Keywords
sarcoidosis - immunopathogenesis - granulomatous inflammation - innate immunity -
adaptive immunity - interstitial lung disease
Introduction
Sarcoidosis is a heterogeneous, multisystem, immune-mediated disease of unknown etiology.
Although it occurs globally, with notable regional and ethnic variation, it is more
prevalent among individuals of Scandinavian or African American descent and is observed
more frequently in women.[1]
[2] The age of onset follows a bimodal distribution, peaking between 30 to 40 and 50
to 60 years, with older patients more likely to be women.[2] Intrathoracic involvement, affecting the lung and/or lymph nodes, occurs in up to
90% of cases, but extrapulmonary manifestations are also common with the skin, eyes,
and/or heart, among others, affected.[3] Clinical manifestations are therefore highly variable and reflect the pattern and
extent of organs involved.
Acute presentations such as Löfgren's syndrome, which is characterized by fever, bilateral
hilar lymphadenopathy, and either ankle arthritis or erythema nodosum, are associated
with an excellent prognosis, with most cases spontaneously resolving within 24 months.[1] In contrast, approximately 10 to 40% of patients develop chronic or progressive
disease, which can result in irreversible organ dysfunction and fibrosis.[2]
[4]
[5] These demographic and clinical features underscore the complexity of sarcoidosis
pathogenesis and highlight the significant heterogeneity in presentation and outcome,
which has long been a barrier to standardized research classification.
The histopathologic hallmark of sarcoidosis is the presence of discrete, well-formed,
non-necrotizing granulomas composed of epithelioid histiocytes and multinucleated
giant cells (MGCs) surrounded by lymphocytes, plasma cells, and fibroblasts, which
form in response to an unidentified antigen.[1] Although the precise trigger remains unknown, two complementary hypotheses of disease
pathogenesis have emerged. One suggests a normal immune response to a persistent,
uncleared, or poorly degraded microbial antigen or auto-antigen. The other proposes
a pathogenic immune response marked by sustained activation, dysfunctional regulation,
and impaired resolution.[1]
In this review, we explore both hypotheses and synthesize the current understandings
of the complex and multifactorial immunologic mechanisms that underly sarcoidosis.
Although traditionally considered a CD4+ T cell–mediated disease with a T-helper (Th)1, Th17, and Th17.1 signature, emerging
evidence from mechanistic studies and novel -omics approaches have broadened this
perspective to include widespread dysregulation of both innate and adaptive immunity.
Abnormalities in monocyte and macrophage function, altered antigen presentation, and
imbalances in effector and regulatory T cell subsets have all been described. Additional
contributions from Th17 cells, B cells, and unconventional T cell populations further
underscore the immunologic complexity of the disease. [Figs. 1] and [2] outline proposed models of granuloma formation and maintenance, highlighting the
cellular interactions that drive sarcoidosis pathogenesis. This review aims to integrate
these diverse insights into a cohesive framework, highlight key immunologic pathways
that are dysregulated in sarcoidosis, and underscore their potential to inform future
therapeutic discovery.
Fig. 1 Model of granuloma formation. Following recognition of an unknown antigen via pattern
recognition receptors such as toll-like receptors (TLRs), macrophages become activated,
differentiate into epithelioid cells, and fuse to form multinucleated giant cells,
establishing the granuloma core. In parallel, dendritic cells recognize and present
antigen via MHC-II to naïve T cells in the lymph node, promoting their activation
and differentiation into Th1 and Th17/Th17.1 effector subsets. These activated T cells
migrate to the lung, where they release cytokines and chemokines that amplify macrophage
activation and drive granuloma assembly. Created in BioRender. Vagts, C. (2025) https://BioRender.com/xjfj4le.
Fig. 2 Model of granuloma maintenance. Hyperactivated and inflammatory macrophages form
the granuloma core and secrete proinflammatory mediators, including IFN-γ, TNF-α,
IL-1β, and additional chemokines that recruit activated T cells to local tissue, fueling
granulomatous inflammation. This process is compounded by impaired regulatory control
from T regulatory (Treg) cells. Hyperactive, dysregulated monocytes are also recruited
to sites of inflammation, where they differentiate into alveolar macrophages, further
driving inflammation in a perpetuating cycle. Additional components, including invariant
natural killer T (iNKT) cells, CD8⁺ T cells, B cells, and fibroblasts, contribute
to the granuloma structure and microenvironment. Patients may have persistent inflammation
and subsequent fibrosis or spontaneous resolution. Created in BioRender. Vagts, C.
(2025) https://BioRender.com/39h3z9v.
Disease Trigger
Genetic Predisposition
Sarcoidosis susceptibility reflects an interplay between genetic predisposition and
environmental or microbial exposures. Familial aggregation studies demonstrate a 3.7-fold
increased risk among first-degree relatives with heritability estimated at 39%.[6] This supports a substantial genetic contribution, though familial prevalence varies
widely across geographic regions.[7]
Genome-wide association studies (GWAS) in sarcoidosis have identified multiple susceptibility
loci, particularly within the HLA class II region including HLA-DRB1, DQA1, and DQB1,
implicating antigen presentation to CD4+ T cells in pathogenesis. Associations are phenotype- and region-specific. For example,
HLA-DRB1*0301 correlates with Löfgren's syndrome; HLA-DRB*12 and *14 with pulmonary
sarcoidosis in the Netherlands[8]; and HLA-DRB1*04 with extrapulmonary disease, including in combination with HLA-DRB*15
in Sweden[9] and with HLA-DQB1*0301 in both Japanese and UK cohorts,[8] where strong links to uveitis and sarcoidosis-associated hypercalcemia have been
observed.[6]
[8]
Although informative, ancestry-restricted studies have limited generalizability and
may fail to capture risk variants present in other populations, potentially overlooking
both shared mechanisms and ancestry-specific contributors to disease. To address this
gap, one of the largest multiethnic GWAS to date, conducted by Liao et al, examined
genetic risk for sarcoidosis in European American and African American cohorts, and
identified HLA alleles DRB1 * 0101, DQA1 * 0101, and DQB1*0501 as shared risk variants
across both groups.[10] These findings reinforce the central role of HLA variation in modulating susceptibility,
phenotype, and prognosis, while clarifying both common and ancestry-specific genetic
determinants of sarcoidosis.
