Sarcoidosis and chronic beryllium disease are noninfectious lung diseases that are characterized by the presence of noncaseating granulomatous inflammation. Chronic beryllium disease is caused by occupational exposure to beryllium containing particles, whereas the etiology of sarcoidosis is not known. Genetic susceptibility for both diseases is associated with particular MHC class II alleles, and CD4+ T cells are implicated in their pathogenesis. The innate immune system plays a critical role in the initiation of pathogenic CD4+ T cell responses as well as the transition to active lung disease and disease progression. In this review, we highlight recent insights into Ag recognition in chronic beryllium disease and sarcoidosis. In addition, we discuss the current understanding of the dynamic interactions between the innate and adaptive immune systems and their impact on disease pathogenesis.

Granulomatous lung diseases include a spectrum of disorders initiated by infectious and noninfectious agents. Mycobacterial and fungal infections are the most common causes of infectious granulomatous lung disease whereas noninfectious etiologies include exposure to damaging particles, hypersensitivity pneumonitis, genetic disorders, and autoimmune diseases, among others (1). Sarcoidosis and chronic beryllium disease (CBD) are noninfectious granulomatous lung diseases with similar lung pathology (2). Whereas CBD is a lung-restricted disorder caused by occupational exposure to beryllium, sarcoidosis is a highly variable systemic disease of unknown etiology that leads to development of lung granulomas in ∼90% of cases (3, 4). Genetic risk factors for both diseases include selected sets of MHC class II molecules, in particular HLA-DPB1 alleles in CBD (5, 6) and HLA-DRB1 alleles in sarcoidosis (710). Alterations in the immune system are evident in pulmonary sarcoidosis and CBD, including the accumulation of activated CD4+ T cells, macrophages, and B cells in the lung (1115). Furthermore, lung pathology in both disorders is defined by the presence of compact, noncaseating granulomas consisting of central epithelioid macrophages and/or multinucleated giant cells surrounded by a layer of lymphocytes (16). Current research suggests that coordinated interactions between the innate and adaptive immune responses and their dysregulation are central to the pathogenesis of granulomatous lung disease (7, 17).

Beryllium is a lightweight metal with unique chemical and physical properties. Beryllium confers strength, thermal conductivity, and corrosion resistance in metal alloys and ceramics that are essential in a variety of aerospace, weapon, computer, and electronic applications. Occupational and indirect community exposure to beryllium in processing, manufacturing, and recycling industries can lead to the development of CBD (1821). Beryllium was identified as a threat to respiratory health after its use was incorporated into manufacturing processes in the United States in the 1940s and 1950s. Initially, its toxicity was linked to severe pneumonitis and granulomatous inflammation, referred to as “acute berylliosis.” This form of beryllium-induced lung disease has largely been eliminated due to the implementation of exposure limits in the workplace (18, 2224). However, a less severe but progressive and chronic form of berylliosis (CBD) continues to impact a percentage of beryllium-exposed workers (25). Genetic susceptibility to CBD is strongly linked to HLA-DPB1 alleles possessing a glutamic acid at the 69th position of the β-chain (βGlu69), and the most prevalent βGlu69-containing molecule is HLA-DP2 (5, 6). The strong HLA association, the identification of delayed hypersensitivity reactions to beryllium in individuals with CBD (26), and the observation that a population of CD4+ T cells is expanded in the lungs of CBD patients that respond to beryllium as an “Ag” in an MHC class II–dependent manner (11) established that beryllium-specific CD4+ T cells are central players in the pathogenesis of CBD.

The natural history of CBD includes distinct phases that lead to progressive worsening of disease (Fig. 1, left panel). Initiation of disease is asymptomatic and often includes a latent phase followed by the expansion of beryllium-specific CD4+ Th1 cells in secondary lymphoid organs and their recirculation in the blood (beryllium sensitization) (27). The prevalence of beryllium sensitization is highly variable, occurring in 1–16% of beryllium-exposed workers (2836). A percentage of beryllium-sensitized individuals (∼6–8% per year) will transition to active lung disease, and in some cases this occurs decades after beryllium exposure has ceased (37, 38). Early CBD is characterized by the infiltration of beryllium-specific CD4+ Th1 effector memory cells and mononuclear phagocytes into the peribronchovascular regions of the lung (27, 39). The onset of symptoms occurs in established lung disease as macrophage/lymphocyte aggregates expand in a peribronchovascular distribution and form granulomas (40). In severe disease, worsening inflammation causes tissue damage and fibrosis in the lung. Most individuals with CBD will exhibit a decline in respiratory function over time, and historically 20–30% will develop pulmonary fibrosis and respiratory failure (38, 41).

FIGURE 1.

Natural histories of CBD and sarcoidosis. Initiation of disease consists of an asymptomatic phase triggered by an exposure (beryllium in CBD; unknown agent [?] in sarcoidosis) that leads to activation of pathogenic adaptive immune responses in lymph nodes. Transition to subclinical lung disease occurs when monocytes and Ag-experienced adaptive immune cells are recruited into the lung interstitium and the alveolus (alveolitis). This is followed by development of interstitial lymphoid aggregates and granuloma maturation, and the onset of clinical symptoms. In resolving sarcoidosis, granulomas involute, inflammation ceases, and symptoms decline as lung tissue returns to a healthy, homeostatic state. In progressive CBD and sarcoidosis, granulomas persist, and chronic inflammation is maintained. Failure to modulate granuloma inflammation reduces airway surface area and diminishes lung function. Progression to end-stage disease includes tissue damage, deposition of collagen, and pulmonary fibrosis, which can lead to respiratory failure.

FIGURE 1.

Natural histories of CBD and sarcoidosis. Initiation of disease consists of an asymptomatic phase triggered by an exposure (beryllium in CBD; unknown agent [?] in sarcoidosis) that leads to activation of pathogenic adaptive immune responses in lymph nodes. Transition to subclinical lung disease occurs when monocytes and Ag-experienced adaptive immune cells are recruited into the lung interstitium and the alveolus (alveolitis). This is followed by development of interstitial lymphoid aggregates and granuloma maturation, and the onset of clinical symptoms. In resolving sarcoidosis, granulomas involute, inflammation ceases, and symptoms decline as lung tissue returns to a healthy, homeostatic state. In progressive CBD and sarcoidosis, granulomas persist, and chronic inflammation is maintained. Failure to modulate granuloma inflammation reduces airway surface area and diminishes lung function. Progression to end-stage disease includes tissue damage, deposition of collagen, and pulmonary fibrosis, which can lead to respiratory failure.

Close modal

An estimated 1 million people are at risk for developing CBD worldwide (40), and efforts have been made to decrease risks of beryllium exposure in workers. However, there is no cure or preventive treatment that limits disease progression. Despite a thorough understanding of innate and adaptive immune processes in CBD, the factors that impact disease initiation, the transition from sensitization to active disease, and disease progression have not been defined. Several preclinical mouse models have been developed to identify targets for early interventions that could pave the way to limit progression to severe disease in patients (4245). However, it is firmly established that beryllium sensitization is a prerequisite for developing CBD and has only been demonstrated in mice that express HLA-DP2 molecules on APCs. Exposure of HLA-DP2 transgenic (Tg) mice (comprised of HLA-DPA1*01:03 and HLA-DPB1*02:01 alleles) to beryllium (42) results in the development of beryllium-specific CD4+ T cell responses with the same functional phenotype and TCR specificity observed in HLA-DP2–expressing CBD patients. In this model, beryllium-specific CD4+ T cells orchestrate and maintain alveolitis and peribronchovascular inflammation that is similar in cell composition to that seen in early stages of the human disease (42). Thus, the animal model confirms a central role for beryllium-specific CD4+ T cells in CBD and has enhanced our understanding of the sequential interactions between cells of the innate and adaptive immune systems in the initiation and progression of beryllium-induced granulomatous inflammation.

After education in the thymus, the naive T cell subset includes CD4+ T cells selected to bind with high affinity to foreign peptides presented on MHC class II molecules and with low affinity to the same MHC class II molecules presenting self-peptides. In vitro studies of human CD4+ T cells suggested that beryllium ions interact with certain MHC class II/self-peptide complexes to form a complete, high-affinity ligand for a subset of TCRs. Analysis of TCR usage in CD4+ T cells from CBD patients indicated that beryllium-specific T cells are oligoclonal and that related CDR3 amino acid sequences are present across HLA-DP2–expressing CBD patients (46). The structure of HLA-DP2 revealed a unique solvent-exposed acidic pocket composed of glutamic acid residues at positions 26, 68, and 69 of the β-chain (47). In vitro studies suggested that self-peptides are required for beryllium recognition, and using a non-biased peptide library approach, Falta et al. (48, 49) delineated multiple self-peptides that complete the αβTCR ligand in CBD. These include constitutively expressed plexin A structural proteins (PLXNA2, PLXNA3, and PLXNA4) that share nearly identical epitope sequences and peptides derived from the chemokines CCL3 and CCL4 that are expressed during inflammation. Fluorescently labeled HLA-DP2 tetramers loaded with either plexin A4, CCL3, or CCL4 peptides bound to CD4+ T cells from CBD patients only in the presence of beryllium ions and detected subsets of beryllium-specific CD4+ T cells in CBD patients and beryllium-exposed HLA-DP2 Tg mice (4850). A common feature of these peptides is the presence of negatively charged amino acids at the p4 and p7 positions, which are adjacent to the acidic pocket. Structural analysis of the HLA-DP2/plexin A4 peptide/beryllium complex showed that beryllium was coordinated by negatively charged amino acids derived from the peptide and HLA-DP2 β-chain (51). Mutation of these beryllium coordinating amino acids abrogated T cell activation, confirming the role of these peptides in beryllium coordination (52). Crystallization of a multimolecular complex of a beryllium-specific TCR interacting with a beryllium-loaded HLA-DP2/peptide complex (51) revealed that the TCR does not directly interact with the beryllium ion itself; rather, it contacts conformational changes in the topology of the HLA-DP2/plexin A4 complex induced only in the presence of beryllium. Thus, beryllium ions create neoantigens that are absent during thymic selection and are recognized by CD4+ T cells circulating in the naive TCR repertoire. In this way, CBD has features of both a metal-induced hypersensitivity and autoimmunity.

