Pathology and pathogenesis of sarcoidosis

INTRODUCTION — Sarcoidosis is a multisystem disorder of unknown etiology characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas in involved tissues [1,2]. The lungs are affected in approximately 90 percent of patients, and pulmonary disease accounts for the majority of the morbidity and mortality associated with this disease. Other tissues commonly involved include the skin, eyes, and lymph nodes (table 1).

The pathology and pathogenesis of sarcoidosis will be reviewed here. The pulmonary and extrapulmonary clinical manifestations, diagnosis, and treatment are discussed separately. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of extrapulmonary manifestations of sarcoidosis" and "Clinical manifestations and diagnosis of cardiac sarcoidosis" and "Cutaneous manifestations of sarcoidosis" and "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis" and "Neurologic sarcoidosis" and "Kidney disease in sarcoidosis" and "Treatment of pulmonary sarcoidosis: Initial approach" and "Cutaneous sarcoidosis: Management".)

PATHOLOGY — Sarcoidosis is a multisystem disease that involves the lungs in 90 percent of cases. It has a predilection for the upper lobes of the lung and bronchovascular bundles more than other lung compartments, although it can affect any area [3-5]. Lung involvement is often associated with hilar and mediastinal lymphadenopathy.

On histopathology, classic sarcoid granulomas are non-necrotizing with a tightly packed central area composed of macrophages, epithelioid cells, multinucleated giant cells, and T lymphocytes that are CD4 positive (picture 1) [3,5]. The central areas are surrounded by CD8 and CD4 positive T lymphocytes, B lymphocytes, monocytes, mast cells, and fibroblasts, which in turn are surrounded by lamellar rings of hyaline collagen. The proportions of lymphocytic infiltrate and fibrosis surrounding the granulomas vary depending on the patient and disease duration. Additional histopathologic features of sarcoid granulomas that may be present include asteroid bodies, Schaumann bodies, and birefringent crystalline particles (calcium oxalate and other calcium salts (picture 2 and picture 3 and picture 4)).

In rare patients with necrotizing sarcoid granulomatosis, the histopathology shows perivascular masses composed of confluent granulomas and necrosis of lung parenchyma. Features that favor a diagnosis of necrotizing sarcoid granulomatosis include the following [6]:

●A background of nonnecrotizing sarcoid granulomas in a lymphangitic distribution

●Negative special stains for fungal and mycobacterial infection

●Negative mycobacterial polymerase chain reaction (PCR)  

●Absence of blood vessel wall fibrinoid necrosis (evaluated by elastin stains) in areas peripheral to the necrotic center

●Negative serum antineutrophil cytoplasmic antibody

IMMUNOPATHOGENESIS — The steps involved in the formation of sarcoid granulomas involve a complex interplay of immune cells and their mediators. One of the first steps is thought to be the phagocytosis and presentation of an (unidentified) antigen by antigen-presenting cells such as macrophages or dendritic cells [7]. (See 'Possible etiologic agents' below.)

The putative antigen is presented to cluster of differentiation 4 (CD4)+ T helper lymphocytes, which then amplify the immune response through elaboration of interferon-gamma, interleukin (IL)-2 and other cytokines, aided by T regulatory cells (Tregs) that also produce interferon-gamma [7-9]. Increased expression of the transcription factor T-bet and chemokine receptor CXCR3 contribute to a Th1 orientation.

The sarcoid granuloma can resolve without sequelae or undergo obliterative fibrosis, with the resultant development of interstitial fibrosis [2,10].

Macrophages and dendritic cells — In general, formation of a granuloma is initiated by the presence of a foreign antigen, which stimulates monocytes to differentiate into antigen-presenting cells, such as macrophages or dendritic cells. When macrophages aggregate in response to antigen they evolve into epithelioid cells. Further stimulation by inflammatory mediators leads to fusion of macrophages and dendritic cells into multinucleated giant cells. As the granuloma matures, these macrophages, epithelioid cells, and a few multinucleated giant cells form a tight central cluster [4,7]. (See "Antigen-presenting cells".)

