[
 {
  "umbrella": "Homeostatic / Surveillant",
  "umbrella_description": "Healthy-brain surveillant microglia and early-transition states. Core: P2RY12, CX3CR1, TMEM119, CSF1R.",
  "n_sub_subtypes": 3,
  "sub_subtypes": [
   {
    "sub_subtype": "Homeostatic",
    "alias": "Homeos1",
    "status": "updated",
    "upregulated_genes_human": "P2RY12, CX3CR1, TMEM119, SALL1, HEXB, CSF1R, TGFBR1, MERTK, ITGB5, SPARC, GPR34, OLFML3, SELPLG, P2RY13, ADGRB1, KBTBD12, RASGEF1C",
    "upregulated_genes_denoised": "P2RY12, CX3CR1, TMEM119, SALL1, HEXB, CSF1R, TGFBR1, MERTK, ITGB5, SPARC, GPR34, OLFML3, SELPLG, P2RY13, ADGRB1, KBTBD12, RASGEF1C",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "ITGAX, APOE, CD74, IL1B, CCL3, CCL4, MKI67",
    "protein_surface_markers": "P2RY12 (S), TMEM119 (S), CX3CR1 (S), CSF1R/CD115 (S), MERTK (S); SALL1 (I, nuclear TF)",
    "context": "Normal healthy brain; dominant in adult brain",
    "references": "Hammond et al. (2019), Immunity; Masuda et al. (2019), Nature; Galatro et al. (2017), Nat Neurosci; Paolicelli et al. (2022), Neuron (nomenclature)",
    "reference_dois": "10.1016/j.immuni.2018.11.004; 10.1038/s41586-019-0924-x; 10.1038/nn.4597; 10.1016/j.neuron.2022.10.020",
    "changes_vs_baseline": "Refreshed to human HUGO symbols; added Paolicelli 2022 nomenclature reference and P2RY12/TMEM119/CSF1R as canonical surface markers.",
    "upregulated_genes_mouse": "P2ry12, Cx3cr1, Tmem119, Sall1, Hexb, Csf1r, Tgfbr1, Mertk, Itgb5, Sparc, Gpr34, Olfml3, Selplg, P2ry13, Adgrb1, Kbtbd12, Rasgef1c, Fcrls, Siglech",
    "downregulated_genes_mouse": "Itgax, Apoe, Cd74, Il1b, Ccl3, Ccl4, Mki67"
   },
   {
    "sub_subtype": "Homeostatic-GRID2+",
    "alias": "Homeos2",
    "status": "updated",
    "upregulated_genes_human": "GRID2, PRDM11, ADGRB3, SYNDIG1, DSCAM, MED12L, NAV2, RASGEF1C, TBC1D4, USP6NL, MAP4K4, DOCK10, RALGAPA2, TBC1D9, TBC1D12, EVI5, SNX13, RAP1GAP2",
    "upregulated_genes_denoised": "GRID2, PRDM11, ADGRB3, SYNDIG1, DSCAM, MED12L, NAV2, RASGEF1C, TBC1D4, USP6NL, MAP4K4, DOCK10, RALGAPA2, TBC1D9, TBC1D12, EVI5, SNX13, RAP1GAP2",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "APOE, CD74, ITGAX, IL1B",
    "protein_surface_markers": "P2RY12 (S), TMEM119 (S); GRID2 (S, glutamate receptor) \u2014 note: largely a snRNA/ambient signature, validate by IHC",
    "context": "Potential response to tau-bearing neurons; specialized homeostatic function",
    "references": "Martins-Ferreira et al. (2025), Nat Commun (HuMicA); Gerrits et al. (2021), Acta Neuropathol",
    "reference_dois": "10.1038/s41467-025-56124-1; 10.1007/s00401-021-02263-w",
    "changes_vs_baseline": "Refreshed to human symbols; flagged that GRID2/neuronal genes may reflect neuronal ambient RNA in snRNA-seq (per Marsh 2022 dissociation-artifact concerns).",
    "upregulated_genes_mouse": "Grid2, Prdm11, Adgrb3, Syndig1, Dscam, Med12l, Nav2, Rasgef1c, Tbc1d4, Usp6nl, Map4k4, Dock10, Ralgapa2, Tbc1d9, Tbc1d12, Evi5, Snx13, Rap1gap2",
    "downregulated_genes_mouse": "Apoe, Cd74, Itgax, Il1b"
   },
   {
    "sub_subtype": "Pre-activated",
    "alias": "Homeos3",
    "status": "updated",
    "upregulated_genes_human": "P2RY12, CX3CR1, SERPINE1, PELI2, FOXP2, INPP5D, ZFP36L2, CARD11, ID2, NCKAP1L, CSF3R, PADI2, PREX1, TRPM2, SWAP70, GAB1, RGS1, CD83, DUSP1, FOS",
    "upregulated_genes_denoised": "P2RY12, CX3CR1, SERPINE1, PELI2, FOXP2, INPP5D, CARD11, ID2, NCKAP1L, CSF3R, PADI2, PREX1, TRPM2, SWAP70, GAB1, RGS1, CD83",
    "dissociation_genes_removed": "ZFP36L2, DUSP1, FOS",
    "downregulated_genes_human": "ITGAX, APOE, CD74",
    "protein_surface_markers": "P2RY12 (S), CX3CR1 (S); CD83 (S, early activation)",
    "context": "Transition state between homeostasis and activation; response to subtle perturbations",
    "references": "Martins-Ferreira et al. (2025), Nat Commun (HuMicA); Marsh et al. (2022), Nat Neurosci",
    "reference_dois": "10.1038/s41467-025-56124-1; 10.1038/s41593-022-01022-8",
    "changes_vs_baseline": "Refreshed to human symbols; added CD83 surface marker and Marsh 2022 caveat (IEGs FOS/JUN/DUSP1 can be ex-vivo dissociation artifacts).",