Sarcoidosis is a systemic, granulomatous disorder that affects the lung in ∼90% of cases (4). The clinical presentation of sarcoidosis ranges from an incidental chest radiographic finding in asymptomatic subjects to lung fibrosis. In many cases, granulomatous inflammation resolves, whereas in progressive disease, granulomas persist and can lead to pulmonary fibrosis (Fig. 1, right panel). Sarcoidosis occurs worldwide, affecting all races, both sexes, and individuals of all ages, although it typically affects individuals between 20 and 50 y of age (4, 53, 54). Variable prevalence and disease severity occur in individuals of different races and ethnic backgrounds (55).

CD4+ T cells are increased in the bronchoalveolar lavage (BAL) and granulomas in sarcoidosis (13, 56, 57). Th1, Th17 cells, and multifunctional cells that express both Th1 and Th17 cytokines, transcription factors, and chemokine receptors (i.e., Th17.1) are increased in sarcoidosis lungs compared with healthy control subjects (reviewed in Ref. 58). Furthermore, local accumulation of Th17.1 cells in the lungs and lung-draining lymph nodes precedes development of granulomatous inflammation in early stages of disease (59). Thus, an asymptomatic phase, in which activation of adaptive immune cells against undefined Ags, likely occurs in the lymph nodes similar to the sensitization phase of CBD. Transcriptome analysis of sarcoid lung and BAL samples consistently show that MHC class II-dependent Ag presentation, T cell signaling, and Th1/IFN-γ signaling pathways are associated with active pulmonary sarcoidosis and CBD (6062).

Familial clustering of sarcoidosis supports a genetic contribution to disease (63), and several MHC class II alleles (e.g., HLA-DRB1*03:01, 04:01, 11:01, and 15:01) have been associated with disease susceptibility. A Case Control Etiologic Study of Sarcoidosis showed that HLA-DRB1*11:01 (DR11) was significantly associated with sarcoidosis in African Americans and whites in the United States (9), and a recent study noted its association with disease persistence (64). In fact, the incidence of DR11 expression is doubled in United States sarcoidosis patients compared with case-matched controls. In Scandinavian subjects with an acute form of sarcoidosis known as Löfgren’s syndrome (LS), an association between the presence of HLA-DRB1*03:01 (DR3) and expansions of oligoclonal TRAV12-1–expressing CD4+ T cell populations in the lung has been described (6569). Taken together, these data suggest that CD4+ T cells play an important role in the pathogenesis of sarcoidosis; however, the Ag specificity is not known. Defining Ag recognition in sarcoidosis could clarify the relationship between environmental exposures, genetic susceptibility, and natural history of the disease.

Speculation regarding causative agents in sarcoidosis have included self-antigens, such as vimentin (70, 71), bacterial-derived Ags from Mycobacterium spp. (7276) or Cutibacterium spp. (77), as well as environmental Ags (38, 78). Using an unbiased pathway of Ag discovery, Greaves et al. (79) recently discovered an epitope derived from the NAD-dependent protein deacetylase hst4 (NDPD) of Aspergillus nidulans that was recognized by TRAV12-1–expressing CD4+ T cells from the lungs of HLA-DR3–expressing LS subjects, a distinct subset of acute sarcoidosis. Serum IgG Abs specific to A. nidulans NDPD were also identified in these patients. Lung CD4+ T cells from HLA-DR3–expressing non-LS sarcoidosis patients also responded to the NDPD peptide (79), suggesting that both sarcoidosis patient groups expressing HLA-DR3 may represent a spectrum of the same disease, rather than two distinct clinical entities. Previous studies have linked exposure to fungal byproducts to more severe cases of sarcoidosis with higher fungal biomass levels found in residences of sarcoidosis patients compared with controls (80, 81). These studies suggest a potential role of A. nidulans in the pathogenesis of LS (82). However, the study raises important questions, such as the role of Aspergillus spp. in non–HLA-DR3 sarcoidosis and its role in countries where LS is uncommon. Thus, validation of these findings in other sarcoidosis cohorts is needed.

There is no consistent dose response relationship that accurately predicts risk of beryllium sensitization (83, 84). Studies of occupational exposure and sensitization in mice suggest that this may, in part, be explained by the divergent effects of different physiochemical forms of beryllium on the release of danger signals that act as endogenous adjuvants in vivo (8587). We and others have shown that low-dose exposures of mice to crystalline and ionic forms of beryllium rapidly induce death of airway macrophages (AMs) that correlates with sensitizing doses in the HLA-DP2 Tg mouse model (Fig. 2A) (8587). In healthy lungs, AMs clear innocuous particles, release surfactants, and secrete immunoregulatory cytokines, thereby maintaining an environment for efficient gas exchange (88). These immunoregulatory functions are disrupted when AMs phagocytose irregular particles or membrane-damaging substances, leading to the secretion of proinflammatory cytokines and/or initiation of regulated cell death (87, 89, 90). Beryllium crystals disrupted lysosomal membranes within minutes of phagocytosis (89) and released TNF-α that enhanced intracellular bioavailability of damage-associated molecular pattern (DAMPs) in AMs (e.g., full-length IL-1α and fragmented nucleosomal DNA) (8991). Subsequent lysosome-dependent cell death led to DAMP release and activation of pulmonary dendritic cells (DCs) via IL-1R1 and TLR9 (42, 89). Using HLA-DP2 Tg MyD88−/− bone marrow to reconstitute the immune compartment of lethally irradiated HLA-DP2 Tg recipient mice, Collins et al. (89) showed that MyD88-dependent pathways in immune cells were required for beryllium-induced DC activation, beryllium sensitization, and granuloma initiation. Furthermore, depletion of DCs and treatment of mice with TNF-α–blocking Abs prevented beryllium sensitization, confirming a critical early role of these pathway in breaking peripheral tolerance (89, 90).

FIGURE 2.

Model of pathways implicated in the pathogenesis of CBD and sarcoidosis. (A) Innate pathways and disease initiation. Environmental exposure to microbes, a possibility in sarcoidosis, or particulate Ags in both CBD and sarcoidosis induce TNF-α, which amplifies intracellular DAMPs in AMs (e.g., IL-1α, fragmented chromatin, HMGB1) released upon cell death. DAMPs engage TLRs and IL-1R1 in DCs (dotted black arrow). In CBD, this pathway may enhance the release of beryllium ions and CCL3 and CCL4 that are engulfed by DCs and presented as neoantigens. (B) Activation of pathogenic CD4+ Th1 cell responses. Activated DCs enter lymph nodes and migrate to T cell–rich regions and promote expansion and survival of effector memory CD4+ Th1 cells (CXCR3+) that in sarcoidosis may coexpress Th17-related cytokines that enter the circulation. (C) Development of granulomatous lung disease. Disruption of barrier integrity in the airways allows entry of persistent Ag and danger signals into the lung interstitium. TNF-α induces upregulation of adhesion molecules on endothelial cells and local release of a spectrum of chemokines that recruit monocytes, effector memory T cells, Tregs, and B cells. Recruited monocytes develop into moDCs and recruited macrophages that process and present Ag. Local release of cytokines by moDCs may enhance polyfunctional cytokines secreted by Th1/Th17.1 cells. IFN-γ promotes macrophage activation and TNF-α release, creating a cycle of persistent inflammation that drives early granuloma formation. Pathways associated with resolution in sarcoidosis versus progression of granulomatous disease in CBD and progressive sarcoidosis and associated signaling pathways are shown. Pathways uniquely associated with sarcoidosis or CBD are highlighted in red or blue, respectively. PAMP, pathogen-associated molecular pattern.

FIGURE 2.

Model of pathways implicated in the pathogenesis of CBD and sarcoidosis. (A) Innate pathways and disease initiation. Environmental exposure to microbes, a possibility in sarcoidosis, or particulate Ags in both CBD and sarcoidosis induce TNF-α, which amplifies intracellular DAMPs in AMs (e.g., IL-1α, fragmented chromatin, HMGB1) released upon cell death. DAMPs engage TLRs and IL-1R1 in DCs (dotted black arrow). In CBD, this pathway may enhance the release of beryllium ions and CCL3 and CCL4 that are engulfed by DCs and presented as neoantigens. (B) Activation of pathogenic CD4+ Th1 cell responses. Activated DCs enter lymph nodes and migrate to T cell–rich regions and promote expansion and survival of effector memory CD4+ Th1 cells (CXCR3+) that in sarcoidosis may coexpress Th17-related cytokines that enter the circulation. (C) Development of granulomatous lung disease. Disruption of barrier integrity in the airways allows entry of persistent Ag and danger signals into the lung interstitium. TNF-α induces upregulation of adhesion molecules on endothelial cells and local release of a spectrum of chemokines that recruit monocytes, effector memory T cells, Tregs, and B cells. Recruited monocytes develop into moDCs and recruited macrophages that process and present Ag. Local release of cytokines by moDCs may enhance polyfunctional cytokines secreted by Th1/Th17.1 cells. IFN-γ promotes macrophage activation and TNF-α release, creating a cycle of persistent inflammation that drives early granuloma formation. Pathways associated with resolution in sarcoidosis versus progression of granulomatous disease in CBD and progressive sarcoidosis and associated signaling pathways are shown. Pathways uniquely associated with sarcoidosis or CBD are highlighted in red or blue, respectively. PAMP, pathogen-associated molecular pattern.

Close modal

Phagocytosis, induction of CCL3 and CCL4 expression, and cell death in macrophages may contribute to neoantigen generation in CBD. The crystal structure of HLA-DP2 indicates that interactions with beryllium ions promote formation of neoantigen complexes as discussed above; however, beryllium oxide and metal dusts encountered in the workplace are highly insoluble. Macrophages incrementally increase the bioavailability of beryllium ions that dissociate from insoluble particles in lysosomes, where the low pH increases solubility. A mixture of beryllium ions and particles is subsequently released from the cells upon cell death and ingested by neighboring phagocytic cells (48, 9294). It is possible that repeated cycles of phagocytosis and cell death may enhance local availability of beryllium ions and chemokines for DCs (Fig. 2A, 2B) (51). Thus, interactions between highly insoluble beryllium particles and macrophages may enhance neoantigen generation to meet a certain threshold over time. This proposed mechanism represents a possible explanation for the delayed onset of beryllium sensitization and CBD, occurring years to decades after occupational exposure has ended.

