Extrafollicular and follicular B cell activation by SARS-CoV-2 (WP5218)

Homo sapiens

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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

Authors

Nuray Talih , Alex Pico , Egon Willighagen , Nhung Pham , John Figueira Hasbun , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

COVID-19

Annotations

Cell Type Ontology

macrophage plasmablast dendritic cell memory B cell follicular B cell T cell

Disease Ontology

severe acute respiratory syndrome COVID-19

Pathway Ontology

signaling pathway disease pathway B cell receptor signaling pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
α-GalCer Metabolite cas:158021-47-7 α-galactosylceramide
FcRL5 GeneProduct ensembl:ENSG00000143297
CD22 GeneProduct ensembl:ENSG00000012124
IRF4 GeneProduct ensembl:ENSG00000137265 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.
IFIT2 GeneProduct ensembl:ENSG00000119922
IFITM1 GeneProduct ensembl:ENSG00000185885
CD80 GeneProduct ensembl:ENSG00000121594
PRDM1 GeneProduct ensembl:ENSG00000057657
IRF8 GeneProduct ensembl:ENSG00000140968 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.
CXCL12 GeneProduct ensembl:ENSG00000107562 CXCL12 is expressed in the medullary cords of the lymph nodes and in the bone marrow.
PD1 GeneProduct ensembl:ENSG00000188389 PDCD1/PD1
ISG15 GeneProduct ensembl:ENSG00000187608 ISG15 acts as a chemoattractant for neutrophils. PBs that secrete ISG15 are a proinflammatory feature in autoimmune diseases like SLE.
CRP GeneProduct ensembl:ENSG00000132693 C-reactive protein (CRP), an acute phase reactant in the IL-6 pathway commonly used as a biomarker of COVID-19 severity.
BLNK GeneProduct ensembl:ENSG00000095585
CD69 GeneProduct ensembl:ENSG00000110848 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.
SLAMF7 GeneProduct ensembl:ENSG00000026751
XBP1 GeneProduct ensembl:ENSG00000100219 X-box binding protein-1 (XBP-1) is esssential for plasma cell differentiation.
IL-10 GeneProduct ensembl:ENSG00000136634
SYK GeneProduct ensembl:ENSG00000165025
Blimp1 GeneProduct ensembl:ENSG00000057657 PRDM1/Blimp1
CD19 GeneProduct ensembl:ENSG00000177455
ZEB2 GeneProduct ensembl:ENSG00000169554 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.
TBET GeneProduct ensembl:ENSG00000073861 TBX21/TBET is expressed in high amounts by DN2 B cells but also aNAV.
APRIL GeneProduct ensembl:ENSG00000161955 TNFSF13/APRILstimulates AID induction independently of CD40.
PTPRC GeneProduct ensembl:ENSG00000081237 CD45
CD11c GeneProduct ensembl:ENSG00000140678 DCs in the medullary cords or the T zone of the lymph nodes express high amounts of CD11c. CD11c forms a heterodimer with CD18
NEAT1 GeneProduct ensembl:ENSG00000245532
