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CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity
Open accessAbstract
CD22 (Siglec 2) is a receptor predominantly restricted to B cells. It was initially characterized over 30 years ago and named "CD22" in 1984 at the 2nd International workshop in Boston (1). Several excellent reviews have detailed CD22 functions, CD22-regulated signaling pathways and B cell subsets regulated by CD22 or Siglec G (2-4). This review is an attempt to highlight recent and possibly forgotten findings. We also describe the role of CD22 in autoimmunity and the great potential for CD22-based immunotherapeutics for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE).
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“In addition, SYK has been identified as the central kinase that instructs signaling and effector functions downstream of TREM2, CD33, and CD22 receptors (Clark and Giltiay, 2018; Wissfeld et al., 2021; Yao et al., 2019).”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Clark and Giltiay, 2018
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“Recently, the use of chimeric antigen receptor (CAR) T-cell therapy, specific for CD22 was reported to provide high response rates for patients with B-cell acute lymphoblastic leukemia (B-ALL) who had failed chemotherapy and/or a CD19-targeted CAR T-cell treatment (119).”
BackgroundSiglec-mediated regulation of immune cell function in disease
Macauley, M. S., Crocker, P. R., & Paulson, J. C. (2014) · Nature Reviews Immunology · doi:10.1038/nri3737 · Cited by 1,122 · cited 1×
“The enzyme α 2,6 sialyltransferase 1 (ST6Gal1) synthesizes this ligand, and ST6Gal1 mice phenocopy many but not all of the defects seen in CD22 mice (12, 13).”
BackgroundChristensen, S. R., Shupe, J., Nickerson, K., Kashgarian, M., Flavell, R. A., & Shlomchik, M. J. (2006) · Immunity · doi:10.1016/j.immuni.2006.07.013 · Cited by 1,090 · cited 1×
“TLR7 and TLR9 in particular have been implicated in the activation of autoreactive cells and antinuclear auto-Ab production inmouse models of lupus (78, 79, 102, 103).”
BackgroundAutoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication
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“Similar egress of MZ B cells can be found in other autoimmune models, particularly those associated with TLR7 overexpression (78, 79).”
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“Thus, they can be regarded as “self-structures” (100).”
BackgroundCD22 is a negative regulator of B-cell receptor signalling.
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“Other studies show that CD22 mice generated using C57BL/6 ES cells do not develop an autoimmune phenotype spontaneously (9).”
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“Mice with a combination of half doses of Lyn, CD22 and SHP-1 have a defective phenotype found in homozygous parents (16).”
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CD22 regulates thymus-independent responses and the lifespan of B cells
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“Although B cell development in the BM is not affected in CD22 mice, numbers of recirculating B220hisIgMlo B cells (or IgDhi B cells) are reduced in CD22 mice (9, 10) as well as CD22L deficient ST6Gal1 mice (58).”
BackgroundInfluentialSelf-citationImmune regulation by the ST6Gal sialyltransferase.
Hennet, T., Chui, D., Paulson, J., & Marth, J. (1998) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.95.8.4504 · Cited by 366 · cited 2×
“The enzyme α 2,6 sialyltransferase 1 (ST6Gal1) synthesizes this ligand, and ST6Gal1 mice phenocopy many but not all of the defects seen in CD22 mice (12, 13).”
Background
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9 of the 138 references couldn’t be matched to a known paper.
Research works printed but not linked: 8
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“LINC00926 is linked with CD22, which is a known B cell associated receptor that regulates B cell signaling, proliferation and survival [58].”
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“Both BTK and CD22 are essential for B cell development and activation (53).”
Two distinct chromatin modules regulate proinflammatory gene expression
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“8d,e), consistent with CD22 being a B cell-specific receptor 38 .”
Kovach, A. E., & Wood, B. L. (2023) · Seminars in Diagnostic Pathology · doi:10.1053/j.semdp.2023.10.001 · Cited by 9
Targeting Human CD22/Siglec-2 with Dimeric Sialosides as Novel Oligosaccharide Mimetics
Prescher, H., Schweizer, A., Frank, M., Kuhfeldt, E., Ring, J., & Nitschke, L. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00765 · Cited by 7
Estrogen Modulation of B Cell Immunity: Implications for HIV Control and Therapeutic Strategies
Kasibante, J., Brown, T. T., Lake, J. E., & Abdel‐Mohsen, M. (2025) · Comprehensive physiology · doi:10.1002/cph4.70050 · Cited by 7
“Estrogen also regulates B cell activation by modulating SHP-1 and CD22 expression, both of which negatively regulate B cell receptor signaling (Grimaldi et al. 2002; Getahun et al. 2016; Clark and Giltiay 2018).”
Traceless Protein-Selective Glycan Labeling and Chemical Modification.