Several non-HLA susceptibility loci have been described, including IL23R, ATXN2/SH2B3,
ANXA11, IL12B, and MANBA/NFKB1.[11]
[12] Functional studies and transcriptome-wide association analyses suggest that these
genes participate in key immunologic processes relevant to sarcoidosis. Specifically,
they are associated with dysregulation of the IL-23/Th17 axis, heightened T cell activation,
and abnormal leukocyte adhesion and trafficking, mechanisms that have emerged as central
features of sarcoidosis pathogenesis.[10]
[11]
[12]
Etiologic Antigens
Granuloma formation in sarcoidosis is initiated by an unidentified antigen, representing
the immune system's attempt to contain a stimulus it cannot fully eliminate. Similar
responses occur in infectious diseases with histologic overlap, such as tuberculosis.[13] Granulomas in sarcoidosis, however, are predominantly non-caseating and lack central
necrosis, in contrast to the caseating granulomas of tuberculosis, where necrosis
reflects the cytotoxicity of actively replicating Mycobacterium tuberculosis and subsequent macrophage apoptosis.[13] Although antimycobacterial therapy has been associated with reduced granuloma burden
in cutaneous sarcoidosis[14] and improved pulmonary function in pulmonary sarcoidosis,[15] the absence of necrosis in sarcoidosis suggests that the inciting antigen is non-viable,
non-replicating, or of low immunogenicity.
Although no single antigen has been definitively established as a universal trigger,
numerous microbial and self-derived candidates have been proposed.[16] These include pathogen-associated molecular patterns (PAMPs) derived from microbes
and self-derived damage-associated molecular patterns (DAMPs) released from stressed
or injured host cells, both of which may activate downstream immune responses.
A wide range of microbial components have been investigated as potential contributors
to sarcoidosis pathogenesis. These include mycobacterial cell wall components, DNA,
cytosolic proteins such as early secreted antigenic target 6 (ESAT-6) and culture
filtrate protein 10 (CFP10), superoxide dismutase A (SODA), and various microbial
heat shock proteins[14] which serve as PAMPs and trigger downstream inflammatory responses. Peripheral blood
mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells from patients with
sarcoidosis have demonstrated altered adaptive immune responses following exposure
to these antigens, including ESAT-6 and mKatG.[17]
[18]
[19] Moreover, molecular analyses have identified both Mycobacterium tuberculosis and non-tuberculous mycobacterial DNA in sarcoidosis tissue samples,[1] supporting a potential role for persistent mycobacterial antigens in driving granulomatous
inflammation.
Non-infectious mechanisms proposed in sarcoidosis pathogenesis include autoimmune
responses to self-antigens or DAMPs, such as serum amyloid A (SAA), vimentin, and
various environmental exposures. SAA is an acute phase apolipoprotein that modulates
inflammation via NF-κB signaling.[20] It is highly expressed in sarcoidosis granulomas,[21] elevated in the serum of sarcoidosis patients,[22]
[23] correlates with treatment need, and may serve as a biomarker for disease. Vimentin,
another prominent self-antigen implicated in sarcoidosis, is an intermediate filament
protein upregulated in response to cellular stress, injury, and inflammation. Elevated
anti-vimentin antibodies (AVA) in serum and bronchoalveolar lavage fluid (BALF), along
with their association with vimentin-rich tertiary lymphoid structures in the lung,
support a role for vimentin in ongoing immune activation and local granulomatous inflammation.[24]
[25] Further, Bagavant et al demonstrated that intratracheal instillation of vimentin-coated
beads in mice induced granuloma formation and a sarcoidosis-like immune response,[26] implicating vimentin as a self-antigen capable of initiating granulomatous inflammation
in the absence of infection. Finally, autoantibody reactivity to four proteins in
BALF and serum, which varied by disease phenotype, suggests a broader autoantigenic
landscape in sarcoidosis.[27]
Environmental exposures such as metals, silica, and inorganic dust are associated
with increased sarcoidosis risk,[28] though specific antigenic drivers remain incompletely defined. These agents may
act as persistent inorganic antigens or adjuvants that amplify immune activation,
promote granuloma formation, and, in some cases, drive fibrotic progression.
In addition to the above mechanisms, the respiratory microbiome likely influences
sarcoidosis pathogenesis, reflecting a complex interplay between host immunity and
microbial composition. Airway microbiome studies have shown shifts in microbial composition,
including increased abundance of Atopobium, Fusobacterium, and various bacterial and fungal taxa in BALF.[29]
[30]
[31]
[32]
Propionibacterium acnes has been localized within granulomas in over 88% of sarcoidosis lymph node samples
using a species-specific monoclonal antibody, suggesting a possible etiologic role.[33] Additionally, increasing attention has been directed toward the gut–lung axis; a
growing evidence suggests the gut microbiota can modulate systemic and pulmonary immune
responses.[34] In sarcoidosis, alterations in microbial populations are observed in both the gastrointestinal
and respiratory tracts, with loss of gut microbial diversity.[35] Collectively, these findings support a model in which dysbiosis in the lungs, gut,
or both may act as a persistent immunologic trigger, driving granuloma formation and
sustaining chronic inflammation in genetically susceptible individuals.
Innate Immune Dysregulation
Innate Immune Dysregulation
Activation of Innate Immunity
PAMPs and DAMPs activate pattern recognition receptors (PRRs) such as Toll-like receptors
(TLRs) and NOD-like receptors (NLRs) on innate immune cells, including macrophages,
dendritic cells (DCs), and monocytes, to initiate innate immune responses that are
critical to granuloma formation.[36] In sarcoidosis, PRR signaling is dysregulated across compartments. In the blood,
TLR2, TLR4, and NOD2 are upregulated on circulating monocytes, and co-stimulation
synergistically amplifies cytokine release, resulting in up to a 4-fold increase in
TNF-α and a 13-fold increase in IL-1β.[37]
[38] In tissue, TLR2 and TLR4 expression is increased in cutaneous sarcoidosis lesions,[39] and TLR2 is also elevated in mediastinal lymph nodes.[40] In contrast, alveolar macrophages from BALF show decreased surface TLR2 expression
compared with healthy controls,[41] yet paradoxically display excessive TNF-α and IL-6 production in response to TLR2/1
stimulation, and a blunted response to TLR2/6 ligation despite preserved TLR2 levels,[42] reflecting functional dysregulation. Additionally, in a Propionibacterium acnes mouse model, TLR2 deletion significantly attenuated granuloma formation, implicating
TLR2 as a central driver of granulomatous inflammation. TLR2 signaling acts through
NF-κB stimulated by SAA,[21] whereas evidence suggests that TLR4-mediated inflammation in sarcoidosis involves
dysregulated p38 MAPK signaling,[43] leading to a heightened proinflammatory cytokine response. Together, these findings
suggest that upregulation and dysregulation of TLR and NOD2 signaling contribute to
persistent innate immune activation and granuloma maintenance in sarcoidosis.