The function of alveolar macrophages as the antigen presenting cell in sarcoidosis is also believed to be relevant to the outcome of disease, promoting either remission or prolonged chronic inflammation in the lungs [11]. Using a quantitative proteomics approach coupled to mass spectrometry, 25 unique proteins were identified in alveolar macrophages from patients with sarcoidosis. Several of the identified proteins were related to key alveolar macrophage functionality, including the Fc-gamma-mediated phagocytosis and clathrin-mediated endocytosis pathways. The importance of these findings will require additional study.

Furthermore, excessive granuloma formation has been described after deletion of the gene encoding tuberous sclerosis 2 (TSC2) [12]. This deletion resulted in activation of the metabolic checkpoint kinase mTORC1 in macrophages. In addition, mTORC1 activation and macrophage proliferation were correlated with clinical disease progression in sarcoidosis patients [12].

T lymphocytes — T lymphocytes with cell surface expression of CD4 include subsets of T helper type 1 (Th1), T helper type 2 (Th2), T helper type 17 (Th17), and Treg cells, among others. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokine profiles and functions of CD4+ T helper cell subsets'.)

T helper cells — Immunohistochemical staining of sarcoid granulomas has demonstrated that the majority of lymphocytes within the granuloma are CD4+ Th1 lymphocytes. However, the periphery of the granuloma is composed of CD4+ as well as CD8+ T cells [13,14]. Since the cells obtained with bronchoalveolar lavage (BAL) in sarcoidosis reflect the degree of alveolitis seen on lung biopsy [15,16], BAL has been used to assess the cellular populations present in the lower respiratory tract.

Examination of BAL fluid from patients with sarcoidosis typically demonstrates dramatic increases in cellularity [2,17,18]. The cell count differential of BAL fluid demonstrates a lymphocytic pleocytosis, with a predominance of CD4+ T cells relative to peripheral blood or lung lymphocytes obtained from healthy controls [2,17,18]. These CD4+ T cells bear surface markers of previous activation and have the ability to spontaneously secrete IL-2, interferon-gamma, and other cytokines characteristic of the Th1 phenotype. Thus, CD4+ T cells may be important in initiating and perpetuating the disease process [2,17,19-22]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokine profiles and functions of CD4+ T helper cell subsets'.)

In comparison to the BAL findings, the peripheral blood of patients with pulmonary sarcoidosis shows a T cell lymphopenia, a decrease in the number of CD4+ T cells, and a decreased ratio of CD4+/CD8+ T cells. One study noted that a specific subset of CD4+ T cells with immunoregulatory properties, known as CD1d-restricted natural killer cells (CD1d-rNKT cells), are profoundly decreased or absent in both the peripheral blood and BAL fluid of patients with sarcoidosis, regardless of disease activity [23]. A decreased in vitro response to T cell mitogens also occurs, and a hypergammaglobulinemia is observed secondary to generalized B cell hyperactivity [13]. Spontaneous clinical resolution has been shown to coincide with restoration of CD4+ Th1 and Treg cell function, whereas continued T cell anergy is a feature of disease progression [24].

A novel population of T follicular helper (Tfh)-like lymphocytes has been identified in BAL samples from patients with sarcoidosis [25]. These Tfh-like cells lack the classical Tfh markers, Bcl-6 and CXCR5, but express high levels of two key B cell helper molecules CD40L and IL-21. Tfh-like cells induce B cell proliferation and antibody production, suggesting an important role for Tfh-like cells in pulmonary sarcoidosis and potentially other immune-mediated lung disorders.

T regulatory cells — T regulatory lymphocytes (Tregs, formerly called T suppressor cells) are CD4+, like Th1 lymphocytes, but their role is to downregulate immune response. (See "Normal B and T lymphocyte development", section on 'Regulatory T cells (Tregs)'.)

