitive answers to this question. In the meantime, it is difficult to refrain from an optimistic outlook that peptide-specific vaccination might be developed to improve clinical outcomes in sarcoidosis.


   Acknowledgments
 
This work was supported in part by Grant No. HL68019 from the National Heart, Lung, and Blood Institute, the Hospital for the Consumptives of Maryland (Eudowood), and the Life and Breath Foundation

Received in original form August 22, 2002


   References
Top
 Introduction
 Role of Human Leukocyte...
 Association of HLA Region...
 Immune Basis of the...
 Genetic Basis of Remitting...
 HLA Association in Sarcoidosis:...
 References
 

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