    "upregulated_genes_mouse": "P2ry12, Cx3cr1, Serpine1, Peli2, Foxp2, Inpp5d, Card11, Id2, Nckap1l, Csf3r, Padi2, Prex1, Trpm2, Swap70, Gab1, Rgs1, Cd83",
    "downregulated_genes_mouse": "Itgax, Apoe, Cd74"
   }
  ]
 },
 {
  "umbrella": "Disease-Associated (DAM / activation continuum)",
  "umbrella_description": "A continuum of activated/disease-associated states (DAM/MGnD/ARM and human/disease-specific variants). They share TREM2/APOE/ITGAX/GPNMB and differ by sub-state-specific markers. NOT discrete clusters \u2014 a trajectory.",
  "n_sub_subtypes": 10,
  "sub_subtypes": [
   {
    "sub_subtype": "Inflammatory DAM",
    "alias": "Inflam.DAM / DAM-2 / MGnD",
    "status": "updated",
    "upregulated_genes_human": "APOE, CLEC7A, ITGAX, LGALS3, SPP1, AXL, LPL, CST7, CD74, TYROBP, TREM2, CD9, CSF1, CD63, LAG3, CD68, CCL3, CCL4, TMEM163, HAMP, HSPA5",
    "upregulated_genes_denoised": "APOE, CLEC7A, ITGAX, LGALS3, SPP1, AXL, LPL, CST7, CD74, TYROBP, TREM2, CD9, CSF1, CD63, LAG3, CD68, CCL3, CCL4, TMEM163, HAMP",
    "dissociation_genes_removed": "HSPA5",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1, HEXB, CSF1R",
    "protein_surface_markers": "TREM2 (S), CD9 (S), ITGAX/CD11c (S), CLEC7A/Dectin-1 (S), CD63 (S/lysosomal), CD68 (I, lysosomal), GPNMB (S); SPP1/osteopontin (secreted)",
    "context": "Alzheimer's disease, amyloid pathology, neurodegeneration, aging",
    "references": "Keren-Shaul et al. (2017), Cell; Krasemann et al. (2017), Immunity; Hammond et al. (2019), Immunity; Martins-Ferreira et al. (2025), Nat Commun (HuMicA); Sun et al. (2023), Cell",
    "reference_dois": "10.1016/j.cell.2017.05.018; 10.1016/j.immuni.2017.08.008; 10.1016/j.immuni.2018.11.004; 10.1038/s41467-025-56124-1; 10.1016/j.cell.2023.08.037",
    "changes_vs_baseline": "Added MGnD (Krasemann 2017) and DAM-2 synonyms; added human DAM confirmation (Sun 2023 MG-AD state); enriched surface panel (TREM2/CD9/CD11c/CLEC7A).",
    "upregulated_genes_mouse": "Apoe, Clec7a, Itgax, Lgals3, Spp1, Axl, Lpl, Cst7, Cd74, Tyrobp, Trem2, Cd9, Csf1, Cd63, Lag3, Cd68, Ccl3, Ccl4, Tmem163, Hamp, Fcrls",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1, Hexb, Csf1r"
   },
   {
    "sub_subtype": "Lipid DAM / Lipid-droplet-accumulating microglia",
    "alias": "Lipo.DAM / LDAM",
    "status": "updated",
    "upregulated_genes_human": "GPNMB, LGALS3, FABP5, LGALS1, LILRB4, CCL15, ANXA5, PLD3, CD9, CD36, LPL, APOE, TREM2, FABP4, NPC1, NPC2, MSR1, PLIN2, APOC1, PPARG, MITF",
    "upregulated_genes_denoised": "GPNMB, LGALS3, FABP5, LGALS1, LILRB4, CCL15, ANXA5, PLD3, CD9, CD36, LPL, APOE, TREM2, FABP4, NPC1, NPC2, MSR1, PLIN2, APOC1, PPARG, MITF",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119",
    "protein_surface_markers": "GPNMB (S), CD9 (S), CD36 (S, scavenger), TREM2 (S), MSR1/CD204 (S); lipid droplets by BODIPY/PLIN2 (I)",
    "context": "Phagocytosis of myelin/lipid debris; expanded in aging, demyelination and AD; LDAM are a dysfunctional aging state",
    "references": "Marschallinger et al. (2020), Nat Neurosci; Hammond et al. (2019), Immunity; Martins-Ferreira et al. (2025), Nat Commun (HuMicA)",
    "reference_dois": "10.1038/s41593-019-0566-1; 10.1016/j.immuni.2018.11.004; 10.1038/s41467-025-56124-1",
    "changes_vs_baseline": "Merged with Marschallinger LDAM concept; added CD36/MSR1 scavenger-receptor surface markers and BODIPY/PLIN2 lipid-droplet detection; clarified aging/dysfunction context.",
    "upregulated_genes_mouse": "Gpnmb, Lgals3, Fabp5, Lgals1, Lilrb4a, Ccl15, Anxa5, Pld3, Cd9, Cd36, Lpl, Apoe, Trem2, Fabp4, Npc1, Npc2, Msr1, Plin2, Apoc1, Pparg, Mitf",
    "downregulated_genes_mouse": "P2ry12, Tmem119"
   },
   {
    "sub_subtype": "Activated Response Microglia (ARM)",
    "alias": "ARM",
    "status": "updated",
    "upregulated_genes_human": "HLA-DRB1, HLA-DRB5, CD74, DKK2, GPNMB, SPP1, APOE, TREM2, TYROBP, ITGAX, LGALS3, CST7, CTSS",
    "upregulated_genes_denoised": "HLA-DRB1, HLA-DRB5, CD74, DKK2, GPNMB, SPP1, APOE, TREM2, TYROBP, ITGAX, LGALS3, CST7, CTSS",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1",
