原發性免疫缺陷疾病 (PID) 是罕見疾病其中包括廣泛的遺傳性基因突變，在臨床上會透過各種免疫系統異常表現出來。我們先前以次世代全基因定序的方法於病患及她先前過世的姊姊的SLC5A6基因上發現一個複合雜合性（compound heterozygous) c.1502C>T (p. P349L) 和c.638T>A (p.M61K) 的基因突變，這個基因編碼突變會導致維生素轉運蛋白 (SMVT) 運輸功能喪失。SLC5A6維生素轉運蛋白對於生物素 (維生素 B7）的運輸扮演著重要的角色。我們發現這個 SLC5A6 複合雜合性的突變會導致細胞內生物素嚴重缺乏，導致 B 細胞終端分化受損和缺乏分泌抗體之能力。我們的研究進一步探討了細胞內生物素的缺乏會造成細胞代謝模組的改變，包括氧化呼吸中斷並轉而對糖解作用的依賴，導致漿細胞成熟失敗。在病人和在複製病人特定SLC5A6M60K突變的 CRISPR-Cas9 基因編輯小鼠模型中，補充高濃度生物素可有效增強 B 細胞成熟過程中的粒線體呼吸並恢復分泌抗體的能力。透過此研究，我們的結果證明了代謝模組重編在 B 細胞成熟中的關鍵角色，並揭示了 SLC5A6 作為免疫缺陷的致病基因。更重要的是，我們發現對於與 SLC5A6 突變相關的免疫缺陷個體來說，補充生物素是一種可行的治療策略。

Primary immunodeficiency diseases (PIDs) comprise a wide spectrum of inherited genetic mutations that manifest clinically through various immune system abnormalities. We diagnosed immunodeficient patients in a family exhibiting low levels of immunoglobulins (Appendix 1). Through comprehensive whole exome sequencing, we characterized defective biotin transport caused by loss of function of compound heterozygous SLC5A6 variants c.1502C>T (p. P349L) and c.638T>A (p.M61K), the gene responsible for encoding a cellular sodium-dependent multivitamin transporter (SMVT) crucial for biotin (vitamin B7) transportation. We found that the identified mutations in SLC5A6 led to an intracellular deficiency in biotin, resulting in impaired B cell development and antibody deficiency. Our investigation further revealed altered cellular metabolic profiles including a disrupted oxidative respiration and reliance on glycolysis, contributing to the failure in plasma cell maturation. The replenishment of biotin proved effective in enhancing the mitochondrial respiration of B cell maturation and restoring antibody-producing activity, both in the affected patient and in a CRISPR-Cas9 gene-edited mouse model designed to replicate the patient's specific SLC5A6 disease mutations. In conclusion, our results demonstrate the pivotal role of metabolic reprogramming in the maturation of B cells and sheds light on SLC5A6 as a causative gene for immunodeficiency. Importantly, our findings propose biotin replenishment as a viable treatment strategy for individuals with immunodeficiency associated with SLC5A6 mutations.

1. Chi, H. Immunometabolism at the intersection of metabolic signaling, cell fate, and systems immunology. Cell Mol Immunol 19, 299-302 (2022).
2. Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annu Rev Immunol 32, 609-634 (2014).
3. Hu, C. et al. Immune cell metabolism and metabolic reprogramming. Mol Biol Rep 49, 9783-9795 (2022).
4. Jung, J., Zeng, H. & Horng, T. Metabolism as a guiding force for immunity. Nat Cell Biol 21, 85-93 (2019).
5. Yen, C.L. et al. Phosphorylation of glycogen synthase kinase-3beta in metabolically abnormal obesity affects immune stimulation-induced cytokine production. Int J Obes (Lond) 39, 270-278 (2015).
6. Palsson-McDermott, E.M. & O'Neill, L.A.J. Targeting immunometabolism as an anti-inflammatory strategy. Cell Res 30, 300-314 (2020).
7. Pearce, E.L. & Pearce, E.J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633-643 (2013).
8. Li, Y. et al. Immune effects of glycolysis or oxidative phosphorylation metabolic pathway in protecting against bacterial infection. J Cell Physiol 234, 20298-20309 (2019).
9. Kornberg, M.D. The immunologic Warburg effect: Evidence and therapeutic opportunities in autoimmunity. Wiley Interdiscip Rev Syst Biol Med 12, e1486 (2020).
10. Lartigue, L. & Faustin, B. Mitochondria: metabolic regulators of innate immune responses to pathogens and cell stress. Int J Biochem Cell Biol 45, 2052-2056 (2013).
