Basophils

Imagine them as the enigmatic sorcerers of your bloodstream, casting a crucial spell in your body’s healing process. Despite their status as the rarest and most short-lived white blood cells, making up less than 1% of your total circulating white blood cells, they are pivotal in responding to injuries and parasitic infections. They possess the power to conjure histamines in response to antigens, potentially leading to hypersensitive reactions such as fevers or asthma attacks. They are the summoners of other significant immune cells, like neutrophils and eosinophils, calling them to action when needed. Their scarcity has long veiled their clinical importance, but an increased count could signal the presence of an infection or even serious medical conditions like leukaemia or autoimmune diseases. In the bustling metropolis of your bloodstream, amidst the rushing crowds of cells, they stand as a silent superhero squad known as the basophils!

What’s in a name?

Basophils belong to the granulocyte category of white blood cells. They are characterized by their morphological resemblance to mast cells and their distinctive S-shaped bilobed nucleus. Within their cytoplasm, basophils contain large round granules filled with heparin and histamine. These granules can be stained by basic dyes such as methylene blue, resulting in the name “basophils.” This unique staining property is imparted by the glycosaminoglycans that bond with histamines inside the granules and give them a characteristic dark appearance when viewed under the microscope (1).

Comprehending their functions:

Basophils were first characterized by Paul Ehrlich during his investigations on the staining characteristics of blood cells to differentiate neutrophilic, eosinophilic, and basophilic cells. Since their discovery in 1879, basophils were initially overlooked for almost a century due to their rarity and were perceived as superfluous cells that merely aided in triggering hypersensitive reactions in conjunction with mast cells and adaptive immune cells. The development of the Basophil Activation Test (BAT) propelled basophils back into the spotlight, indicating their significant role in the polarization of helper T cells (Th2) and IgE synthesis (2). Today, their most prominent role is as effectors in allergic reactions. This has led to their application in the development of new diagnostic procedures and treatment methods, as well as in the characterization of naturally occurring and synthetic allergens and hypoallergens. A breakthrough in understanding basophil function occurred recently with the advent of transgenic mice that are over 90% basophil-deficient and basophil-depleting antibodies (3). These models greatly accelerated basophil research and illuminated the previously unknown functions of basophils in innate and adaptive immunity, distinct from those of mast cells. These remarkable recent discoveries also revealed the significant impact of basophils on a wide range of immunologic illnesses despite their small quantity in peripheral blood and inflammatory tissues. While their physiological function is not fully understood, their involvement in hypersensitive events, particularly adverse medication reactions, continues to intrigue and inspire researchers (4,5).

The origin story

Basophils are produced from granulocyte-monocyte progenitors through a process called hematopoiesis. Once fully differentiated, they exit the bone marrow and move into the bloodstream, eventually migrating into the body’s tissues, especially during certain types of inflammation (6). Several factors influence the development of basophils and mast cells. The main growth factor for basophil formation is interleukin-3, but other growth factors, such as FMS-like tyrosine kinase 3 ligands (Flt3L), also contribute to their growth and function (7). Certain markers are constitutively expressed in both humans and mice, which makes them useful for identifying basophils. For example, FcεRIhi, IgEhi, CD49bhi, etc., are reliable surface markers for phenotypic identification of mature basophils. These cells have a typical lifespan of about 60 hours and are the rarest type of granulocytes, making up only 0.5–1% of the white blood cells in circulation (4).

Activation and the process of degranulation

Basophil counts (number of basophils per microliter of blood) sharply rise in response to inflammatory signals generated during the early phases of infection. This is happening along basophils migration to the infection site. Observational studies suggest IL-3 may facilitate basophil recruitment (8). In vitro mouse studies have demonstrated that IL-3 primes basophils to secrete more IL-4, a function that basophils may accomplish as soon as they are activated. Along with IL-3, thymic stromal lymphopoietin has been identified as a critical regulator of basophil growth and activation, and it may grant basophils a variety of activities (9). However, as noted by Min et al. (10), several factors together influence basophil growth, activation, and function. The entire process includes basophils being classically activated when the antigen attaches to and crosses-links the Fc region of the IgE and IgE receptor FcεRI on the basophil surface (11). After that, the signaling pathway mediated by Syk is activated, which causes the secretion of cytoplasmic granules through a process known as degranulation and release of the allergic mediators (histamine) to the external milieu (12). Histamines act as vasodilators leading to increased blood flow to tissues. This results in symptoms such as redness, swelling, and itching, all being inflammation-related responses. Subsequently, the body releases newly produced pro-inflammatory cytokines, chemokines, and lipid mediators of inflammation, such as leukotriene C4, contributing to the ongoing inflammatory response.