    "protein_surface_markers": "TREM2 (S), ITGAX/CD11c (S), GPNMB (S), CD9 (S), HLA-DR/CD74 (S/MHC-II)",
    "context": "Activated in early stages of neurodegeneration; associated with AD risk genes",
    "references": "Sala Frigerio et al. (2019), Cell Reports; Sierksma et al. (2020), EMBO Mol Med",
    "reference_dois": "10.1016/j.celrep.2019.03.099; 10.15252/emmm.201910606",
    "changes_vs_baseline": "Refreshed to human symbols; added HLA-DR surface marker; clarified ARM overlaps DAM/MGnD in the unifying activation trajectory.",
    "upregulated_genes_mouse": "H2-Ab1, H2-Eb1, Cd74, Dkk2, Gpnmb, Spp1, Apoe, Trem2, Tyrobp, Itgax, Lgals3, Cst7, Ctss",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1"
   },
   {
    "sub_subtype": "Advanced DAM (S100+)",
    "alias": "Adv.DAM",
    "status": "updated",
    "upregulated_genes_human": "HLA-DRB1, HLA-DRB5, CD74, S100A6, S100A8, S100A9, CCL15, LGALS3, CD63, ITGAX, CYBB, TREM2, APOE, TYROBP",
    "upregulated_genes_denoised": "HLA-DRB1, HLA-DRB5, CD74, S100A6, S100A8, S100A9, CCL15, LGALS3, CD63, ITGAX, CYBB, TREM2, APOE, TYROBP",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1, ISG15, IFI44L",
    "protein_surface_markers": "TREM2 (S), ITGAX/CD11c (S), CD63 (S); S100A8/A9 alarmins (I/secreted), HLA-DR (S)",
    "context": "Advanced neurodegeneration; Late stage AD, chronic inflammation",
    "references": "Mathys et al. (2017), Cell Reports",
    "reference_dois": "10.1016/j.celrep.2017.09.039",
    "changes_vs_baseline": "Refreshed mouse H2-*/S100a* to human symbols; added HLA-DR and alarmin (S100A8/A9) detail.",
    "upregulated_genes_mouse": "H2-Ab1, H2-Eb1, Cd74, S100a6, S100a8, S100a9, Ccl15, Lgals3, Cd63, Itgax, Cybb, Trem2, Apoe, Tyrobp",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1, Isg15, Ifi44l"
   },
   {
    "sub_subtype": "Human MG-AD / GPNMB+ DAM-like state",
    "alias": "MG-AD / Mic.12-13",
    "status": "NEW",
    "upregulated_genes_human": "GPNMB, APOC1, APOE, TREM2, CD9, ITGAX, SPP1, MYO1E, PPARG, NUPR1, CTSB, CTSD, GRN, ASAH1, LPL, CD63",
    "upregulated_genes_denoised": "GPNMB, APOC1, APOE, TREM2, CD9, ITGAX, SPP1, MYO1E, PPARG, NUPR1, CTSB, CTSD, GRN, ASAH1, LPL, CD63",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, CX3CR1, TMEM119",
    "protein_surface_markers": "GPNMB (S), TREM2 (S), CD9 (S), ITGAX/CD11c (S), CD68 (I)",
    "context": "Human Alzheimer's disease cortex; lipid/cholesterol handling; defines the disease end of the human activation trajectory",
    "references": "Sun et al. (2023), Cell; Prater et al. (2023), Nat Aging; Green et al. (2024), Nature; Martins-Ferreira et al. (2025), Nat Commun (HuMicA)",
    "reference_dois": "10.1016/j.cell.2023.08.037; 10.1038/s43587-023-00424-y; 10.1038/s41586-024-07871-6; 10.1038/s41467-025-56124-1",
    "changes_vs_baseline": "NEW: human-specific DAM-equivalent state defined across Sun 2023, Prater 2023, Green 2024 and HuMicA \u2014 GPNMB-anchored; distinct from the originally mouse-derived 'Inflammatory DAM'.",
    "upregulated_genes_mouse": "Gpnmb, Apoc1, Apoe, Trem2, Cd9, Itgax, Spp1, Myo1e, Pparg, Nupr1, Ctsb, Ctsd, Grn, Asah1, Lpl, Cd63",
    "downregulated_genes_mouse": "P2ry12, Cx3cr1, Tmem119"
   },
   {
    "sub_subtype": "ALS/FTLD cortical disease-associated microglia",
    "alias": "ALS-MG / DAM-ALS",
    "status": "NEW",
    "upregulated_genes_human": "CD68, SPP1, APOC1, APOE, FTL, GPNMB, LPL, CD63, MS4A6A, MS4A7, CD83, HLA-DRA, ITGAX, TREM2",
    "upregulated_genes_denoised": "CD68, SPP1, APOC1, APOE, FTL, GPNMB, LPL, CD63, MS4A6A, MS4A7, CD83, HLA-DRA, ITGAX, TREM2",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, CX3CR1, TMEM119, SALL1",
    "protein_surface_markers": "CD68 (I), HLA-DR (S), TREM2 (S), GPNMB (S), MS4A6A/MS4A7 (S)",
    "context": "ALS and FTLD motor & prefrontal cortex; reactive/phagocytic microglia expanded with TDP-43 pathology and C9orf72 status",
    "references": "Pineda et al. (2024), Cell (ALS/FTLD cortex)",
    "reference_dois": "10.1016/j.cell.2024.02.031",