Macrophages: Granuloma Initiation and Effector Function
Macrophages are versatile innate immune cells that maintain tissue homeostasis through
phagocytic function, while also serving as antigen-presenting cells to link innate
and adaptive immunity.[44] Classically, activated M1 macrophages arise in response to Th1-derived cytokines
such as IFN-γ and are characterized by a proinflammatory phenotype, promoting antigen
presentation and cytokine production (e.g., TNF-α, IL-12). In contrast, alternatively
activated M2 macrophages, induced by Th2-associated cytokines like IL-4 and IL-13,
exhibit anti-inflammatory and tissue remodeling functions with the potential to promote
fibrosis.
Macrophages are central to sarcoidosis immunopathogenesis. Following PRR stimulation,
monocyte-derived macrophages are recruited to sites of inflammation where they differentiate
into epithelioid histiocytes and MGCs, hallmark components of the granuloma core.
Epithelioid cells form adherens junctions and interdigitated membranes, creating a
physical barrier around the antigen, while MGCs retain phagocytic capabilities for
ongoing antigen processing.[45]
[46]
[47] Beyond structural roles, macrophages drive disease progression through persistent
cytokine secretion, antigen presentation, and immune recruitment.
Functionally, granuloma-associated macrophages display both proinflammatory and profibrotic
programs. They exhibit increased spontaneous production of TNF-α and IL-1β,[48]
[49] which correlates with disease severity.[48]
[49] Heightened SAA-driven NLRP3 inflammasome activation has been identified as a key
mechanism of IL-1β production, with granuloma formation attenuated in NLRP3-deficient
mice.[50] Despite evidence of proinflammatory activation states, sarcoidosis has been characterized
by a heterogeneous landscape, with evidence of both M1- and M2-like activation across
disease stages and anatomical compartments.[41]
[51]
[52]
[53]
[54] Shamaei et al identified increased expression of CD163 and CD206 in lung and lymph
node granulomas, consistent with alternatively activated macrophages with an M2 phenotype.52 In an in vitro granuloma model, Locke et al demonstrated that IL-13–driven STAT6
signaling promoted CD163+ macrophage differentiation, suggesting that a Th2-skewed cytokine environment may
contribute to alternative macrophage activation within sarcoid granulomas.[51] This profibrotic skew is further supported by increased expression of CCL18 in sarcoidosis
BALF alveolar macrophages, a chemokine associated with fibrosis and poor prognosis
in idiopathic pulmonary fibrosis.[55]
[56] Despite these M2-like and fibrotic features, Crouser et al showed that granulomas
generated from sarcoidosis patient–derived PBMCs released higher levels of IFN-γ,
TNF-α, IL-1β, and IL-10 compared with those from individuals with latent tuberculosis
infection, underscoring their persistent proinflammatory potential.[57] These findings collectively support a context-dependent, transitional activation
state in sarcoidosis macrophages. The coexistence of proinflammatory and profibrotic
features highlights the plasticity of macrophage activation and underscores the limitations
of applying a binary M1/M2 framework to granulomatous inflammation in sarcoidosis.
Mechanistically, impaired antigen clearance and sustained mTORC1 signaling underlie
persistent macrophage activation in sarcoidosis. In a myeloid-specific knockout mouse
model, Linke et al demonstrated that constitutive mTORC1 activation promotes granuloma
initiation and persistence through increased macrophage proliferation, inhibition
of apoptosis, and metabolic reprogramming, levels of which correlated with disease
progression in sarcoidosis lung samples.[58] mTORC1 also promotes alternative M2 macrophage activation, as observed in human
sarcoidosis tissues and in a complementary in vitro granuloma model. In this model,
sarcoid granulomas exhibited enhanced phagolysosomal activity, persistent intracellular
antigen processing, and upregulation of mTORC1/S6/STAT3 signaling compared with granulomas
from latent tuberculosis infection.[57] Transcriptomic profiling revealed upregulation of genes involved in phagosome–lysosome
fusion, antigen presentation, and innate immune sensing. Differentially expressed
genes included those supporting microbial opsonization (C1QA, C1QB), pattern recognition
(MRC1 [CD206], TREM1/TYROBP complex), scavenger receptor signaling (CD163), intracellular
killing, and MHC class II–mediated T cell activation. Prior studies similarly demonstrated
enhanced antigen presentation and T cell co-stimulation by alveolar macrophages in
sarcoidosis.[59]
[60] Together, these findings highlight the essential role of mTORC1-driven metabolic
and functional programming in granuloma formation and persistence in sarcoidosis.
Recent advances in spatial transcriptomics, single-cell RNA sequencing (scRNA-seq),
and multiplex imaging have illuminated the central role of macrophages in orchestrating
sarcoid granuloma architecture and immune function. In a multi-omic spatial and scRNA-seq
analysis of cutaneous sarcoidosis granulomas, Krausgruber et al identified granuloma-associated
(GA) macrophages and homeostatic macrophages as predominant macrophage subpopulations.
GA macrophages exhibited a strong IFN-γ–driven activation profile, marked by high
IFNGR1 and IFN-γ–inducible chemokines, alongside enrichment in antigen presentation, lysosomal
function, extracellular matrix (ECM) remodeling, and mTORC1 pathways. Canonical inflammatory
mediators (IL1, IL10, TNF, NFKB) and apoptosis-related genes were downregulated, suggesting a non-classical, sustained
activation state. Subclusters were characterized by differential expression of several
classical sarcoidosis-related genes, including ACE and CHIT1, which serve as clinically recognized biomarkers of sarcoidosis, alongside marked
upregulation of MMP9, MMP12, and MMP14, implicating these cells in tissue remodeling and potential fibrotic progression.
Cross-cell communication mapping revealed spatially relevant ligand–receptor interactions,
notably CXCL9-CXCR3 and CCL5-CCL1/CCR5 between macrophages and T cells, supporting
macrophage-directed chemotactic recruitment and cellular organization within the granuloma
microenvironment.[61] These findings suggest that granuloma-associated macrophages in sarcoidosis function
as persistently activated proinflammatory orchestrators of immune cell recruitment
and matrix remodeling that contribute to granuloma formation and maintenance.
Additional technologic advances including in situ sequencing and multiplex immunofluorescence
have enabled high-resolution spatial analysis of granuloma structure and gene expression
in sarcoidosis. Using these techniques, Carow et al showed that sarcoidosis granulomas
lack the tertiary lymphoid structures and organized antigen-specific niches characteristic
of tuberculosis, and are instead composed of myeloid-rich, lymphocyte-poor cores enriched
in macrophage-associated transcripts including CD11b (ITGAM), CD11c (ITGAX), CD14, and HLA-DRA.[62] These findings suggest that sarcoidosis granulomas are maintained through distinct
immunologic mechanisms, driven largely by macrophages and their microenvironment.
In addition, macrophages secrete chemokines such as macrophage inflammatory proteins
MIP-1α, MIP-1β, and MIP-3β,[63]
[64] promoting immune cell recruitment and reinforcing their central role in sustaining
the granulomatous response. These findings highlight macrophages as dynamic, plastic
cells whose dysregulated behavior sustains chronic inflammation and contributes to
sarcoidosis heterogeneity.