Tregs play a key role in immunoregulation, in particular suppressing the activation and expansion of effector CD4⁺ and CD8⁺ T cells [26,27]. Naturally-occurring Treg cells are derived in the thymus and are characterized as CD4⁺ with a high level of CD25 expression (CD4⁺CD25^hi). Depletion of these CD4⁺CD25⁺ T cells, which comprise 5 to 10 percent of circulating CD4⁺ T cells, results in the spontaneous onset of multiorgan autoimmunity [26-29]. Naturally-occurring Treg cells are thought to mediate their effects through cell contact and are anergic to in vitro stimulation [30,31].

FoxP3, a member of the forkhead winged helix family of transcription factors, has been identified as the most specific molecular marker for naturally-occurring Treg cells, and its expression is essential for programming both thymic development and the function of Treg cells [32-34]. In sarcoidosis, a decreased frequency of FoxP3-expressing CD4⁺ T cells was seen in blood and BAL of subjects with active disease [35]. In contrast, two other studies in sarcoidosis noted an increased frequency of CD4⁺CD25^hi T cells in the BAL of subjects with active disease [36,37]. Despite the ability of CD4⁺CD25^hi T cells derived from the sarcoid lung to inhibit T cell proliferation, these cells failed to suppress effector cytokine secretion (ie, IFN-γ and TNF-alpha) even in the presence of a global Treg cell amplification [36].

It has been suggested that a subpopulation of regulatory T cells, known as follicular regulatory T (Tfr) cells, may have a role in disease progression [38].

T cell receptor — Due to the intimate association between CD4+ T cells and the pathogenesis of sarcoidosis, numerous groups have investigated the T cell antigen receptor (TCR) (figure 1) [17,20-22,39,40]. The TCR is composed of an alpha and a beta chain and is responsible for recognizing processed peptide antigens in the context of class I or II MHC [41]. The enormous diversity of the TCR is acquired through somatic rearrangement of the variable (V), diversity (D), and joining (J) segments along with the random addition and/or deletion of N-region nucleotides to form a unique V(D)J region (figure 2).

Studies of the TCR Vbeta repertoire in patients with active sarcoidosis has demonstrated bias in certain TCR Vbeta subsets, including Vbeta2, Vbeta8, Vbeta12, and Valpha2.3 [17,20-22,39,40]. In addition, different Vbeta gene segments are expanded in different individuals. A possible explanation for this observation is that the HLA class II type might select the predominant Vbeta expressed among different patients. Some studies, for example, have found an increased number of Valpha2.3+ T cells in patients with sarcoidosis who express HLA-DR3. Another explanation for the different Vbetas is that different epitopes or antigens are being recognized at the site of disease activity.

Junctional region sequencing has demonstrated that the preferential expression of specific Vbeta regions in the BAL is oligoclonal in nature, suggesting conventional antigenic (Ag) stimulation [17,20-22]. This is in contrast with superantigenic stimulation, which results in polyclonal expansion of a particular Vbeta gene segment [42]. Interestingly, the Kveim reaction site is also characterized by a limited TCR Vbeta repertoire consistent with an Ag-driven immune response [21]. Taken together, these observations suggest that the activated, disease-specific CD4+ T cell clones accumulate at sites of disease activity in response to unknown sarcoid antigen(s).

TCRs derived from BAL lymphocytes of HLA-DR3-expressing Löfgren syndrome patients recognize a peptide derived from the NAD-dependent protein deacetylase hst4 (NDPD) of the airborne mold species, Aspergillus nidulans [43]. A. nidulans NDPD stimulated CD4⁺ T cells from the BAL of the majority of HLA-DR3⁺ Löfgren syndrome patients, and IgG antibody responses to A. nidulans NDPD were increased in the serum of these patients. These observations suggest that Aspergillus species may have a role in the pathogenesis of Löfgren syndrome.

