Extrafollicular and follicular B cell activation by SARS-CoV-2 (Homo sapiens)

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112131286861285211DN2 B cellauto-antibody1CCL21PAX5IFIT2FOXO1APRILPRDM1ETS1PD1IFITM1SYKNEAT1CXCL12CD22SLAMF7CD82TBETBLNKZEB2CD69HSPA8FcRL5TMSB10CD80CD19CR1EBI3CD11cBAFFBlimp1IRF4ISG15CD18IRF8IGHV4-34BACH2CCL19IL-10CD79ACRPMS4A1IFNG-AS1PTPRCXBP1XBP1CD196, 8126, 12112128312638310615879771413411137774713B cell4, 18B cellT celliNKT cell16MacrophageTfh cell 4plasmablast3, 8B cell8, 12Tfh cellDendritic cell4B cellDendriticcellMemory B cell418Extrafollicular areaT cell - B cell borderLymph nodeFollicleCXCL13IgMIL6 IL-2IgGPTCRAα-GalCerCD1dIgMBTLACD40L4IgMIFN-γCD40CD40IL-67IL-21MHCIIBCL6CXCR513TNF-αTLR7IgGSTAT5AIL-2197IgGIgMSomatic Hypermutation BCRCD40LCD40LPD1c-MafAntibody diversification IFN-αSAPICOSTLR4TBX21AID7IgG7IgMIL127Class Switch RecombinationIL-4CXCR5Blimp1128plasma cellCD1dIL-21plasmablastCXCR5plasmablastClass Switch RecombinationIgGSomatic Hypermutation Class switch recombinationIL-21IL127IFN-γTNF-αIL-67IFN-γBCL64, 8, 13AID7IFN-γIL-44Follicular dendritic cell18CD35Compl. C4-ACompl. C3CD21MFGE8CCR7EBI21712, 19CCR7ICOSL12ICOSL55CXCR412CD11c128IgG66IL-212auto-antibodySELLCXCR48IGHV4-34CD11cPAX58ISG156, 83IL-4BAFF3N3SNSSNSSNSCCR717


Description

The pathway model depicts the initial B cell activation inside the lymph node and the following activation routes to differentiate to either plasmablast cells following the extrafollicular pathway

or memory B cells through the follicular pathway.

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Ontology Terms

 

