Sarcoidosis

1. Disease Information

Overview. Sarcoidosis is a multisystem granulomatous inflammatory disease of unknown cause, characterized by the formation of non-caseating (non-necrotizing) epithelioid-cell granulomas in affected organs — most commonly the lungs and intrathoracic lymph nodes (>90% of patients), but potentially almost any organ. It results from an exaggerated immune response, in genetically susceptible individuals, to one or more poorly defined antigens. Disease behavior ranges from asymptomatic and spontaneously resolving (e.g., Löfgren syndrome) to chronic, progressive, fibrotic, and occasionally fatal.

"Sarcoidosis is an inflammatory disease of unknown cause involving the formation of granulomas in almost any organ, although typically in the lungs." — Grunewald et al., Nat Rev Dis Primers 2019 (article)

Key identifiers: | Resource | ID | |---|---| | MONDO | MONDO:0019338 (sarcoidosis) — verify with runoak -i sqlite:obo:mondo info MONDO:0019338 | | OMIM | 181000 (SARCOIDOSIS, SS1 / susceptibility) | | Orphanet | ORPHA:797 (Sarcoidosis) | | ICD-10 | D86 (D86.0 pulmonary; D86.2 lung w/ lymph nodes; D86.3 skin; D86.8x specified sites; D86.9 unspecified) | | ICD-11 | 4B20 (Sarcoidosis) | | MeSH | D012507 (Sarcoidosis) | | DOID | DOID:11335 | | UMLS | C0036202 |

Synonyms / alternative names: Besnier-Boeck-Schaumann disease; Boeck sarcoid; Boeck disease; Schaumann disease; benign lymphogranulomatosis; sarcoid; (historical) "lupus pernio" refers specifically to the chronic cutaneous facial form.

Data derivation: Information here is aggregated disease-level knowledge (society guidelines, registries, GWAS meta-analyses, cohort studies) rather than individual EHR records. Major cohorts referenced: ACCESS (A Case Control Etiologic Study of Sarcoidosis, US, n=736), GRADS, WASOG registry, Swedish national registers, and the DZL/GenPhenReSa European cohort.

2. Etiology

Disease causal factors. Sarcoidosis is a complex (multifactorial) disease: a combination of genetic susceptibility + environmental/microbial antigen exposure → dysregulated immune granulomatous response. No single cause is established. The leading paradigm is an antigen-driven, Th1/Th17-polarized immune reaction.

Candidate antigenic triggers (all unproven as causal): - Microbial: Mycobacterium tuberculosis-derived proteins (notably mKatG, catalase-peroxidase) and ESAT-6; Cutibacterium (Propionibacterium) acnes — the only microorganism repeatedly isolated from sarcoid granulomas, especially in Japanese cohorts. (NCBITaxon:1747 Cutibacterium acnes; NCBITaxon:1773 M. tuberculosis.) These are thought to act as persistent poorly degradable antigens rather than active infection. - Environmental/occupational: insecticides, mold/musty odors, agricultural employment, and inorganic particulates. The strongest occupational signal is the WTC (World Trade Center) dust "sarcoidosis-like granulomatous disease" among first responders. - Autoimmune component: increasing evidence of autoantigen recognition (e.g., vimentin presented by HLA-DRB1*03).

Risk factors — genetic (see §4): HLA class II (HLA-DRB1, HLA-DQB1) is the dominant locus; non-HLA loci include BTNL2, ANXA11, NOTCH4, IL23R, RAB23, OS9, IL12B, FAM177B, C-C chemokine genes.

Risk factors — environmental/demographic: - Race/ancestry: African ancestry → higher incidence and severity (see §9). - Family history: first-degree relatives have a ~3.7–5× increased risk (ACCESS study; sibling relative risk highest). - Sex: roughly equal; female peak slightly later. - Occupational/inhalational exposures (above); firefighting/WTC.