Together, these data assert macrophages as metabolically reprogrammed, persistently
activated orchestrators of granuloma architecture and immune recruitment. Their sustained
activation depends on continuous crosstalk with T cells, as this review will further
highlight, which provides critical cytokine signals, maintains macrophage function,
and shapes granuloma fate.
Circulating Monocytes: Hyperactive Perpetuators of Granulomatous Inflammation
Monocytes are circulating innate immune cells that not only serve as precursors to
monocyte-derived macrophages and monocyte-derived dendritic cells (moDC) but also
play key roles in immune surveillance, inflammation, and tissue remodeling. Functionally,
distinct subsets are defined by differential surface expression of CD14 and CD16,
which correspond to classical (CD14++CD16−), intermediate (CD14++CD16+), and non-classical (CD14+CD16++) monocyte populations. Classical monocytes (CD14++CD16−) are dominant in the circulation and possess strong phagocytic potential, while intermediate
(CD14++CD16+) are expanded in inflammatory states and produce high levels of proinflammatory cytokines
while also exhibiting antigen-presenting capacity, and non-classical (CD14+CD16++) monocytes are involved in vascular surveillance and tissue repair.[65]
[66]
Monocytes are increasingly recognized as key contributors to sarcoidosis pathogenesis,
with alterations in their abundance, phenotype, and function observed across tissue
compartments. Several groups have demonstrated a reduction in circulating classical
monocytes, particularly among patients with untreated or progressive disease, and
an expansion of intermediate monocytes in those with chronic, non-resolving phenotypes.[66]
[67]
[68]
[69]
[70] In contrast, monocytes and monocyte-derived cells are significantly increased in
the alveolar space in frequency compared with healthy controls,[67]
[69]
[70] consistent with active recruitment into sites of active disease. Recruited monocytes
are a major source of alveolar macrophages in sarcoidosis.[71] They exhibit increased expression of P2X7 receptors which enhances their ability
to form MGCs, a hallmark of granulomatous inflammation.[72] These phenotypic and functional shifts position monocytes as pivotal drivers of
the persistent antigen presentation and dysregulated inflammation that sustain granuloma
formation in sarcoidosis.
Functionally, monocytes in sarcoidosis display an activated, proinflammatory phenotype.
Circulating monocytes exhibit increased expression of PRRs such as TLR2 and TLR4[37] primed for activation, as well as markers of migration and activation, including
CD16, CD69, VLA-1, and various chemokine receptors.[73]
[74] Intermediate monocytes, distinguished by 6-sulfo LacNAc expression for improved
functional phenotyping, reveals increased MHCII expression consistent with heightened antigen-presenting capacity in sarcoidosis.[66] Furthermore, single-cell transcriptomic analyses further reveal enrichment in genes
involved in trafficking, immune regulation, and inflammatory signaling, including
mTOR, HMGB1, and ephrin receptor pathways,[74] indicating that circulating monocytes are not only pre-activated but also transcriptionally
equipped to migrate into tissues and perpetuate local inflammation.
Monocyte recruitment to inflamed tissue is orchestrated by chemokines, CCL2, CCL7,
and CCL20, which are upregulated in response to proinflammatory stimuli, as well as
by cytokines such as IFN-γ and TNF-α, both of which are elevated in the granulomatous
microenvironment.[75]
[76] Monocytes in sarcoidosis demonstrate enhanced migratory potential, shaped by dynamic
regulation of chemokine receptors across compartments. CCR2, the receptor for CCL2,
is highly expressed on classical monocytes and promotes recruitment into inflamed
tissue, SNPs of which are associated with increased sarcoidosis risk.[77] While circulating classical monocytes express minimal CCR7, this receptor is markedly
upregulated in monocytes from BALF and endobronchial biopsies, suggesting localized
acquisition of lymph node–homing potential and tissue-specific immune programming.[69] Other trafficking molecules, including CD11b and integrins, are similarly upregulated.[73] Once recruited into the lung or lymphatic tissue, monocytes differentiate into monocyte-derived
macrophages or DCs, where they actively contribute to granuloma formation, cytokine
production, and T cell activation.[78] This dynamic recruitment and differentiation process not only supports granuloma
architecture but also sustains local inflammation, particularly when antigen clearance
is impaired. The central role of monocytes is further evidenced by the recurrence
of sarcoidosis in transplanted lungs, underscoring their systemic contribution to
disease pathogenesis.[79]
[80]
Once in the lung, monocytes are potent amplifiers of inflammation. In BALF, they produce
high levels of TNF-α in the absence of exogenous stimulation.[70] Notably, the frequency of TNF-producing monocytes/monocyte-derived cells in BALF
at diagnosis is highest among patients who later develop progressive disease, implicating
these cells in chronic immune activation and disease worsening.[70] Their proinflammatory function is further amplified by BALF exosomes, which are
increased in sarcoidosis and induce monocyte production of IL-1β, IL-6, TNF-α, and
CCL2 in a dose-dependent manner.[81] Compounding this activation is impaired negative regulation, as demonstrated by
reduced expression of the inhibitory receptor CD200R, which is associated with enhanced
TNF and IL-6 production, both at baseline and following stimulation.[82] These findings characterize a monocyte compartment that is both hyperresponsive
and insufficiently restrained, positioning it as a key driver of persistent inflammation
and fibrotic progression in sarcoidosis.
In contrast, monocytes isolated from lung-draining lymph nodes are less abundant and
display a more immature, less activated phenotype, and reduced levels of maturation
markers and migratory proteins compared with BALF and endobronchial biopsy samples.[69]
[83] These features are consistent with a more quiescent state, potentially shaped by
a suppressive or regulatory lymph node microenvironment, and underscore the lung as
the predominant site of monocyte activation and inflammatory programming in sarcoidosis.
Beyond inflammatory activation, monocytes in sarcoidosis exhibit altered phagocytic
capacity. Increased expression of Fcγ receptors and reduced expression of complement
receptors CR1 and CR4 suggest disordered handling of opsonized antigens and impaired
clearance of inflammatory stimuli.[84]
[85] Transcriptional profiling of BAL monocytes demonstrates upregulation of genes associated
with lysosomal processing and phagocytosis, alongside downregulation of proteasomal
and ribosomal pathways, suggesting a shift toward sustained antigen processing.[86]
[87] More recently, altered regulation of key transcriptional repressors, including TLE3 and CBX8, has been implicated in monocyte dysfunction, with downstream effects on CD4+ T cell depletion.[88] Together, these findings highlight a monocyte compartment that is not only overactivated
but also deficient in regulatory and resolution mechanisms, perpetuating chronic inflammation
and fibrosis in sarcoidosis.