11. Liao, Y.C. et al. NOX2-Deficient Neutrophils Facilitate Joint Inflammation Through Higher Pro-Inflammatory and Weakened Immune Checkpoint Activities. Front Immunol 12, 743030 (2021).
12. Huang, Y.F. et al. Redox Regulation of Pro-IL-1beta Processing May Contribute to the Increased Severity of Serum-Induced Arthritis in NOX2-Deficient Mice. Antioxid Redox Signal 23, 973-984 (2015).
13. Huang, Y.F., Liu, S.Y., Yen, C.L., Yang, P.W. & Shieh, C.C. Thapsigargin and flavin adenine dinucleotide ex vivo treatment rescues trafficking-defective gp91phox in chronic granulomatous disease leukocytes. Free Radic Biol Med 47, 932-940 (2009).
14. West, A.P. & Shadel, G.S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol 17, 363-375 (2017).
15. Riley, J.S. & Tait, S.W. Mitochondrial DNA in inflammation and immunity. EMBO Rep 21, e49799 (2020).
16. Zhong, F., Liang, S. & Zhong, Z. Emerging Role of Mitochondrial DNA as a Major Driver of Inflammation and Disease Progression. Trends Immunol 40, 1120-1133 (2019).
17. Urbanczyk, S. et al. Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle. Cell Rep 39, 110912 (2022).
18. Shyer, J.A., Flavell, R.A. & Bailis, W. Metabolic signaling in T cells. Cell Res 30, 649-659 (2020).
19. Chapman, N.M., Boothby, M.R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol 20, 55-70 (2020).
20. Corrado, M. & Pearce, E.L. Targeting memory T cell metabolism to improve immunity. J Clin Invest 132 (2022).
21. Almeida, L., Lochner, M., Berod, L. & Sparwasser, T. Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol 28, 514-524 (2016).
22. Geltink, R.I.K., Kyle, R.L. & Pearce, E.L. Unraveling the Complex Interplay Between T Cell Metabolism and Function. Annu Rev Immunol 36, 461-488 (2018).
23. van der Windt, G.J. & Pearce, E.L. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 249, 27-42 (2012).
24. Palmieri, E.M. et al. Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase. Nat Commun 11, 698 (2020).
25. Wang, Y., Li, N., Zhang, X. & Horng, T. Mitochondrial metabolism regulates macrophage biology. J Biol Chem 297, 100904 (2021).
26. Hamers, A.A.J. & Pillai, A.B. A sweet alternative: maintaining M2 macrophage polarization. Sci Immunol 3 (2018).
27. Wculek, S.K., Dunphy, G., Heras-Murillo, I., Mastrangelo, A. & Sancho, D. Metabolism of tissue macrophages in homeostasis and pathology. Cell Mol Immunol 19, 384-408 (2022).
28. Koo, S.J. & Garg, N.J. Metabolic programming of macrophage functions and pathogens control. Redox Biol 24, 101198 (2019).
29. Ryan, D.G. & O'Neill, L.A.J. Krebs Cycle Reborn in Macrophage Immunometabolism. Annu Rev Immunol 38, 289-313 (2020).
30. Patel, C.H. & Powell, J.D. Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. Curr Opin Immunol 46, 82-88 (2017).
31. Shi, W. et al. Transcriptional profiling of mouse B cell terminal differentiation defines a signature for antibody-secreting plasma cells. Nat Immunol 16, 663-673 (2015).
32. Jellusova, J. The role of metabolic checkpoint regulators in B cell survival and transformation. Immunol Rev 295, 39-53 (2020).
33. Waters, L.R., Ahsan, F.M., Wolf, D.M., Shirihai, O. & Teitell, M.A. Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling. iScience 5, 99-109 (2018).
34. Kunisawa, J. Metabolic changes during B cell differentiation for the production of intestinal IgA antibody. Cell Mol Life Sci 74, 1503-1509 (2017).
35. Choi, S.C. & Morel, L. Immune metabolism regulation of the germinal center response. Exp Mol Med 52, 348-355 (2020).
36. Sharma, R. et al. Distinct metabolic requirements regulate B cell activation and germinal center responses. Nat Immunol 24, 1358-1369 (2023).
37. Weisel, F.J. et al. Germinal center B cells selectively oxidize fatty acids for energy while conducting minimal glycolysis. Nat Immunol 21, 331-342 (2020).
38. Singh, A., Jindal, A.K., Joshi, V., Anjani, G. & Rawat, A. An updated review on phenocopies of primary immunodeficiency diseases. Genes Dis 7, 12-25 (2020).