Human studies of T cell responses in pulmonary sarcoidosis are largely restricted to later stages of disease because patients are only identified after pulmonary inflammation is evident. Thus, there are gaps in our understanding of the role of innate immunity in disease initiation and activation of CD4+ T cells in sarcoidosis. Murine models have been developed that exhibit similar features to pulmonary sarcoidosis; unfortunately, these models do not replicate the systemic features of the disease (95). Because multiple organs can be impacted by sarcoidosis, it is possible that presentation of neoantigens, autoantigens, or Ags from colonizing or infectious microbes could be presented to the immune system by DCs located in tissues outside of the lung. However, because innate pathways are needed to break peripheral tolerance, it is likely that DAMPs and/or microbial pathogen-associated molecular patterns play a role in the initiation of CD4+ T cell responses. Innate signaling pathways through TLRs are enriched in the lung of sarcoidosis subjects (96), and those engaged by putative infectious or environmental etiological agents may play a primary role in addition to being enhanced during granulomatous inflammation. Gene association studies suggest that polymorphisms in MyD88, TLR2, and TLR9 may play a minor role in conferring susceptibility to sarcoidosis (9799). TLR2 recognizes components of Gram-positive bacteria, fungal cell walls, and serum amyloid A, all of which have been detected in sarcoid granulomas, whereas TLR9 is engaged by bacterial or nucleosomal DNA in endosomal compartments (72, 77, 81, 100). TLR2 expression is elevated on peripheral blood monocytes and expressed in innate and adaptive cells in the mediastinal lymph nodes of sarcoidosis subjects, and BAL cells from sarcoidosis lungs released increased cytokine in response to TLR2/1 ligation (101, 102). AMs from sarcoidosis subjects express increased TLR9 expression and secrete CXCL10 in response to CpG-enriched DNA compared with AMs from healthy controls (103). In addition, mycobacterial heat shock proteins, endogenous heat shock proteins, and high mobility group box protein 1 (HMGB1) and associated signaling pathways are enhanced in AMs in both CBD and sarcoidosis and are discussed in more detail below (104, 105).

Granulomas serve as a barrier between toxic substances and healthy tissues, and studies of granulomas induced during mycobacterial infection have shown that interactions between innate and adaptive immune cells drive the formation and regulation of granulomatous inflammation to limit bystander damage and fibrosis (106). Although beryllium sensitization may occur with any exposure in genetically susceptible individuals, progression to CBD is associated with higher cumulative exposures to aerosolized insoluble beryllium dusts (40, 107). Single-cell transcriptome analysis of recruited BAL macrophages showed that pathways related to MHC class II mediated Ag presentation, complement, cytokine signaling, heat shock protein signaling, and TLR signaling pathways were enriched in CBD compared with beryllium-sensitized controls and in sarcoidosis compared with healthy controls (108). These associations have previously been reported in numerous genomic and epigenomic studies of lung biopsies and BAL and blood studies in sarcoidosis versus healthy control subjects (6062, 96, 109112).

Beryllium-sensitized CD4+ Th1 cells with an effector memory phenotype are present in the BAL in early stages of CBD (113117). Disruption of the epithelial barrier in the inflamed airways may promote penetration of causative Ags into the lung parenchyma along with danger signals and cytokines where they may be taken up by interstitial macrophages (Fig. 2C). TLR and TNFR1 signaling induces upregulation of adhesion molecules on endothelial cells and release of proinflammatory chemokines that promote recruitment of monocytes, effector memory T cells, and B cells to lung granulomas (118). Monocytes recruited to the lung can develop into monocyte-derived macrophages and monocyte-derived DCs (moDCs) that are evident in sarcoidosis granulomas and in mice chronically exposed to beryllium (43, 119). moDCs interact with CD4+ T cells in early lymphoid aggregates in beryllium-exposed mice (43, 120) and are observed in lymphocyte-rich regions of sarcoid granulomas (121). Release of IL-12 by moDCs within granulomas amplifies T cell release of TNF-α and IFN-γ. These cytokines divert phagocytosed Ags away from lysosomal compartments and into MHC class II compartments for presentation (122, 123), upregulate adhesion molecules, and amplify the release of TNF-α from macrophages, creating a positive feedback loop that sustains inflammatory cytokine production (Fig. 2C) (123).

CD8+ effector memory T cells are present in sarcoid granulomas, and B cells are present in the BAL and are detected in CBD and sarcoidosis lung biopsies (15, 124); however, their role in disease pathogenesis is not known. B cells in the lungs of individuals with CBD and sarcoidosis exhibit a unique phenotype (CD11chiCD21loT-betlo) that is shared by autoreactive B cells in systemic lupus erythematosus and other autoimmune diseases (15). Abs and autoantibodies, complement, and immune complexes are elevated in individuals with sarcoidosis compared with healthy control subjects (43, 70, 125). B cells accumulate in BAL and early granulomas in beryllium-exposed mice in response to innate signaling pathways (14). Treatment of mice with B cell–depleting Ab did not impact beryllium sensitization or Ab levels in the HLA-DP2 Tg CBD mouse model; however, infiltrating CD4+ T cells and macrophages failed to form aggregates resulting in a pattern of diffuse inflammation and increased airway injury (14). These data suggest that B cells may play a role in the formation of lymphoid aggregates and highlight the protective role of granulomas in sequestering damaging particles. In addition, disease resolution has been reported in refractory sarcoidosis patients treated with rituximab (126, 127). Paradoxically, sarcoidosis-like granulomas were reported in an autoimmune patient treated with rituximab (128). Thus, further study is needed to understand the role of B cells and Abs in the pathogenesis of CBD and sarcoidosis (129).

In LS and in many non-LS sarcoidosis patients, granulomas resolve (Fig. 2C). Effective Ag clearance and effector T cell responses followed by downmodulation of macrophage activation are associated with resolution. There are conflicting data regarding the role of Th17 cytokines in resolving sarcoidosis (reviewed in Ref. 130). In LS, a resolving form of the sarcoidosis, Th17.1 cells that express high levels of IFN-γ, IL-17A, IL-10, and IL-22 are elevated in patients with a better prognosis (131). Conversely, in non-LS sarcoidosis cohorts, Th17.1 cells have been associated with disease progression and are less polyfunctional and produce high levels of IFN-γ and low levels of IL-17A (59). Based on previous associations between potent effector T cell responses in self-limited sarcoidosis (111) and the association of fungal Ag recognition by CD4+ T cells in HLA-DR3–expressing LS patients (7, 79), it is tempting to speculate that Th17 cytokines are more effective at clearing the causative agents in LS versus those driving disease progression in non-LS sarcoidosis. Although neutrophils are recruited by IL-17A cells, longitudinal studies or development of a relevant mouse model may be needed to define their role due to their short half-life and clearance by resident AMs in vivo.

Persistent release of Th1 cytokines, STAT1 signaling pathways, chronic inflammation, and alterations in TCR signaling are consistently associated with CBD and progressive sarcoidosis (6062, 109112). Ab-mediated depletion of regulatory T cells (Tregs) in the HLA-DP2 Tg mouse model of CBD results in persistent and progressive granulomatous inflammation with evidence of centralized multinuclear giant cells and enhanced deposition of collagen over time (42). In the lung, Tregs in progressive sarcoidosis and CBD are present but have reduced suppressive activity (132134). Tregs from the lungs of subjects with nonresolving sarcoidosis exhibit reduced capacity to suppress inflammatory cytokine production compared with Tregs from the lungs of subjects with resolving sarcoidosis (132, 135138). Single-cell transcriptome analysis of peripheral blood Tregs from sarcoidosis subjects suggests that dysfunctional p53, cell death, and TNFR2 signaling pathways in Tregs may limit their survival and ability to suppress macrophage activation (139). TNFR2 promotes Treg survival and suppressive function in inflammatory environments (140142), and restored Treg function has been associated with resolution of granulomatous inflammation in sarcoidosis (143, 144).

Dysregulation of key macrophage pathways that regulate macrophage immunometabolism are associated with disease progression in sarcoidosis. PPARγ, a negative regulator of inflammatory gene expression and Ag presentation in macrophages, is reduced in progressive sarcoidosis (145). Furthermore, PPARγ-deficient mice exposed to mycobacterial peptide/particle conjugates exhibit exacerbated granulomatous inflammation and fibrosis in the lung. Conversely, dysfunctional activation of the mTOR pathway was associated with disease progression in sarcoidosis (146). Mechanistic analysis of this pathway in mice showed that hyperactivation of mTORC1 in macrophages enhanced their proliferation and survival, inhibited autophagic repair, and disrupted lysosome function. These mice spontaneously developed sarcoidosis-like granulomas in the lungs and other tissues, an effect that was prevented by an mTORC1 inhibitor (146). Single-cell RNA sequencing analysis of differentially expressed pathways in classical monocytes from sarcoidosis subjects showed increased expression of inflammatory genes enhanced by pattern recognition receptors (TLR2/HMGB1) and cytokine receptors (TNFR1, IL-6, GM-CSF) that could be regulated with immunosuppressive agents (139). In contrast, predictive modeling suggested that enhanced mTOR signaling and TGF-β are key drivers of monocyte hyperactivation in sarcoidosis and were not altered in the presence of immunosuppressive agents (139). Taken together, these data suggest that progression to persistent granulomatous inflammation is associated with a failure to regulate hyperactivated macrophages (147, 148).

Persistent TCR stimulation in CBD and sarcoidosis promotes T cell upregulation of PD-1 and PD-L1, reduced T cell proliferation, and anergy (117, 149). PD-1/PD-L1 interactions between exhausted T cells and macrophages may in part promote disease progression by impairing the ability of macrophages to degrade particulate Ags (150). PD-1 and TGF-β enhance STAT3-dependent pathways that promote production of collagen by human lung fibroblasts (151). In addition, expression of genes, including thioredoxin, CXCL2, and CXCL3, were significantly reduced in macrophages in CBD and progressive sarcoidosis (108, 152). Recent results from the multicenter Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study suggest that the combination of signatures in the BAL may reflect distinct clinical involvements (153). For example, T cell activation pathways were enriched in subjects with lymphadenopathy, enhanced TGF-β1 and mTOR signaling pathways were enriched in individuals with interstitial granulomatous disease, and innate and adaptive immune pathways were enriched in individuals with multiorgan involvement.