Zheng, X., Li, Y., Cui, T., Yang, J., Meng, X., Wang, H., Chen, L., He, J., Chen, N., Meng, L., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c07889 · Cited by 5
Bhattacharyya, P., Christopherson, R. I., Skarratt, K. K., Chen, Z., Balle, T., & Fuller, S. J. (2023) · Cancers · doi:10.3390/cancers15112881 · Cited by 7
“CD22 binds to α 2,6-linked sialic acid ligands linked to galactose that are expressed on several cell types including T and B cells [109].”
BackgroundCharacterization of the immune regulatory property of CD22+ CD9+ B cells
Yang, G., Suo, L., Hu, S.-Q., Liu, H.-Z., Wang, X.-X., Xiao, X.-J., Liu, J., Zeng, X., Hong, J.-Y., Guan, L., et al. (2022) · Immunology · doi:10.1111/imm.13539 · Cited by 5
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Shivam, S., El-Matbouli, M., & Kumar, G. (2021) · Biology · doi:10.3390/biology10121244 · Cited by 5
Bacterial lectin BambL acts as a B cell superantigen
Frensch, M., Jäger, C., Müller, P. F., Tadić, A., Wilhelm, I., Wehrum, S., Diedrich, B., Fischer, B., Meléndez, A. V., Dengjel, J., et al. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04009-z · Cited by 5
Siglecs in immunotherapy: current clinical landscape and prospects
Purohit, A., Joshi, I., Bhojnagarwala, P. S., Boyer, J., Kim, J. J., Weiner, D. B., & Bordoloi, D. (2025) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2025.11.004 · Cited by 4
A gasdermin-based life–death evolution system for reprogramming protease specificity
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“CD22 is a B cell-specific membrane protein and a druggable target for treating lymphoma and rheumatoid arthritis 30–32 .”
Positron Emission Tomography Imaging of the Adaptive Immune System in Cardiovascular Diseases
Otaegui, J. R., Sultan, D. H., Heo, G. S., & Liu, Y. (2025) · Chemical & Biomedical Imaging · doi:10.1021/cbmi.4c00117 · Cited by 4
“63 This surface biomarker, together with CD19 and CD20 proteins are well recognized biomarkers for B cells, making them emerging targets for diagnosis and therapy in cardiovascular diseases.”
Immune Cell Networks Uncover Candidate Biomarkers of Melanoma Immunotherapy Response
Vo, D. H. T., McGleave, G., & Overton, I. M. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12060958 · Cited by 3
Sartor, C., Arpinati, M., Chirumbolo, G., Dozza, L., Cristiano, G., Nanni, J., Marconi, G., Robustelli, V., Vigliotta, I., Parisi, S., et al. (2022) · Hematological Oncology · doi:10.1002/hon.3029 · Cited by 4
Abdu-Allah, H. H. M., Wu, S., Lin, C., & Tseng, Y. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112707 · Cited by 5
Longitudinal protein profiling of blood during childhood into early adulthood
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Zhu, Y. F., Gao, L., Han, Y., Liu, F., Xie, X., Dai, X., Wang, Y., Ym, G., Luo, C., Chen, Y., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1750557 · Cited by 2
“CD22, an inhibitory receptor that dampens BCR signaling, has been explored as a therapeutic target (188).”
Parveen, A., Bhat, S. A., Elnaggar, M. M., & Meade, K. G. (2024) · PLoS ONE · doi:10.1371/journal.pone.0311854 · Cited by 3
“1 + also highlights the potential involvement of these γδ T cell subsets in B-cell-mediated immunity [60, 61].”
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“Like other immune check point receptors, elevated DCIR after stimulation can be a feedback mechanism to prevent excessive inflammation in activated immune cells (14).”
BackgroundMohty, R., Alotaibi, S., Gadd, M. E., Luo, Y., Parrondo, R. D., Qin, H., & Kharfan‐Dabaja, M. A. (2023) · Clinical Hematology International · doi:10.46989/001c.88382 · Cited by 3
Klymus, K. E., Hrabik, R. A., Thompson, N. L., & Cornman, R. S. (2022) · PeerJ · doi:10.7717/peerj.13954 · Cited by 4
Immunological and pathological roles of Siglecs: a molecular review
Lakshmi, K., & Sundararajan, V. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1826359 · Cited by 1
Carpén, N., Helve, O., Ericsson, S., Kervinen, I., Stewart-Linnonmaa, M., Heinonen, S., Andersson, S., & Helle, E. (2025) · Acta paediatrica · doi:10.1111/apa.70343 · Cited by 2
Flynn, J., Baird, A., Breen, E. P., Carty, M., McNevin, C. S., McDermott, L., Kenny, E. M., Coakley, J. D., Ryan, T., Doherty, D. G., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1667186 · Cited by 2
“The impairment mechanism observed in B cells during sepsis might be further explained by the loss of important activation markers and proliferation genes such as CD22 , CD27 and CD74 (87, 88).”