Protective factors: - Smoking is paradoxically inversely associated with sarcoidosis risk (one of the few granulomatous/ILD conditions where smoking appears protective) — though it may worsen some outcomes. ⚠ verify. - Genetic: HLA-DRB101 and HLA-DRB104 are associated with reduced risk; DRB1*03:01 (DR3) is strongly associated with the self-limiting, good-prognosis Löfgren phenotype (acts as a prognostic protective allele, not a susceptibility-reducing one).

Gene–environment interactions: HLA-DRB103-restricted T-cell responses to specific antigens (e.g., vimentin) define the Löfgren-syndrome resolving phenotype — a paradigmatic GxE/GxImmunogenetic interaction. C. acnes*-reactive responses are modulated by HLA background (CTD/PheGenI candidate area).

3. Phenotypes

Sarcoidosis is defined by organ-specific granulomatous involvement plus constitutional features. Approximate frequencies (ACCESS, WASOG, GenPhenReSa cohorts):

Onset & severity: Adult-onset (peak 25–45y; second female peak >50y). Severity variable; ~50–70% remit (often spontaneously), ~10–30% develop chronic/progressive disease, and ~5–10% develop pulmonary fibrosis. Quality-of-life impact is substantial and often disproportionate to organ burden — driven by fatigue, dyspnea, depression, and small-fiber neuropathy; measured by the disease-specific King's Sarcoidosis Questionnaire (KSQ) and SF-36/FAS (Fatigue Assessment Scale).

4. Genetic / Molecular Information

Sarcoidosis is polygenic with no monogenic causal gene; OMIM lists multiple susceptibility loci (SS1–SS6).

Major susceptibility loci (germline; all common variants, not "pathogenic" in ACMG Mendelian sense):

eQTL study (2024): "Examination of eQTL Polymorphisms Associated with Increased Risk of Progressive Complicated Sarcoidosis in European and African Descent Subjects" — implicates innate immunity, MHC class II, and allograft-rejection pathways (PMID 38390497 ⚠).

Clinical-course associations: ANXA11 rs1049550 C/T, BTNL2 rs2076530 G/A, and HLA class I/II alleles modulate disease course (PMID 27662826 ✓, Morais 2018 Clin Respir J).

Variant classification note: These are susceptibility/risk alleles, not Mendelian pathogenic variants — for the dismech entry, model them as GENO susceptibility associations, not causal pathogenic variants. Allele frequencies are common (MAF often 0.1–0.4 in gnomAD); origin is germline; functional consequence is largely altered antigen presentation (HLA), altered immune signaling (BTNL2 = loss of negative T-cell costimulation; ANXA11 = apoptosis modulation).

Somatic/acquired: A key recent insight is acquired mTORC1 pathway activation in granuloma macrophages (see §6) — i.e., a somatic/functional signaling lesion, not inherited.

Modifier genes: TNF-α promoter polymorphisms (−308A) and HLA alleles modify severity/Löfgren prognosis. Epigenetics: altered DNA methylation and miRNA profiles reported in BAL cells and granulomas (DiseaseMeth/GEO candidate area); not yet definitively mechanistic. No characteristic chromosomal abnormality.

5. Environmental Information

• Environmental/occupational factors (CTD/ACCESS): agricultural/musty/mold environments, insecticides, metal/silica dust, WTC dust (granulomatous "sarcoid-like" disease in responders); firefighting; possibly photocopier toner. Beryllium exposure causes chronic beryllium disease (berylliosis) — a clinically/histologically near-identical mimic that must be excluded (BeLPT test).
• Lifestyle: Smoking is inversely associated with risk (protective signal). Diet/obesity links weak.
• Infectious agents (trigger candidates, not established pathogens): Cutibacterium acnes (NCBITaxon:1747), Mycobacterium tuberculosis antigens mKatG/ESAT-6 (NCBITaxon:1773). The "latent microbial reactivation + immune dysregulation" model is reviewed in 2025 work (PMC12362391). Sarcoidosis is not contagious.