Cytokines — The granulomatous response in sarcoidosis is characterized by a highly-polarized Th1 cytokine response. After T cell recognition of antigen(s), CD4+ T cells secrete Th1-type cytokines such as IL-2, interferon (IFN) gamma, and tumor necrosis factor (TNF) alpha. The release of IFN gamma and TNF alpha promotes macrophage accumulation, activation, and aggregation, resulting in the development of granulomatous inflammation (figure 3) [44]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokine profiles and functions of CD4+ T helper cell subsets'.)

●Interleukins-2 and 15 – IL-2 is important in expanding the activated lymphocyte population within the lung, either by in situ proliferation or by cellular redistribution from the peripheral blood [13]. In addition, IL-2 is involved in the differentiation of B cells with the resultant development of hypergammaglobulinemia. Activated CD4+ T cells possess IL-2 receptors and have the ability to proliferate in vitro in the presence of IL-2 [17]. IL-15 is produced by macrophages and cooperates with IL-2 in initiating cell-mediated immune responses [45]. IL-15 shares several biologic functions with IL-2, including stimulating the proliferation of T cells and B cells. Even though IL-15 and IL-2 are structurally dissimilar, the effects of IL-15 occur through the IL-2 receptor system and may trigger the proliferation of CD4+ T cells in sarcoidosis [45].

●Stimulation of interferon-gamma – Several cytokines (eg, IL-12, IL-18, and IL-27) promote Th1 immune responses and are increased in the lungs of sarcoidosis patients [46-48]. These cytokines act synergistically to stimulate IFN-gamma production from CD4+ Th1 cells. In addition, Th17 cells, which have been identified in blood and BAL fluid of patients with active sarcoidosis, secrete interferon-gamma and may play a role in the alveolitis phase of disease, potentially leading to fibrosis [9,18]. IL-17A–secreting cells have been found in BAL from patients with sarcoidosis.

In addition, a marked expansion of Th17.1 cells that only produce IFN-gamma has been identified [9,49,50]. These findings suggest that Th17.1 cells may be the predominant producer of IFN-gamma in pulmonary sarcoidosis, but raise concerns about possible misclassification of Th17.1 cells as Th1 cells [9].

Upregulation of genes related to Type I and II interferon signaling pathways has been identified in the blood and BAL fluid of patients with sarcoidosis [51]. In addition, interferon-gamma-inducible chemokines, CXCL9 and CXCL10, are elevated in the serum of sarcoidosis subjects compared with controls. The levels of these chemokines correlate with the lung function measurements (eg, diffusing capacity for carbon monoxide [DLCO] and forced vital capacity [FVC]) [52-54].

●Interleukins 6 and 8 – Elevated levels of IL-6 and IL-8 have been identified in the BAL fluid of patients with active pulmonary sarcoidosis [55,56]. IL-6 is produced by macrophages, fibroblasts, and T and B cells, and is a signal for T and B cell proliferation. IL-8 is a potent neutrophil chemotactic factor released from macrophages. A positive correlation existed between IL-6 and IL-8 levels in the BAL fluid and BAL neutrophilia [55]. An association has previously been noted between BAL neutrophilia and a worse prognosis in sarcoidosis [56]. Thus, IL-6 and IL-8 may be important in modifying the disease process.

●Shift to Th2 profile – In some patients, the Th1 type profile shifts to a Th2 type profile with the release of Th2 cytokines, such as IL-4, which stimulates the production of extracellular matrix proteins, acts as a chemoattractant for fibroblasts, and contributes to the evolution of lung fibrosis [13].

POSSIBLE ETIOLOGIC AGENTS — Despite advances in our knowledge of the immunopathogenesis of sarcoidosis, the exact stimulus that initiates the disease process remains elusive. The presence of granulomatous inflammation is thought to result from an exaggerated cell-mediated immune response to one or more unidentified antigen(s) [2,13,57]. The multicenter National Institutes of Health (NIH)-funded ACCESS case-control study of over 700 patients and nearly 30,000 relatives found no single etiologic agent and no genetic locus was clearly implicated in the pathogenesis of sarcoidosis [58-60]. Several possible associations have been investigated, as outlined below.