The discovery of CD4+ T cells that recognize CCL3 and CCL4 peptide-containing neoantigens in the context of HLA-DP2/Be2+ provides a direct link between innate and adaptive immunity in CBD. A similar approach used to identify CD4+ T cell responses specific to an HLA-DR3–presented peptide from A. nidulans in LS provides a pathway to facilitate discovery of the inciting Ags that drive CD4+ T cell alveolitis and granulomatous inflammation in non-LS sarcoidosis. Persistent Ag presentation, chronic macrophage activation, and Treg dysfunction are associated with disease progression in both CBD and sarcoidosis. The functional analysis of novel pathways in larger cohorts is needed to better understand the pathogenesis of CBD and sarcoidosis and to define useful biomarkers, diagnostic tools, and novel therapies.

This work was supported by National Institutes of Health Grants HL62410, HL102245, HL136137, and HL152756, ES011810 (to A.P.F.), and HL126736 (to A.S.M.), as well as by National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards Grant UL1 TR002535.

Abbreviations used in this article:

     
  • AM

    airway macrophage

  •  
  • BAL

    bronchoalveolar lavage

  •  
  • CBD

    chronic beryllium disease

  •  
  • DAMP

    damage-associated molecular pattern

  •  
  • DC

    dendritic cell

  •  
  • HMBG1

    high mobility group box protein 1

  •  
  • LS

    Löfgren’s syndrome

  •  
  • moDC

    monocyte-derived DC

  •  
  • NDPD

    NAD-dependent protein deacetylase hst4

  •  
  • Tg

    transgenic

  •  
  • Treg

    regulatory T cell

1.
Ohshimo
S.
,
J.
Guzman
,
U.
Costabel
,
F.
Bonella
.
2017
.
Differential diagnosis of granulomatous lung disease: clues and pitfalls: number 4 in the series “Pathology for the clinician” edited by Peter Dorfmuller and Alberto Cavazza.
Eur. Respir. Rev.
26
:
170012
.
2.
Rossman
M. D.
,
M. E.
Kreider
.
2003
.
Is chronic beryllium disease sarcoidosis of known etiology?
Sarcoidosis Vasc. Diffuse Lung Dis.
20
:
104
109
.
3.
Grunewald
J.
,
J. C.
Grutters
,
E. V.
Arkema
,
L. A.
Saketkoo
,
D. R.
Moller
,
J.
Müller-Quernheim
.
2019
.
Sarcoidosis. [Published erratum appears in 2019 Nat. Rev. Dis. Primers 5: 49.]
Nat. Rev. Dis. Primers
5
:
45
.
4.
1999
.
Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999.
Am. J. Respir. Crit. Care Med.
160
:
736
755
.
5.
Richeldi
L.
,
K.
Kreiss
,
M. M.
Mroz
,
B.
Zhen
,
P.
Tartoni
,
C.
Saltini
.
1997
.
Interaction of genetic and exposure factors in the prevalence of berylliosis.
Am. J. Ind. Med.
32
:
337
340
.
6.
Richeldi
L.
,
R.
Sorrentino
,
C.
Saltini
.
1993
.
HLA-DPB1 glutamate 69: a genetic marker of beryllium disease.
Science
262
:
242
244
.
7.
Greaves
S. A.
,
S. M.
Atif
,
A. P.
Fontenot
.
2020
.
Adaptive immunity in pulmonary sarcoidosis and chronic beryllium disease.
Front. Immunol.
11
:
474
.
8.
Wang
Z.
,
P. S.
White
,
M.
Petrovic
,
O. L.
Tatum
,
L. S.
Newman
,
L. A.
Maier
,
B. L.
Marrone
.
1999
.
Differential susceptibilities to chronic beryllium disease contributed by different Glu69 HLA-DPB1 and -DPA1 alleles.
J. Immunol.
163
:
1647
1653
.
9.
Rossman
M. D.
,
B.
Thompson
,
M.
Frederick
,
M.
Maliarik
,
M. C.
Iannuzzi
,
B. A.
Rybicki
,
J. P.
Pandey
,
L. S.
Newman
,
E.
Magira
,
B.
Beznik-Cizman
,
D.
Monos
;
ACCESS Group
.
2003
.
HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites.
Am. J. Hum. Genet.
73
:
720
735
.
10.
Grunewald
J.
2012
.
HLA associations and Löfgren’s syndrome.
Expert Rev. Clin. Immunol.
8
:
55
62
.
11.
Saltini
C.
,
K.
Winestock
,
M.
Kirby
,
P.
Pinkston
,
R. G.
Crystal
.
1989
.
Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells.
N. Engl. J. Med.
320
:
1103
1109
.
12.
Keogh
B. A.
,
G. W.
Hunninghake
,
B. R.
Line
,
R. G.
Crystal
.
1983
.
The alveolitis of pulmonary sarcoidosis. Evaluation of natural history and alveolitis-dependent changes in lung function.
Am. Rev. Respir. Dis.
128
:
256
265
.
13.
Hunninghake
G. W.
,
R. G.
Crystal
.
1981
.
Mechanisms of hypergammaglobulinemia in pulmonary sarcoidosis. Site of increased antibody production and role of T lymphocytes.
J. Clin. Invest.
67
:
86
92
.
14.
Atif
S. M.
,
D. G.
Mack
,
A. S.
McKee
,
J.
Rangel-Moreno
,
A. K.
Martin
,
A.
Getahun
,
L. A.
Maier
,
J. C.
Cambier
,
R.
Tuder
,
A. P.
Fontenot
.
2019
.
Protective role of B cells in sterile particulate-induced lung injury.
JCI Insight
5
:
e125494
.
15.
Phalke
S.
,
K.
Aviszus
,
K.
Rubtsova
,
A.
Rubtsov
,
B.
Barkes
,
L.
Powers
,
B.
Warner
,
J. L.
Crooks
,
J. W.
Kappler
,
E. R.
Fernández-Pérez
, et al
2020
.
Age-associated B cells appear in patients with granulomatous lung diseases.
Am. J. Respir. Crit. Care Med.
202
:
1013
1023
.
16.
Kosjerina
Z.
,
B.
Zaric
,
D.
Vuckovic
,
D.
Lalosevic
,
G.
Djenadic
,
B.
Murer
.
2012
.
The sarcoid granuloma: “epithelioid” or “lymphocytic-epithelioid” granuloma?
Multidiscip. Respir. Med.
7
:
11
.
17.
Sawyer
R. T.
,
L. A.
Maier
,
L. A.
Kittle
,
L. S.
Newman
.
2002
.
Chronic beryllium disease: a model interaction between innate and acquired immunity.
Int. Immunopharmacol.
2
:
249
261
.
18.
Chesner
C.
1950
.
Chronic pulmonary granulomatosis in residents of a community near a beryllium plant; 3 autopsied cases.
Ann. Intern. Med.
32
:
1028
1048
.
19.
Henneberger
P. K.
,
S. K.
Goe
,
W. E.
Miller
,
B.
Doney
,
D. W.
Groce
.
2004
.
Industries in the United States with airborne beryllium exposure and estimates of the number of current workers potentially exposed.
J. Occup. Environ. Hyg.
1
:
648
659
.
20.
Eisenbud
M.
,
R. C.
Wanta
, et al
1949
.
Non-occupational berylliosis.
J. Ind. Hyg. Toxicol.
31
:
282
294
.
21.
Maier
L. A.
,
J. W.
Martyny
,
J.
Liang
,
M. D.
Rossman
.
2008
.
Recent chronic beryllium disease in residents surrounding a beryllium facility.
Am. J. Respir. Crit. Care Med.
177
:
1012
1017
.
22.
Hardy
H. L.
1947
.
New clinical syndrome; delayed chemical pneumonitis occurring in workers exposed to beryllium compounds.
Bull New Engl Med Cent
9
:
16
24
.
23.
1984
.
Archives of the Cleveland Clinic Quarterly 1943: chemical pneumonia in workers extracting beryllium oxide. Report of three cases. By H.S. VanOrdstrand, Robert Hughes and Morris G. Carmody.
Cleve. Clin. Q.
51
:
431
439
.
24.
Eisenbud
M.
,
J.
Lisson
.
1983
.
Epidemiological aspects of beryllium-induced nonmalignant lung disease: a 30-year update.
J. Occup. Med.
25
:
196
202
.
25.
Kreiss
K.
,
F.
Miller
,
L. S.
Newman
,
E. A.
Ojo-Amaize
,
M. D.
Rossman
,
C.
Saltini
.
1994
.
Chronic beryllium disease—from the workplace to cellular immunology, molecular immunogenetics, and back.
Clin. Immunol. Immunopathol.
71
:
123
129
.
26.
Hanifin
J. M.
,
W. L.
Epstein
,
M. J.
Cline
.
1970
.
In vitro studies on granulomatous hypersensitivity to beryllium.
J. Invest. Dermatol.
55
:
284
288
.
27.
Newman
L. S.
,
K.
Kreiss
,
T. E.
King
Jr.
,
S.
Seay
,
P. A.
Campbell
.
1989
.
Pathologic and immunologic alterations in early stages of beryllium disease. Re-examination of disease definition and natural history.
Am. Rev. Respir. Dis.
139
:
1479
1486
.
28.
Welch
L.
,
K.
Ringen
,
E.
Bingham
,
J.
Dement
,
T.
Takaro
,
W.
McGowan
,
A.
Chen
,
P.
Quinn
.
2004
.
Screening for beryllium disease among construction trade workers at Department of Energy nuclear sites.
Am. J. Ind. Med.
46
:
207
