Methods and composition for modulating immune response and immune homeostasis

1 . A method of acquiring or maintaining lymph node (LN) homeostasis in skin-draining LNs, comprising

administering a genetic modifying agent comprising a CRISPR-Cas protein and a guide RNA capable of forming a complex with the CRISPR-Cas protein and directing sequence-specific binding to the Calca gene encoding the protein of SEQ ID NO: 1 to a skin-draining LN of a subject with an autoimmune or inflammatory disease,

wherein the genetic modifying agent modulates neural stimulation and/or efferent signaling of LN-innervating peptidergic nociceptor sensory neurons by regulating Calca expression or function.

2 . The method of claim 1 , wherein the LN-innervating nociceptor sensory neurons are characterized by the expression of one or more genes or gene products selected from:

a. one or more gene or gene products of Dhdh, Grin3a, Fam198b, Plekhg2, Rab8b, Cetn3, Slc30a7, Ankrd45, Prmt2, C530008M17Rik, Epb4.112, Klh124, Tead1, Aplpl, 2610035D17Rik, Sort1, Csf2ra, Slc1a5, Hn1, Plxdc2, Ccdc85a, Serpinb8, Fam174b, Plscr4, Axl, Rab3b, Caskin2, Prdx1, Efemp1, Gabrb1, Myt11, Lamb2, Ern2, Col6a5, Slc39a6, Fads3, Nrip3, Ncoa7, Tbc1d8, Plekho2, Rcn3, Sostdc1, Syt4, Bhlhb9, Ppp1r14c, Hmgn2, Mpzl1, Ifi2711, Lhfpl5, Lrrc58, Flrt1, Il13ra1, Mtmr11, Slc47a2, Calca, Rspo1, Rasip1, Cyp4v3, As3mt, Rcan3, Arxes1, Fam3a, Cnih2, Neat1, Ctnnd2, Jam2, Afap112, 9830001H06Rik, Tceal8, Sorbs2, Steap3, Bnip2, Sdc4, Pcsk5, Rarres2, Wnt9a, Hsd17b11, P4ha3, Tmem74, Itm2a, Terf1, Plxna3, Ctsc, Adamts2, Prkra, Rassf7, Npcd, Stard13, Tax1bp3, Dgkg, Malat1, Metrn, Slc9a3r1, Grn, Prss35, Psd, Ppfia2, Gm5424, Cd63, Adcy7, Kif13b, Syt16, Daam2, Prex2, Dusp16, Svil, Gpr35, Rgs16, Col1a2, Lsp1, Galnt10, Stac, Chd3, Nudt11, 2900008C10Rik, Shisa5, Pgrmc1, Pkn1, Rdh5, Shd, Fstl1, Lss, Nrxn1, Impact, Ap3b1, Sipx, H2afy, Pmepal, Cp, Hey2, Ptgerl, Nudt10, Snap47, Dgka, Tmtc4, Phip, Vldlr, Sepp1, Slc4a4, Lgr5, Bst2, Aldoc, Npy5r, Rasl11a, Tmem130, Zfp3611, Hap1, Syf2, Limd1, Cd79a, Jun, Zhx2, Gpr149, Hspg2, Agrp, Them4, Tada1, Smpdl3a, Gprasp1, Pnmal1, Tspan5, Nfkbia, Nxn, Cdkn1b, Tmbim1, Cyp2j9, Pip5klb, Kirrel3, Foxo1, F3, Arnt2, Mfsd2a, Entpd2, Col5a3, Tiam2, Cebpd, Pgm2l1, Cry1, Kenj10, Rnh1, Tmem229a, Pld5, Abcc4, Gprasp2, Fads2, Pnp, Ramp2, Col28a1, Arxes2, Fdps, Fam108c, Fkbp1b, Lima1, Slc7a14, Trp53i13, Dcaf12l1, A4galt, Rab31, Pla2g16, Sstr1, Junb, Irf6, Sod3, Pik3r1, Cyb561, Vwa1, Il4ra, Lcor1, Slc7a2, C1qtnf7, Asl, Abca8a, Qk, Slc25a27, Tle3, Rab34, Peli2, Notch1, 1700001L19Rik, Fbn1, Spint2, Tmem140, Man2a1, Fads1, Gja1, 5430417L22Rik, Psmb8, Fgf13, Fmo1, Fat1, Cyp2d22, Grb10, C4b, Itih5, Col8a1, Fam129b, Eif4ebp1, Pnck, Ezr, Fabp7, Camk2b, Ahi1, Whm, Samsn1, Hr, Bgn, Sox10, Dock6, Arhgef2, Lepre14, D4Wsu53e, Tspan6, Sema4d, Pik3ip1, Gria1, Wls, Rnase4, Megf10, Pdpn, Car11, St3gal1, Cyr61, Trip10, Acaa1a, Arhgap22, Slc41a3, Dpyd, Ngb, Vamp4, Sparc, Smarca1, Egfl8, Cartpt, Necab1, Gstp1, Ppap2b, Celf3, Igfbp5, Tceal5, Cald1, Hrh3, Psme1, Wnt3, Lrig1, Prss23, Phc1, Cdh19, Pdia5, Slc6a7, Ralgps2, Pls3, Kcnh6, Litaf, Shf, 