Bibliography

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  1. Robbiani DF, Gaebler C, Muecksch F, Lorenzi JCC, Wang Z, Cho A, Agudelo M, Barnes CO, Gazumyan A, Finkin S, Hägglöf T, Oliveira TY, Viant C, Hurley A, Hoffmann HH, Millard KG, Kost RG, Cipolla M, Gordon K, Bianchini F, Chen ST, Ramos V, Patel R, Dizon J, Shimeliovich I, Mendoza P, Hartweger H, Nogueira L, Pack M, Horowitz J, Schmidt F, Weisblum Y, Michailidis E, Ashbrook AW, Waltari E, Pak JE, Huey-Tubman KE, Koranda N, Hoffman PR, West AP Jr, Rice CM, Hatziioannou T, Bjorkman PJ, Bieniasz PD, Caskey M, Nussenzweig MC; ''Convergent antibody responses to SARS-CoV-2 in convalescent individuals.''; Nature, 2020 PubMed Europe PMC Scholia
  2. Jenks SA, Cashman KS, Woodruff MC, Lee FE, Sanz I; ''Extrafollicular responses in humans and SLE.''; Immunol Rev, 2019 PubMed Europe PMC Scholia
  3. Heesters BA, Chatterjee P, Kim YA, Gonzalez SF, Kuligowski MP, Kirchhausen T, Carroll MC; ''Endocytosis and recycling of immune complexes by follicular dendritic cells enhances B cell antigen binding and activation.''; Immunity, 2013 PubMed Europe PMC Scholia
  4. Cerutti A, Cols M, Puga I; ''Activation of B cells by non-canonical helper signals.''; EMBO Rep, 2012 PubMed Europe PMC Scholia
  5. Gatto D, Wood K, Brink R; ''EBI2 operates independently of but in cooperation with CXCR5 and CCR7 to direct B cell migration and organization in follicles and the germinal center.''; J Immunol, 2011 PubMed Europe PMC Scholia
  6. Elsner RA, Shlomchik MJ; ''Germinal Center and Extrafollicular B Cell Responses in Vaccination, Immunity, and Autoimmunity.''; Immunity, 2020 PubMed Europe PMC Scholia
  7. Barral P, Polzella P, Bruckbauer A, van Rooijen N, Besra GS, Cerundolo V, Batista FD; ''CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes.''; Nat Immunol, 2010 PubMed Europe PMC Scholia
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  9. Reif K, Ekland EH, Ohl L, Nakano H, Lipp M, Förster R, Cyster JG; ''Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position.''; Nature, 2002 PubMed Europe PMC Scholia
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  11. Silk JD, Hermans IF, Gileadi U, Chong TW, Shepherd D, Salio M, Mathew B, Schmidt RR, Lunt SJ, Williams KJ, Stratford IJ, Harris AL, Cerundolo V; ''Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy.''; J Clin Invest, 2004 PubMed Europe PMC Scholia
  12. Cerutti A, Puga I, Cols M; ''New helping friends for B cells.''; Eur J Immunol, 2012 PubMed Europe PMC Scholia
  13. He B, Liu S, Wang Y, Xu M, Cai W, Liu J, Bai W, Ye S, Ma Y, Hu H, Meng H, Sun T, Li Y, Luo H, Shi M, Du X, Zhao W, Chen S, Yang J, Zhu H, Jie Y, Yang Y, Guo D, Wang Q, Liu Y, Yan H, Wang M, Chen YQ; ''Rapid isolation and immune profiling of SARS-CoV-2 specific memory B cell in convalescent COVID-19 patients via LIBRA-seq.''; Signal Transduct Target Ther, 2021 PubMed Europe PMC Scholia
  14. Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ, Monticelli L, Lao C, Crotty S; ''ICOS receptor instructs T follicular helper cell versus effector cell differentiation viainduction of the transcriptional repressor Bcl6.''; Immunity, 2011 PubMed Europe PMC Scholia
  15. Schultheiß C, Paschold L, Willscher E, Simnica D, Wöstemeier A, Muscate F, Wass M, Eisenmann S, Dutzmann J, Keyßer G, Gagliani N, Binder M; ''Maturation trajectories and transcriptional landscape of plasmablasts and autoreactive B cells in COVID-19.''; iScience, 2021 PubMed Europe PMC Scholia
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  17. Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M, Qi X, Huang H, Wen R, Wang J, Li HS, Watowich SS, Qi H, Dong C, Wang D; ''STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function.''; J Biol Chem, 2012 PubMed Europe PMC Scholia
  18. Li Y, Li Z, Hu F; ''Double-negative (DN) B cells: an under-recognized effector memory B cell subset in autoimmunity.''; Clin Exp Immunol, 2021 PubMed Europe PMC Scholia
  19. Crotty S, Johnston RJ, Schoenberger SP; ''Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation.''; Nat Immunol, 2010 PubMed Europe PMC Scholia
  20. Kelly LM, Pereira JP, Yi T, Xu Y, Cyster JG; ''EBI2 guides serial movements of activated B cells and ligand activity is detectable in lymphoid and nonlymphoid tissues.''; J Immunol, 2011 PubMed Europe PMC Scholia
  21. Jenks SA, Cashman KS, Zumaquero E, Marigorta UM, Patel AV, Wang X, Tomar D, Woodruff MC, Simon Z, Bugrovsky R, Blalock EL, Scharer CD, Tipton CM, Wei C, Lim SS, Petri M, Niewold TB, Anolik JH, Gibson G, Lee FE, Boss JM, Lund FE, Sanz I; ''Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus.''; Immunity, 2018 PubMed Europe PMC Scholia