218
.
29.
Kreiss
K.
,
M. M.
Mroz
,
L. S.
Newman
,
J.
Martyny
,
B.
Zhen
.
1996
.
Machining risk of beryllium disease and sensitization with median exposures below 2 μg/m3.
Am. J. Ind. Med.
30
:
16
25
.
30.
Kreiss
K.
,
M. M.
Mroz
,
B.
Zhen
,
J. W.
Martyny
,
L. S.
Newman
.
1993
.
Epidemiology of beryllium sensitization and disease in nuclear workers.
Am. Rev. Respir. Dis.
148
:
985
991
.
31.
Rosenman
K.
,
V.
Hertzberg
,
C.
Rice
,
M. J.
Reilly
,
J.
Aronchick
,
J. E.
Parker
,
J.
Regovich
,
M.
Rossman
.
2005
.
Chronic beryllium disease and sensitization at a beryllium processing facility.
Environ. Health Perspect.
113
:
1366
1372
.
32.
Deubner
D. C.
,
P.
Sabey
,
W.
Huang
,
D.
Fernandez
,
A.
Rudd
,
W. P.
Johnson
,
J.
Storrs
,
R.
Larson
.
2011
.
Solubility and chemistry of materials encountered by beryllium mine and ore extraction workers: relation to risk.
J. Occup. Environ. Med.
53
:
1187
1193
.
33.
Taiwo
O. A.
,
M. D.
Slade
,
L. F.
Cantley
,
S. R.
Kirsche
,
J. C.
Wesdock
,
M. R.
Cullen
.
2010
.
Prevalence of beryllium sensitization among aluminium smelter workers.
Occup. Med. (Lond.)
60
:
569
571
.
34.
Sackett
H. M.
,
L. A.
Maier
,
L. J.
Silveira
,
M. M.
Mroz
,
L. G.
Ogden
,
J. R.
Murphy
,
L. S.
Newman
.
2004
.
Beryllium medical surveillance at a former nuclear weapons facility during cleanup operations.
J. Occup. Environ. Med.
46
:
953
961
.
35.
Stange
A. W.
,
D. E.
Hilmas
,
F. J.
Furman
,
T. R.
Gatliffe
.
2001
.
Beryllium sensitization and chronic beryllium disease at a former nuclear weapons facility.
Appl. Occup. Environ. Hyg.
16
:
405
417
.
36.
Kreiss
K.
,
M. M.
Mroz
,
B.
Zhen
,
H.
Wiedemann
,
B.
Barna
.
1997
.
Risks of beryllium disease related to work processes at a metal, alloy, and oxide production plant.
Occup. Environ. Med.
54
:
605
612
.
37.
Seidler
A.
,
U.
Euler
,
J.
Müller-Quernheim
,
K. I.
Gaede
,
U.
Latza
,
D.
Groneberg
,
S.
Letzel
.
2012
.
Systematic review: progression of beryllium sensitization to chronic beryllium disease.
Occup. Med. (Lond.)
62
:
506
513
.
38.
Newman
L. S.
,
M. M.
Mroz
,
R.
Balkissoon
,
L. A.
Maier
.
2005
.
Beryllium sensitization progresses to chronic beryllium disease: a longitudinal study of disease risk.
Am. J. Respir. Crit. Care Med.
171
:
54
60
.
39.
Newman
L. S.
,
C.
Bobka
,
B.
Schumacher
,
E.
Daniloff
,
B.
Zhen
,
M. M.
Mroz
,
T. E.
King
Jr
.
1994
.
Compartmentalized immune response reflects clinical severity of beryllium disease.
Am. J. Respir. Crit. Care Med.
150
:
135
142
.
40.
MacMurdo
M. G.
,
M. M.
Mroz
,
D. A.
Culver
,
R. A.
Dweik
,
L. A.
Maier
.
2020
.
Chronic beryllium disease: update on a moving target.
Chest
158
:
2458
2466
.
41.
Mroz
M. M.
,
J. H.
Ferguson
,
A. V.
Faino
,
A.
Mayer
,
M.
Strand
,
L. A.
Maier
.
2018
.
Effect of inhaled corticosteroids on lung function in chronic beryllium disease.
Respir. Med.
138
(
Suppl
):
S14
S19
.
42.
Mack
D. G.
,
M. T.
Falta
,
A. S.
McKee
,
A. K.
Martin
,
P. L.
Simonian
,
F.
Crawford
,
T.
Gordon
,
R. R.
Mercer
,
M. D.
Hoover
,
P.
Marrack
, et al
2014
.
Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease.
Proc. Natl. Acad. Sci. USA
111
:
8553
8558
.
43.
KleinJan
A.
,
van Nimwegen
M.
,
Leman
K.
,
Wen
K.X.
,
Boon
L.
,
Hendriks
R.W.
2021
.
Involvement of dendritic cells and Th17 cells in induced tertiary lymphoid structures in a chronic beryllium disease mouse model.
Mediators Inflamm.
2021
:
8845966
.
44.
Tarantino-Hutchison
L. M.
,
C.
Sorrentino
,
A.
Nadas
,
Y.
Zhu
,
E. M.
Rubin
,
S. S.
Tinkle
,
A.
Weston
,
T.
Gordon
.
2009
.
Genetic determinants of sensitivity to beryllium in mice.
J. Immunotoxicol.
6
:
130
135
.
45.
Gordon
T.
,
D.
Bowser
.
2003
.
Beryllium: genotoxicity and carcinogenicity.
Mutat. Res.
533
:
99
105
.
46.
Bowerman
N. A.
,
M. T.
Falta
,
D. G.
Mack
,
F.
Wehrmann
,
F.
Crawford
,
M. M.
Mroz
,
L. A.
Maier
,
J. W.
Kappler
,
A. P.
Fontenot
.
2014
.
Identification of multiple public TCR repertoires in chronic beryllium disease.
J. Immunol.
192
:
4571
4580
.
47.
Falta
M. T.
,
N. A.
Bowerman
,
S.
Dai
,
J. W.
Kappler
,
A. P.
Fontenot
.
2010
.
Linking genetic susceptibility and T cell activation in beryllium-induced disease.
Proc. Am. Thorac. Soc.
7
:
126
129
.
48.
Falta
M. T.
,
J. C.
Crawford
,
A. N.
Tinega
,
L. G.
Landry
,
F.
Crawford
,
D. G.
Mack
,
A. K.
Martin
,
S. M.
Atif
,
L.
Li
,
R. G.
Santos
, et al
2021
.
Beryllium-specific CD4+ T cells induced by chemokine neoantigens perpetuate inflammation.
J. Clin. Invest.
131
:
e144864
.
49.
Falta
M. T.
,
C.
Pinilla
,
D. G.
Mack
,
A. N.
Tinega
,
F.
Crawford
,
M.
Giulianotti
,
R.
Santos
,
G. M.
Clayton
,
Y.
Wang
,
X.
Zhang
, et al
2013
.
Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease.
J. Exp. Med.
210
:
1403
1418
.
50.
Falta
M. T.
,
A. N.
Tinega
,
D. G.
Mack
,
N. A.
Bowerman
,
F.
Crawford
,
J. W.
Kappler
,
C.
Pinilla
,
A. P.
Fontenot
.
2016
.
Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice.
Mucosal Immunol.
9
:
218
228
.
51.
Clayton
G. M.
,
Y.
Wang
,
F.
Crawford
,
A.
Novikov
,
B. T.
Wimberly
,
J. S.
Kieft
,
M. T.
Falta
,
N. A.
Bowerman
,
P.
Marrack
,
A. P.
Fontenot
, et al
2014
.
Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity.
Cell
158
:
132
142
.
52.
Dai
S.
,
G. A.
Murphy
,
F.
Crawford
,
D. G.
Mack
,
M. T.
Falta
,
P.
Marrack
,
J. W.
Kappler
,
A. P.
Fontenot
.
2010
.
Crystal structure of HLA-DP2 and implications for chronic beryllium disease.
Proc. Natl. Acad. Sci. USA
107
:
7425
7430
.
53.
Newman
L. S.
,
C. S.
Rose
,
L. A.
Maier
.
1997
.
Sarcoidosis.
N. Engl. J. Med.
336
:
1224
1234
.
54.
Baughman
R. P.
,
E. E.
Lower
,
R. M.
du Bois
.
2003
.
Sarcoidosis.
Lancet
361
:
1111
1118
.
55.
Baughman
R. P.
,
A. S.
Teirstein
,
M. A.
Judson
,
M. D.
Rossman
,
H.
Yeager
Jr.
,
E. A.
Bresnitz
,
L.
DePalo
,
G.
Hunninghake
,
M. C.
Iannuzzi
,
C. J.
Johns
, et al
Case Control Etiologic Study of Sarcoidosis (ACCESS) research group
.
2001
.
Clinical characteristics of patients in a case control study of sarcoidosis.
Am. J. Respir. Crit. Care Med.
164
:
1885
1889
.
56.
Kita
S.
,
T.
Tsuda
,
K.
Sugisaki
,
E.
Miyazaki
,
T.
Matsumoto
.
1995
.
Characterization of distribution of T lymphocyte subsets and activated T lymphocytes infiltrating into sarcoid lesions.
Intern. Med.
34
:
847
855
.
57.
Wahlström
J.
,
M.
Berlin
,
C. M.
Sköld
,
H.
Wigzell
,
A.
Eklund
,
J.
Grunewald
.
1999
.
Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis.
Thorax
54
:
339
346
.
58.
Zhang
H.
,
U.
Costabel
,
H.
Dai
.
2021
.
The role of diverse immune cells in sarcoidosis.
Front. Immunol.
12
:
788502
.
59.
Broos
C. E.
,
L. L.
Koth
,
M.
van Nimwegen
,
J. C. C. M.
In ’t Veen
,
S. M. J.
Paulissen
,
J. P.
van Hamburg
,
J. T.
Annema
,
R.
Heller-Baan
,
A.
Kleinjan
,
H. C.
Hoogsteden
, et al
2018
.
Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes.
Eur. Respir. J.
51
:
1701124
.
60.
Crouser
E. D.
,
D. A.
Culver
,
K. S.
Knox
,
M. W.
Julian
,
G.
Shao
,
S.
Abraham
,
S.
Liyanarachchi
,
J. E.
Macre
,
M. D.
Wewers
,
M. A.
Gavrilin
, et al
2009
.
Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis.
Am. J. Respir. Crit. Care Med.
179
:
929
938
.
61.
Rosenbaum
J. T.
,
S.
Pasadhika
,
E. D.
Crouser
,
D.
Choi
,
C. A.
Harrington
,
J. A.
Lewis
,
C. R.
Austin
,
T. N.
Diebel
,
E. E.
Vance
,
R. M.
Braziel
, et al
2009
.
Hypothesis: sarcoidosis is a STAT1-mediated disease.