    "changes_vs_baseline": "NEW: ALS/FTLD-relevant cortical DAM-like state (Pineda 2024 human atlas) \u2014 directly relevant to the project's ALS datasets; MS4A6A/MS4A7 and HLA-DR feature prominently.",
    "upregulated_genes_mouse": "Cd68, Spp1, Apoc1, Apoe, Ftl, Gpnmb, Lpl, Cd63, Ms4a6a, Ms4a7, Cd83, H2-Aa, Itgax, Trem2",
    "downregulated_genes_mouse": "P2ry12, Cx3cr1, Tmem119, Sall1"
   },
   {
    "sub_subtype": "Chronic-active MS rim microglia (MIMS-iron)",
    "alias": "MIMS / iron-rim MG",
    "status": "NEW",
    "upregulated_genes_human": "FTL, FTH1, CD163, APOC1, APOE, GPNMB, MSR1, SPP1, CD68, ACSL1, NAMPT, SLC11A1",
    "upregulated_genes_denoised": "FTL, FTH1, CD163, APOC1, APOE, GPNMB, MSR1, SPP1, CD68, ACSL1, NAMPT, SLC11A1",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1",
    "protein_surface_markers": "FTL/ferritin (I, by IHC), CD163 (S), MSR1/CD204 (S), CD68 (I); paramagnetic iron rim on 7T MRI",
    "context": "Rim of chronic-active (smoldering) MS lesions; iron accumulation; drives lesion expansion and disability",
    "references": "Absinta et al. (2021), Nature",
    "reference_dois": "10.1038/s41586-021-03892-7",
    "changes_vs_baseline": "NEW: MS-specific iron-rim microglia (MIMS) state \u2014 links a transcriptomic signature to the clinically important paramagnetic-rim lesion.",
    "upregulated_genes_mouse": "Ftl, Fth1, Cd163, Apoc1, Apoe, Gpnmb, Msr1, Spp1, Cd68, Acsl1, Nampt, Slc11a1",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1"
   },
   {
    "sub_subtype": "Transitional IFN-DAM",
    "alias": "IFN-DAM",
    "status": "updated",
    "upregulated_genes_human": "ISG15, IFI44L, IRF9, IFITM3, IRF7, ZBP1, CXCL10, STAT1, MX1, OASL, ISG20, IFIT1, IFIT2, IFIT3, APOE, TREM2",
    "upregulated_genes_denoised": "ISG15, IFI44L, IRF9, IFITM3, IRF7, ZBP1, CXCL10, STAT1, MX1, OASL, ISG20, IFIT1, IFIT2, IFIT3, APOE, TREM2",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1",
    "protein_surface_markers": "TREM2 (S) + BST2 (S); transitional \u2014 defined transcriptionally (ISG + DAM)",
    "context": "Early phase of disease-associated transformation; transition state",
    "references": "Mathys et al. (2017), Cell Reports; Sun et al. (2023), Cell",
    "reference_dois": "10.1016/j.celrep.2017.09.039; 10.1016/j.cell.2023.08.037",
    "changes_vs_baseline": "Refreshed to human symbols; cross-referenced human MG trajectory (Sun 2023).",
    "upregulated_genes_mouse": "Isg15, Ifi44l, Irf9, Ifitm3, Irf7, Zbp1, Cxcl10, Stat1, Mx1, Oasl1, Oasl2, Isg20, Ifit1, Ifit2, Ifit3, Apoe, Trem2",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1"
   },
   {
    "sub_subtype": "Axon Tract-associated Microglia (ATM) / White-matter-associated (WAM)",
    "alias": "ATM / WAM",
    "status": "updated",
    "upregulated_genes_human": "ITGAX, IGF1, SPP1, GPNMB, LGALS3, CD68, CD9, FABP5, PLD3, CTSL, LGALS1, LILRB4, CD63, CTSB",
    "upregulated_genes_denoised": "ITGAX, IGF1, SPP1, GPNMB, LGALS3, CD68, CD9, FABP5, PLD3, CTSL, LGALS1, LILRB4, CD63, CTSB",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1",
    "protein_surface_markers": "CLEC7A (S), ITGAX/CD11c (S), CD9 (S), GPNMB (S), CD68 (I); TREM2-dependent",
    "context": "Developmental white matter (corpus callosum); aging white matter (WAM). TREM2-dependent, clear myelin debris",
    "references": "Hammond et al. (2019), Immunity; Safaiyan et al. (2021), Neuron",
    "reference_dois": "10.1016/j.immuni.2018.11.004; 10.1016/j.neuron.2021.01.027",
    "changes_vs_baseline": "Merged developmental ATM with aging White-Matter-Associated Microglia (WAM, Safaiyan 2021) \u2014 same DAM-like CLEC7A/ITGAX/CD9 program; new WAM reference added.",
    "upregulated_genes_mouse": "Itgax, Igf1, Spp1, Gpnmb, Lgals3, Cd68, Cd9, Fabp5, Pld3, Ctsl, Lgals1, Lilrb4a, Cd63, Ctsb",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1"
   },
   {
    "sub_subtype": "Neonatal CD11c+ / Proliferative-region-associated (PAM)",
    "alias": "CD11c+ / PAM / ATM",
    "status": "updated",
    "upregulated_genes_human": "ITGAX, IGF1, SPP1, GPNMB, CLEC7A, TREM2, LGALS3, CD68, FABP5, LPL, CSF1, MRC1, CD74",