PAX5 GeneProduct ensembl:ENSG00000196092 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.
XBP1 GeneProduct ensembl:ENSG00000100219
FOXO1 GeneProduct ensembl:ENSG00000150907 Transcription factor FOXO1 inhibits T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation.
CR1 GeneProduct ensembl:ENSG00000203710 CR1 (CD35)
CCL19 GeneProduct ensembl:ENSG00000172724
CD18 GeneProduct ensembl:ENSG00000160255
TMSB10 GeneProduct ensembl:ENSG00000034510 gene TMSB10 is Pax5-repressed
IFNG-AS1 GeneProduct ensembl:ENSG00000255733
HSPA8 GeneProduct ensembl:ENSG00000109971 associated with metabolic processes and autophagy
BACH2 GeneProduct ensembl:ENSG00000112182 Stabilizes GC B cells while aantagonizing plasma cell differeentiation.
CCL21 GeneProduct ensembl:ENSG00000137077
MS4A1 GeneProduct ensembl:ENSG00000156738 MS4A1/CD20
IGHV4-34 GeneProduct ensembl:ENSG00000211956
BAFF GeneProduct uniprot:Q9Y275 B cell activating factor (BAFF)
EBI3 GeneProduct ensembl:ENSG00000105246
ETS1 GeneProduct ensembl:ENSG00000134954 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.
CD79A GeneProduct ensembl:ENSG00000105369
CD82 GeneProduct ensembl:ENSG00000085117
IL-2 GeneProduct ensembl:ENSG00000109471
PTCRA GeneProduct ensembl:ENSG00000171611 Pre T-cell antigen receptor alpha, pT-alpha, pTa (pT-alpha-TCR)
CD40 GeneProduct ensembl:ENSG00000101017
IL-6 GeneProduct ensembl:ENSG00000136244 IL-6 mainly promotes differentiation of antigen-specific B cells to plasmablasts.
BCL6 GeneProduct ensembl:ENSG00000113916 transcription factor; critical regulator of Tfh differentiation. Lack of Bcl6 in CD4+T cells leads to inability to differentiate into Tfh cells.
CXCR5 GeneProduct ensembl:ENSG00000160683
TLR7 GeneProduct ensembl:ENSG00000196664
STAT5A GeneProduct ensembl:ENSG00000126561
BCR GeneProduct ensembl:ENSG00000186716
PD1 GeneProduct ensembl:ENSG00000188389 inhibitory receptor
c-Maf GeneProduct uniprot:O75444 musculoaponeurotic fibrosarcoma (c-Maf)
ICOS GeneProduct ensembl:ENSG00000163600
TLR4 GeneProduct ensembl:ENSG00000136869
IL12 GeneProduct ensembl:ENSG00000168811 IL-12 regulates humoral immunity by strongly inhibiting TFH differentiation. In vitro, it induces IFNγ and IL-21 in human T cells. (IL12A)
IL-4 GeneProduct ensembl:ENSG00000113520
CXCR5 GeneProduct ensembl:ENSG00000160683 the chemokine receptor CXCR5 is increasingly expressed upon follicle entry via the CXCL13 gradient.
Blimp1 GeneProduct ensembl:ENSG00000057657 PRDM1/Blimp-1 (B lymphocyte-induced maturation protein-1): Upregulation of Blimp-1 expression is associated with plasmablast differentiation.
BCL6 GeneProduct ensembl:ENSG00000113916 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
CD35 GeneProduct ensembl:ENSG00000203710 CD35 or CR1
CD21 GeneProduct ensembl:ENSG00000117322 CR2 or CD21