Clin. Immunol.
132
:
174
183
.
62.
Lockstone
H. E.
,
S.
Sanderson
,
N.
Kulakova
,
D.
Baban
,
A.
Leonard
,
W. L.
Kok
,
S.
McGowan
,
A. J.
McMichael
,
L. P.
Ho
.
2010
.
Gene set analysis of lung samples provides insight into pathogenesis of progressive, fibrotic pulmonary sarcoidosis.
Am. J. Respir. Crit. Care Med.
181
:
1367
1375
.
63.
Rybicki
B. A.
,
M. C.
Iannuzzi
,
M. M.
Frederick
,
B. W.
Thompson
,
M. D.
Rossman
,
E. A.
Bresnitz
,
M. L.
Terrin
,
D. R.
Moller
,
J.
Barnard
,
R. P.
Baughman
, et al
ACCESS Research Group
.
2001
.
Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).
Am. J. Respir. Crit. Care Med.
164
:
2085
2091
.
64.
Levin
A. M.
,
I.
Adrianto
,
I.
Datta
,
M. C.
Iannuzzi
,
S.
Trudeau
,
J.
Li
,
W. P.
Drake
,
C. G.
Montgomery
,
B. A.
Rybicki
.
2015
.
Association of HLA-DRB1 with sarcoidosis susceptibility and progression in African Americans.
Am. J. Respir. Cell Mol. Biol.
53
:
206
216
.
65.
Grunewald
J.
,
C. H.
Janson
,
A.
Eklund
,
M.
Ohrn
,
O.
Olerup
,
U.
Persson
,
H.
Wigzell
.
1992
.
Restricted Vα2.3 gene usage by CD4+ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3.
Eur. J. Immunol.
22
:
129
135
.
66.
Grunewald
J.
,
O.
Olerup
,
U.
Persson
,
M. B.
Ohrn
,
H.
Wigzell
,
A.
Eklund
.
1994
.
T-cell receptor variable region gene usage by CD4+ and CD8+ T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients.
Proc. Natl. Acad. Sci. USA
91
:
4965
4969
.
67.
Grunewald
J.
,
T.
Hultman
,
A.
Bucht
,
A.
Eklund
,
H.
Wigzell
.
1995
.
Restricted usage of T cell receptor Vα/Jα gene segments with different nucleotide but identical amino acid sequences in HLA-DR3+ sarcoidosis patients.
Mol. Med.
1
:
287
296
.
68.
Grunewald
J.
,
M.
Berlin
,
O.
Olerup
,
A.
Eklund
.
2000
.
Lung T-helper cells expressing T-cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis.
Am. J. Respir. Crit. Care Med.
161
:
814
818
.
69.
Grunewald
J.
,
J.
Wahlström
,
M.
Berlin
,
H.
Wigzell
,
A.
Eklund
,
O.
Olerup
.
2002
.
Lung restricted T cell receptor AV2S3+ CD4+ T cell expansions in sarcoidosis patients with a shared HLA-DRβ chain conformation.
Thorax
57
:
348
352
.
70.
Kinloch
A. J.
,
Y.
Kaiser
,
D.
Wolfgeher
,
J.
Ai
,
A.
Eklund
,
M. R.
Clark
,
J.
Grunewald
.
2018
.
In situ humoral immunity to vimentin in HLA-DRB1*03+ patients with pulmonary sarcoidosis.
Front. Immunol.
9
:
1516
.
71.
Wahlström
J.
,
J.
Dengjel
,
B.
Persson
,
H.
Duyar
,
H. G.
Rammensee
,
S.
Stevanović
,
A.
Eklund
,
R.
Weissert
,
J.
Grunewald
.
2007
.
Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis.
J. Clin. Invest.
117
:
3576
3582
.
72.
Gupta
D.
,
R.
Agarwal
,
A. N.
Aggarwal
,
S. K.
Jindal
.
2007
.
Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis.
Eur. Respir. J.
30
:
508
516
.
73.
Chen
E. S.
,
J.
Wahlström
,
Z.
Song
,
M. H.
Willett
,
M.
Wikén
,
R. C.
Yung
,
E. E.
West
,
J. F.
McDyer
,
Y.
Zhang
,
A.
Eklund
, et al
2008
.
T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis.
J. Immunol.
181
:
8784
8796
.
74.
Oswald-Richter
K. A.
,
D. A.
Culver
,
C.
Hawkins
,
R.
Hajizadeh
,
S.
Abraham
,
B. E.
Shepherd
,
C. A.
Jenkins
,
M. A.
Judson
,
W. P.
Drake
.
2009
.
Cellular responses to mycobacterial antigens are present in bronchoalveolar lavage fluid used in the diagnosis of sarcoidosis.
Infect. Immun.
77
:
3740
3748
.
75.
Song
Z.
,
L.
Marzilli
,
B. M.
Greenlee
,
E. S.
Chen
,
R. F.
Silver
,
F. B.
Askin
,
A. S.
Teirstein
,
Y.
Zhang
,
R. J.
Cotter
,
D. R.
Moller
.
2005
.
Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.
J. Exp. Med.
201
:
755
767
.
76.
Drake
W. P.
,
M. S.
Dhason
,
M.
Nadaf
,
B. E.
Shepherd
,
S.
Vadivelu
,
R.
Hajizadeh
,
L. S.
Newman
,
S. A.
Kalams
.
2007
.
Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis.
Infect. Immun.
75
:
527
530
.
77.
Eishi
Y.
,
M.
Suga
,
I.
Ishige
,
D.
Kobayashi
,
T.
Yamada
,
T.
Takemura
,
T.
Takizawa
,
M.
Koike
,
S.
Kudoh
,
U.
Costabel
, et al
2002
.
Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis.
J. Clin. Microbiol.
40
:
198
204
.
78.
Demirkok
S. S.
,
M.
Basaranoglu
,
O.
Akbilgic
.
2006
.
Seasonal variation of the onset of presentations in stage 1 sarcoidosis.
Int. J. Clin. Pract.
60
:
1443
1450
.
79.
Greaves
S. A.
,
A.
Ravindran
,
R. G.
Santos
,
L.
Chen
,
M. T.
Falta
,
Y.
Wang
,
A. M.
Mitchell
,
S. M.
Atif
,
D. G.
Mack
,
A. N.
Tinega
, et al
2021
.
CD4+ T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope.
J. Exp. Med.
218
:
e20210785
.
80.
Terčelj
M.
,
S.
Stopinšek
,
A.
Ihan
,
B.
Salobir
,
S.
Simčič
,
R.
Rylander
.
2014
.
Fungal exposure and low levels of IL-10 in patients with sarcoidosis.
Pulm. Med.
2014
:
164565
.
81.
Terčelj
M.
,
S.
Stopinšek
,
A.
Ihan
,
B.
Salobir
,
S.
Simčič
,
B.
Wraber
,
R.
Rylander
.
2011
.
In vitro and in vivo reactivity to fungal cell wall agents in sarcoidosis.
Clin. Exp. Immunol.
166
:
87
93
.
82.
Lim
C. X.
,
T.
Weichhart
.
2021
.
A fungal antigenic driver for Löfgren’s syndrome sarcoidosis.
J. Exp. Med.
218
:
e20211572
.
83.
Schuler
C. R.
,
M. S.
Kent
,
D. C.
Deubner
,
M. T.
Berakis
,
M.
McCawley
,
P. K.
Henneberger
,
M. D.
Rossman
,
K.
Kreiss
.
2005
.
Process-related risk of beryllium sensitization and disease in a copper-beryllium alloy facility.
Am. J. Ind. Med.
47
:
195
205
.
84.
Henneberger
P. K.
,
D.
Cumro
,
D. D.
Deubner
,
M. S.
Kent
,
M.
McCawley
,
K.
Kreiss
.
2001
.
Beryllium sensitization and disease among long-term and short-term workers in a beryllium ceramics plant.
Int. Arch. Occup. Environ. Health
74
:
167
176
.
85.
Wade
M. F.
,
M. K.
Collins
,
D.
Richards
,
D. G.
Mack
,
A. K.
Martin
,
C. A.
Dinarello
,
A. P.
Fontenot
,
A. S.
McKee
.
2018
.
TLR9 and IL-1R1 promote mobilization of pulmonary dendritic cells during beryllium sensitization.
J. Immunol.
201
:
2232
2243
.
86.
McKee
A. S.
,
D. G.
Mack
,
F.
Crawford
,
A. P.
Fontenot
.
2015
.
MyD88 dependence of beryllium-induced dendritic cell trafficking and CD4+ T-cell priming.
Mucosal Immunol.
8
:
1237
1247
.
87.
Sawyer
R. T.
,
B. J.
Day
,
V. A.
Fadok
,
M.
Chiarappa-Zucca
,
L. A.
Maier
,
A. P.
Fontenot
,
L.
Silveira
,
L. S.
Newman
.
2004
.
Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease.
Am. J. Respir. Cell Mol. Biol.
31
:
470
477
.
88.
Hussell
T.
,
T. J.
Bell
.
2014
.
Alveolar macrophages: plasticity in a tissue-specific context.
Nat. Rev. Immunol.
14
:
81
93
.
89.
Collins
M. K.
,
A. M.
Shotland
,
M. F.
Wade
,
S. M.
Atif
,
D. K.
Richards
,
M.
Torres-Llompart
,
D. G.
Mack
,
A. K.
Martin
,
A. P.
Fontenot
,
A. S.
McKee
.
2020
.
A role for TNF-α in alveolar macrophage damage-associated molecular pattern release.
JCI Insight
5
:
e134356
.
90.
Shotland
A. M.
,
A. P.
Fontenot
,
A. S.
McKee
.
2021
.
Pulmonary macrophage cell death in lung health and disease.
Am. J. Respir. Cell Mol. Biol.
64
:
547
556
.
91.
Sawyer
R. T.
,
D. R.
Dobis
,
M.
Goldstein
,
L.
Velsor
,
L. A.
Maier
,
A. P.
Fontenot
,
L.
Silveira
,
L. S.
Newman
,
B. J.
Day
.
2005
.
Beryllium-stimulated reactive oxygen species and macrophage apoptosis.
Free Radic. Biol. Med.
38
:
928
937
.
92.
Stefaniak
A. B.
,
G. A.
Day
,
M. D.
Hoover
,
P. N.
Breysse
,
R. C.
Scripsick
.
2006
.
Differences in dissolution behavior in a phagolysosomal simulant fluid for single-constituent and multi-constituent materials associated with beryllium sensitization and chronic beryllium disease.