    "upregulated_genes_denoised": "ITGAX, IGF1, SPP1, GPNMB, CLEC7A, TREM2, LGALS3, CD68, FABP5, LPL, CSF1, MRC1, CD74",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119",
    "protein_surface_markers": "ITGAX/CD11c (S), CLEC7A (S), CD9 (S), TREM2 (S), GPNMB (S), SPP1 (secreted)",
    "context": "Early postnatal development (P1-P8); synaptic pruning, brain wiring",
    "references": "Wlodarczyk et al. (2017), EMBO J; Benmamar-Badel et al. (2020), Front Immunol",
    "reference_dois": "10.15252/embj.201696056; 10.3389/fimmu.2020.00430",
    "changes_vs_baseline": "Refreshed to human symbols; added PAM (proliferative-region-associated microglia) synonym; clarified shared DAM-like program with ATM.",
    "upregulated_genes_mouse": "Itgax, Igf1, Spp1, Gpnmb, Clec7a, Trem2, Lgals3, Cd68, Fabp5, Lpl, Csf1, Mrc1, Cd74",
    "downregulated_genes_mouse": "P2ry12, Tmem119"
   }
  ]
 },
 {
  "umbrella": "Interferon-Responsive",
  "umbrella_description": "Type-I IFN signature. Define by ISG transcripts (ISG15, IFITM3, IRF7, STAT1); BST2 surface.",
  "n_sub_subtypes": 1,
  "sub_subtypes": [
   {
    "sub_subtype": "Interferon-Responsive Microglia (IRM)",
    "alias": "IRM / IFN-MG",
    "status": "updated",
    "upregulated_genes_human": "IFI27, IFITM3, CCL2, BST2, IFIT3, ISG15, IFI16, IRF7, CXCL10, OASL, RTP4, B2M, STAT1, IRF9, IFIH1, IFIT1, IRF1, IRF8, ZBP1, CH25H",
    "upregulated_genes_denoised": "IFI27, IFITM3, CCL2, BST2, IFIT3, ISG15, IFI16, IRF7, CXCL10, OASL, RTP4, B2M, STAT1, IRF9, IFIH1, IFIT1, IRF1, IRF8, ZBP1, CH25H",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1",
    "protein_surface_markers": "BST2/CD317 (S), ISG15 (I, secreted); MHC-I/HLA-A,B,C (S) often up. No unique surface epitope \u2014 define by ISG transcripts",
    "context": "Viral infections, sterile inflammation, neurodegeneration with type-I IFN",
    "references": "Hammond et al. (2019), Immunity; Martins-Ferreira et al. (2025), Nat Commun (HuMicA); Sun et al. (2023), Cell",
    "reference_dois": "10.1016/j.immuni.2018.11.004; 10.1038/s41467-025-56124-1; 10.1016/j.cell.2023.08.037",
    "changes_vs_baseline": "Refreshed to human symbols; confirmed in human AD (Sun 2023); added BST2 surface marker and MHC-I note.",
    "upregulated_genes_mouse": "Ifi27, Ifitm3, Ccl2, Bst2, Ifit3, Isg15, Ifi16, Irf7, Cxcl10, Oasl1, Oasl2, Rtp4, B2m, Stat1, Irf9, Ifih1, Ifit1, Irf1, Irf8, Zbp1, Ch25h",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1"
   }
  ]
 },
 {
  "umbrella": "Antigen-Presenting (MHC-II / DC-like)",
  "umbrella_description": "MHC class II / antigen presentation. HLA-DR, CD74, CIITA; DC-like fraction adds LAMP3/CCR7.",
  "n_sub_subtypes": 2,
  "sub_subtypes": [
   {
    "sub_subtype": "MHC-II-high",
    "alias": "MHCII-high",
    "status": "updated",
    "upregulated_genes_human": "HLA-DRB1, HLA-DRB5, CD74, CIITA, HLA-A, B2M, CD86, IL1B, TNF, HLA-DRA, CD40, NLRC5, TAP1, TAP2, PSMB8, PSMB9",
    "upregulated_genes_denoised": "HLA-DRB1, HLA-DRB5, CD74, CIITA, HLA-A, B2M, CD86, IL1B, TNF, HLA-DRA, CD40, NLRC5, TAP1, TAP2, PSMB8, PSMB9",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TREM2, CX3CR1",
    "protein_surface_markers": "HLA-DR (S, via HLA-DRA/DRB), CD74 (S/I), CD86 (S), CD40 (S)",
    "context": "Antigen presentation; increased in EAE, MS models, and aging",
    "references": "Mathys et al. (2017), Cell Reports; Mrdjen et al. (2018), Immunity; Martins-Ferreira et al. (2025), Nat Commun (HuMicA)",
    "reference_dois": "10.1016/j.celrep.2017.09.039; 10.1016/j.immuni.2018.01.011; 10.1038/s41467-025-56124-1",
    "changes_vs_baseline": "Refreshed mouse H2-* to human HLA-* symbols; added CD86/CD40 co-stimulatory surface markers; confirmed in HuMicA human atlas.",
    "upregulated_genes_mouse": "H2-Ab1, H2-Eb1, Cd74, Ciita, H2-K1, B2m, Cd86, Il1b, Tnf, H2-Aa, Cd40, Nlrc5, Tap1, Tap2, Psmb8, Psmb9",
    "downregulated_genes_mouse": "P2ry12, Trem2, Cx3cr1"
   },
   {
    "sub_subtype": "Antigen-presenting / dendritic-like microglia (HLA-high II)",