The allergy avengers

Basophils are renowned for their roles in various allergic reactions affecting the skin, GI tract, respiratory system, and autoimmune responses. Certain autoimmune diseases, such as inflammatory bowel diseases and systemic lupus erythematosus, are associated with basophil activation (13). In response to an allergen, basophils release inflammatory mediators vasoamines and eicosanoids (such as histamines and LTC4), which results in hay fever-like symptoms. This can occasionally be severe enough to cause anaphylactic responses that need to be treated right away by medical professionals. It is believed that one of the mechanisms causing inflammation mediated by Th2 cells in these circumstances is the release of IL-4 by invading basophils. Anti-IgE therapy has been used to treat certain human allergy illnesses, and reducing basophil has been shown to reduce allergic inflammation in mice models (2).

Vital roles in immunity

Basophils have been shown to combat bacterial, viral, and venomous infections, as well as play a crucial role in immune responses against parasitic attacks, including helminthic worms. Studies have demonstrated that basophils from individuals infected with Toxocara, Ascaris, Strongyloides, Schistosoma, and others produce histamine in reaction to parasite antigens and release IL-4 (14). Additionally, basophils connect the innate and adaptive arms of immunity by secreting IL-4 and IL-13, which stimulate the development of T-cells and macrophages and assist in the removal of parasites. Furthermore, IL-4 released by basophils has been linked to macrophage differentiation, B-cell activation, and eosinophil migration (15–17).

Basophils as therapeutic targets

A number of underlying disorders can be indicated by anomalies in the number of circulating basophils, whether their number is increased or reduced. An increase in basophil count, known as basophilia, is commonly seen in myeloid neoplasms like chronic myeloid leukemia (CML). Basophilia can also occur in non-cancerous conditions such as atopy, iron deficiency anaemia, and diabetes. Thus, basophils can be a useful marker for diagnosing and predicting the course of CML and other myeloproliferative neoplasms. In CML, idiopathic myelofibrosis, and myelodysplastic syndrome, elevated levels of tryptase in neoplastic basophils can have prognostic significance (18,19). Basopenia is a rare condition characterized by a low number of basophils in the blood. It can be caused by corticosteroid administration, chronic urticaria, and systemic lupus erythematosus (SLE), in which and basophil count may serve as a marker for disease severity and predictor for response to treatment (20).

Basophils play a role in various diseases, such as allergies, autoimmune conditions, and cancer, making them a potential target for treatment. Therapies targeting basophils include medications that modulate specific pathways involved in allergic reactions, such as the use of monoclonal antibodies (e.g., omalizumab, bevacizumab, and dupilumab). These treatments have shown effectiveness in reducing basophil activation in conditions like food allergy, asthma, and allergic rhinitis. Additionally, therapies targeting specific pathways associated with asthma and atopic dermatitis have shown promise in clinical improvement. Overall, therapies targeting basophils have the potential to impact several allergic, autoimmune, and malignant diseases (21,22).

Recognizing and appreciating the labs working in this space

• Dr. Kensuke Miyake, Tokyo Medical and Dental University (TMDU), Japan. https://www.cbms.k.u-tokyo.ac.jp/en/labs/kmiyake/
• Dr. Olaf Rötzschke, Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Singapore. https://www.a-star.edu.sg/sign/people/principal-investigators/olaf-r%C3%B6tzschke
• Dr. Jagadeesh Bayry, IIT Palakkad, India. https://iitpkd.ac.in/people/bayry
• Dr. Martin Himly, Paris Lodron University of Salzburg, Austria. https://www.plus.ac.at/biosciences/the-department/research-groups/ag-himly/martin-himly/?lang=en
• Dr. John Thomas Schroeder, Johns Hopkins School of Medicine, USA. https://www.hopkinsmedicine.org/research/labs/j/john-schroeder-lab
• Galli Lab, Departments of Pathology, Stanford University School of Medicine, California, USA. https://med.stanford.edu/gallilab/about.html
• Peter Valent, Department of Medicine I, Medical University of Vienna, Vienna, Austria. https://innere-med-1.meduniwien.ac.at/en/our-departments/haematologie-und-haemostaseologie-en/staff-members/univ-prof-dr-med-univ-peter-valent/
• European Mast Cell and Basophil Research Network, https://embrn.eu/
• Santos Group, King’s College London, UK. https://www.kcl.ac.uk/research/santos-group , Twitter; @alex_fsantos
• The Falcone Lab, University of Nottingham, UK. https://www.nottingham.ac.uk/research/groups/allergy-and-infectiousdiseases/index.aspx