2900056M20Rik, Celf2, Adamts5, 2810468N07Rik, Adcy5, Syt5, Bhlhe40, Chd5, Plekha4, Sema3b, Cnp, Vim, Nid1, Caly, Nudt17, Cst3, Ivns1abp, Slc16a2, Itgb8, Ptprz1, Aspa, Cmtm5, Fxyd1, Ssbp2, Ntrk2, Cdk18, Ucp2, Rgs9, Cdh13, Atpla2, Tagln2, St5, Ntsr2, Arhgap15, Tle2, Nynrin, Dusp1, Ttyh1, D430019H16Rik, Pde11a, Gadd45g, Chrna6, Tcp1112, Haus4, Fam89a, Lyn, Mmd2, Rit2, Hpcal4, Lama4, 6330403K07Rik, Kcnc2, Ndn, Emp2, Paqr6, Sft2d2, Atp2b4, Rnd3, Sh3kbp1, C530044C16Rik, Pcbd1, Ptn, Ncam1, Mboat2, Phactr2, Gpr3711, Scg2, Ndrg2, Btg2, Tle6, Ndrg1, Slc10a6, Klf6, Atp1b2, Gpr68, Dcn, Gpm6b, Ctxn1, Plp1, Marcksl1, Zbtb20, Pttg1ip, Hmgn3, Bex4, Hmgcs2, Phgdh, Mpz, Csrp2, Fbln5, Plekhb11, Usp11, Kl, Lpar1, Bex1, Fxyd6, Gal, Gfra3, Gpx3, Kcnmb2, Lig1, Npy1r, S100a11, Sstr2, Tac1, Tmem176a, Zcchc12, Tipv1, Nrsn1, Tmem176b, Ppfibp2, Adcyap1, Rxrg, Tcn2, Ly6e, Chrnb3, Serpine2, A730017C20Rik, Stmn1, Igfbp2, Acsbg1, Ednrb, Kcnk3, Gabrg3, Rsph9, Celf4, Sv2a, Bid, Entpd3, Capn9, Gpr137b, Tnr, Atg7, Acsl5, St3gal6, 6720468P15Rik, Seipina3g, Ctdsp1, Syt51, Mbnl2, Gm20139, Zfp954, Hs6st3, Selk, Tpk1, Ggta1, Hexb, Lrrn3, Plekhg1, Rasgef1b, Ube2e3, Cdh8, Actr3, Pdlim1, Nap111, Lpar5, Hmga2-ps1, 1830012O16Rik, Shcl, Lclatl, Aff2, 1700066M21Rik, Ttc39c, Xylt2, Sdcl, Mrgpra2b, Praf2, 2810032G03Rik, Trpv2, Gpr116, Adarb1, Hexa, Txndc11, Gm2115, Fam5b, 1700003M02Rik, Egfem1, Runx2, Mboat1, Camk2a, Ank, Luzp2, Ngfrap1, Arhgap1, Ptprt, Stt3b, Hagh, Tbrg1, Cited1, Igsf3, Rpl36a, Mapk4, Tm7sf3, Cntnap4, Anxa11, Tspan1, Lbh, Zdhhc13, Psd4, Tnfaip813, Ism1, Fam189a2, Arsb, Cyp2j12, Mrgpra2a, Ncf2, Gpr179, Oas1a, Tmem154, Gng12, Il17rc, Rnf125, Tubb2b, Otoa, Dcx, Far2, Samd12, Irak3, Tmem164, Spns2, Dgkz, Fbxo22, Kctd16, Lhfpl2, Hcn4, Acbd4, Rasgrp1, Ifit2, Samd14, Bhlhe41, Ddah1, Myt1, Cpe, Rnf7, Ahnak, Fam19a4, Ret, Bag2, Kdelc2, Slc35f5, Gnaq, Pvrl1, Rasgef1a, Kcnk18, Kenj11, Gnao1, Fam43a, Abcc8, Gpd11, Cpn1, Prokr1, Tpm4, 9530053A07Rik, Isl2, Lrrc59, Mvp, Actn1, Cab391, Bcar3, Lix1, Pitpnc1, Wnt2b, Cmtm7, Ttr, Zfp945, Ccdc43, Smyd3, Snx9, Zfp40, Gadl1, Atpla3, Abca5, Adam8, Paqr4, Ifi2712a, Prkar2b, Slc35f4, Grhl3, H2-D1, Snx7, Med10, 5830473C10Rik, Slc7a8, Hdac9, Mcfd2, Sh2d4a, Cds2, Fam83h, Slc7a7, Inadl, Lipa, Ugcg, Ssbp3, Tmem200a, Mrgprd, Cdk15, Agtrap, Ldb2, Pop5, Stom, Elk3, Eml1, Tpd52, Htr4, Etv1, Slc45a3, Dyrk4, Rpp25, Ap1ar, Rasa4, Kcnk13, Txn1, Serpina11, Aprt, Dtnbp1, Ptrh1, N28178, Ptma, Mustn1, Rarg, Ghr, Dok1, Arhgap6, Zadh2, Mlc1, Mal, Cd47, P2rx3, Rgs3, Osmr, Krt27, Hmox1, Mal2, Snx10, Klk5, Gnal, Ifit3, Fam107b, Gng2, Ets1, Pkig, Fam83d, Lap3, 3632451006Rik, Myola, Plcb3, Tspan14, Slc4a11, Zfp385b, Prkca, Cadm1, Dnajc5b, Cav2, Rab27b, Rcan2, Ston2, Dusp26, Tmem158, Kcng3, Kcnt1, Skp1a, Rab15, 