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  24. Xu H, Chaudhri VK, Wu Z, Biliouris K, Dienger-Stambaugh K, Rochman Y, Singh H; ''Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8.''; Nat Immunol, 2015 PubMed Europe PMC Scholia
  25. Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS, Haddad NS, Ley AM, Kyu S, Howell JC, Ozturk T, Lee S, Suryadevara N, Case JB, Bugrovsky R, Chen W, Estrada J, Morrison-Porter A, Derrico A, Anam FA, Sharma M, Wu HM, Le SN, Jenks SA, Tipton CM, Staitieh B, Daiss JL, Ghosn E, Diamond MS, Carnahan RH, Crowe JE Jr, Hu WT, Lee FE, Sanz I; ''Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19.''; Nat Immunol, 2020 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
129276view19:28, 16 March 2024EweitzOntology Term : 'memory B cell' added !
129275view19:24, 16 March 2024EweitzOntology Term : 'T cell' added !
129274view19:22, 16 March 2024EweitzOntology Term : 'plasmablast' added !
129273view19:20, 16 March 2024EweitzOntology Term : 'macrophage' added !
129272view19:19, 16 March 2024EweitzOntology Term : 'dendritic cell' added !
124884view10:52, 22 December 2022NhungPAdd preprint link to description
124874view15:57, 19 December 2022NhungPadd ref
124873view15:55, 19 December 2022NhungPadd ref
124872view15:53, 19 December 2022NhungPadd ref
124871view15:50, 19 December 2022NhungPadd ref
124870view15:48, 19 December 2022NhungPadd ref
124869view15:42, 19 December 2022NhungPadd ref
124868view15:38, 19 December 2022NhungPadd ref
124867view15:37, 19 December 2022NhungPadd reference
124866view15:29, 19 December 2022NhungPupdate pathway description
124865view15:28, 19 December 2022NhungPAdd pathway description
124690view08:44, 24 November 2022NhungPadd reference
124689view08:30, 24 November 2022NhungPupdate node annotation
124688view08:25, 24 November 2022NhungPupdate node annotation
124687view08:22, 24 November 2022NhungPchange uniprot-swissprot to trembl
124686view08:20, 24 November 2022NhungPupdate node annotation
124685view08:09, 24 November 2022NhungPfix 1 unconnected line
124684view07:49, 24 November 2022NhungPupdate viral protein label colors
124664view13:57, 18 November 2022JfigueirahasbunUpdated viral protein color and shapes
124326view11:08, 14 October 2022NhungPModified title
122962view17:03, 3 June 2022NhungPAdjust layout
122961view17:01, 3 June 2022NhungPAdjust layout
122960view16:55, 3 June 2022NhungPAdjust layout
122959view16:43, 3 June 2022NhungPadjust layout
122958view16:15, 3 June 2022NhungPAdjust layout
122930view10:25, 3 June 2022NhungPAdjust layout
122929view10:14, 3 June 2022NhungPAdjust layout
122925view09:34, 3 June 2022NhungPAdd anchor to edges
122923view09:27, 3 June 2022NhungPAdjust layout, increase font
122921view08:44, 3 June 2022NhungPIncrease font to improve readability
122920view08:30, 3 June 2022NhungPIncrease font to improve readability
122451view12:13, 8 April 2022Nuraytalihremoved one IFITM1
122426view18:38, 2 April 2022EgonwUse Uniprot-TrEMBL to make the linkout works
122422view22:20, 1 April 2022AlexanderPicoOntology Term : 'signaling pathway' added !
122421view22:20, 1 April 2022AlexanderPicoOntology Term : 'B cell receptor signaling pathway' added !
122420view22:17, 1 April 2022AlexanderPicoOntology Term : 'disease pathway' added !
122419view22:16, 1 April 2022AlexanderPicoOntology Term : 'follicular B cell' added !
122418view22:15, 1 April 2022AlexanderPicoOntology Term : 'severe acute respiratory syndrome' added !
122417view22:15, 1 April 2022AlexanderPicoOntology Term : 'COVID-19' added !
122352view09:19, 23 March 2022NuraytalihNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AIDProteinQ9GZX7 (Uniprot-TrEMBL) activation-induced cytidine deaminase (AID) - enzyme required for both SHM and isotype switching. AID is expressed and active in non-GC proliferating B cells.
APRILGeneProductENSG00000161955 (Ensembl) TNFSF13/APRILstimulates AID induction independently of CD40.
Antibody diversification Pathway
BACH2GeneProductENSG00000112182 (Ensembl) Stabilizes GC B cells while aantagonizing plasma cell differeentiation.
BAFFGeneProductQ9Y275 (Uniprot-TrEMBL) B cell activating factor (BAFF)
BCL6GeneProductENSG00000113916 (Ensembl) Follicular pathway leads to Bcl6-expressing germinal center B cells known as centroblasts and centrocytes. Bcl6 is a transcriptional repressor that inhibits the diffenertiation towarrds plasmablasts by repressing Blimp1
BCRGeneProductENSG00000186716 (Ensembl)
BLNKGeneProductENSG00000095585 (Ensembl)
BTLAProteinQ7Z6A9 (Uniprot-TrEMBL)
Blimp1GeneProductENSG00000057657 (Ensembl) PRDM1/Blimp-1 (B lymphocyte-induced maturation protein-1): Upregulation of Blimp-1 expression is associated with plasmablast differentiation.
CCL19GeneProductENSG00000172724 (Ensembl)
CCL21GeneProductENSG00000137077 (Ensembl)
CCR7GeneProductENSG00000126353 (Ensembl) Increased expression of the CCR7 receptor indicates the interaction of B cells with the antigens.