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References

1. Chirumbolo S. State-of-the-art review about basophil research in immunology and allergy: is the time right to treat these cells with the respect they deserve? Blood Transfus. 2012 Apr;10(2):148–64.
2. Shah H, Eisenbarth S, Tormey CA, Siddon AJ. Behind the scenes with basophils: an emerging therapeutic target. Immunotherapy Advances. 2021 Jan 1;1(1):ltab008.
3. Matsuoka K, Shitara H, Taya C, Kohno K, Kikkawa Y, Yonekawa H. Novel Basophil- or Eosinophil-Depleted Mouse Models for Functional Analyses of Allergic Inflammation. PLoS One. 2013 Apr 8;8(4):e60958
4. Steiner M, Huber S, Harrer A, Himly M. The Evolution of Human Basophil Biology from Neglect towards Understanding of Their Immune Functions. Biomed Res Int. 2016;2016:8232830.
5. Marone G, Borriello F, Varricchi G, Genovese A, Granata F. Basophils: historical reflections and perspectives. Chem Immunol Allergy. 2014;100:172–92.
6. Y A, H I, Mf G, S M, H S, H O, et al. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proceedings of the National Academy of Sciences of the United States of America. 2005 Dec;102(50).
7. Varricchi G, Poto R, Marone G, Schroeder JT. IL-3 in the development and function of basophils. Semin Immunol. 2021 Apr;54:101510.
8. Shen T, Kim S, Do J su, Wang L, Lantz C, Urban JF, et al. T cell-derived IL-3 plays key role in parasite infection-induced basophil production but is dispensable for in vivo basophil survival. Int Immunol. 2008 Sep;20(9):1201–9.
9. Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature. 2011 Aug 14;477(7363):229–33.
10. Min B, Brown MA, LeGros G. Understanding the roles of basophils: breaking dawn. Immunology. 2012 Mar;135(3):192–7.
11. Prussin C, Metcalfe DD. 5. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2006 Feb;117(2 Suppl Mini-Primer):S450–456.
12. Joulia R, Mailhol C, Valitutti S, Didier A, Espinosa E. Direct monitoring of basophil degranulation by using avidin-based probes. Journal of Allergy and Clinical Immunology. 2017 Oct 1;140(4):1159–1162.e6.
13. Karasuyama H, Miyake K, Yoshikawa S, Yamanishi Y. Multifaceted roles of basophils in health and disease. J Allergy Clin Immunol. 2018 Aug;142(2):370–80.
14. Mitre E, Nutman TB. Basophils, basophilia and helminth infections. Chem Immunol Allergy. 2006;90:141–56.
15. Chirumbolo S, Bjørklund G, Sboarina A, Vella A. The role of basophils as innate immune regulatory cells in allergy and immunotherapy. Hum Vaccin Immunother. 2018 Apr 3;14(4):815–31.
16. Cohen M, Giladi A, Gorki AD, Solodkin DG, Zada M, Hladik A, et al. Lung Single-Cell Signaling Interaction Map Reveals Basophil Role in Macrophage Imprinting. Cell. 2018 Nov 1;175(4):1031–1044.e18.
17. Pellefigues C, Dema B, Lamri Y, Saidoune F, Chavarot N, Lohéac C, et al. Prostaglandin D2 amplifies lupus disease through basophil accumulation in lymphoid organs. Nat Commun. 2018 Feb 20;9(1):725.
18. Hochhaus A, Saussele S, Rosti G, Mahon FX, Janssen JJWM, Hjorth-Hansen H, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of Oncology. 2017 Jul 1;28:iv41–51.
19. Samorapoompichit P, Kiener HP, Schernthaner GH, Jordan JH, Agis H, Wimazal F, et al. Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms. Blood. 2001 Oct 15;98(8):2580–3.
20. Kishimoto I, Kambe N, Ly NTM, Nguyen CTH, Okamoto H. Basophil count is a sensitive marker for clinical progression in a chronic spontaneous urticaria patient treated with omalizumab. Allergol Int. 2019 Jul;68(3):388–90.
21. Zhang J, Yin H, Chen Q, Zhao G, Lou W, Wu W, et al. Basophils as a potential therapeutic target in cancer. J Zhejiang Univ Sci B. 2021 Dec 1;22(12):971–84.
22. Miyake K, Ito J, Karasuyama H. Role of Basophils in a Broad Spectrum of Disorders. Front Immunol. 2022 May.

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About the author:

Dr. Eshita Paul

Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Paul did her Ph.D. in Biochemical Engineering (Constructor University, Germany) studying the outer membrane channels and efflux pumps of Gram-negative bacteria in the context of antibiotic resistance. Before moving into science communication, she worked as a Research Associate on rare pediatric genetic disorders at the Centre for DNA Fingerprinting and Diagnostics, India. Dr. Paul is passionate about scientific storytelling and an ardent admirer of scientific illustrations. She enjoys listening to podcasts and decorating the home in free time.

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NELLI AGHEKYAN

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Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.

About the animator:

DR. EMANUELE PETRETTO

Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.

Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.

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About the series:

The League of Extraordinary Cell types

The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.

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