    "alias": "APC-MG / cDC-like",
    "status": "NEW",
    "upregulated_genes_human": "HLA-DRA, HLA-DRB1, HLA-DPA1, CD74, CIITA, HLA-DQA1, CD83, LAMP3, CCR7, FLT3, ZBTB46",
    "upregulated_genes_denoised": "HLA-DRA, HLA-DRB1, HLA-DPA1, CD74, CIITA, HLA-DQA1, CD83, LAMP3, CCR7, FLT3, ZBTB46",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119",
    "protein_surface_markers": "HLA-DR (S), CD74 (S), CD86 (S); LAMP3/DC-LAMP (I) and CCR7 (S) in the cDC-like fraction",
    "context": "Antigen presentation in MS, AD, aging; overlaps MHC-II-high but extends to a dendritic-cell-like CNS-myeloid program",
    "references": "Martins-Ferreira et al. (2025), Nat Commun (HuMicA); Mrdjen et al. (2018), Immunity",
    "reference_dois": "10.1038/s41467-025-56124-1; 10.1016/j.immuni.2018.01.011",
    "changes_vs_baseline": "NEW: separates a strongly antigen-presenting / DC-like program (CIITA-high, LAMP3/CCR7) recurrent in human atlases from the classic MHC-II-high microglia state.",
    "upregulated_genes_mouse": "H2-Aa, H2-Ab1, H2-Ea, Cd74, Ciita, Cd83, Lamp3, Ccr7, Flt3, Zbtb46",
    "downregulated_genes_mouse": "P2ry12, Tmem119"
   }
  ]
 },
 {
  "umbrella": "Inflammatory / Monocyte-derived",
  "umbrella_description": "Cytokine-releasing and monocyte-derived (DIM) cells. DIM is SALL1-neg/CCR2+ (monocyte origin), distinct from microglial DAM.",
  "n_sub_subtypes": 2,
  "sub_subtypes": [
   {
    "sub_subtype": "Cytokine / Chemokine-enriched (CRM)",
    "alias": "CRM / Inflammatory-cytokine MG",
    "status": "NEW",
    "upregulated_genes_human": "CCL2, CCL3, CCL4, CXCL8, IL1B, TNF, NFKBIA, NFKB1, CCL3L1, CCL4L2, EGR2, EGR3, ATF3",
    "upregulated_genes_denoised": "CCL2, CCL3, CCL4, CXCL8, IL1B, TNF, NFKBIA, NFKB1, CCL3L1, CCL4L2",
    "dissociation_genes_removed": "EGR2, EGR3, ATF3",
    "downregulated_genes_human": "P2RY12, CX3CR1, TMEM119",
    "protein_surface_markers": "No unique surface marker; CD83 (S) and CD14 (S) often up; define by cytokine secretion (IL-1\u03b2, TNF by intracellular flow/ELISA)",
    "context": "Acute/chronic inflammation across AD, MS, ALS; NF-\u03baB\u2013driven cytokine program; partly overlaps DIM",
    "references": "Sun et al. (2023), Cell; Martins-Ferreira et al. (2025), Nat Commun (HuMicA); Absinta et al. (2021), Nature",
    "reference_dois": "10.1016/j.cell.2023.08.037; 10.1038/s41467-025-56124-1; 10.1038/s41586-021-03892-7",
    "changes_vs_baseline": "NEW: cytokine/chemokine inflammatory state recurrent in human atlases (HuMicA) and chronic-active MS lesions (Absinta 2021).",
    "upregulated_genes_mouse": "Ccl2, Ccl3, Ccl4, Il1b, Tnf, Nfkbia, Nfkb1",
    "downregulated_genes_mouse": "P2ry12, Cx3cr1, Tmem119"
   },
   {
    "sub_subtype": "Disease-Inflammatory Macrophages (DIMs)",
    "alias": "DIM",
    "status": "updated",
    "upregulated_genes_human": "SLC2A3, CD83, CCL3, DUSP1, CH25H, NAMPT, DNAJB1, FOS, HSPA1A, SRGN, RHOB, HSPH1, HSPA1B, IRAK2, HIF1A, RGS1, BTG2, MCL1, CREM, JUN, JUNB, IER2",
    "upregulated_genes_denoised": "SLC2A3, CD83, CCL3, CH25H, NAMPT, SRGN, IRAK2, HIF1A, RGS1, MCL1",
    "dissociation_genes_removed": "DUSP1, DNAJB1, FOS, HSPA1A, RHOB, HSPH1, HSPA1B, BTG2, CREM, JUN, JUNB, IER2",
    "downregulated_genes_human": "P2RY12, TMEM119, SALL1",
    "protein_surface_markers": "CD44 (S), CD83 (S), CCR2 (S, monocyte origin); SALL1-negative (distinguishes from yolk-sac microglia)",
    "context": "BBB disruption, traumatic injury, experimental autoimmune encephalomyelitis",
    "references": "Silvin et al. (2022), Immunity; Martins-Ferreira et al. (2025), Nat Commun (HuMicA)",
    "reference_dois": "10.1016/j.immuni.2022.07.004; 10.1038/s41467-025-56124-1",
    "changes_vs_baseline": "Refreshed to human symbols; added Silvin 2022 dual-ontogeny framing and CCR2/SALL1-neg discriminators separating DIM (monocyte) from DAM (microglia).",
    "upregulated_genes_mouse": "Slc2a3, Cd83, Ccl3, Ch25h, Nampt, Srgn, Irak2, Hif1a, Rgs1, Mcl1",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Sall1"
   }
  ]
 },
 {
  "umbrella": "Proliferative",
