# CD52

## Overview
CD52 is a gene that encodes the CD52 molecule, a glycosylphosphatidylinositol (GPI)-anchored glycoprotein predominantly expressed on the surface of mature lymphocytes and other hematopoietic cells. The CD52 molecule plays a critical role in immune regulation, particularly in modulating immune responses and maintaining immune homeostasis. It is characterized by a notably small peptide backbone and significant post-translational modifications, which are crucial for its function and interaction with cellular membranes. The protein's interactions, particularly with the Siglec-10 receptor on T cells, are essential for its immunosuppressive effects, which include inhibiting T-cell activation and inducing regulatory T cells. Due to its pivotal role in immune modulation, CD52 is also a target in various clinical contexts, including autoimmune diseases and hematologic malignancies, where it serves both as a biomarker and a therapeutic target (Zhao2017The; Toh2013Immune; Albitar2004Free).

## Structure
The CD52 molecule is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein characterized by a notably small peptide backbone, which consists of only 12 amino acids in its mature form. The primary structure of CD52 includes a short peptide sequence (GQNDTSQTSSPS), with a significant post-translational modification at Asn-3, where an N-linked glycosylation site is located (Schröter1999Male-specific; Xia1993Structure). This glycosylation is crucial for the molecule's function and interaction with cellular membranes.

The secondary, tertiary, and quaternary structures of CD52 are not detailed in the available literature, indicating a lack of specific information about folding patterns or complex structural formations. This is likely due to the small size of the peptide backbone, which does not allow for extensive folding or distinct domain formations typically seen in larger proteins.

The GPI anchor attached at Ser-12 is a critical feature for anchoring the protein to the cell membrane, contributing significantly to the molecular mass and functional positioning of the protein on the cell surface (Xia1993Structure). The GPI anchor also exhibits variations such as inositol acylation, which affects the molecule's resistance to enzymatic cleavage and may influence its interaction with the cellular environment (Kirchhoff2000New).

Overall, the structure of CD52 is defined primarily by its GPI anchorage and N-linked glycosylation, with a lack of complex secondary to quaternary structures due to its minimal peptide length.

## Function
CD52 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein expressed predominantly on the surface of mature lymphocytes and plays a crucial role in immune regulation. The protein is involved in modulating immune responses through its interactions with other molecules and receptors, particularly in the suppression of T-cell activation. Soluble CD52, released from cells upon activation, binds to the Siglec-10 receptor on T cells, inhibiting their function by impairing the phosphorylation of key signaling proteins such as Lck and Zap-70, which are associated with the T-cell receptor (Zhao2017The; Toh2013Immune). This interaction helps maintain immune homeostasis by preventing overactivation of the immune system, which could lead to autoimmune responses.

Additionally, CD52 plays a role in the induction of regulatory T cells (Treg cells), which are crucial for maintaining immune tolerance. The costimulatory signal provided by CD52 is essential for the induction of these Treg cells, which can suppress the proliferation of other T cells, including both CD4+ and CD8+ T cells, under various stimulation conditions (Watanabe2006CD52). This regulatory activity is enhanced by secondary CD52-costimulation and is crucial in controlling immune responses, as demonstrated in models like graft-versus-host disease (GvHD) (Watanabe2006CD52).

Furthermore, CD52 has broader immune suppressive effects, as it inhibits Toll-like receptor (TLR) and tumor necrosis factor receptor (TNFR) signaling pathways in innate immune cells, thereby limiting the activation of NF-κB and reducing the production of inflammatory cytokines by macrophages, monocytes, and dendritic cells (Rashidi2017CD52). At higher concentrations, soluble CD52 can also induce apoptotic cell death by depleting MCL-1, a pro-survival protein, and activating the intrinsic apoptotic proteins BAX and BAK, further helping in suppressing inflammation (Rashidi2017CD52).

## Clinical Significance
CD52 is implicated in several autoimmune diseases and hematologic malignancies, where alterations in its expression or function contribute to disease pathogenesis and progression. In systemic lupus erythematosus (SLE), differential expression of CD52 on T cells, particularly CD4+ CD52 low cells, is associated with the disease's development, suggesting a role in the autoimmune pathology (Umeda2018CD4+). Similarly, elevated levels of CD52 on B cells in SLE patients correlate with disease activity, indicating its potential as a biomarker and therapeutic target (Bhamidipati2021CD52).

In hematologic cancers, CD52 expression serves as a critical marker and therapeutic target. Chronic lymphocytic leukemia (CLL) patients exhibit high levels of soluble CD52, which correlates with advanced disease stages and poorer prognosis. This has therapeutic implications, as CD52-targeting antibodies like alemtuzumab are used in CLL treatment (Albitar2004Free). Additionally, in systemic mastocytosis, particularly its advanced forms, CD52 is highly expressed on neoplastic mast cells, making it a viable target for alemtuzumab-induced cytotoxicity (Hoermann2014CD52).