Toxicol. In Vitro
20
:
82
95
.
93.
Day
G. A.
,
M. D.
Hoover
,
A. B.
Stefaniak
,
R. M.
Dickerson
,
E. J.
Peterson
,
N. A.
Esmen
,
R. C.
Scripsick
.
2005
.
Bioavailability of beryllium oxide particles: an in vitro study in the murine J774A.1 macrophage cell line model.
Exp. Lung Res.
31
:
341
360
.
94.
Stefaniak
A. B.
,
R. A.
Guilmette
,
G. A.
Day
,
M. D.
Hoover
,
P. N.
Breysse
,
R. C.
Scripsick
.
2005
.
Characterization of phagolysosomal simulant fluid for study of beryllium aerosol particle dissolution.
Toxicol. In Vitro
19
:
123
134
.
95.
Jeny
F.
,
J. C.
Grutters
.
2020
.
Experimental models of sarcoidosis: where are we now?
Curr. Opin. Pulm. Med.
26
:
554
561
.
96.
Li
L.
,
L. J.
Silveira
,
N.
Hamzeh
,
M.
Gillespie
,
P. M.
Mroz
,
A. S.
Mayer
,
T. E.
Fingerlin
,
L. A.
Maier
.
2016
.
Beryllium-induced lung disease exhibits expression profiles similar to sarcoidosis.
Eur. Respir. J.
47
:
1797
1808
.
97.
Daniil
Z.
,
V.
Mollaki
,
F.
Malli
,
A.
Koutsokera
,
K. M.
Antoniou
,
P.
Rodopoulou
,
K.
Gourgoulianis
,
E.
Zintzaras
,
G.
Vassilopoulos
.
2013
.
Polymorphisms and haplotypes in MyD88 are associated with the development of sarcoidosis: a candidate-gene association study.
Mol. Biol. Rep.
40
:
4281
4286
.
98.
Pabst
S.
,
O.
Bradler
,
A.
Gillissen
,
G.
Nickenig
,
D.
Skowasch
,
C.
Grohe
.
2013
.
Toll-like receptor-9 polymorphisms in sarcoidosis and chronic obstructive pulmonary disease.
Adv. Exp. Med. Biol.
756
:
239
245
.
99.
Veltkamp
M.
,
P. A.
Wijnen
,
C. H.
van Moorsel
,
G. T.
Rijkers
,
H. J.
Ruven
,
M.
Heron
,
O.
Bekers
,
A. M.
Claessen
,
M.
Drent
,
J. M.
van den Bosch
,
J. C.
Grutters
.
2007
.
Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis.
Clin. Exp. Immunol.
149
:
453
462
.
100.
Chen
E. S.
,
Z.
Song
,
M. H.
Willett
,
S.
Heine
,
R. C.
Yung
,
M. C.
Liu
,
S. D.
Groshong
,
Y.
Zhang
,
R. M.
Tuder
,
D. R.
Moller
.
2010
.
Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2.
Am. J. Respir. Crit. Care Med.
181
:
360
373
.
101.
Chen
X.
,
D.
Zhao
,
Y.
Ning
,
Y.
Zhou
.
2020
.
Toll-like receptors 2 expression in mediastinal lymph node of patients with sarcoidosis.
Ann. Transl. Med.
8
:
1182
.
102.
Wikén
M.
,
J.
Grunewald
,
A.
Eklund
,
J.
Wahlström
.
2009
.
Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis.
J. Clin. Immunol.
29
:
78
89
.
103.
Schnerch
J.
,
A.
Prasse
,
D.
Vlachakis
,
K. L.
Schuchardt
,
D. V.
Pechkovsky
,
T.
Goldmann
,
K. I.
Gaede
,
J.
Müller-Quernheim
,
G.
Zissel
.
2016
.
Functional Toll-like receptor 9 expression and CXCR3 ligand release in pulmonary sarcoidosis.
Am. J. Respir. Cell Mol. Biol.
55
:
749
757
.
104.
Dubaniewicz
A.
2013
.
Microbial and human heat shock proteins as “danger signals” in sarcoidosis.
Hum. Immunol.
74
:
1550
1558
.
105.
Suchankova
M.
,
V.
Durmanova
,
E.
Tibenska
,
E.
Tedlova
,
I.
Majer
,
H.
Novosadova
,
J.
Demian
,
M.
Tedla
,
M.
Bucova
.
2018
.
High mobility group box 1 protein in bronchoalveolar lavage fluid and correlation with other inflammatory markers in pulmonary diseases.
Sarcoidosis Vasc. Diffuse Lung Dis.
35
:
268
275
.
106.
Sandor
M.
,
J. V.
Weinstock
,
T. A.
Wynn
.
2003
.
Granulomas in schistosome and mycobacterial infections: a model of local immune responses.
Trends Immunol.
24
:
44
52
.
107.
Sawyer
R. T.
,
J. L.
Abraham
,
E.
Daniloff
,
L. S.
Newman
.
2005
.
Secondary ion mass spectroscopy demonstrates retention of beryllium in chronic beryllium disease granulomas.
J. Occup. Environ. Med.
47
:
1218
1226
.
108.
Liao
S. Y.
,
S. M.
Atif
,
K.
Mould
,
I. R.
Konigsberg
,
R.
Fu
,
E.
Davidson
,
L.
Li
,
A. P.
Fontenot
,
L. A.
Maier
,
I. V.
Yang
.
2021
.
Single-cell RNA sequencing identifies macrophage transcriptional heterogeneities in granulomatous diseases.
Eur. Respir. J.
57
:
2003794
.
109.
Garman
L.
,
C. G.
Montgomery
,
N. V.
Rivera
.
2020
.
Recent advances in sarcoidosis genomics: epigenetics, gene expression, and gene by environment (G × E) interaction studies.
Curr. Opin. Pulm. Med.
26
:
544
553
.
110.
Gharib
S. A.
,
A.
Malur
,
I.
Huizar
,
B. P.
Barna
,
M. S.
Kavuru
,
L. M.
Schnapp
,
M. J.
Thomassen
.
2016
.
Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells.
Respir. Res.
17
:
93
.
111.
Rutherford
R. M.
,
F.
Staedtler
,
J.
Kehren
,
S. D.
Chibout
,
L.
Joos
,
M.
Tamm
,
J. J.
Gilmartin
,
M. H.
Brutsche
.
2004
.
Functional genomics and prognosis in sarcoidosis—the critical role of antigen presentation.
Sarcoidosis Vasc. Diffuse Lung Dis.
21
:
10
18
.
112.
Schupp
J. C.
,
M.
Vukmirovic
,
N.
Kaminski
,
A.
Prasse
.
2017
.
Transcriptome profiles in sarcoidosis and their potential role in disease prediction.
Curr. Opin. Pulm. Med.
23
:
487
492
.
113.
Fontenot
A. P.
,
S. J.
Canavera
,
L.
Gharavi
,
L. S.
Newman
,
B. L.
Kotzin
.
2002
.
Target organ localization of memory CD4+ T cells in patients with chronic beryllium disease.
J. Clin. Invest.
110
:
1473
1482
.
114.
Chain
J. L.
,
A. K.
Martin
,
D. G.
Mack
,
L. A.
Maier
,
B. E.
Palmer
,
A. P.
Fontenot
.
2013
.
Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation.
J. Immunol.
191
:
1648
1656
.
115.
Fontenot
A. P.
,
D. M.
Edwards
,
Y. K.
Chou
,
D. G.
Mack
,
D.
LaTocha
,
A. A.
Vandenbark
,
G. G.
Burrows
.
2006
.
Self-presentation of beryllium by BAL CD4+ T cells: T cell-T cell interactions and their potential role in chronic beryllium disease.
Eur. J. Immunol.
36
:
930
939
.
116.
Mack
D. G.
,
A. K.
Lanham
,
B. E.
Palmer
,
L. A.
Maier
,
T. H.
Watts
,
A. P.
Fontenot
.
2008
.
4-1BB enhances proliferation of beryllium-specific T cells in the lung of subjects with chronic beryllium disease.
J. Immunol.
181
:
4381
4388
.
117.
Palmer
B. E.
,
D. G.
Mack
,
A. K.
Martin
,
M.
Gillespie
,
M. M.
Mroz
,
L. A.
Maier
,
A. P.
Fontenot
.
2008
.
Up-regulation of programmed death-1 expression on beryllium-specific CD4+ T cells in chronic beryllium disease.
J. Immunol.
180
:
2704
2712
.
118.
Broos
C. E.
,
M.
van Nimwegen
,
H. C.
Hoogsteden
,
R. W.
Hendriks
,
M.
Kool
,
B.
van den Blink
.
2013
.
Granuloma formation in pulmonary sarcoidosis.
Front. Immunol.
4
:
437
.
119.
Ota
M.
,
R.
Amakawa
,
K.
Uehira
,
T.
Ito
,
Y.
Yagi
,
A.
Oshiro
,
Y.
Date
,
H.
Oyaizu
,
T.
Shigeki
,
Y.
Ozaki
, et al
2004
.
Involvement of dendritic cells in sarcoidosis.
Thorax
59
:
408
413
.
120.
Li
L.
,
Z.
Huang
,
M.
Gillespie
,
P. M.
Mroz
,
L. A.
Maier
.
2014
.
p38 mitogen-activated protein kinase in beryllium-induced dendritic cell activation.
Hum. Immunol.
75
:
1155
1162
.
121.
Lepzien
R.
,
M.
Nie
,
P.
Czarnewski
,
S.
Liu
,
M.
Yu
,
A.
Ravindran
,
S.
Kullberg
,
A.
Eklund
,
J.
Grunewald
,
A.
Smed-Sörensen
.
2021
.
Pulmonary and blood dendritic cells from sarcoidosis patients more potently induce IFNγ-producing Th1 cells compared with monocytes.
J. Leukoc. Biol.
DOI: 10.1002/JLB.5A0321-162R.
122.
Saketkoo
L. A.
,
R. P.
Baughman
.
2016
.
Biologic therapies in the treatment of sarcoidosis.
Expert Rev. Clin. Immunol.
12
:
817
825
.
123.
Maier
L. A.
,
B. Q.
Barkes
,
M.
Mroz
,
M. D.
Rossman
,
J.
Barnard
,
M.
Gillespie
,
A.
Martin
,
D. G.
Mack
,
L.
Silveira
,
R. T.
Sawyer
, et al
2012
.
Infliximab therapy modulates an antigen-specific immune response in chronic beryllium disease.
Respir. Med.
106
:
1810
1813
.
124.
Fazel
S. B.
,
S. E.
Howie
,
A. S.
Krajewski
,
D.
Lamb
.
1992
.
B lymphocyte accumulations in human pulmonary sarcoidosis.