Occupational and environmental exposures — Certain occupational exposures, such as beryllium [61], zirconium [62,63], and aluminum [64], are associated with development of granulomas that are similar to sarcoid granulomas. These associations have raised the possibility that other occupational or environmental exposures might be etiologic in sarcoidosis [65-67].

A case series suggested that exposure to World Trade Center (WTC) dust during the collapse, rescue, or recovery was associated with an increased incidence of sarcoidosis-like granulomatous pulmonary disease during the five years following the disaster [65]. The series reported 26 patients who had pathologic evidence of new onset sarcoidosis following WTC dust exposure. The estimated annual incidence rate was 86 cases per 100,000 population during the first year after the WTC collapse and 22 cases per 100,000 population during the next four years. In comparison, the estimated annual incidence rate was 15 cases per 100,000 during the 15 years prior to the disaster. Eighteen of the 26 patients (69 percent) also developed findings consistent with asthma. Further, an elevated risk of sarcoidosis-like granulomatous pulmonary disease was not limited to the year immediately after the disaster among people who performed intensive rescue and recovery work [66].

Infectious agents — Numerous microorganisms, most notably mycobacteria and cutibacteria (formerly propionibacteria), have been implicated as possible etiologic agents of sarcoidosis [67-82]. In addition, the apparent transmission of sarcoidosis following lung, cardiac and bone marrow transplantation has also provided support for an infectious etiologic agent [83-87].

The histologic similarity of sarcoidosis to Mycobacterium tuberculosis infection led to the extensive evaluation of this organism as a possible etiologic factor [68,80]. A number of studies, including those using hybridization techniques and the polymerase chain reaction, found evidence of M. tuberculosis in sarcoid tissue [69,70]; however, these findings have not been confirmed in other reports using similar techniques [71-75].

One intriguing study demonstrated growth of acid-fast cell-wall-deficient forms of bacteria (L forms) from the blood of 19 of 20 patients with sarcoidosis but none of 20 controls [76]. However, a large case-control study found no difference in the number of cell wall-deficient mycobacterial forms in blood cultures from patients with and without sarcoidosis [77].

A mycobacterial antigen, M. tuberculosis catalase-peroxidase (mKatG), was found in most sarcoidosis tissue samples examined, but not in control tissues [88]. In a related study, an increased number of T cells reactive to mKatG were found in peripheral blood and bronchoalveolar lavage (BAL) fluid from patients with sarcoidosis, compared with healthy controls [89]. In sarcoidosis, the mKatG-reactive T cells preferentially accumulated in the lung, indicating a compartmentalized response and are consistent with the profile expected for a pathogenic antigen.

A study from Japan reported detection of Propionibacterium acnes (now Cutibacterium acnes) in lymph nodes from 12 of 15 patients with sarcoidosis using the polymerase chain reaction; positive results, but with many fewer genome copies, were also found in 2 of 15 patients with tuberculosis and in 3 of 15 controls [75]. All three patients with sarcoidosis who did not have detectable P. acnes did have another species of cutibacteria (Propionibacterium granulosum, now Cutibacterium granulosum) found by the polymerase chain reaction. Cutibacteria may act to "prime" the immune system prior to the development of sarcoidosis [90]. Although this theory is intriguing, it is not yet known whether there is any causal relationship between cutibacteria and sarcoidosis. (See "Invasive Cutibacterium (formerly Propionibacterium) infections".)

While human herpes virus (HHV)-8 DNA sequences were detected in lung biopsies in eight of eight sarcoid patients compared with 3 of 56 controls [91] in one study, subsequent studies have not confirmed these findings [92,93]. High titers of antibodies against a number of lymphotropic viruses (eg, HHV6, HHV8, HIV, HTLV1, cytomegalovirus) have been observed in patients with sarcoid, but it seems likely that this reflects generalized B cell activation rather than being indicative of an etiology [67].