6. Mechanism / Pathophysiology

Core causal chain (upstream → downstream):

1. Antigen exposure (microbial/environmental/auto-) in a genetically susceptible host →
2. Antigen presentation by APCs (dendritic cells, macrophages) via HLA class II to CD4⁺ T cells →
3. Th1 / Th17.1 polarization with IFN-γ, IL-2, TNF-α, IL-12, IL-18, IL-23 production; oligoclonal T-cell expansion (BAL CD4:CD8 ratio often >3.5) →
4. Macrophage activation and epithelioid/multinucleated giant cell differentiation → non-caseating granuloma formation; macrophages secrete ACE and 1α-hydroxylase (→ hypercalcemia) →
5. Granuloma maintenance by persistent antigen + cytokines →
6. Either resolution (Treg-mediated) or M2-macrophage / TGF-β-driven fibrosis → irreversible organ damage.

Key molecular pathways (suggested GO/KEGG): - mTORC1 / PI3K-AKT-mTOR — landmark mechanism. Macrophage-specific Tsc2 deletion → constitutive mTORC1 activation → CDK4-driven proliferation → spontaneous granulomas in mice, and mTORC1 activity marks progressive human disease (Linke et al., Nat Immunol 2017; PMID 28092373 ✓ / DOI 10.1038/ni.3655). GO:0031929 (TOR signaling). A 2023 mTORC1-dependent cardiac sarcoidosis mouse model extends this (PMID 37750561 ✓). - JAK–STAT (IFN-γ / STAT1) — drives the granuloma transcriptome; targetable (tofacitinib normalizes it — see §12). GO:0007259. - TNF-α / NF-κB — central to granuloma integrity; basis for anti-TNF therapy. GO:0033209. - NLRP3 inflammasome / IL-1β — innate amplification. Simultaneous mTORC1/JAK-STAT/NLRP3 activation documented in patients (PMC10454122). - CCL24–CCR3 axis (mTORC1-dependent) controls granuloma formation/maintenance (PMC12338499 ⚠ 2025).

"Activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce … excessive granuloma formation in vivo." — Linke et al. 2017

Cellular processes & cell types (suggested CL): CD4⁺ T helper cell CL:0000492, Th17 cell CL:0000899, regulatory T cell CL:0000815, macrophage CL:0000235, epithelioid cell / multinucleated giant cell, dendritic cell CL:0000451. Treg dysfunction is restored experimentally by IL-33 via PI3K/Akt/mTOR and TGF-β/Smad inhibition.

Immune involvement: Paradoxical state — heightened local (granuloma) Th1/Th17 activity but peripheral anergy/lymphopenia and T-cell exhaustion (PD-1↑); increasingly framed as having an autoimmune component. "Sarcoidosis pathogenesis reflects dysregulated crosstalk between innate and adaptive immunity … sustained by persistent antigen presentation to T cells" (Immunopathogenesis review, J Autoimmun 2024).

Tissue damage: chronic inflammation → fibrosis (TGF-β, M2 macrophages) — links to the dismech fibrotic_response module for pulmonary fibrosis; granuloma-driven destruction of cardiac conduction tissue, optic/cranial nerves.

Biochemical hallmarks: macrophage ACE overproduction; 1α-hydroxylase (CYP27B1)-mediated extrarenal calcitriol synthesis → hypercalcemia/hypercalciuria; elevated soluble IL-2 receptor (sIL-2R), chitotriosidase, neopterin.

Comprehensive mechanism reviews: Sarcoidosis: molecular mechanisms and therapeutic strategies (PMC11794924 ✓ 2025); Advance in pathogenesis of sarcoidosis (PMC10938127 2024).