9430021M05Rik, Fli1, Gna14, Scn11a, Neurog3, Golga7b, Lgals3, Dgkh, Fam178b, Cysltr2, Dpp10, Ptgdr, Stogal2, Arpc1b, Socs2, Rgs8, Ly86, Fez1, Cpne3, Bcl2114, Ccdc68, Slc22a18, Arap1, Arhgap36, Rgs10, Dapk2, Kcnip4, Tec, Tmem63a, Mrgpra3, Rhov, Uaca, Pstpip2, Serinc2, A3galt2, Acpp, Adk, Carhsp1, Cav1, Cd55, Cd82, Ctxn3, Fxyd2, Kcnip2, Klf5, Lxn, Moxd1, Nnat, Nt5e, Paqr5, Ppp1r1a, Scg3, Synpr, Tmem45b, Tmem79, Trpc3, Trpc6, Mmp25, Plxnc1, Cmtm8, Serping1, Mrgpra9, Gpm6a, Dgki, Grik1, Fam114a1, Plaur, Rgs4, Slc16a12, Slc9a3r2, Mical1, Rarres1, Hs6st2, Klhl5, Nbl1, Cyp4f39, Kcnn1, Ms4a3, Cd24a, Prkcd, Mrgprb5, Wipf3, Ryr2, Tecr, Dym, Diras2, Lrrc4c, Dclk2, Hrsp12, Egfl7, Dcunld4, Prrt2, Dbc1, Tsc22d3, Stx11, P2rx6, Greb1, Coro6, Wnt5a, Kif5c, Pld3, Fam69a, Nacc2, Tubb4a, Gnwd1, Krt28, Galm, Vamp1, Raly1, Pak3, Adcy8, Slitrk3, Luzp1, Ndp, Upp2, Klhl25, Rell2, Orai2, Opcml, Cntnap2, Lrrc8c, Sv2c, Foxj1, Camk1d, Scn4b, Adam23, Dpp6, Ankrd52, Ankrd29, Snap25, Tmem229b, Hs3st1, Ncam2, Abhd2, Camk2g, Tspyl4, Tm4sf1, Pcolce2, Cntn6, Eda, Adam22, Clu, Kank4, Nptn, Dkk3, Kndc1, Mmp15, Brmsl1, Hs3st3b1, P2ry2, Pid1, C1qtnf1, Irs2, Cyp46a1, Fgfr1, Depdc7, Grm8, Cnih3, Pqlc1, Esr1, Kcna2, Impdh1, Hgf, Sema5a, Pllp, Ppp3ca, Itgb6, Vstm2a, Sytl2, Mgll, Vwc21, Lingo3, Mctp1, Calm3, Lrrn1, Scn1a, Clec21, Cadm3, Mgst1, Lhfpl3, Pygb, Akr1b8, Chga, Lin7b, Parva, Rasgeflc, Begain, Fzd1, Bace2, Hapln3, Egflam, Chn2, Plcb1, Col11a1, Slc16a6, L3mbtl4, Fat3, Pde 2a, Cfh, Nrp2, Ptger3, Cplx1, Pvrl4, Syt2, Kit1, Tgfb2, Tnfrsf21, Pwwp2b, Golim4, Kcnab2, Lhfpl4, Prlr, Prrt3, Scn1b, Gm10754, Kcnip3, Sorcs3, Ngfr, Col16a1, Shank1, Scn8a, Ywhag, Nfasc, Hist1h2bc, 3110043O21Rik, Canikk1, Olfml3, Tuba4a, Nfia, Igsf21, Nr4a2, Ndrg3, Glrb, Pcdhac2, Atp1a1, Stbd1, Kcnt2, Prokr2, Lcp1, Fam81a, Rnf157, Tmem56, Paqr9, Nat81, Kcnv1, Kcnq2, Plxna2, Elfn1, Scn7a, Sorl1, Airn, Syt6, Tm9sf2, Spock3, Grm4, Cyp1b1, Cntn1, Epb4.1l3, Aox1, Kcnd1, Nap1l2, Plch2, P2ry1, Cntnap1, Adam11, 1110008P14Rik, Tmem47, Lgmn, Nefh, Vangl1, Sv2b, Pcp411, Fam126b, Chst2, Ckmt1, Phyhipl, Clrn1, Efhd2, Gpr158, Ust, Pcdhac1, Cdh4, Lpl, Hopx, Tagln3, Atp1b1, Pak1ip1, Lynx1, Serpinb1b, Spock1, Gng8, Smpd3, Bet3l, Prkcb, AI593442, Kcnip1, Fam19a1, Sh3gl2, Serpinb1a, Tmem25, Nefm, Rph3a, Thy1, Rasgrf1, Rasl10b, Nptx1, Cgnl1, Cplx2, Fgf12, Ly6h, S100b, Cpne6, Fxyd7, Rimkla, Nefl, Creg2, Susd2, Htr3b, Gm7271, D930028M14Rik, Htr3a, Abcg2, Fbxo2, S100a16, Lgi2, Gda, Fam196b, Acs16, Necab3, Adamtsl5, Lmo1, Cplx11, Clu1, Fgf9, Esrrg, Hs3st2, Fam65c, Lgi3, Fabp3, B3galt1, Gabra1, Epha6, Kcng4, Ptk7, Arhgef3, Htr7, Rnf128, Ppm1j, Prokrl1, Ntng1, Sema3d, Nefm1, Neto1, A330050F15Rik, Chchd10, Ehd3, Cish, Pcdh7, Nlgn1, Slc4a2, Endod1, Car2, Ano4, Kcnk1, Mest, Fam57b, Syt3, Cacng5, Lrrn11, Fam19a2, Vamp11, Kcna1, Lingo4, Nell2, Ankrd34c, Stac2, Cygb, Slitrk4, Hhatl, Arhgef4, Meis2, Elmo1, Tesc, P2rx61, Epn3, Bcat1, Atp2b2, Mab2112, Pcp4, Rcan21, Gm4980, Tmem163, Hapln1, Ptgfr, Mgst3, Hapln4, Baiap211, Htr1d, Tmem108;