Kveim-Siltzbach reagent — Approximately 70 percent of patients with early sarcoidosis develop granulomatous inflammation identical to sarcoidosis four to six weeks after the intradermal injection of the Kveim-Siltzbach reagent (consisting of homogenates of human sarcoid tissue) [94]. Vimentin is a type III filament protein that is part of the cytoskeleton of human mesenchymal cells and bacteria and a component of the Kveim-Siltzbach reagent.

While multiple previous studies of the components of the Kveim-Siltzbach reagent failed to identify a responsible antigen, one study used mass spectrometry to identify proteins in the Kveim reagent [95]. Three potential protein candidates (vimentin, tubulin, and alpha-actinin-4) were selected. Peripheral blood mononuclear cells (PBMCs) from sarcoidosis patients and healthy individuals were exposed to the three candidate proteins and the reactions compared with those to Kveim reagent. Kveim reagent and vimentin induced similar patterns of cytokine secretion by sarcoidosis PBMCs, which were different from healthy PBMCs.

Potential role for vimentin — Vimentin has also been implicated as an antigenic factor causing clonal expansion of CD4+ T lymphocytes carrying the T cell receptor Valpha2.3⁺Vbeta22⁺ in patients with Löfgren syndrome [7,96]. Molecular modelling suggests that a vimentin-derived protein fits into the HLA binding cleft of a specific T cell receptor (HLA-DRB1*03) [96].

Serum amyloid A — Serum amyloid A (SAA) is an acute phase protein that participates in the inflammatory response in sarcoidosis [97-99]. Increased SAA levels have been noted in serum from patients with sarcoidosis and correlate with measures of disease burden [97]. In a study of SAA staining of samples from patients with sarcoid and nonsarcoid granulomas, SAA staining was 84 percent specific for sarcoid granulomas, but 44 percent sensitive [99].

GENETIC PREDISPOSITION — The occasional occurrence of sarcoidosis in more than one member of a family suggests the possibility of a genetic contribution [100-105]. An ambitious case-control study of 706 patients and over 27,000 first- and second-degree relatives confirmed that first-degree relatives are at increased risk for developing sarcoidosis (odds ratio [OR] 4.7, 95% CI 2.3-9.7) [58]. This risk was greater for relatives of White patients than for Black patients (OR 18 versus 2.8).

Major histocompatibility complex — Genetic susceptibility to sarcoidosis has been most closely linked with antigens of the major histocompatibility complex (MHC) [44,106]. However, the pattern varies depending upon the ethnic and racial makeup of the population studied, and the associations are relatively weak [107-110]. In ACCESS, the HLA-DR allele, DRB1*1101, was significantly associated with sarcoidosis development in both Black and White participants [111]. This study and others suggest that the genetic background of the individual may account for the clinical heterogeneity of sarcoidosis [110,112]. For example, in Scandinavian subjects with acute sarcoidosis (Löfgren syndrome) and other White populations with sarcoidosis, an association between the presence of HLA-DRB1*0301 and remitting sarcoidosis has been described [113].

Other genes — Genome wide linkage and association studies have identified some additional genes that may be associated with increased susceptibility to sarcoidosis [114-118]. These include the butyrophilin-like 2 gene (BTNL2) and annexin A11 (ANXA11) [104,119-121]. Other studies have suggested an association between the presence and/or severity of sarcoidosis and angiotensin converting enzyme variants in certain subgroups of patients, including Black Americans and Finns [122,123].

Gene expression analysis has been used to identify networks of genes that may be involved in sarcoidosis [124,125]. As an example, gene array studies on lung tissue from healthy controls and patients with active sarcoidosis identified over-expression of two gene networks [124]. One network includes genes associated with T helper 1 (Th1) type antigen responses (ie, interleukin [IL]-7, IL-15, the transcription factor family STAT1, and lymphocyte chemoattractant genes); the second network includes the proteases MMP-12 and ADAMDEC1. It is thought that these proteases participate in lung remodeling, although their exact role is not known.