7. Anatomical Structures Affected

• Primary organs: lung UBERON:0002048, intrathoracic/hilar & mediastinal lymph nodes UBERON:0000029. Body system: respiratory system UBERON:0001004.
• Secondary / multi-organ: skin UBERON:0002097; eye UBERON:0000970; heart UBERON:0000948 (myocardium UBERON:0002349, conduction system); CNS/peripheral nerves (brain UBERON:0000955; cranial nerve VII / facial nerve UBERON:0001647); liver UBERON:0002107; spleen UBERON:0002106; kidney UBERON:0002113; bone/bone marrow; parotid gland UBERON:0001831; joints.
• Tissue/cell level: alveolar macrophages, epithelioid histiocytes, multinucleated giant cells (Langhans type), CD4⁺ lymphocytes; granulomas are typically perilymphatic in lung (bronchovascular bundles, septa, pleura — basis for transbronchial/EBUS yield).
• Subcellular (GO Cellular Component): within macrophages — asteroid bodies and Schaumann bodies (calcified inclusions) are characteristic histologic inclusions; lysosomal/phagosomal compartments (GO:0005764).
• Localization/laterality: pulmonary involvement is bilateral (bilateral hilar lymphadenopathy is the imaging signature); skin/eye often bilateral/symmetric.

8. Temporal Development

• Onset: typically adult (20–45y), with a second peak in women >50y; pediatric sarcoidosis rare (early-onset Blau syndrome / NOD2 is a distinct Mendelian granulomatous mimic — do not conflate). Onset acute (Löfgren) or insidious.
• Scadding chest-radiograph stages (prognostic): Stage 0 (normal) → I (bilateral hilar adenopathy) → II (adenopathy + parenchymal infiltrates) → III (parenchymal infiltrates alone) → IV (fibrosis/honeycombing). Higher stage → lower spontaneous remission.
• Course patterns: self-limiting/remitting (~50–70%, often within 2–3 yrs), chronic-persistent, relapsing-remitting, or progressive-fibrotic. Löfgren syndrome (acute triad: bilateral hilar adenopathy + erythema nodosum + arthralgia/fever) has >85–90% spontaneous resolution, especially with HLA-DRB1*03.
• Critical windows: treatment decisions typically deferred in asymptomatic Stage I; intervention prioritized for threatened vital-organ function (cardiac, neuro, ocular, progressive pulmonary).

9. Inheritance and Population

Epidemiology: - Incidence: ~1–15 per 100,000/yr, region-dependent — lowest in East Asia (~0.5–1), intermediate in N. America/Australia (~5–10), highest in Scandinavia (~11–15) (Rossides et al., J Intern Med 2023, DOI 10.1111/joim.13629). - Prevalence: roughly 1–40 per 100,000 (population-dependent); US lifetime risk ~2.4% (Black) vs ~0.85% (White). - Race: In the US, Black > White ~3–4:1; highest age-specific incidence in Black women aged 30–39 (~107/100,000) (Sarcoidosis Epidemiology: Race Matters, PMC7522309). Black patients have more multiorgan disease, more severe pulmonary disease, higher hospitalization and mortality. - Sex: approximately equal (slight female predominance); female onset peaks later. - Age: classic peak 25–45y; rising incidence in older adults (>65y); mean diagnosis age now >50 in some datasets.

Inheritance: Not Mendelian — complex/polygenic with environmental contribution. Familial clustering exists: ACCESS found first-degree relatives at ~5× risk (sibling relative risk highest); concordance higher in monozygotic twins. No classic penetrance/expressivity/anticipation/founder figures apply in the Mendelian sense. (For dismech: model inheritance as multifactorial/polygenic, GENO susceptibility, not AD/AR.)

England population-based study (2024) provides recent incidence/prevalence/mortality figures (PMC12002749); Japan nationwide claims study (PMC12127000).

10. Diagnostics

Diagnosis is one of exclusion + compatible clinico-radiologic picture + histologic non-caseating granulomas with no alternative cause (per ATS 2020 guideline, Crouser et al., Am J Respir Crit Care Med 2020;201(8):e26–e51; PMID 32293205 ✓).

Histopathology (gold standard, SNOMED/path): non-necrotizing (non-caseating) epithelioid-cell granulomas; Langhans giant cells; asteroid & Schaumann bodies; must exclude infection (special stains for AFB/fungi) and beryllium.

Tissue acquisition: EBUS-TBNA (endobronchial ultrasound–guided transbronchial needle aspiration) of mediastinal nodes is now first-line (higher yield, ATS-recommended); transbronchial lung biopsy; skin/peripheral node biopsy when accessible.