39. Picard, C. et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol 35, 696-726 (2015).
40. Shieh, C.C. & Hung, C.H. Beyond the apparent: subtle presentation of immunodeficiencies in the age of personalized medicine. J Microbiol Immunol Infect 45, 395-397 (2012).
41. Tangye, S.G. et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 42, 1473-1507 (2022).
42. Ochs, H.D. & Petroni, D. From clinical observations and molecular dissection to novel therapeutic strategies for primary immunodeficiency disorders. Am J Med Genet A 176, 784-803 (2018).
43. Marwaha, S., Knowles, J.W. & Ashley, E.A. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Med 14, 23 (2022).
44. Liao, C.Y. et al. A novel pathogenic mutation on Interleukin-7 receptor leading to severe combined immunodeficiency identified with newborn screening and whole exome sequencing. J Microbiol Immunol Infect 53, 99-105 (2020).
45. Wang, L.H., Yen, C.L., Chang, T.C., Liu, C.C. & Shieh, C.C. Impact of molecular diagnosis on treating Mendelian susceptibility to mycobacterial diseases. J Microbiol Immunol Infect 45, 411-417 (2012).
46. Jha, A.K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419-430 (2015).
47. Chan, T.Y. et al. Increased ILC3s associated with higher levels of IL-1beta aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase. Eur J Immunol 49, 2063-2073 (2019).
48. Morita, H., Moro, K. & Koyasu, S. Innate lymphoid cells in allergic and nonallergic inflammation. J Allergy Clin Immunol 138, 1253-1264 (2016).
49. Kumar, B.V., Connors, T.J. & Farber, D.L. Human T Cell Development, Localization, and Function throughout Life. Immunity 48, 202-213 (2018).
50. Victora, G.D. & Nussenzweig, M.C. Germinal Centers. Annu Rev Immunol 40, 413-442 (2022).
51. Ersching, J. et al. Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase. Immunity 46, 1045-1058 e1046 (2017).
52. Viant, C. et al. Germinal center-dependent and -independent memory B cells produced throughout the immune response. J Exp Med 218 (2021).
53. Laidlaw, B.J. & Cyster, J.G. Transcriptional regulation of memory B cell differentiation. Nat Rev Immunol 21, 209-220 (2021).
54. Suan, D., Sundling, C. & Brink, R. Plasma cell and memory B cell differentiation from the germinal center. Curr Opin Immunol 45, 97-102 (2017).
55. Lau, A.W. & Brink, R. Selection in the germinal center. Curr Opin Immunol 63, 29-34 (2020).
56. Jourdan, M. et al. An in vitro model of differentiation of memory B cells into plasmablasts and plasma cells including detailed phenotypic and molecular characterization. Blood 114, 5173-5181 (2009).
57. Young, C. & Brink, R. The unique biology of germinal center B cells. Immunity 54, 1652-1664 (2021).
58. Wong, R. et al. Affinity-Restricted Memory B Cells Dominate Recall Responses to Heterologous Flaviviruses. Immunity 53, 1078-1094 e1077 (2020).
59. Reusch, L. & Angeletti, D. Memory B-cell diversity: From early generation to tissue residency and reactivation. Eur J Immunol 53, e2250085 (2023).
60. Quick, M. & Shi, L. The sodium/multivitamin transporter: a multipotent system with therapeutic implications. Vitam Horm 98, 63-100 (2015).
61. Neophytou, C. & Pitsouli, C. Biotin controls intestinal stem cell mitosis and host-microbiome interactions. Cell Rep 38, 110505 (2022).
62. Holling, T. et al. Novel biallelic variants expand the SLC5A6-related phenotypic spectrum. Eur J Hum Genet 30, 439-449 (2022).
63. Montomoli, M. et al. A novel SLC5A6 homozygous variant in a family with multivitamin-dependent neurometabolic disorder: Phenotype expansion and long-term follow-up. Eur J Med Genet 66, 104808 (2023).
64. Byrne, A.B. et al. Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6. NPJ Genom Med 4, 28 (2019).
65. Ghosal, A., Lambrecht, N., Subramanya, S.B., Kapadia, R. & Said, H.M. Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption. Am J Physiol Gastrointest Liver Physiol 304, G64-71 (2013).
66. Subramanian, V.S., Constantinescu, A.R., Benke, P.J. & Said, H.M. Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child. Hum Genet 136, 253-261 (2017).