Dendritic Cells: The Bridge Between Innate and Adaptive Immunity
DCs are rare, comprising less than 1% of hematopoietic cells in blood and lymphoid
tissues,[89] and highly specialized antigen-presenting cells that play a pivotal role in initiating
and sustaining adaptive immune responses. Despite representing a small fraction of
immune cells, DCs are among the most efficient antigen-presenting cells,[90] characterized by high expression of MHC class II molecules[91] and a potent ability to initiate and augment T cell responses.[92]
[93] In sarcoidosis, DCs contribute significantly to granuloma formation and maintenance,
with evidence that both conventional and plasmacytoid DCs exhibit compartment-specific
phenotypes and functions that shape granulomatous inflammation. A focused understanding
of their spatial distribution, activation state, and crosstalk with T cells and macrophages
is critical to uncovering their precise contributions to sarcoidosis pathogenesis.
At steady state, DCs, derived from common DC precursors, exist in multiple phenotypic
subsets defined by distinct surface markers and functional capacities. Conventional
DCs (cDCs), formally known as myeloid DC, express CD11c, and are further classified
into cDC1 and cDC2 subsets. cDC1 cells are marked by CLEC9A and XCR1 expression and promote Th1 responses, while cDC2 cells express SIRPα and CD1c, contributing
to Th2 and Th17 polarization.[94] These cells express a broad array of TLR and become activated upon recognizing PAMPs
or DAMPs, upon which they migrate to secondary lymphoid organs[95] where they present processed antigens to naïve CD4+ T cells via MHC class II, driving the differentiation of naïve T cells into effector
subsets.[96]
[97]
[98]
[99]
[100] Plasmacytoid DCs (pDC), formally known as lymphoid DC, are found in blood and lymphoid
organs and also exist at steady state. The cells are potent producers of type I interferons
in response to viral nucleic acids and are increasingly implicated in autoimmunity
due to inappropriate activation by self-antigens. Finally, upon initiation of a proinflammatory
state, stimuli such as TNF-α promotes differentiation of moDC, also known as inflammatory
DC, which express high levels of CD1a, CD11c, and HLA II surface molecules and contribute
to Th1- and Th17-skewed responses,[101]
[102] which is highly relevant to sarcoidosis pathophysiology. Through their capacity
to integrate innate sensing, antigen presentation, and cytokine-mediated T cell programming,
DCs serve as key orchestrators of adaptive immunity. Their ability to direct T helper
differentiation and perpetuate inflammatory cascades positions them as central players
in granulomatous inflammation.
Experimental models demonstrate DCs are critical for the initiation and persistence
of granulomatous inflammation. In a Propionibacterium acnes mouse model, administration of exogenous cDCs enhanced granuloma formation, which
was reduced by CXCR3 and CCR5 blockade,[103] underscoring the importance of chemokine-driven DC recruitment. In a carbon nanotube
model, ongoing DC-mediated antigen presentation and T cell activation were necessary
to sustain granulomatous inflammation.[104] Collectively, these findings indicate that DCs drive granuloma formation and maintenance
through antigen presentation, co-stimulation, and continuous recruitment of immune
cells.
In sarcoidosis, DCs are found in increased numbers and exhibit a more mature, activated
phenotype within lymph nodes and affected tissues.[105]
[106] Among these, cDCs are the predominant subset involved in granuloma formation.[105]
[106] Within affected tissues, cDCs are functionally upregulated, characterized by high
immunocompetence and increased expression of costimulatory molecules, a proinflammatory
profile with increased expression of inflammatory cytokines including IL-1, IL-6,
and TNF-α.[107]
[108]
[109] Additionally, they reside in close proximity to T cells[109] and are capable of driving robust T cell proliferation and polarization toward Th1
and Th17.1 phenotypes, both of which contribute to granulomatous inflammation and
disease progression.[105]
[110]
Activated DCs are central to the propagation of Th1 responses through modulation of
IFN-γ. They secrete IL-12, which increases T-bet (Tbx21) transcription factor expression through IFN-γ–mediated STAT1 activation. This in
turn further enhances IFN-γ transcription, increases IL-12 receptor (IL-12RB2) expression, and suppresses GATA3, which is a key regulator of Th2 differentiation.[111] Additionally, IL-12 upregulates IL-18, which amplifies both IL-12R and IFN-γ signaling.
Elevated levels of IL-12 and IL-18 have been found in BALF from patients with sarcoidosis,[112]
[113] underscoring the role of DC-driven Th1 skewing in disease pathogenesis.
Plasmacytoid dendritic cells (pDCs) are overall less abundant and serve an immune
regulatory function mediated through IFN-γ signaling.[69]
[105]
[110]
[114] Notably, while pDCs are consistently detected in cutaneous sarcoidosis lesions,
they exhibit reduced type I interferon production, suggesting impaired regulatory
capacity.[114]
In contrast to their tissue counterparts, both cDCs and pDCs are decreased in peripheral
blood of patients with sarcoidosis compared with healthy controls,[69]
[109]
[115] suggesting active recruitment and dynamic trafficking to sites of inflammation.
Moreover, peripheral cDCs demonstrate reduced functional capacity, with a diminished
ability to stimulate allogeneic T cell proliferation despite upregulation of costimulatory
markers, consistent with a state of functional anergy.[116] In contrast, moDCs exhibit proinflammatory function by stimulating increased TNF-α
release when cultured with naïve CD4+ T cells.[105] These findings highlight the compartment-specific behavior of DC subsets in sarcoidosis
and suggest that distinct tissue microenvironments play a critical role in shaping
their phenotype and function.
Dendritic Cell and Macrophage Feedback
DCs and macrophages engage in tightly regulated feedback mechanisms that help balance
immune activation and suppression within the granuloma. Under normal conditions, macrophages
suppress DC release of TNF-α, IL-12, and MMPs through PPAR-γ–mediated IL-10 production.
In sarcoidosis, IL-10 release is inhibited by IFN-γ, thus allowing DCs to release
proinflammatory cytokines and MMPs and contributing to tissue damage and disease progression.[117] Additionally, DC activate T cells, which stimulate macrophage differentiation into
epithelioid and MGCs, further contributing to the granuloma core.[118] These reciprocal interactions between DCs and macrophages are central to granuloma
organization and persistence, and their disruption may represent a key immunopathologic
mechanism in sarcoidosis progression.
Adaptive Immune Dysregulation
Adaptive Immune Dysregulation
CD4+ T Cell Activation
Sarcoidosis has long been considered a CD4+ T cell/Th1–mediated disease as CD4+ cells are central to the immunopathogenesis. They accumulate in affected organs,
particularly the lungs, where they dominate the BAL compartment[119] and are critical to granuloma formation and maintenance.[120] Their selective enrichment, oligoclonality, and activated phenotype suggest a persistent,
antigen-driven response, implicating them as key orchestrators of local inflammation
and granuloma maintenance.