CCR7 interacts with the chemokines CCL19 and CCL21

CD11cGeneProductENSG00000140678 (Ensembl) DCs in the medullary cords or the T zone of the lymph nodes express high amounts of CD11c. CD11c forms a heterodimer with CD18
CD18GeneProductENSG00000160255 (Ensembl)
CD19GeneProductENSG00000177455 (Ensembl)
CD1dProteinP15813 (Uniprot-TrEMBL) Antigen-presenting glycoprotein CD1d
CD21GeneProductENSG00000117322 (Ensembl) CR2 or CD21
CD22GeneProductENSG00000012124 (Ensembl)
CD35GeneProductENSG00000203710 (Ensembl) CD35 or CR1
CD40GeneProductENSG00000101017 (Ensembl)
CD40LProteinP29965 (Uniprot-TrEMBL)
CD69GeneProductENSG00000110848 (Ensembl) Upon encounter with their cognate antigen, B cells rapidly upregulate CD69. CD69 is an inhibitor the lymphoid egress , mediating receptor S1P1 and resulting in secondary lymphoid organ retention.
CD79AGeneProductENSG00000105369 (Ensembl)
CD80GeneProductENSG00000121594 (Ensembl)
CD82GeneProductENSG00000085117 (Ensembl)
CR1GeneProductENSG00000203710 (Ensembl) CR1 (CD35)
CRPGeneProductENSG00000132693 (Ensembl) C-reactive protein (CRP), an acute phase reactant in the IL-6 pathway commonly used as a biomarker of COVID-19 severity.
CXCL12GeneProductENSG00000107562 (Ensembl) CXCL12 is expressed in the medullary cords of the lymph nodes and in the bone marrow.
CXCL13ProteinO43927 (Uniprot-TrEMBL)
CXCR4GeneProductENSG00000121966 (Ensembl) CXCR4 is expressed by plasmablasts. It is assumed that CXCR4 is responisble for residing of the plasmablasts in the extrafollicular foci. Plasmablasts deficient in CXCR4 fail to migrate to normal sites of antibody.
CXCR5GeneProductENSG00000160683 (Ensembl)
Class Switch RecombinationPathway
Class Switch RecombinationPathway
Class switch recombination Pathway
Compl. C3ProteinP01024 (Uniprot-TrEMBL) Complement C3
Compl. C4-AProteinP0C0L4 (Uniprot-TrEMBL)
EBI2GeneProductENSG00000169508 (Ensembl) EBI2 or GPR183 is highly expressed in B cells and is increased following their activation. EBI2 is required for the proper localization to inter- and outer-follicular niches of B cells following T-dependent antibody response.

EBI2 is downregulated when B cells differentiate into GC cells. Lack of EBI2 correlates with reduced T-dependent antibody response. Differentiation between germinal center and extrafollicular-destined B cells occurs during this process of acivation through the expression of EBI2. Loss of EBI2 --> GC incorporation

persistance of EBI2 receptor --> integration of activated B cell into EF pathway
EBI3GeneProductENSG00000105246 (Ensembl)
ETS1GeneProductENSG00000134954 (Ensembl) DN2 B cells and aNAV B cells express the lowest amounts of ETS1.

ETS1 inhibits PC differentiation.

Deficiency of ETS1 may cause extrafollicular accumulation of autoreactive plasma cells.
FOXO1GeneProductENSG00000150907 (Ensembl) Transcription factor FOXO1 inhibits T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation.
FcRL5GeneProductENSG00000143297 (Ensembl)
HSPA8GeneProductENSG00000109971 (Ensembl) associated with metabolic processes and autophagy
ICOSGeneProductENSG00000163600 (Ensembl)
ICOSLGeneProductENSG00000160223 (Ensembl) ICOSL - inducible T-cell co-stimulator ligand, also known as ICOSLG When GC competition proceeds without ICOSL, selection of high-affinity variants in otherwise normal GC reactions is impaired.
IFIT2GeneProductENSG00000119922 (Ensembl)
IFITM1GeneProductENSG00000185885 (Ensembl)
IFN-αProteinP48551 (Uniprot-TrEMBL)
IFN-γ ProteinP01579 (Uniprot-TrEMBL)
IFNG-AS1GeneProductENSG00000255733 (Ensembl)
IGHV4-34GeneProductENSG00000211956 (Ensembl)
IL-10GeneProductENSG00000136634 (Ensembl)
IL-21ProteinQ9HBE4 (Uniprot-TrEMBL) IL21 stimulates DN2 B cell differentiation into PCs.
IL-2GeneProductENSG00000109471 (Ensembl)
IL-4GeneProductENSG00000113520 (Ensembl) IL6, IL4 and BAFF are predominantly produced by innate immune cells and promote B cell differentiation into plasmablasts. Dysregulation of B cells may therefore be caused by the innate response.
IL-6GeneProductENSG00000136244 (Ensembl) IL-6 mainly promotes differentiation of antigen-specific B cells to plasmablasts.
IL12GeneProductENSG00000168811 (Ensembl) IL-12 regulates humoral immunity by strongly inhibiting TFH differentiation.