Thorax
47
:
964
967
.
125.
Kobak
S.
,
H.
Yilmaz
,
F.
Sever
,
A.
Duran
,
N.
Sen
,
A.
Karaarslan
.
2014
.
The prevalence of antinuclear antibodies in patients with sarcoidosis.
Autoimmune Dis.
2014
:
351852
.
126.
Sweiss
N. J.
,
E. E.
Lower
,
M.
Mirsaeidi
,
S.
Dudek
,
J. G.
Garcia
,
D.
Perkins
,
P. W.
Finn
,
R. P.
Baughman
.
2014
.
Rituximab in the treatment of refractory pulmonary sarcoidosis.
Eur. Respir. J.
43
:
1525
1528
.
127.
Lower
E. E.
,
M.
Sturdivant
,
L.
Grate
,
R. P.
Baughman
.
2020
.
Use of third-line therapies in advanced sarcoidosis.
Clin. Exp. Rheumatol.
38
:
834
840
.
128.
Galimberti
F.
,
A. P.
Fernandez
.
2016
.
Sarcoidosis following successful treatment of pemphigus vulgaris with rituximab: a rituximab-induced reaction further supporting B-cell contribution to sarcoidosis pathogenesis?
Clin. Exp. Dermatol.
41
:
413
416
.
129.
Cinetto
F.
,
R.
Scarpa
,
A.
Dell’Edera
,
M. G.
Jones
.
2020
.
Immunology of sarcoidosis: old companions, new relationships.
Curr. Opin. Pulm. Med.
26
:
535
543
.
130.
Miedema
J. R.
,
Y.
Kaiser
,
C. E.
Broos
,
M. S.
Wijsenbeek
,
J.
Grunewald
,
M.
Kool
.
2018
.
Th17-lineage cells in pulmonary sarcoidosis and Löfgren’s syndrome: friend or foe?
J. Autoimmun.
87
:
82
96
.
131.
Kaiser
Y.
,
R.
Lepzien
,
S.
Kullberg
,
A.
Eklund
,
A.
Smed-Sörensen
,
J.
Grunewald
.
2016
.
Expanded lung T-bet+RORγT+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype.
Eur. Respir. J.
48
:
484
494
.
132.
Miyara
M.
,
Z.
Amoura
,
C.
Parizot
,
C.
Badoual
,
K.
Dorgham
,
S.
Trad
,
M.
Kambouchner
,
D.
Valeyre
,
C.
Chapelon-Abric
,
P.
Debré
, et al
2006
.
The immune paradox of sarcoidosis and regulatory T cells.
J. Exp. Med.
203
:
359
370
.
133.
Mack
D. G.
,
A. M.
Lanham
,
B. E.
Palmer
,
L. A.
Maier
,
A. P.
Fontenot
.
2009
.
CD27 expression on CD4+ T cells differentiates effector from regulatory T cell subsets in the lung.
J. Immunol.
182
:
7317
7324
.
134.
Mack
D. G.
,
A. M.
Lanham
,
M. T.
Falta
,
B. E.
Palmer
,
L. A.
Maier
,
A. P.
Fontenot
.
2010
.
Deficient and dysfunctional regulatory T cells in the lungs of chronic beryllium disease subjects.
Am. J. Respir. Crit. Care Med.
181
:
1241
1249
.
135.
Broos
C. E.
,
M.
van Nimwegen
,
A.
Kleinjan
,
B.
ten Berge
,
F.
Muskens
,
J. C.
in ’t Veen
,
J. T.
Annema
,
B. N.
Lambrecht
,
H. C.
Hoogsteden
,
R. W.
Hendriks
, et al
2015
.
Impaired survival of regulatory T cells in pulmonary sarcoidosis.
Respir. Res.
16
:
108
.
136.
Taflin
C.
,
M.
Miyara
,
D.
Nochy
,
D.
Valeyre
,
J. M.
Naccache
,
F.
Altare
,
P.
Salek-Peyron
,
C.
Badoual
,
P.
Bruneval
,
J.
Haroche
, et al
2009
.
FoxP3+ regulatory T cells suppress early stages of granuloma formation but have little impact on sarcoidosis lesions.
Am. J. Pathol.
174
:
497
508
.
137.
Rappl
G.
,
S.
Pabst
,
D.
Riemann
,
A.
Schmidt
,
C.
Wickenhauser
,
W.
Schütte
,
A. A.
Hombach
,
B.
Seliger
,
C.
Grohé
,
H.
Abken
.
2011
.
Regulatory T cells with reduced repressor capacities are extensively amplified in pulmonary sarcoid lesions and sustain granuloma formation.
Clin. Immunol.
140
:
71
83
.
138.
Idali
F.
,
J.
Wahlström
,
C.
Müller-Suur
,
A.
Eklund
,
J.
Grunewald
.
2008
.
Analysis of regulatory T cell associated forkhead box P3 expression in the lungs of patients with sarcoidosis.
Clin. Exp. Immunol.
152
:
127
137
.
139.
Garman
L.
,
R. C.
Pelikan
,
A.
Rasmussen
,
C. A.
Lareau
,
K. A.
Savoy
,
U. S.
Deshmukh
,
H.
Bagavant
,
A. M.
Levin
,
S.
Daouk
,
W. P.
Drake
,
C. G.
Montgomery
.
2020
.
Single cell transcriptomics implicate novel monocyte and T cell immune dysregulation in sarcoidosis.
Front. Immunol.
11
:
567342
.
140.
Fischer
R.
,
R. E.
Kontermann
,
K.
Pfizenmaier
.
2020
.
Selective targeting of TNF receptors as a novel therapeutic approach.
Front. Cell Dev. Biol.
8
:
401
.
141.
Chen
X.
,
X.
Wu
,
Q.
Zhou
,
O. M.
Howard
,
M. G.
Netea
,
J. J.
Oppenheim
.
2013
.
TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T cell phenotype in the inflammatory environment.
J. Immunol.
190
:
1076
1084
.
142.
Atretkhany
K. N.
,
I. A.
Mufazalov
,
J.
Dunst
,
A.
Kuchmiy
,
V. S.
Gogoleva
,
D.
Andruszewski
,
M. S.
Drutskaya
,
D. L.
Faustman
,
M.
Schwabenland
,
M.
Prinz
, et al
2018
.
Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity.
Proc. Natl. Acad. Sci. USA
115
:
13051
13056
.
143.
Oswald-Richter
K. A.
,
B. W.
Richmond
,
N. A.
Braun
,
J.
Isom
,
S.
Abraham
,
T. R.
Taylor
,
J. M.
Drake
,
D. A.
Culver
,
D. S.
Wilkes
,
W. P.
Drake
.
2013
.
Reversal of global CD4+ subset dysfunction is associated with spontaneous clinical resolution of pulmonary sarcoidosis.
J. Immunol.
190
:
5446
5453
.
144.
Huang
H.
,
Z.
Lu
,
C.
Jiang
,
J.
Liu
,
Y.
Wang
,
Z.
Xu
.
2013
.
Imbalance between Th17 and regulatory T-cells in sarcoidosis.
Int. J. Mol. Sci.
14
:
21463
21473
.
145.
Malur
A.
,
A.
Mohan
,
R. A.
Barrington
,
N.
Leffler
,
A.
Malur
,
B.
Muller-Borer
,
G.
Murray
,
K.
Kew
,
C.
Zhou
,
J.
Russell
, et al
2019
.
Peroxisome proliferator-activated receptor-γ deficiency exacerbates fibrotic response to mycobacteria peptide in murine sarcoidosis model.
Am. J. Respir. Cell Mol. Biol.
61
:
198
208
.
146.
Linke
M.
,
H. T.
Pham
,
K.
Katholnig
,
T.
Schnöller
,
A.
Miller
,
F.
Demel
,
B.
Schütz
,
M.
Rosner
,
B.
Kovacic
,
N.
Sukhbaatar
, et al
2017
.
Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.
Nat. Immunol.
18
:
293
302
.
147.
Dubaniewicz
A.
,
M.
Typiak
,
M.
Wybieralska
,
M.
Szadurska
,
S.
Nowakowski
,
A.
Staniewicz-Panasik
,
K.
Rogoza
,
A.
Sternau
,
P.
Deeg
,
P.
Trzonkowski
.
2012
.
Changed phagocytic activity and pattern of Fcγ and complement receptors on blood monocytes in sarcoidosis.
Hum. Immunol.
73
:
788
794
.
148.
Kjellin
H.
,
E.
Silva
,
R. M.
Branca
,
A.
Eklund
,
P. J.
Jakobsson
,
J.
Grunewald
,
J.
Lehtiö
,
A. M.
Wheelock
.
2016
.
Alterations in the membrane-associated proteome fraction of alveolar macrophages in sarcoidosis.
Sarcoidosis Vasc. Diffuse Lung Dis.
33
:
17
28
.
149.
Hawkins
C.
,
G.
Shaginurova
,
D. A.
Shelton
,
J. D.
Herazo-Maya
,
K. A.
Oswald-Richter
,
J. E.
Rotsinger
,
A.
Young
,
L. J.
Celada
,
N.
Kaminski
,
C.
Sevin
,
W. P.
Drake
.
2017
.
Local and systemic CD4+ T cell exhaustion reverses with clinical resolution of pulmonary sarcoidosis.
J. Immunol. Res.
2017
:
3642832
.
150.
Diskin
B.
,
S.
Adam
,
M. F.
Cassini
,
G.
Sanchez
,
M.
Liria
,
B.
Aykut
,
C.
Buttar
,
E.
Li
,
B.
Sundberg
,
R. D.
Salas
, et al
2020
.
PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.
Nat. Immunol.
21
:
442
454
.
151.
Celada
L. J.
,
J. A.
Kropski
,
J. D.
Herazo-Maya
,
W.
Luo
,
A.
Creecy
,
A. T.
Abad
,
O. S.
Chioma
,
G.
Lee
,
N. E.
Hassell
,
G. I.
Shaginurova
, et al
2018
.
PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production.
Sci. Transl. Med.
10
:
eaar8356
.
152.
Boleto
G.
,
M.
Vieira
,
A. C.
Desbois
,
D.
Saadoun
,
P.
Cacoub
.
2020
.
Emerging molecular targets for the treatment of refractory sarcoidosis.
Front. Med. (Lausanne)
7
:
594133
.
153.
Vukmirovic
M.
,
X.
Yan
,
K. F.
Gibson
,
M.
Gulati
,
J. C.
Schupp
,
G.
DeIuliis
,
T. S.
Adams
,
B.
Hu
,
A.
Mihaljinec
,
T. N.
Woolard
, et al
GRADS Investigators
.
2021
.
Transcriptomics of bronchoalveolar lavage cells identifies new molecular endotypes of sarcoidosis.
Eur. Respir. J.
58
:
2002950
.

The authors have no financial conflicts of interest.