Naïve CD4+ T cells are activated in secondary lymphoid organs by antigen-presenting cells, primarily
DCs and macrophages. This activation requires two signals, antigen recognition via
the T cell receptor (TCR) binding to peptide–MHC class II complexes, and a costimulatory
signal via CD80/CD86 binding to CD28 on the antigen-presenting cell. Together, these
signals initiate clonal expansion, effector differentiation, and cytokine production,
notably interleukin-2 (IL-2), which supports T cell proliferation and survival.[121]
[122] In addition, signals are significantly influenced by metabolic programming within
the antigen-presenting cells, which further influence T cell fate decisions, including
early memory programming and lineage commitment.
Effector CD4+ T cells in sarcoidosis patients display a limited and skewed TCR repertoire, indicating
that a small number of T cell clones have expanded in response to specific antigens,
often linked to specific MHC II polymorphisms, and correlating with disease activity.[123]
[124]
[125]
[126] Notably, increased proportions of CD4+ Vα2.3+ T cells in BALF have been shown to be highly specific for sarcoidosis, supporting
sustained local T cell activation.[127] These T cells also express elevated activation markers and proliferate in response
to sarcoidosis-associated antigens, supporting a role for specific exogenous or persistent
antigens in driving the disease.[128]
Beyond TCR specificity, sarcoidosis is marked by defects in key costimulatory and
inhibitory signaling pathways. CD28-mediated co-stimulation, essential for cell cycle
progression through PI3K/AKT signaling, is counteracted by the immune checkpoint receptor
PD-1.[129] In progressive sarcoidosis, CD4+ T cells exhibit high PD-1 expression, which suppresses TCR-driven activation of the
PI3K/AKT/mTOR pathway, impairing proliferation and cell cycle progression[130] and subsequently contributing to T cell exhaustion. Increased PD-1 expression on
memory T cells predicted treatment response,[131] and PD-1 blockade restores signaling and proliferation in vitro.[132] These findings suggest that PD-1–mediated suppression of costimulatory signaling
is a central feature of T cell dysfunction in sarcoidosis and may represent a promising
target for therapeutic modulation in progressive disease.
CD4+ T Cell Recruitment and Polarization
CD4+ T cells are actively recruited to local tissue through chemokine gradients, adhesion
molecules, and chemoattractants secreted by macrophages.[61]
[133] Once localized, these T cells contribute to the inflammatory environment by secreting
cytokines and chemokines, including GM-CSF, IFN-γ, and IL-23R, that reinforce macrophage
activation and promote granuloma maintenance.[61] In early disease, T cell activity is particularly prominent, with tissue infiltrates
enriched in IFN-γ, TNF-α, and IL-2–producing Th1 cells.[134]
[135] IL-2 supports continued CD4+ T cell expansion, while IFN-γ and TNF-α shape the inflammatory microenvironment required
for granuloma persistence. This heightened effector response and substantial T cell
accumulation within granulomas contrasts with the peripheral lymphopenia and anergic
phenotype observed in circulation, reflecting a compartmentalized and dysregulated
immune response.[88]
[116]
T cells within the airways and affected tissues of sarcoidosis patients predominantly
exhibit Th1, Th17, and Th17.1 phenotypes.[61]
[134]
[136]
[137]
[138] Ramstein et al identified an enrichment of Th17.1 cells in BALF of sarcoidosis compared
with healthy controls.[136] More recently, spatial single transcriptomics confirmed Th17.1 cells, driven by
IL-12 and IL-23, as the predominant CD4+ T cell subset within granulomas. These cells express elevated levels of PDCD1 and CTLA-4, which encodes PD-1 and CTLA1, respectively, with concurrent downregulation of autophagy
and cell cycle–related genes, which is consistent with chronic antigenic stimulation
and an exhausted phenotype. At the protein level, these cells produce high levels
of IFN-γ and GM-CSF, which serve as potent mediators of macrophage activation and
myeloid cell recruitment.[61] Together, these features highlight Th17.1 cells as key effectors in sustaining the
inflammatory milieu of chronic sarcoidosis. Together, these findings suggest that
Th17.1 cells are central orchestrators of granulomatous inflammation in sarcoidosis,
with dual roles in promoting both proinflammatory and regulatory signaling. Their
functional plasticity, exhaustion markers, and antigen-specific activation highlight
their potential as both biomarkers of disease chronicity and targets for immunomodulatory
therapy.
Peripheral CD4 T Cell Dysfunction
Circulating CD4+ T cells are reduced in sarcoidosis, likely reflecting a combination of recruitment
to sites of inflammation, increased apoptosis, and disrupted homeostatic regulation.[74]
[88]
[139]
[140] Functionally, both naïve and effector T cell subsets exhibit alterations suggestive
of systemic immune dysregulation that contributes to sarcoidosis.
Naive CD4+ T cells are reduced and primed toward an activation state in sarcoidosis.[74]
[139] In vitro stimulation of these cells reveals an altered cytokine profile characterized
by increased IL-2 and TNF-α but decreased IFN-γ, along with reduced CD69 upregulation
following TCR engagement, indicating a blunted or atypical activation response.[139] A subset of naïve T cells displayed increased CD25 expression, the α chain of IL-2
receptor, indicating heightened IL-2 responsiveness and early T cell activation that
was also associated with chronic active disease at follow-up.[139] Additionally, scRNA-seq revealed upregulated expression of activation-associated
pathways, including JAK/STAT, PI3K/AKT, and ERK/MAPK signaling, as well as dysregulation
of apoptotic pathways and TGF-β/HIPPO signaling, which govern Th17 and Treg differentiation.[74]
Effector T cells are also functionally impaired. Peripheral early effector T cells
demonstrate downregulation of TCR and ICOS-ICOSL signaling, as well as suppression
of PI3K/AKT and mTOR pathways, consistent with an anergic or hyporesponsive phenotype.[74] Similarly, Oswald-Richter et al reported diminished TCR-mediated activation in peripheral
CD4+ T cells, including reduced signaling through IL-2, Lck, NF-κB, and Src kinases, further
supporting the presence of peripheral T cell anergy in sarcoidosis.[137] Together, these findings suggest that in sarcoidosis, circulating CD4+ T cells are numerically reduced and functionally dysregulated, with naïve cells primed
toward activation and effector differentiation, while peripheral effector T cells
display features of anergy. This dual dysfunction possibly contributes to chronic
immune activation and impaired granulomatous resolution in sarcoidosis.