Duxfield, A., Garnham, R., Hutton, E., Dowle, A., Wills, J., Luzzi, S., Nelson, R., Lishman-Walker, E., Magee, R., Buskin, A., et al. (2025) · bioRxiv · doi:10.1101/2025.10.15.682547 · Cited by 2
“CD22 has often been described as a B-cell restricted marker 59–61 .”
Li, L.-Z., Wu, J., Cao, G.-X., Yao, J.-K., Miao, Y.-P., Zhuang, Y., Xiang, Y., Zhong, X., Liu, Y., Chen, F., et al. (2025) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1587166 · Cited by 2
Xiong, Z.-Y., Shen, Y., Zhang, S., & Zhu, H. (2024) · Hematology · doi:10.1080/16078454.2024.2335856 · Cited by 3
“CD22 belongs to the Siglec protein family and is primarily expressed in the bone marrow and spleen during the early stages of B-cell development, with minimal expression outside the haematopoietic system [118].”
Wu, P.-S., Liu, H.-Y., Wong, T.-H., Lin, J.-T., Hu, F.-R., & Lin, M.-H. (2023) · Journal of Proteome Research · doi:10.1021/acs.jproteome.3c00383 · Cited by 2
Papoutsopoulou, S., Tang, J. M., Elramli, A., Williams, J. M., Gupta, N., Ikuomola, F. I., Sheibani-Tezerji, R., Alam, M., Hernández-Fernaud, J. R., Caamaño, J., et al. (2022) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00037.2022 · Cited by 2
“by the enzyme a-2,6 sialyltransferase 1 (ST6Gal1) (46, 49).”
BackgroundYasuike, M., Kumon, K., Tanaka, Y., Saitoh, K., & Sugaya, T. (2021) · Current Issues in Molecular Biology · doi:10.3390/cimb43030145 · Cited by 2
“In contrast, ♀412-dammed families highly expressed immune-related genes, including GTPase IMAP family members [28], perforin [29], glucose-dependent insulinotropic receptor [30], Toll-like receptor 13 [31], and B cell receptor CD22 [32] (Table S1).”
BackgroundMulti-antigen chimeric antigen receptor-T cell therapy for relapsed/refractory B cell lymphomas
Pandey, T., Samat, D., Dahiya, S., & Patel, S. A. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1900443 · Cited by 1
“There are two antigen-drug conjugates (ADCs), inotuzumab ozogamicin and moxetumomab pasudotox that are CD22-directed and have received FDA approval for B-ALL and hairy cell leukemia, respectively (32 – 34).”
Microglial ITAM & ITIM Signaling in Neurodegenerative Disease and Brain Aging
Mangalmurti, A., Bonheur, A., & Lukens, J. R. (2026) · Journal of Molecular Biology · doi:10.1016/j.jmb.2026.169910 · Cited by 1
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“Under hypoxia, hepatic macrophages secrete cytokines such as TNF-α and IL-10, and IL-10 down-regulates cd22 at the mRNA level [72].”
Smyth, C. H., Mollé, L. M., McLeod, V., Chen, M. Z., & Johnston, A. P. R. (2026) · Small Science · doi:10.1002/smsc.70313 · Cited by 1
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“…adaptive immune and antigen-presentation-related transcripts within the bead-enriched fraction than with a purely T-cell-intrinsic program (Castro and Flaj-nik, 2014; Chen and Jensen, 2008; Clark and Giltiay, 2018; Li et al., 2017; Pavlasova and Mraz, 2020; Su et al., 2017; Tkachenko et al., 2023).”
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“It plays a crucial role in modulating immune responses and is targeted by therapies such as Inotuzumab ozogamicin (Clark and Giltiay, 2018).”
Barbosa, B. M., Fabro, A. T., Gomes, R. D. S., & Rainho, C. A. (2025) · Epigenomes · doi:10.3390/epigenomes9030034 · Cited by 1
“Pathways essential for antigen processing and presentation alongside CD22-mediated B-cell receptor (BCR) regulation are pivotal for adaptive immunity mediated by lymphoid lineage cells [47,48].”
Dias, A., & Litzow, M. R. (2025) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2025.09.008 · Cited by 1
Anis, H. M., Rakha, N. M., Kassem, D., & Kamal, A. M. (2025) · BMC Cancer · doi:10.1186/s12885-025-14292-9 · Cited by 1
“It is a differentiation antigen expressed on the surface of B-lineage cells from the early progenitor stage of development [54] until before terminal differentiation into plasma cells, which are mostly CD22 − [55].”