67. Zempleni, J., Wijeratne, S.S. & Hassan, Y.I. Biotin. Biofactors 35, 36-46 (2009).
68. Sabui, S. et al. Biotin and pantothenic acid oversupplementation to conditional SLC5A6 KO mice prevents the development of intestinal mucosal abnormalities and growth defects. Am J Physiol Cell Physiol 315, C73-C79 (2018).
69. Baez-Saldana, A. & Ortega, E. Biotin deficiency blocks thymocyte maturation, accelerates thymus involution, and decreases nose-rump length in mice. J Nutr 134, 1970-1977 (2004).
70. Baez-Saldana, A., Diaz, G., Espinoza, B. & Ortega, E. Biotin deficiency induces changes in subpopulations of spleen lymphocytes in mice. Am J Clin Nutr 67, 431-437 (1998).
71. Said, H.M. Biotin: biochemical, physiological and clinical aspects. Subcell Biochem 56, 1-19 (2012).
72. Kuroishi, T. Regulation of immunological and inflammatory functions by biotin. Can J Physiol Pharmacol 93, 1091-1096 (2015).
73. Petrelli, F., Moretti, P. & Campanati, G. Studies on the relationships between biotin and behaviour of B and T lymphocytes in the guinea-pig. Experientia 37, 1204-1206 (1981).
74. Jiang, Y.Z. et al. Methylmalonic and propionic acidemia among hospitalized pediatric patients: a nationwide report. Orphanet J Rare Dis 14, 292 (2019).
75. Kruisbeek, A.M. Isolation of mouse mononuclear cells. Curr Protoc Immunol Chapter 3, Unit 3 1 (2001).
76. Kim, D.I. et al. An improved smaller biotin ligase for BioID proximity labeling. Mol Biol Cell 27, 1188-1196 (2016).
77. Mock, D.M. & Mock, N.I. Lymphocyte propionyl-CoA carboxylase is an early and sensitive indicator of biotin deficiency in rats, but urinary excretion of 3-hydroxypropionic acid is not. J Nutr 132, 1945-1950 (2002).
78. Tosato, F. et al. Lymphocytes subsets reference values in childhood. Cytometry A 87, 81-85 (2015).
79. Bousfiha, A. et al. The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity. J Clin Immunol 42, 1508-1520 (2022).
80. Roy, A., Kucukural, A. & Zhang, Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5, 725-738 (2010).
81. Zhang, Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9, 40 (2008).
82. Jourdan, M. et al. Characterization of a transitional preplasmablast population in the process of human B cell to plasma cell differentiation. J Immunol 187, 3931-3941 (2011).
83. Ochoa-Ruiz, E. et al. Biotin deprivation impairs mitochondrial structure and function and has implications for inherited metabolic disorders. Mol Genet Metab 116, 204-214 (2015).
84. Jellusova, J. Metabolic control of B cell immune responses. Curr Opin Immunol 63, 21-28 (2020).
85. Raybuck, A.L. et al. B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity. J Immunol 200, 2627-2639 (2018).
86. Caro-Maldonado, A. et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol 192, 3626-3636 (2014).
87. van Raam, B.J. et al. Mitochondrial membrane potential in human neutrophils is maintained by complex III activity in the absence of supercomplex organisation. PLoS One 3, e2013 (2008).
88. Kurmi, K. et al. Metabolic modulation of mitochondrial mass during CD4(+) T cell activation. Cell Chem Biol 30, 1064-1075 e1068 (2023).
89. Igarashi, K., Ochiai, K., Itoh-Nakadai, A. & Muto, A. Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network. Immunol Rev 261, 116-125 (2014).
90. Ochiai, K., Muto, A., Tanaka, H., Takahashi, S. & Igarashi, K. Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6. Int Immunol 20, 453-460 (2008).
91. Weisel, F.J., Zuccarino-Catania, G.V., Chikina, M. & Shlomchik, M.J. A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells. Immunity 44, 116-130 (2016).
92. Lin, K.I., Lin, Y. & Calame, K. Repression of c-myc is necessary but not sufficient for terminal differentiation of B lymphocytes in vitro. Mol Cell Biol 20, 8684-8695 (2000).
93. Figgett, W.A., Vincent, F.B., Saulep-Easton, D. & Mackay, F. Roles of ligands from the TNF superfamily in B cell development, function, and regulation. Semin Immunol 26, 191-202 (2014).
94. Chevrier, S. et al. CD93 is required for maintenance of antibody secretion and persistence of plasma cells in the bone marrow niche. Proc Natl Acad Sci U S A 106, 3895-3900 (2009).
95. Morgan, D. & Tergaonkar, V. Unraveling B cell trajectories at single cell resolution. Trends Immunol 43, 210-229 (2022).