Furthermore, CD52's role extends to metabolic disorders. In obesity and type 2 diabetes mellitus (T2DM), CD52 is upregulated in adipocytes, linking its expression to insulin resistance and suggesting its potential as a therapeutic target (Mao2021High). This broad spectrum of diseases associated with CD52 underscores its significance in clinical research and therapy.

## Interactions
CD52, a glycoprotein expressed on various hematopoietic cells and in the male reproductive tract, engages in several critical interactions that modulate immune function and inflammation. One of the primary interactions of CD52 is with the Siglec-10 receptor on T cells, mediated by its sialic acid-binding domain. This interaction is essential for the suppression of T cell function, as it leads to the recruitment of SHP1 phosphatase, thereby affecting the T cell receptor (TCR) signaling pathway (Bandala-Sanchez2018CD52).

Additionally, CD52 interacts with HMGB1, a proinflammatory protein. This interaction, which involves the binding of the sialylated CD52 glycan to the proinflammatory Box B domain of HMGB1, is crucial for the anti-inflammatory effects of CD52. The engagement of CD52 with HMGB1 facilitates the subsequent binding to Siglec-10, enhancing the immunosuppressive function of CD52 (Bandala-Sanchez2018CD52).

Moreover, CD52 forms a trimolecular complex with HMGB1 and Siglec-10, which interacts with the TCR complex, further implicating CD52 in the modulation of T cell activity. This complex formation and interaction with TCR are confirmed through immunoprecipitation and immunoblotting experiments, demonstrating the physical association of these molecules within activated T cells (Bandala-Sanchez2018CD52).


## References


[1. (Zhao2017The) Yang Zhao, Huiting Su, Xiaofei Shen, Junfeng Du, Xiaodong Zhang, and Yong Zhao. The immunological function of cd52 and its targeting in organ transplantation. Inflammation Research, 66(7):571–578, March 2017. URL: http://dx.doi.org/10.1007/s00011-017-1032-8, doi:10.1007/s00011-017-1032-8. (108 citations) 10.1007/s00011-017-1032-8](https://doi.org/10.1007/s00011-017-1032-8)

[2. (Kirchhoff2000New) Christiane Kirchhoff and Sabine Schröter. New insights into the origin, structure and role of cd52: a major component of the mammalian sperm glycocalyx. Cells Tissues Organs, 168(1–2):93–104, November 2000. URL: http://dx.doi.org/10.1159/000016810, doi:10.1159/000016810. (84 citations) 10.1159/000016810](https://doi.org/10.1159/000016810)

[3. (Watanabe2006CD52) Tomoko Watanabe, Jun-ichi Masuyama, Yoshiaki Sohma, Hiroko Inazawa, Kaori Horie, Kumiko Kojima, Yasunori Uemura, Yumi Aoki, Shuji Kaga, Seiji Minota, Toshiyuki Tanaka, Yasunori Yamaguchi, Tetsuto Kobayashi, and Isao Serizawa. Cd52 is a novel costimulatory molecule for induction of cd4+ regulatory t cells. Clinical Immunology, 120(3):247–259, September 2006. URL: http://dx.doi.org/10.1016/j.clim.2006.05.006, doi:10.1016/j.clim.2006.05.006. (176 citations) 10.1016/j.clim.2006.05.006](https://doi.org/10.1016/j.clim.2006.05.006)

[4. (Albitar2004Free) Maher Albitar, Kim‐Anh Do, Marcella M. Johnson, Francis J. Giles, Iman Jilani, Susan O’Brien, Jorge Cortes, Deborah Thomas, Laura Z. Rassenti, Thomas J. Kipps, Hagop M. Kantarjian, and Michael Keating. Free circulating soluble cd52 as a tumor marker in chronic lymphocytic leukemia and its implication in therapy with anti‐cd52 antibodies. Cancer, 101(5):999–1008, August 2004. URL: http://dx.doi.org/10.1002/cncr.20477, doi:10.1002/cncr.20477. (93 citations) 10.1002/cncr.20477](https://doi.org/10.1002/cncr.20477)

[5. (Umeda2018CD4+) Masataka Umeda, Tomohiro Koga, Kunihiro Ichinose, Takashi Igawa, Tomohito Sato, Ayuko Takatani, Toshimasa Shimizu, Shoichi Fukui, Ayako Nishino, Yoshiro Horai, Yasuko Hirai, Shin-ya Kawashiri, Naoki Iwamoto, Toshiyuki Aramaki, Mami Tamai, Hideki Nakamura, Kazuo Yamamoto, Norio Abiru, Tomoki Origuchi, Yukitaka Ueki, and Atsushi Kawakami. Cd4+ cd52lo t-cell expression contributes to the development of systemic lupus erythematosus. Clinical Immunology, 187:50–57, February 2018. URL: http://dx.doi.org/10.1016/j.clim.2017.10.004, doi:10.1016/j.clim.2017.10.004. (13 citations) 10.1016/j.clim.2017.10.004](https://doi.org/10.1016/j.clim.2017.10.004)