Genetically Engineered Hypoimmune Human Muscle Progenitor Cells Can Reduce Immune Rejection
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Gayen, S., Mukherjee, S., Dasgupta, S., & Roy, S. (2024) · APOPTOSIS · doi:10.1007/s10495-024-02022-8 · Cited by 1
“Interestingly, CD22 is the major downstream regulator of B lymphocyte activation by interaction with CD22L which orchestrates to controlling self-tolerance [22].”
Inhibition of B cell receptor signaling induced by the human adenovirus species D E3/49K protein
Hildenbrand, A., Cramer, P., Bertolotti, M., Kaiser, N. S., Kläsener, K., Nickel, C., Reth, M. G., Heim, A., Hengel, H., Burgert, H.-G., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1432226 · Cited by 1
“Phosphorylation of the ITIMs by Lyn facilitates the recruitment of the SHP-1 and SHIP1 phosphatases (71).”
Ansari, M. A., Nguyen, T.-T., Kocurek, K., Kim, W. T. H., Kim, T., & Mulenga, A. (2024) · Pathogens · doi:10.3390/pathogens13070560 · Cited by 1
“…SERPING1, which cause hereditary angioedema [48], CD22 (receptor predominantly restricted to B cells)- mediated BCR (B-cell receptors) regulation, and the recycling of bile acids and salts [49]. group C proteins included anchoring fibril formation, the degradation of ECM, and laminin interactions.”
BackgroundYou, J., Maksimovic, K., Metri, M. N., Schoeppe, A., Chen, K., Lee, J., Santos, J. R., Youssef, M., Salter, M. W., & Park, J. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e37926 · Cited by 3
“Furthermore, there exist several other receptors that could potentially leverage SYK signaling and modify neurodegeneration, including CD22, CD33, CR3, CLEC16A, CLECL1, CLEC2D, FCRL2, and FCRL3 [18,38 – 43].”
Carruthers, N., Guo, C., Gill, R., Stemmer, P., & Rosenspire, A. (2023) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2023.116607 · Cited by 1
Satitsuksanoa, P., van de Veen, W., Tan, G., Wirz, O., Jansen, K., Sokolowska, M., Mirer, D., Głobińska, A., Boonpiyathad, T., Schneider, S. R., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-1134709/v1 · Cited by 1
The pink salmon genome: uncovering the genomic consequences of a strict two-year life-cycle
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Xiong, Z.-H., Cao, X.-S., Guan, H.-L., & Zheng, H.-L. (2020) · World Journal of Clinical Cases · doi:10.12998/wjcc.v8.i24.6396 · Cited by 1
Каххаровна, С. Н., Khachatryan, L., Amonov, A., Normatov, M., Khalmatova, N., Rashidov, A., & Babamuratov, B. E. (2026) · Neurological Sciences · doi:10.1007/s10072-026-09421-6
“Given CD22’s inhibitory role in regulating B-cell activation, targeting CD22 with CAR cells could offer unique advantages by not only depleting B-cells but also modulating their signaling pathways, potentially dampening hyperactivation [ 48].”
Möes, B., Mostafa, A., Malempré, R., Renson, O., Piel, G., Matagne, A., Schurmans, S., & Mayer, A. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1934292
“Negative control of BCR signaling is mediated by surface molecules such as Fc g RIIB/CD32B, CD72, CD5, CD45 and CD22 (7 – 11) which act through cytoplasmic proteins, and by phosphatases, including the protein tyrosine phosphatases PTPN22 and SHP1/2 and the lipid phosphatases SHIP1 and PTEN (12 – 16).”
Karachentsev, Y. I., Gopkalova, I., Дубовик, В., Dubovyk, V. M., Ashurov, E. M., Герасименко, Л. В., & Makedonska, V. O. (2026) · INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine) · doi:10.22141/2224-0721.22.5.2026.1735 · Cited by 1
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“CD22, a marker of marginal zone precursors 30 , is expressed in ARID3a + naïve B cells (Fig.”
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Metadata
- Authors
- Clark, E. A., & Giltiay, N. V.
- Affiliations
- University of Washington (US)
- Corresponding author
- Clark, Edward A.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2018-09-28
- Volume
- 9
- Pages
- 2235-2235
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC6173129
- OpenAlex
- W2893525181
- Cited by
- 197
- References
- 138
- Citations by year
- 2026: 24 · 2025: 29 · 2024: 28 · 2023: 31 · 2022: 35 · 2021: 23 · 2020: 20 · 2019: 7
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- CD22, B cells, B cell signaling, innate immunity, adaptive immunity, autoimmunity, systemic lupus erythematosus, immunotherapeutics, Siglec-G
- MeSH terms
- Alleles, Animals, Autoantibodies, B-Lymphocytes, Humans, Receptors, Antigen, B-Cell, Autoimmunity, Polymorphism, Single Nucleotide, Toll-Like Receptor 7, Mice, Sialic Acid Binding Ig-like Lectin 2, Molecular Targeted Therapy
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