Biomarkers (supportive, not diagnostic alone): - Serum ACE — sensitivity ~62%, specificity ~76%. - Soluble IL-2 receptor (sIL-2R) — superior to ACE (sens ~88%, spec ~85%) (PMC6797090); also activity marker. - Hypercalcemia/hypercalciuria; chitotriosidase; lysozyme; neopterin. BAL CD4:CD8 ratio >3.5 supports diagnosis (high specificity). - LOINC: ACE LOINC:2004-6 ⚠; serum calcium LOINC:17861-6.

Imaging: - Chest radiograph (Scadding staging) and HRCT (perilymphatic micronodules, beaded fissures, hilar/mediastinal adenopathy). - ¹⁸F-FDG-PET/CT — disease activity, occult sites, viable inflammation vs fibrosis. - Cardiac MRI (late gadolinium enhancement) + FDG-PET — cornerstone of cardiac sarcoidosis detection; ECG/Holter for conduction disease/arrhythmia. - MRI brain/spine + CSF (↑protein, lymphocytic pleocytosis, ↑CSF ACE) for neurosarcoidosis. - Ophthalmologic slit-lamp exam (uveitis screening — recommended in all patients).

Differential diagnosis: tuberculosis & other mycobacterial/fungal infection, chronic beryllium disease (clinically identical — BeLPT distinguishes), lymphoma, hypersensitivity pneumonitis, granulomatosis with polyangiitis, IgG4-related disease, common variable immunodeficiency–associated granulomatous disease, Blau syndrome/NOD2 (pediatric), sarcoid-like reactions to malignancy or checkpoint-inhibitor immunotherapy.

Genetic testing: not used for diagnosis (polygenic); research/HLA-typing only (DRB103 for prognosis). No screening program*; cascade/newborn screening N/A.

11. Outcome / Prognosis

• Overall mortality: low overall — death in roughly 5–10% of patients; mortality is rising in some registries. Leading causes: progressive pulmonary fibrosis with respiratory failure / pulmonary hypertension (esp. US/Europe) and cardiac sarcoidosis (sudden death, arrhythmia, heart failure) (esp. Japan).
• Prognosis by phenotype: Löfgren syndrome → excellent (>85–90% remission); lupus pernio, cardiac, neuro, Stage IV fibrotic, and multiorgan disease in Black patients → worse.
• Morbidity/QoL: fatigue, dyspnea, depression, and small-fiber neuropathy dominate disability; steroid toxicity is a major iatrogenic morbidity (drives the steroid-sparing agenda below).
• Complications: pulmonary fibrosis, pulmonary hypertension (SAPH), aspergilloma/mycetoma in fibrocavitary disease, complete heart block / ventricular arrhythmia / sudden cardiac death, blindness (untreated uveitis), nephrocalcinosis/renal failure (hypercalcemia), neuroendocrine dysfunction.
• Prognostic factors: Scadding stage, lupus pernio, cardiac/neuro involvement, race, age >40 at onset, splenomegaly, need for treatment >6 months, and biomarkers (persistently ↑sIL-2R, FDG-PET activity). HLA-DRB1*03:01 = favorable.

12. Treatment

Guidelines: ERS 2021 treatment guideline (Baughman, Wells et al., Eur Respir J 2021;58(6):2004079; PMID 34140301 ✓) and BTS 2021. Many patients (esp. asymptomatic Stage I/Löfgren) need no treatment; treat to preserve organ function/QoL.

Stepwise pharmacotherapy (suggest MAXO terms; treatment_term NCIT:C15986 Pharmacotherapy + CHEBI therapeutic_agent): 1. First-line: oral glucocorticoids (prednisone) — for symptomatic/threatened-organ disease; ERS advises limiting to a 3–6 month trial, maintenance <10 mg/day. MAXO: MAXO:0000950 supportive? better generic Pharmacotherapy; CHEBI:8378 prednisone / CHEBI:8382 prednisolone. 2. Second-line steroid-sparing: methotrexate (CHEBI:44185; most-used), azathioprine (CHEBI:2948), leflunomide, mycophenolate, hydroxychloroquine (CHEBI:5801; cutaneous/hypercalcemia/neuro). 3. Third-line biologics: anti-TNF-α — infliximab (NCIT:C1296; therapeutic_modality MONOCLONAL_ANTIBODY) for refractory pulmonary, neuro, lupus pernio; adalimumab alternative. ERS: conditional recommendation, low-quality evidence. Real-world data: Respir Res 2022.