  "umbrella_description": "Cell-cycle microglia. Ki-67/TOP2A (intracellular).",
  "n_sub_subtypes": 1,
  "sub_subtypes": [
   {
    "sub_subtype": "Proliferating / Cycling",
    "alias": "Proliferating / Cyc-MG",
    "status": "updated",
    "upregulated_genes_human": "MKI67, TOP2A, CENPE, MCM5, BIRC5, CDK1, CCNB2, PCNA, AURKB, CENPF, PLK1, CDCA8, CDCA3, CDC20, CCNA2, CCNB1",
    "upregulated_genes_denoised": "MKI67, TOP2A, CENPE, MCM5, BIRC5, CDK1, CCNB2, PCNA, AURKB, CENPF, PLK1, CDCA8, CDCA3, CDC20, CCNA2, CCNB1",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TREM2, CX3CR1",
    "protein_surface_markers": "MKI67 (I, Ki-67 by IHC/flow), TOP2A (I); no unique surface marker \u2014 identify by cell-cycle proteins",
    "context": "Injury response, development, repopulation after depletion",
    "references": "Hammond et al. (2019), Immunity; Martins-Ferreira et al. (2025), Nat Commun (HuMicA)",
    "reference_dois": "10.1016/j.immuni.2018.11.004; 10.1038/s41467-025-56124-1",
    "changes_vs_baseline": "Refreshed to human symbols; specified Ki-67 protein detection (intracellular).",
    "upregulated_genes_mouse": "Mki67, Top2a, Cenpe, Mcm5, Birc5, Cdk1, Ccnb2, Pcna, Aurkb, Cenpf, Plk1, Cdca8, Cdca3, Cdc20, Ccna2, Ccnb1",
    "downregulated_genes_mouse": "P2ry12, Trem2, Cx3cr1"
   }
  ]
 },
 {
  "umbrella": "Border-Associated (BAM / CAM)",
  "umbrella_description": "CNS-border macrophages (perivascular/meningeal/choroid). CD163/CD206/LYVE1 \u2014 NOT parenchymal microglia.",
  "n_sub_subtypes": 1,
  "sub_subtypes": [
   {
    "sub_subtype": "Border-Associated Macrophages (BAMs)",
    "alias": "BAM / CAMs / PVM",
    "status": "updated",
    "upregulated_genes_human": "F13A1, CD163, MRC1, MS4A7, LYVE1, FOLR2, STAB1, PF4, CBR1, CD209, CD163L1, CLEC10A",
    "upregulated_genes_denoised": "F13A1, CD163, MRC1, MS4A7, LYVE1, FOLR2, STAB1, PF4, CBR1, CD209, CD163L1, CLEC10A",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, CX3CR1, TMEM119",
    "protein_surface_markers": "CD163 (S), MRC1/CD206 (S), LYVE1 (S), CD209 (S), F13A1, FOLR2 (S)",
    "context": "Meninges, choroid plexus, perivascular spaces; CNS-immune interface",
    "references": "Mrdjen et al. (2018), Immunity; Utz et al. (2020), Cell",
    "reference_dois": "10.1016/j.immuni.2018.01.011; 10.1016/j.cell.2020.03.021",
    "changes_vs_baseline": "Refreshed to human symbols; added CAMs/PVM synonyms; emphasized CD163/CD206/LYVE1 surface panel that cleanly separates BAMs from microglia.",
    "upregulated_genes_mouse": "F13a1, Cd163, Mrc1, Ms4a7, Lyve1, Folr2, Stab1, Pf4, Cbr1, Cd209a, Cd163l1, Clec10a",
    "downregulated_genes_mouse": "P2ry12, Cx3cr1, Tmem119"
   }
  ]
 },
 {
  "umbrella": "Developmental",
  "umbrella_description": "Embryonic/early-postnatal microglia (developmental context).",
  "n_sub_subtypes": 1,
  "sub_subtypes": [
   {
    "sub_subtype": "Embryonic / Early-postnatal Microglia",
    "alias": "Embryonic",
    "status": "updated",
    "upregulated_genes_human": "SPI1, CX3CR1, FABP5, MCM5, CCND1, DAB2, MRC1, MS4A7, FN1, CSF1R, CD4, RUNX1, F13A1",
    "upregulated_genes_denoised": "SPI1, CX3CR1, FABP5, MCM5, CCND1, DAB2, MRC1, MS4A7, FN1, CSF1R, CD4, RUNX1, F13A1",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, SALL1",
    "protein_surface_markers": "CX3CR1 (S), CSF1R (S), MRC1/CD206 (S, early); SPI1/PU.1 (I, nuclear TF)",
    "context": "Embryonic and early postnatal brain development (E14.5-P4)",
    "references": "Hammond et al. (2019), Immunity",
    "reference_dois": "10.1016/j.immuni.2018.11.004",
    "changes_vs_baseline": "Refreshed to human symbols; added PU.1 (SPI1) lineage TF.",
    "upregulated_genes_mouse": "Spi1, Cx3cr1, Fabp5, Mcm5, Ccnd1, Dab2, Mrc1, Ms4a7, Fn1, Csf1r, Cd4, Runx1, F13a1",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Sall1"
   }
  ]
 },
 {
  "umbrella": "Ribosomal / translation-high (interpret with caution)",