[6. (Toh2013Immune) Ban-Hock Toh, Tin Kyaw, Peter Tipping, and Alex Bobik. Immune regulation by cd52-expressing cd4 t cells. Cellular & Molecular Immunology, 10(5):379–382, August 2013. URL: http://dx.doi.org/10.1038/cmi.2013.35, doi:10.1038/cmi.2013.35. (31 citations) 10.1038/cmi.2013.35](https://doi.org/10.1038/cmi.2013.35)

[7. (Mao2021High) Rui Mao, Fan Yang, Yu Zhang, Hongtao Liu, Pengsen Guo, Yanjun Liu, and Tongtong Zhang. High expression of cd52 in adipocytes: a potential therapeutic target for obesity with type 2 diabetes. Aging, 13(8):11043–11060, March 2021. URL: http://dx.doi.org/10.18632/aging.202714, doi:10.18632/aging.202714. (5 citations) 10.18632/aging.202714](https://doi.org/10.18632/aging.202714)

[8. (Bandala-Sanchez2018CD52) Esther Bandala-Sanchez, Naiara G. Bediaga, Ethan D. Goddard-Borger, Katrina Ngui, Gaetano Naselli, Natalie L. Stone, Alana M. Neale, Lesley A. Pearce, Ahmad Wardak, Peter Czabotar, Thomas Haselhorst, Andrea Maggioni, Lauren A. Hartley-Tassell, Timothy E. Adams, and Leonard C. Harrison. Cd52 glycan binds the proinflammatory b box of hmgb1 to engage the siglec-10 receptor and suppress human t cell function. Proceedings of the National Academy of Sciences, 115(30):7783–7788, July 2018. URL: http://dx.doi.org/10.1073/pnas.1722056115, doi:10.1073/pnas.1722056115. (61 citations) 10.1073/pnas.1722056115](https://doi.org/10.1073/pnas.1722056115)

[9. (Hoermann2014CD52) Gregor Hoermann, Katharina Blatt, Georg Greiner, Eva Maria Putz, Angelika Berger, Harald Herrmann, Sabine Cerny‐Reiterer, Karoline V. Gleixner, Christoph Walz, Konrad Hoetzenecker, Leonhard Müllauer, Andreas Reiter, Karl Sotlar, Veronika Sexl, Peter Valent, and Matthias Mayerhofer. Cd52 is a molecular target in advanced systemic mastocytosis. The FASEB Journal, 28(8):3540–3551, April 2014. URL: http://dx.doi.org/10.1096/fj.14-250894, doi:10.1096/fj.14-250894. (34 citations) 10.1096/fj.14-250894](https://doi.org/10.1096/fj.14-250894)

[10. (Bhamidipati2021CD52) Kartik Bhamidipati, John L. Silberstein, Yashaar Chaichian, Matthew C. Baker, Tobias V. Lanz, Amin Zia, Yusuf S. Rasheed, Jennifer R. Cochran, and William H. Robinson. Cd52 is elevated on b cells of sle patients and regulates b cell function. Frontiers in Immunology, February 2021. URL: http://dx.doi.org/10.3389/fimmu.2020.626820, doi:10.3389/fimmu.2020.626820. (17 citations) 10.3389/fimmu.2020.626820](https://doi.org/10.3389/fimmu.2020.626820)

[11. (Rashidi2017CD52) Maryam Rashidi, Esther Bandala-Sanchez, Kate E Lawlor, Yuxia Zhang, Alana M Neale, Swarna L Vijayaraj, Robert O’Donoghue, John M Wentworth, Timothy E Adams, James E Vince, and Leonard C Harrison. Cd52 inhibits toll-like receptor activation of nf-κb and triggers apoptosis to suppress inflammation. Cell Death & Differentiation, 25(2):392–405, December 2017. URL: http://dx.doi.org/10.1038/cdd.2017.173, doi:10.1038/cdd.2017.173. (39 citations) 10.1038/cdd.2017.173](https://doi.org/10.1038/cdd.2017.173)

[12. (Schröter1999Male-specific) Sabine Schröter, Petra Derr, Harald S. Conradt, Manfred Nimtz, Geoffrey Hale, and Christiane Kirchhoff. Male-specific modification of human cd52. Journal of Biological Chemistry, 274(42):29862–29873, October 1999. URL: http://dx.doi.org/10.1074/jbc.274.42.29862, doi:10.1074/jbc.274.42.29862. (101 citations) 10.1074/jbc.274.42.29862](https://doi.org/10.1074/jbc.274.42.29862)

[13. (Xia1993Structure) M Q Xia, G Hale, M R Lifely, M A J Ferguson, D Campbell, L Packman, and H Waldmann. Structure of the campath-1 antigen, a glycosylphosphatidylinositol-anchored glycoprotein which is an exceptionally good target for complement lysis. Biochemical Journal, 293(3):633–640, August 1993. URL: http://dx.doi.org/10.1042/bj2930633, doi:10.1042/bj2930633. (154 citations) 10.1042/bj2930633](https://doi.org/10.1042/bj2930633)