MFGE8 GeneProduct ensembl:ENSG00000140545 Mfge8 or FDC-M1
CCR7 GeneProduct ensembl:ENSG00000126353 Increased expression of the CCR7 receptor indicates the interaction of B cells with the antigens. In B cells that lack CCR7, antigen engagement fails to cause movement to the T zone. CCR7 interacts with the chemokines CCL19 and CCL21.
EBI2 GeneProduct ensembl:ENSG00000169508 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
CCR7 GeneProduct ensembl:ENSG00000126353 Reduction of CCR7 expression (along with increased expression of CXCR5) Th cells migrate to the T-B border, to aid in humoral response.
ICOSL GeneProduct ensembl:ENSG00000160223 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.
ICOSL GeneProduct ensembl:ENSG00000160223 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.
CXCR4 GeneProduct ensembl:ENSG00000121966 The increased expression of the chemokine receptor CXCR4 indicates that the B cell will enter the extrafollicular pathway.
SELL GeneProduct ensembl:ENSG00000188404 homing receptor CD62L (SELL)
CXCR4 GeneProduct ensembl:ENSG00000121966 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.
ISG15 GeneProduct ensembl:ENSG00000187608 ISG15 acts as a chemoattractant for neutrophils. ISG15 is an autoimmune feature in autoimmune of memory-like B cells in SLE.
IL-4 GeneProduct ensembl:ENSG00000113520 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.
CCR7 GeneProduct ensembl:ENSG00000126353 Increased expression of the CCR7 receptor indicates the interaction of B cells with the antigens. CCR7 interacts with the chemokines CCL19 and CCL21
CXCL13 Protein uniprot:O43927
IgM Protein uniprot:P0DOX6
IL6 Protein uniprot:Q75MH2
IgG Protein uniprot:P0DOX5
CD1d Protein uniprot:P15813 Antigen-presenting glycoprotein CD1d
BTLA Protein uniprot:Q7Z6A9
CD40L Protein uniprot:P29965 tumor necrosis factor (TNF) family member
IFN-γ Protein uniprot:P01579
IL-21 Protein uniprot:Q9HBE4
TNF-α Protein uniprot:P01375
IL-21 Protein uniprot:Q9HBE4 IL-21 promotes both EF and GC responses and is therefore considered to be a stimulator of B cell response.
CD40L Protein uniprot:P29965
IFN-α Protein uniprot:P48551
SAP Protein uniprot:O60880
TBX21 Protein uniprot:Q9UL17 T-bet expression influences TFH, as a lack of T-bet correlates with increased frequency of TFH
AID Protein uniprot:Q9GZX7 activation-induced cytidine deaminase (AID) - enzyme required for both SHM and isotype switching. AID is expressed and active in non-GC proliferating B cells.
Compl. C4-A Protein uniprot:P0C0L4
Compl. C3 Protein uniprot:P01024 Complement C3
IL-21 Protein uniprot:Q9HBE4 IL21 stimulates DN2 B cell differentiation into PCs.
N Protein uniprot:P0DTC9 Nucleocapsid protein, N
S Protein uniprot:P0DTC2 Spike protein
N Protein uniprot:P0DTC9 Nucleocapsid protein, N