Emerging / mechanism-targeted: - JAK inhibitors — tofacitinib (CHEBI:71200): striking responses in cutaneous and multiorgan sarcoidosis; reverses the IFN-γ/JAK-STAT granuloma transcriptome (Damsky et al., NEJM 2018;379:2540–2546; PMID 30586519 ✓ / DOI 10.1056/NEJMoa1805958); also ruxolitinib, laryngeal case PMID 39295484 ⚠. - Efzofitimod (ATYR1923) — first-in-class neuropilin-2 (NRP2) immunomodulator. Phase 3 EFZO-FIT (Sept 2025): MISSED primary endpoint (steroid-dose reduction 2.79 vs 3.52 mg, p=0.33) but 52.6% vs 40.2% achieved complete steroid withdrawal with QoL/FVC benefit and good safety (aTyr topline release; NCT03824392 / EFZO-FIT NCT05415137 ⚠). - mTOR-pathway and CCL24/CCR3 inhibition are preclinical targets (see §6).

Organ-specific/interventional: - Cardiac: immunosuppression + ICD (device; arrhythmia/sudden-death prevention), pacemaker for heart block, antiarrhythmics. - Hypercalcemia: corticosteroids, hydroxychloroquine, low calcium/vit-D intake, sun avoidance. - End-stage: lung transplantation (MAXO:0010039 organ transplantation) / heart transplant; pulmonary rehabilitation; treat SAPH. - Supportive: fatigue/neuropathy management, antidepressants, pulmonary rehab (MAXO:0000950 supportive care; MAXO:0000011 physical therapy).

Pharmacogenomics: TPMT/NUDT15 genotyping before azathioprine (myelotoxicity risk; CPIC guideline). Steroid response heterogeneous.

13. Prevention

• No primary prevention exists (cause unknown, not vaccine-preventable). Risk reduction limited to avoiding implicated occupational/inhalational exposures (e.g., WTC-type dust, beryllium control) — more occupational hygiene than personal prevention.
• Secondary prevention: early ophthalmologic screening (prevent uveitis blindness), baseline + periodic ECG/cardiac screening (detect occult cardiac sarcoidosis → prevent sudden death), monitoring calcium/renal function.
• Tertiary prevention: steroid-sparing strategies to prevent iatrogenic harm; FDG-PET/CMR-guided escalation to prevent fibrosis; ICD in high-risk cardiac disease.
• Counseling: family risk is modestly elevated but routine genetic counseling/testing is not indicated (polygenic). Smoking cessation advised for general health despite the inverse risk association.
• No immunization, no prophylactic medication, no public-health/vector measures (non-infectious).

14. Other Species / Natural Disease

• Taxonomy: primarily a human (NCBITaxon:9606) disease — no validated naturally occurring animal homolog.
• Veterinary: A clinically and histologically analogous idiopathic systemic granulomatous disease occurs in horses (NCBITaxon:9796) — equine sarcoidosis / equine systemic granulomatous disease (generalized granulomatous dermatitis ± internal organs). Granulomatous diseases occur in dogs/cats but are not true sarcoidosis homologs.
• Comparative biology: the closest experimental analog is chronic beryllium disease (HLA-DPB1*Glu69-restricted) — a defined-antigen model of an otherwise sarcoidosis-like granulomatosis.
• Zoonosis: none — sarcoidosis is non-infectious and non-transmissible.

15. Model Organisms

No model fully recapitulates human sarcoidosis; granuloma-focused models dominate (review, Front Immunol 2020).