  "umbrella_description": "Ribosome-biogenesis / translation-high microglia. Defined as two separate clusters in HuMicA (Ribo.DAM1, Ribo.DAM2), both mapping to Sun 2023's MG3 'Ribosome Biogenesis' state. HuMicA retained them after filtering nuclei with >5% ribosomal-RNA content, so they are not simply high-ribosomal contamination \u2014 but ribosomal/translation signatures can also reflect ambient RNA or low-QC nuclei (Marsh 2022). Interpret with caution: verify QC (mito %, ambient fraction, doublets) before annotating, and treat their biological role as not yet fully established.",
  "n_sub_subtypes": 2,
  "sub_subtypes": [
   {
    "sub_subtype": "Ribosomal DAM 1",
    "alias": "Ribo.DAM1",
    "status": "updated",
    "upregulated_genes_human": "SYT1, PCDH9, LSAMP, CADM2, CALM1, KCNIP4, PEBP1, RBFOX1, CNTNAP2, RPL39, DYNLL1, COXFA4, MT-ATP6, RPS27, DLG2, RTN3, MT-ND1, ATP5F1E, RPL18A, RPS18",
    "upregulated_genes_denoised": "SYT1, PCDH9, LSAMP, CADM2, CALM1, KCNIP4, PEBP1, RBFOX1, CNTNAP2, RPL39, DYNLL1, COXFA4, MT-ATP6, RPS27, DLG2, RTN3, MT-ND1, ATP5F1E, RPL18A, RPS18",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1",
    "protein_surface_markers": "No specific validated surface marker (signature dominated by ribosomal/mito + neuronal ambient genes; likely low-quality/ambient cluster)",
    "context": "Ribosome-biogenesis / translation-high state (HuMicA cluster 3; Sun MG3). Headed by SYT1/PCDH9; found in neurodegenerative contexts. Possibly a distinct population, but ribosomal signatures also flag potential ambient-RNA / low-QC nuclei \u2014 confirm QC before use.",
    "references": "Martins-Ferreira et al. (2025), Nat Commun (HuMicA); Sun et al. (2023), Cell; Marsh et al. (2022), Nat Neurosci",
    "reference_dois": "10.1038/s41467-025-56124-1; 10.1016/j.cell.2023.08.037; 10.1038/s41593-022-01022-8",
    "changes_vs_baseline": "Reframed from 'artifact, exclude' to 'interpret with caution': HuMicA defines this as a distinct ribosomal cluster (Ribo.DAM1) retained after >5% ribosomal-RNA filtering and maps it to Sun 2023 MG3 (Ribosome Biogenesis), so it is not simply contamination; Marsh 2022 QC caveat retained.",
    "upregulated_genes_mouse": "Syt1, Pcdh9, Lsamp, Cadm2, Calm1, Kcnip4, Pebp1, Rbfox1, Cntnap2, Rpl39, Dynll1, Ndufa4, mt-Atp6, Rps27, Dlg2, Rtn3, mt-Nd1, Atp5f1e, Rpl18a, Rps18",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1"
   },
   {
    "sub_subtype": "Ribosomal DAM 2",
    "alias": "Ribo.DAM2",
    "status": "updated",
    "upregulated_genes_human": "PLEKHA7, MECOM, OOEP, ATP5F1E, FTH1, BAIAP2L1, PLEKHA6, BDNF-AS, FTL, NACA, SLC27A4, APOO, SLC47A1, ZNF90, TXNRD1, XPO5, RPL19, TMSB10, UBA52, TOMM7",
    "upregulated_genes_denoised": "PLEKHA7, MECOM, OOEP, ATP5F1E, FTH1, BAIAP2L1, PLEKHA6, BDNF-AS, FTL, NACA, SLC27A4, APOO, SLC47A1, ZNF90, TXNRD1, XPO5, RPL19, TMSB10, UBA52, TOMM7",
    "dissociation_genes_removed": "",
    "downregulated_genes_human": "P2RY12, TMEM119, CX3CR1",
    "protein_surface_markers": "No specific validated surface marker (ferritin FTL/FTH1-high; iron handling); validate by ferritin IHC if used",
    "context": "Second ribosome-biogenesis / translation-high state (HuMicA cluster 5; Sun MG3) with a distinct signature including ferritin (FTL/FTH1). HuMicA speculates Ribo.DAM1 and Ribo.DAM2 may be two biologically distinct populations, but notes their role requires further investigation; confirm QC before use.",
    "references": "Martins-Ferreira et al. (2025), Nat Commun (HuMicA); Sun et al. (2023), Cell; Marsh et al. (2022), Nat Neurosci",
    "reference_dois": "10.1038/s41467-025-56124-1; 10.1016/j.cell.2023.08.037; 10.1038/s41593-022-01022-8",
    "changes_vs_baseline": "Reframed from 'artifact, exclude' to 'interpret with caution': HuMicA reports Ribo.DAM2 as a separate cluster from Ribo.DAM1 (each with distinct traits, both mapping to Sun MG3) and explicitly speculates they are two biologically distinct populations 'requiring further investigation'; ferritin (FTL/FTH1) component noted; Marsh 2022 QC caveat retained.",
    "upregulated_genes_mouse": "Plekha7, Mecom, Ooep, Atp5f1e, Fth1, Baiap2l1, Plekha6, Ftl, Naca, Slc27a4, Apoo, Slc47a1, Txnrd1, Xpo5, Rpl19, Tmsb10, Uba52, Tomm7",
    "downregulated_genes_mouse": "P2ry12, Tmem119, Cx3cr1"
   }
  ]
 }
]