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

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16, 23218161824221, 102, 51821821241513, 1562191622DN2 B cellauto-antibody18CD19TBETPTPRCSYKCCL21IFITM1BLNKZEB2IFIT2IRF4PD1IGHV4-34IL-10IRF8XBP1CXCL12CCL19FOXO1SLAMF7CD11cBACH2CD19HSPA8CD69EBI3CD80PAX5CD22FcRL5IFNG-AS1CD18CD82NEAT1CRPMS4A1ETS1PRDM1TMSB10CR1Blimp1BAFFCD79AISG15APRILXBP1215158242, 241625242161516, 2422181, 101661766121441114664, 1064610B cell143, 4B cellT celliNKT cellMacrophage7Tfh cell 4plasmablastB cell15, 162, 16Tfh cellDendritic cell4B cellDendriticcellMemory B cell43Extrafollicular areaT cell - B cell borderLymph nodeFollicle4, 10CXCL13IgMIL6 IL-2IgGPTCRAα-GalCerCD1dIgMBTLACD40L4IgMIFN-γCD40CD40IL-66IL-21MHCIIBCL6CXCR514TNF-αTLR7IgGSTAT5A17IL-216IgGIgMSomatic Hypermutation BCRCD40LCD40LPD1c-MafAntibody diversification IFN-αSAPICOSTLR4TBX21AID66IgGIgMIL126Class Switch RecombinationIL-4CXCR5Blimp1216plasma cellCD1dIL-21plasmablastCXCR5plasmablastClass Switch RecombinationIgGSomatic Hypermutation Class switch recombinationIL-21IL12IFN-γ6TNF-αIL-66IFN-γBCL64, 14, 16AID6IFN-γIL-44Follicular dendritic cell3CD35Compl. C4-ACompl. C3CD21MFGE8CCR7EBI29CCR72, 20ICOSL222ICOSLCXCR4222CD11c216IgG2424IL-2121auto-antibodySELLCXCR4IGHV4-3416CD11cPAX51616, 24ISG1515IL-4BAFF15N15SNSSNSSNSCCR79


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. Detailed pathway description and its application for data visualization can be found in this preprint doi: https://doi.org/10.1101/2022.12.19.521064

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Bibliography

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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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