Decreased Immunoregulatory Mechanisms
Decreased Immunoregulatory Mechanisms
Regulatory T Cells
Regulatory T cells (Tregs), defined by the expression of FOXP3 and CD25, constitute
approximately 5 to 10% of the circulating CD4+ T cell population and are essential for maintaining immune tolerance and suppressing
excessive effector T cell response. They function by suppressing autoreactive T cells
and limiting excessive inflammatory responses, thereby preserving immune homeostasis.[141] Disruption of Treg function can lead to immune dysregulation, as evidenced by autoimmune
disease in the absence of adequate Treg activity or mutations.[142]
[143]
Tregs are implicated in the immune dysregulation underlying sarcoidosis. Most studies
report a numerical expansion of Tregs, with increased frequencies observed in peripheral
blood, BALF, and within granulomatous tissue in patients with active or chronic disease,[144]
[145]
[146]
[147] though studies are not consistent. These Tregs typically express canonical suppressive
markers including FoxP3, CD25, and CTLA-4.[144] Treg number correlates with markers of immune activation, such as thoracic lymphadenopathy
and increased systemic symptom burden, but shows no consistent association with fibrosis
or radiographic stage.[147]
[148] Huang et al, however, reported decreased Treg numbers in both peripheral blood and
BAL, accompanied by a reciprocal increase in Th17 cells and an elevated Th17:Treg
ratio.[149] These findings normalized with corticosteroid therapy, suggesting that Treg and
Th17 frequencies are dynamic and responsive to immunosuppression. The reduction in
Tregs observed in this cohort may also reflect underlying genetic influences, as Wikén
et al previously demonstrated decreased Treg numbers in the BAL of sarcoidosis patients
carrying the HLA-DRB1*0301 allele.[150]
Despite their numeric expansion, Tregs in sarcoidosis fail to adequately suppress
inflammatory cytokine production, permitting persistent immune activation and granuloma
formation. In affected tissues, Tregs exhibit reduced suppressive capacity, shortened
telomeres consistent with proliferative exhaustion, and aberrant secretion of proinflammatory
cytokines such as IL-4, which may contribute to fibroblast activation and granuloma
persistence.[151] In mediastinal lymph nodes, decreased CTLA-4 expression on both Tregs and Th17 cells
may impair local regulatory control and promote unchecked Th17-driven inflammation.[152] In the periphery, Tregs also exhibit increased CD95 expression and are more prone
to apoptosis, further limiting their persistence and effectiveness.[144] Patterson et al assessed peripheral blood Tregs using flow cytometry and suppression
assays, finding preserved in vitro function but reduced in vivo activity among patients
with mediastinal lymphadenopathy or high symptom burden.[148] Transcriptomic analyses of PBMC further reveal downregulation of BACH2 and NR1D1, transcription factors critical for Treg differentiation and concurrent Th17 suppression,
in cases with advanced organ involvement and severe pulmonary disease.[153] Together, these findings highlight a state of functional Treg insufficiency that
may permit chronic inflammation, tissue remodeling, and progression to fibrosis.
Importantly, Treg dysfunction appears to associate more strongly with chronic and
fibrotic disease phenotypes than with acute inflammation. Miedema et al used multi-color
flow cytometry and longitudinal follow-up to identify a distinctive Treg phenotype
associated with chronic sarcoidosis, characterized by increased expression of CD25,
CTLA-4, CD69, PD-1, and CD95.[139] These findings suggest that dysfunctional Tregs not only persist in chronic disease
but may acquire an activated yet ineffective phenotype. Taflin et al further demonstrated
that tissue Treg number did not correlate with granulomatous inflammation but was
positively associated with interstitial fibrosis in renal sarcoidosis, supporting
a role for regulatory failure in fibrotic remodeling.[147] Moreover, in vitro studies showed that Treg depletion enhanced granuloma formation
in healthy donor cultures but had no effect in sarcoidosis-derived cells, underscoring
the presence of disease-associated Treg dysfunction. Restoration of Treg and Th1 cell
function has been observed in patients with spontaneous clinical resolution, highlighting
the importance of intact regulatory mechanisms in disease control.[137] Taken together, these data support a model in which Tregs in sarcoidosis are not
simply reduced or expanded but are functionally impaired in ways that allow for ongoing
immune activation, granuloma persistence, and possibly fibrotic progression.
Role of iNKT Cells
Invariant natural killer T (iNKT) cells are a specialized subset of T lymphocytes
that co-express TCR and surface markers typically associated with natural killer (NK)
cells. Unlike conventional T cells, iNKT cells recognize lipid antigens presented
by the non-polymorphic, MHC class I–like molecule CD1d, allowing them to respond rapidly
to stress signals and pathogen-associated lipids. Upon activation, iNKT cells secrete
a broad array of cytokines, including IFN-γ, IL-4, and IL-10, and play important roles
in immunoregulation, immune surveillance, and the modulation of inflammatory and autoimmune
responses.[154]
[155]
[156] Two main subsets exist: CD1d-dependent invariant NKT cells (iNKT cells), which possess
immunoregulatory properties, and CD1d-independent NKT-like cells with more variable
phenotypes.
Multiple studies have shown that iNKT cells are reduced in the peripheral blood and
BALF of sarcoidosis patients, particularly in those with chronic or progressive disease.
Markedly diminished levels have been observed in circulation and are often absent
in mediastinal lymph nodes, granulomas, and cutaneous lesions.[157]
[158] In the lung, reduced iNKT cell frequencies in BALF negatively correlate with CD4+ T cell abundance, suggesting a potential role in regulating local T cell expansion.[159] In contrast, patients with acute, self-limited disease such as Löfgren syndrome
often exhibit preserved or increased iNKT cells in BALF, a pattern associated with
better prognosis.[159]
[160]
iNKT cells also exhibit functional impairments marked by diminished cytokine secretion
and reduced regulatory capacity. This dysfunction is especially evident in chronic
disease, where circulating iNKT cells produce less IFN-γ, indicating a loss of Th1-driven
immune modulation.[157]
[160] Loss of iNKT cells in sarcoidosis has been associated with impaired monocyte-derived
IL-10 production and reduced suppression of T cell proliferation, deficits that are
reversible with iNKT cell reconstitution in vitro.[161] Functionally, the absence of IFN-γ and dual IFN-γ/TNF-α iNKT subsets correlates
with markers of disease severity, including reduced forced vital capacity, elevated
C-reactive protein, and radiographic evidence of fibrosis.[162]
These findings suggest that iNKT cell loss and dysfunction contribute to the exaggerated
T cell activation, deficient immune regulation, and persistence of inflammation that
characterize sarcoidosis. Preservation of iNKT cell number and function in resolving
disease further supports their role as modulators of disease course and severity.