96. Stanley, J.S., Mock, D.M., Griffin, J.B. & Zempleni, J. Biotin uptake into human peripheral blood mononuclear cells increases early in the cell cycle, increasing carboxylase activities. J Nutr 132, 1854-1859 (2002).
97. Lam, W.Y. et al. Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells. Immunity 45, 60-73 (2016).
98. Miklas, J.W. et al. TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. Nat Commun 10, 4671 (2019).
99. LeBien, T.W. & Tedder, T.F. B lymphocytes: how they develop and function. Blood 112, 1570-1580 (2008).
100. Nojima, T. et al. In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo. Nat Commun 2, 465 (2011).
101. McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. Antigen-specific memory B cell development. Annu Rev Immunol 23, 487-513 (2005).
102. Ripperger, T.J. & Bhattacharya, D. Transcriptional and Metabolic Control of Memory B Cells and Plasma Cells. Annu Rev Immunol 39, 345-368 (2021).
103. Hasbold, J., Corcoran, L.M., Tarlinton, D.M., Tangye, S.G. & Hodgkin, P.D. Evidence from the generation of immunoglobulin G-secreting cells that stochastic mechanisms regulate lymphocyte differentiation. Nat Immunol 5, 55-63 (2004).
104. Teng, X., Cornaby, C., Li, W. & Morel, L. Metabolic regulation of pathogenic autoimmunity: therapeutic targeting. Curr Opin Immunol 61, 10-16 (2019).
105. MacIver, N.J., Michalek, R.D. & Rathmell, J.C. Metabolic regulation of T lymphocytes. Annu Rev Immunol 31, 259-283 (2013).
106. O'Brien, K.L. & Finlay, D.K. Immunometabolism and natural killer cell responses. Nat Rev Immunol 19, 282-290 (2019).
107. Cucchi, D. et al. Fatty acids - from energy substrates to key regulators of cell survival, proliferation and effector function. Cell Stress 4, 9-23 (2019).
108. Pucino, V. et al. Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4(+) T Cell Metabolic Rewiring. Cell Metab 30, 1055-1074 e1058 (2019).
109. Yao, C. et al. BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8(+) T cells. Nat Immunol 22, 370-380 (2021).
110. Sidwell, T. et al. Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis. Nat Commun 11, 252 (2020).
111. Igarashi, K. & Watanabe-Matsui, M. Wearing red for signaling: the heme-bach axis in heme metabolism, oxidative stress response and iron immunology. Tohoku J Exp Med 232, 229-253 (2014).
112. Jeon, J.H. et al. Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: Therapeutic targets in metabolic diseases. J Diabetes Investig 12, 21-31 (2021).
113. Wakil, S.J. & Abu-Elheiga, L.A. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res 50 Suppl, S138-143 (2009).
114. Gleason, J.L. et al. Gestational age at term delivery and children's neurocognitive development. Int J Epidemiol 50, 1814-1823 (2022).
115. Cheong, J.L. et al. Association Between Moderate and Late Preterm Birth and Neurodevelopment and Social-Emotional Development at Age 2 Years. JAMA Pediatr 171, e164805 (2017).
116. Lapuente, D., Winkler, T.H. & Tenbusch, M. B-cell and antibody responses to SARS-CoV-2: infection, vaccination, and hybrid immunity. Cell Mol Immunol (2023).
117. Chen, S. et al. The role of B cells in COVID-19 infection and vaccination. Front Immunol 13, 988536 (2022).
118. Kim, W. et al. Germinal centre-driven maturation of B cell response to mRNA vaccination. Nature 604, 141-145 (2022).
119. Luo, W. & Yin, Q. B Cell Response to Vaccination. Immunol Invest 50, 780-801 (2021).
120. Laidlaw, B.J. & Ellebedy, A.H. The germinal centre B cell response to SARS-CoV-2. Nat Rev Immunol 22, 7-18 (2022).
121. Woodruff, M.C. et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol 21, 1506-1516 (2020).
122. Montague, Z. et al. Dynamics of B-cell repertoires and emergence of cross-reactive responses in COVID-19 patients with different disease severity. medRxiv (2021).
123. Kreer, C., Gruell, H., Mora, T., Walczak, A.M. & Klein, F. Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies. Vaccines (Basel) 8 (2020).
124. Georgiou, G. et al. The promise and challenge of high-throughput sequencing of the antibody repertoire. Nat Biotechnol 32, 158-168 (2014).
125. Hagglof, T. et al. Continuous germinal center invasion contributes to the diversity of the immune response. Cell 186, 147-161 e115 (2023).