References

  1. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Reif K, Ekland EH, Ohl L, Nakano H, Lipp M, Förster R, et al. Nature. 2002 Mar 7;416(6876):94–9. PubMed Europe PMC Scholia
  2. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Lin KI, Angelin-Duclos C, Kuo TC, Calame K. Mol Cell Biol. 2002 Jul;22(13):4771–80. PubMed Europe PMC Scholia
  3. Extrafollicular antibody responses. MacLennan ICM, Toellner KM, Cunningham AF, Serre K, Sze DMY, Zúñiga E, et al. Immunol Rev. 2003 Aug;194:8–18. PubMed Europe PMC Scholia
  4. Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy. Silk JD, Hermans IF, Gileadi U, Chong TW, Shepherd D, Salio M, et al. J Clin Invest. 2004 Dec;114(12):1800–11. PubMed Europe PMC Scholia
  5. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Crotty S, Johnston RJ, Schoenberger SP. Nat Immunol. 2010 Feb;11(2):114–20. PubMed Europe PMC Scholia
  6. CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Barral P, Polzella P, Bruckbauer A, van Rooijen N, Besra GS, Cerundolo V, et al. Nat Immunol. 2010 Apr;11(4):303–12. PubMed Europe PMC Scholia
  7. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ, Monticelli L, et al. Immunity. 2011 Jun 24;34(6):932–46. PubMed Europe PMC Scholia
  8. EBI2 guides serial movements of activated B cells and ligand activity is detectable in lymphoid and nonlymphoid tissues. Kelly LM, Pereira JP, Yi T, Xu Y, Cyster JG. J Immunol. 2011 Sep 15;187(6):3026–32. PubMed Europe PMC Scholia
  9. EBI2 operates independently of but in cooperation with CXCR5 and CCR7 to direct B cell migration and organization in follicles and the germinal center. Gatto D, Wood K, Brink R. J Immunol. 2011 Nov 1;187(9):4621–8. PubMed Europe PMC Scholia
  10. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M, Qi X, et al. J Biol Chem. 2012 Mar 30;287(14):11234–9. PubMed Europe PMC Scholia
  11. Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. Rao RR, Li Q, Gubbels Bupp MR, Shrikant PA. Immunity. 2012 Mar 23;36(3):374–87. PubMed Europe PMC Scholia
  12. New helping friends for B cells. Cerutti A, Puga I, Cols M. Eur J Immunol. 2012 Aug;42(8):1956–68. PubMed Europe PMC Scholia
  13. Activation of B cells by non-canonical helper signals. Cerutti A, Cols M, Puga I. EMBO Rep. 2012 Sep;13(9):798–810. PubMed Europe PMC Scholia
  14. Endocytosis and recycling of immune complexes by follicular dendritic cells enhances B cell antigen binding and activation. Heesters BA, Chatterjee P, Kim YA, Gonzalez SF, Kuligowski MP, Kirchhausen T, et al. Immunity. 2013 Jun 27;38(6):1164–75. PubMed Europe PMC Scholia
  15. T-B-cell entanglement and ICOSL-driven feed-forward regulation of germinal centre reaction. Liu D, Xu H, Shih C, Wan Z, Ma X, Ma W, et al. Nature. 2015 Jan 8;517(7533):214–8. PubMed Europe PMC Scholia
  16. Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8. Xu H, Chaudhri VK, Wu Z, Biliouris K, Dienger-Stambaugh K, Rochman Y, et al. Nat Immunol. 2015 Dec;16(12):1274–81. PubMed Europe PMC Scholia
  17. Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus. Jenks SA, Cashman KS, Zumaquero E, Marigorta UM, Patel AV, Wang X, et al. Immunity. 2018 Oct 16;49(4):725-739.e6. PubMed Europe PMC Scholia
  18. Extrafollicular responses in humans and SLE. Jenks SA, Cashman KS, Woodruff MC, Lee FEH, Sanz I. Immunol Rev. 2019 Mar;288(1):136–48. PubMed Europe PMC Scholia
  19. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Robbiani DF, Gaebler C, Muecksch F, Lorenzi JCC, Wang Z, Cho A, et al. Nature. 2020 Aug;584(7821):437–42. PubMed Europe PMC Scholia
  20. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS, Haddad NS, et al. Nat Immunol. 2020 Dec;21(12):1506–16. PubMed Europe PMC Scholia
  21. Germinal Center and Extrafollicular B Cell Responses in Vaccination, Immunity, and Autoimmunity. Elsner RA, Shlomchik MJ. Immunity. 2020 Dec 15;53(6):1136–50. PubMed Europe PMC Scholia
  22. Double-negative (DN) B cells: an under-recognized effector memory B cell subset in autoimmunity. Li Y, Li Z, Hu F. Clin Exp Immunol. 2021 Aug;205(2):119–27. PubMed Europe PMC Scholia
  23. Rapid isolation and immune profiling of SARS-CoV-2 specific memory B cell in convalescent COVID-19 patients via LIBRA-seq. He B, Liu S, Wang Y, Xu M, Cai W, Liu J, et al. Signal Transduct Target Ther. 2021 May 17;6(1):195. PubMed Europe PMC Scholia
  24. Maturation trajectories and transcriptional landscape of plasmablasts and autoreactive B cells in COVID-19. Schultheiß C, Paschold L, Willscher E, Simnica D, Wöstemeier A, Muscate F, et al. iScience. 2021 Nov 19;24(11):103325. PubMed Europe PMC Scholia
  25. The role of B cells in COVID-19 infection and vaccination. Chen S, Guan F, Candotti F, Benlagha K, Camara NOS, Herrada AA, et al. Front Immunol. 2022 Aug 30;13:988536. PubMed Europe PMC Scholia