b. Trpc4, Trpm8, Kchnh5, and Ache;

c. Thxa2r, Il33, Ptgir, and Cd1d; or

d. Ptgir and Prokr2.

3 . The method of claim 1 , wherein, preferably, the nociceptor sensory neurons innervate an outer cortical region or medulla of LNs, more preferably, wherein the outer cortical region comprises a perivascular space and a capsular/sub-capsular space.

4 . The method of claim 1 , wherein the CRISPR-Cas protein is part of a CRISPR system, and the CRISPR system comprises a guide RNA capable of forming a complex with the CRISPR-Cas protein and directing sequence-specific binding to the Calca gene, and wherein the CRISPR system comprises a CRISPR-Cas base editing system, a prime editor system, or a CAST system.

5 . The method of claim 1 , wherein modulating neural stimulation and/or efferent signaling of LN-innervating nociceptor sensory neurons comprises modulating an interaction with non-endothelial stroma by administering an agent that modulates the expression or function of one or more of:

a. Col3a1, Col5a2, Col5a1, Col6a1, Col6a2, Col6a3, Col1a2, Col1a2, Lama2, Thbs2, Fn1;

b. Vegfa, Ptn, Mdk, Cxcl12; and

c. Pdgfra, Pdgfrb, Ntrk2.

6 . The method of claim 1 , wherein modulating neural stimulation and/or efferent signaling of LN-innervating nociceptor sensory neurons comprises modulating an interaction with non-venular blood endothelial cells (BEC 1) by administering an agent that modulates the expression or function of one or more of:

a. Lama5, Itga5, Hspg2;

b. Flt1, Notch4, Fzd5;

c. Sema3f, Sema7a, Nrp1, Plxnd1, Efnb1, Epha4; and

d. Selp, Cxcl1.

7 . The method of claim 1 , wherein acquiring or maintaining lymph node (LN) homeostasis in skin-draining LNs is used to treat a subject suffering from a disease characterized by aberrant homeostasis or inflammation in the skin selected from the group consisting of an inflammatory disease and an autoimmune disease.