Lung gene expression profiles have been compared between patients with nodular self-limiting sarcoidosis and those with progressive fibrotic pulmonary sarcoidosis [125]. A greater number of up-regulated genes than down-regulated genes were noted in patients with progressive fibrotic disease, compared with self-limiting disease. In a separate study using whole genome expression profiles in a cohort of sarcoidosis patients, an unbiased gene signature comprised of 20 autosomal genes was identified that appears to distinguish patients with complicated sarcoidosis from patients with uncomplicated sarcoidosis [126].

OTHER ASSOCIATIONS — Non-necrotizing granulomas are seen in some patients with common variable immunodeficiency (CVID), which may provide some insight into the pathogenesis of sarcoid granulomas.

Granulomatous and lymphocytic interstitial lung disease — Granulomatous and lymphocytic interstitial lung disease (GLILD) has been reported in patients with CVID and other primary immunodeficiency diseases. GLILD is characterized by non-necrotizing (sarcoid-like) granulomas, lymphoid interstitial pneumonia, and follicular bronchiolitis on lung biopsy. The clinical features of GLILD are discussed separately. (See "Pulmonary complications of primary immunodeficiencies", section on 'Granulomatous and lymphocytic interstitial lung disease'.)

Like sarcoidosis, GLILD is often accompanied by hilar and mediastinal lymphadenopathy [127]. However, sarcoidosis has a number of features that distinguish it from GLILD, including normal or elevated serum immunoglobulin levels and frequent spontaneous remissions. An association between herpes virus 8 (HHV8) and GLILD has been noted, suggesting a possible relationship between HHV8 infection and granuloma formation in predisposed individuals [128].

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SUMMARY

●Sarcoidosis is a multisystem disorder of unknown etiology. Approximately 90 percent of patients with sarcoidosis have lung involvement. Sarcoidosis has a predilection for the upper lung zones and bronchovascular bundles, but can affect any area of the lung. Lung involvement is often associated with hilar and mediastinal lymphadenopathy. (See 'Introduction' above and 'Pathology' above.)

●Classic sarcoid granulomas are non-necrotizing with a tightly packed central area composed of macrophages, epithelioid cells, multinucleated giant cells, and T lymphocytes that are CD4 positive. This central area is surrounded by a mixture CD8 and CD4 positive T lymphocytes, B lymphocytes, monocytes, mast cells, and fibroblasts, which in turn are surrounded by lamellar rings of hyaline collagen. (See 'Pathology' above.)

●The steps involved in the formation of sarcoid granulomas involve a complex interplay of immune cells, including macrophages, dendritic cells, T helper lymphocytes, T regulatory cells (Tregs), and their mediators. (See 'Immunopathogenesis' above.)

●While studies of the T cell antigen receptor (TCR) Vbeta repertoire suggest conventional antigenic stimulation, the exact etiologic agent(s) remain a mystery. Potential culprits include occupational and environmental exposures, infectious agents (eg, components of mycobacteria or cutibacteria), Kveim-Siltzbach reagent, and vimentin. (See 'Possible etiologic agents' above.)

●The occasional occurrence of sarcoidosis in more than one member of a family suggests the possibility of a genetic contribution.

•Genetic susceptibility has been most closely linked with antigens of the major histocompatibility complex (MHC), although the associations vary depending on racial and ethnic factors. (See 'Major histocompatibility complex' above.)

•Genome wide linkage and association studies have identified genes that may be associated with increased susceptibility to sarcoidosis, such as butyrophilin-like 2 gene (BTNL2), annexin A11 (ANXA11), and angiotensin converting enzyme variants, although the associations vary across populations. (See 'Other genes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Andrew Fontenot, MD, who contributed to earlier versions of this topic review.