In vitro, it induces IFNγ and IL-21 in human T cells.

(IL12A)
IL6 ProteinQ75MH2 (Uniprot-TrEMBL)
IRF4GeneProductENSG00000137265 (Ensembl) Induction of high concentration of IRF4 after B cell activation drives the rapid generation of plasmablasts. On the contrary, low concentrations of IRF4 may enable sustained expression of AID, CSR, and GC B cell response.
IRF8GeneProductENSG00000140968 (Ensembl) IRF8 dampens signaling via BCR and facilitates antigen-specific interaction with T helper cells. It also promotes antibody affinity maturation while antagonizing IRF4 driven differentiation of plasmablasts. High IRF8:IRF4 ratio promotes GC differentiation.
ISG15GeneProductENSG00000187608 (Ensembl) ISG15 acts as a chemoattractant for neutrophils. ISG15 is an autoimmune feature in autoimmune of memory-like B cells in SLE.
IgG ProteinP0DOX5 (Uniprot-TrEMBL)
IgGProteinP0DOX5 (Uniprot-TrEMBL)
IgM ProteinP0DOX6 (Uniprot-TrEMBL)
IgMProteinP0DOX6 (Uniprot-TrEMBL)
MFGE8GeneProductENSG00000140545 (Ensembl) Mfge8 or FDC-M1
MHCIIProtein
MS4A1GeneProductENSG00000156738 (Ensembl) MS4A1/CD20
NEAT1GeneProductENSG00000245532 (Ensembl)
NProteinP0DTC9 (Uniprot-TrEMBL) Nucleocapsid protein, N
PAX5GeneProductENSG00000196092 (Ensembl) PAX5 is a dual function activator and suppressor and is required for germinal center formation. PAX5 along with Bach2 and Bcl6 stabilize The GC B cell state while antagonizing plasma cell differntiation.
PD1GeneProductENSG00000188389 (Ensembl) inhibitory receptor
PRDM1GeneProductENSG00000057657 (Ensembl)
PTCRAGeneProductENSG00000171611 (Ensembl) Pre T-cell antigen receptor alpha, pT-alpha, pTa (pT-alpha-TCR)
PTPRCGeneProductENSG00000081237 (Ensembl) CD45
SAP ProteinO60880 (Uniprot-TrEMBL)
SELLGeneProductENSG00000188404 (Ensembl) homing receptor CD62L (SELL)
SLAMF7GeneProductENSG00000026751 (Ensembl)
SProteinP0DTC2 (Uniprot-TrEMBL) Spike protein
STAT5AGeneProductENSG00000126561 (Ensembl)
SYKGeneProductENSG00000165025 (Ensembl)
Somatic Hypermutation Pathway
TBETGeneProductENSG00000073861 (Ensembl) TBX21/TBET is expressed in high amounts by DN2 B cells but also aNAV.
TBX21 ProteinQ9UL17 (Uniprot-TrEMBL) T-bet expression influences TFH, as a lack of T-bet correlates with increased frequency of TFH
TLR4GeneProductENSG00000136869 (Ensembl)
TLR7GeneProductENSG00000196664 (Ensembl)
TMSB10GeneProductENSG00000034510 (Ensembl) gene TMSB10 is Pax5-repressed
TNF-αProteinP01375 (Uniprot-TrEMBL)
XBP1GeneProductENSG00000100219 (Ensembl)
ZEB2GeneProductENSG00000169554 (Ensembl) ZEB2 is a transcription factor that is highly expressed in DN2 cells and aNAV cells. ZEB2 cooperatively acts with T-bet to promote effector differentiation and inhibit memory differentiation in cytotoxic T cells.
c-MafGeneProductO75444 (Uniprot-TrEMBL) musculoaponeurotic fibrosarcoma (c-Maf)
α-GalCerMetabolite158021-47-7 (CAS) α-galactosylceramide

Annotated Interactions

No annotated interactions

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