Additional Implicated Cell Types
Additional Implicated Cell Types
Although macrophages are at the granulomatous core, surrounded and supported by recruited
CD4+ T cells and monocyte precursors, multiple other immune and structural cell types
are present within granulomas and affected tissues. These include CD8+ T cells, B cells, NK cells, as well as structural cells such as fibroblasts and endothelial
cells. Studies reveal numerous phenotypic and functional differences in these populations
compared with healthy controls, but it remains unclear whether these changes reflect
primary dysregulation or a secondary response to upstream immune activation.
CD8+ T cells, or cytotoxic T lymphocytes, are essential for antiviral and antitumor immunity
through direct cytotoxic killing, and their abnormal expansion and hyperactive effector
function have been implicated in various autoimmune diseases.[163] In sarcoidosis, CD8+ T cells are expanded in circulation, with higher levels correlating with worse clinical
outcomes.[164]
[165]
[166] BAL shows reduced CD8+ abundance, and a high CD4+:CD8+ ratio is sometimes used to help distinguish sarcoidosis from alternate diagnoses,
albeit with limited sensitivity.[167] In contrast, cerebrospinal fluid from patients with neurosarcoidosis demonstrates
clonal expansion of CD8+ T cells, underscoring the tissue- and phenotype-specific nature of CD8+ T cell responses.[168] Phenotypically, CD8+ T cells exhibit a Th1-skewed profile with elevated IFN-γ and TNF-α[164]
[166] and overexpress activation, adhesion, and senescence markers, consistent with persistent
antigen-driven activation, similar to CD4+ T cells, highlighting the role of the microenvironment in shaping effector function.[169] Genetic associations with CD8-related variants in Löfgren's syndrome suggest a role
for CD8+ biology in clinical phenotype variation.[170] Mechanistically, progressive disease involves aberrant SHP2 signaling in CD8+ T cells, which disrupts SKP2-mediated TBET ubiquitination, driving sustained TBET
activity, excessive IFN-γ production, and macrophage-mediated fibrosis. CD8+ T cells are therefore important in granuloma persistence, disease severity, and progression.
B cells, characterized by CD20 surface expression, are adaptive immune lymphocytes
that bridge humoral and cellular immunity. They function as professional antigen-presenting
cells to activate T cells and, upon activation, can differentiate into memory B cells
or antibody-secreting plasmablasts and plasma cells. Additionally, B cells influence
immune regulation through cytokine secretion and modulation of T cell responses, including
both effector and regulatory pathways. In sarcoidosis, B cells and IgA-producing plasma
cells localize to the outer layer and between granulomas.[171]
[172] In circulation, naïve, activated, and regulatory B cells are expanded, whereas memory
B cells are reduced.[173]
[174] T follicular helper cells, which drive B cell activation, are also increased and
express markers of enhanced B cell crosstalk.[173]
[175] Chronic stimulation is evident from elevated plasma B cell activating factor (BAFF)
and hypergammaglobulinemia across multiple phenotypes.[176]
[177] Age-associated B cells, a distinct subset of B cells that arise from chronic antigenic
stimulation and display proinflammatory function, are additionally expanded in sarcoidosis
and are responsive to treatment.[178] B cells also exhibit features of exhaustion and produce immunoglobulins with high
frequencies of somatic hypermutation and increased downstream IgG subclass usage,
consistent with prolonged or repetitive antigen exposure. Although B cell depletion
with anti-CD20 monoclonal antibodies has shown clinical benefit in refractory disease,[179]
[180] the extent to which B cell alterations directly drive granuloma persistence remains
unclear.
NK cells are innate lymphocytes whose functions correlate with CD56 expression: CD56bright cells primarily regulate immune responses through cytokine secretion, whereas CD56dim cells provide rapid cytotoxic defense against infected and malignant cells. In sarcoidosis,
lung NK cells are enriched for the CD56bright subset, while CD56dim cells predominate in blood.[181] Higher NK cell proportions in BAL are associated with worse clinical outcomes and
greater need for treatment,[182]
[183] yet their overall abundance is lower than in other fibrotic interstitial lung diseases.[184] Conversely, reduced NK cell percentages in peripheral blood have been linked to
cardiac involvement,[185] suggesting NK cell abundance varies by disease phenotype and may reflect organ-specific
recruitment or regulation. Pulmonary NK cells produce high levels of IFN-γ and TNF-α,
contributing to the Th1-polarized inflammatory environment of granulomas.[181] These findings suggest NK cells in sarcoidosis adopt a cytokine-producing, proinflammatory
phenotype that may sustain local inflammation rather than serving solely in cytotoxic
clearance.
Finally, structural cells, including endothelial cells and fibroblasts located at
the granuloma border, are increasingly recognized as active participants in sustaining
granulomatous inflammation. In sarcoidosis, endothelial cells promote ECM remodeling,
focal adhesion, and immune cell migration, while granuloma-associated fibroblasts
display an inflammatory phenotype characterized by macrophage activation and recruitment,
antigen presentation, and TGF-β–mediated signaling, as well as a tissue-remodeling
phenotyping that supports ECM and angiogenesis.[61] Together, these cells coordinate the structural and immunologic support needed to
maintain chronic granulomatous inflammation.
Other immune and stromal cell types may also contribute to granuloma initiation and
maintenance but are outside the scope of this review.
Conclusion
Sarcoidosis is a multisystem, heterogeneous disease arising from an aberrant immune
response to an unidentified antigen in genetically susceptible individuals. It results
in a well-organized, non-caseating granuloma consisting of tightly clustered epithelioid
histiocytes and MGCs, encircled predominantly by CD4+ T lymphocytes and fibroblasts, with additional contributions from CD8+ T cells and NK cells. Granuloma development and persistence reflect the coordinated
activity of these immune cell populations. Macrophages and DCs initiate and sustain
granulomatous inflammation through antigen presentation, cytokine production, and
recruitment of monocytes, which differentiate into epithelioid cells, MGCs, and inflammatory
DCs. Within granulomas, CD4+ T cells, particularly Th1, Th17, and Th17.1 subsets, are oligoclonally expanded and
exhibit a phenotype consistent with chronic antigenic stimulation and partial exhaustion,
driving ongoing inflammation. Impaired Treg cell function, loss and dysfunction of
iNKT cells, and enrichment of other immune effectors including cytotoxic CD8+ T cells, activated B cells, NK cells, and tissue-resident structural cells further
amplify and perpetuate the inflammatory milieu.
Despite advances in defining the cellular and molecular landscape of sarcoidosis,
key questions remain unanswered. The initiating antigens, the mechanisms linking systemic
immune activation to diverse clinical phenotypes, and the determinants of resolution
versus progression to fibrosis are still incompletely understood. Future studies integrating
high-resolution spatial, single-cell, and functional approaches will be essential
to disentangle primary drivers from secondary changes, clarify the interplay between
immune and structural cells, and identify actionable pathways that could alter the
natural history of this enigmatic disease.