• Mouse (NCBITaxon:10090):
• mTORC1/Tsc2-knockout macrophage model (Linke 2017, PMID 28092373 ✓): myeloid Tsc2 deletion → constitutive mTORC1 → spontaneous progressive granulomas; best genetic model, recapitulates macrophage proliferation/granuloma growth and progression marker biology. Conditional/Cre-lox (LysM-Cre).
• mTORC1-dependent cardiac sarcoidosis mouse (2023, PMID 37750561 ✓): models cardiac granulomas/conduction disease.
• Antigen-induced granuloma models: C. acnes, mycobacterial mKatG/ESAT-6, and bead/multiwall carbon nanotube + sarcoid-antigen induction models reproduce granuloma histology.
• Adoptive-transfer / Th17 / IL-33 Treg-dysfunction models for immune mechanism.
• In vitro / human: granuloma-in-a-dish — PBMC-derived granuloma models (with C. acnes or beads); iPSC-derived macrophages; BAL-cell transcriptomics (GEO datasets).
• Limitations: no single model captures the multiorgan, chronic-relapsing, antigen-ambiguous human disease; most are acute/induced or single-pathway (mTORC1) and lack the human HLA-restricted adaptive arm.
• Resources: MGI (Tsc2 conditional alleles), IMPC/KOMP, GEO/ArrayExpress for transcriptomic datasets.

Suggested dismech modeling anchors

• Module reuse: link fibrotic pulmonary endpoint to fibrotic_response (tissue injury → inflammation → mesenchymal activation → ECM → organ dysfunction); cardiac arrhythmic complications could cross-reference electrical-remodeling concepts. Consider whether a new granuloma-formation mechanism module (Th1/Th17 → macrophage epithelioid differentiation → mTORC1-driven granuloma) is warranted given recurrence across granulomatous diseases (TB, Crohn, berylliosis, Blau).
• Inheritance: model as multifactorial/polygenic, GENO susceptibility associations (HLA-DRB1, BTNL2, ANXA11) — not Mendelian causal variants.
• Evidence sourcing: core mechanism = MODEL_ORGANISM (Linke mouse) + IN_VITRO; epidemiology/prognosis/treatment = HUMAN_CLINICAL; mTORC1 marker work mixes IN_VITRO + HUMAN_CLINICAL — split evidence items accordingly.

Key References (verify all before committing)

Sources (web): - Grunewald 2019 Nat Rev Dis Primers - ATS 2020 diagnosis guideline (Crouser) - ERS 2021 treatment guideline - Linke 2017 mTORC1, Nat Immunol - Damsky 2018 tofacitinib, NEJM - Rossides 2023 epidemiology, J Intern Med - Sarcoidosis Epidemiology: Race Matters - Morais 2018 ANXA11/BTNL2/HLA, PMID 27662826 - eQTL progressive sarcoidosis, PMID 38390497 - Cardiac sarcoidosis mTORC1 mouse, PMID 37750561 - Molecular mechanisms & therapeutics 2025, PMC11794924 - Immunopathogenesis review, J Autoimmun 2024 - mTORC1/JAK-STAT/NLRP3 in patients, PMC10454122 - sIL-2R diagnostic accuracy, PMC6797090 - aTyr EFZO-FIT Phase 3 topline - ANXA11 association, Genes & Immunity - Sarcoidosis models review, Front Immunol 2020 - Latent microbial reactivation review 2025, PMC12362391 - England population-based study 2024, PMC12002749

Bottom line: sarcoidosis is best modeled in dismech as a complex (polygenic + environmental) immune granulomatous disease whose pathophysiology runs HLA-restricted antigen presentation → Th1/Th17.1 activation → IFN-γ/TNF-driven macrophage epithelioid differentiation → mTORC1-sustained non-caseating granuloma → resolution (Treg) or TGF-β/M2 fibrosis. The two highest-value, well-verified mechanistic citations are Linke 2017 (mTORC1, PMID 28092373) and Crouser 2020 (ATS diagnosis, PMID 32293205); the freshest clinical development is the 2025 efzofitimod Phase 3 miss-but-signal. Re-verify every PMID with just fetch-reference before it lands in a YAML evidence block.