Introduction and Classification

Natural Killer (NK) cells represent a category of cytotoxic lymphocytes primarily associated with the innate immune system while exhibiting functionalities that bridge innate and adaptive immunity. Classified as unconventional lymphocytes and members of the innate lymphoid cell (ILC) family, specifically Group 1 ILCs, NK cells constitute a principal effector population capable of mediating cytotoxicity before the full maturation of an adaptive immune response. Despite operating within the innate arm, NK cells demonstrate target selectivity rather than indiscriminate action. They serve as a crucial link, interfacing immediate non-specific defenses with delayed antigen-specific immunity.

Origin and Maturation

NK cells originate from hematopoietic precursors within the bone marrow, where initial maturation occurs. Further differentiation and maturation processes can also occur in peripheral tissues, notably secondary lymphoid organs.

Anatomical Distribution and Migration

NK cells exhibit broad distribution throughout the organism, residing within both lymphoid organs and non-lymphoid tissues. They are present in:

• Lymphoid Organs: Found within lymph nodes (though sparsely in the parenchyma) and the spleen particularly concentrated in the marginal zone. Also, present in peritoneal and pleural “milky spots”.
• Peripheral Tissues: NK cells maintain tissue residency under homeostatic conditions. They are identified within the skin, primarily localized to the dermis subcutaneous adipose tissue and superficial dermal layers. Specialized uterine NK (uNK) cells populate the decidua during pregnancy.
• Circulation: A significant population circulates within the peripheral blood where the CD56^dim^CD16^+ subset constitutes the vast majority (>90%) of human blood NK cells.
• Migration: NK cells can extravasate from the bloodstream into lymph nodes via high endothelial venules (HEVs), a process potentially enhanced during inflammatory conditions. The CD56^bright^CD16^- subset demonstrates preferential localization within lymph nodes and lymphoid organs.

Location	Specifics
Lymphoid organs	Spleen (marginal zone), lymph nodes (sparse), peritoneal/pleural milky spots
Peripheral tissues	Dermis, subcutaneous adipose tissue, superficial dermis
Special sites	Uterus (decidua – uterine NK cells during pregnancy)
Circulation	CD56^dim^CD16^+ subset (>90% of blood NK cells)
Migration	Via HEVs into lymph nodes, especially CD56^bright^CD16^- subset during inflammation

Phenotypic Markers and Subpopulations

NK cells can be identified and subcategorized based on their differential expression of surface markers, primarily CD56 (an isoform of the Neural Cell Adhesion Molecule N-CAM) and CD16 (FcγRIIIa, the low-affinity receptor for the Fc portion of IgG). Two major subpopulations can be found in human peripheral blood:

• CD56^bright^CD16^- Cells:
  • Characterized by high-level expression of CD56 and absent or minimal expression of CD16.
  • It is considered a less mature phenotype.
  • Predominantly reside in secondary lymphoid organs.
  • Exhibit potent cytokine-producing capacity secreting significant amounts of IFN-γ GM-CSF and TNF-α.
  • Possess relatively weak cytotoxic potential.
• CD56^dim^CD16^+ Cells:
  • Display lower levels of CD56 expression alongside positive expression of CD16.
  • Represent the dominant circulating NK cell population (>90% in blood).
  • Contain abundant cytoplasmic lytic granules housing cytotoxic effector proteins.
  • Mediate vigorous cytotoxic activity and are considered the most terminally differentiated NK cell subset.
  • Primarily involved in direct target cell elimination and ADCC.

Subpopulation	Characteristics
CD56^bright^CD16^-	High CD56, low/absent CD16; cytokine producers; weak cytotoxicity; secondary lymphoid organs
CD56^dim^CD16^+	Low CD56, positive CD16; strong cytotoxicity; dominant in blood (>90%); high lytic granule content

Receptor Repertoire and Signal Integration

A complex array of inhibitory and activating surface receptors govern NK cell activation and function, rendering them phenotypically heterogeneous. Key receptor families include:

• Killer cell Immunoglobulin-like Receptors (KIRs): These receptors belong to the immunoglobulin superfamily and primarily recognize MHC class I molecules. Upon engagement, they often transduce inhibitory signals, thereby preventing autologous attack.
• NKG2D is an activating receptor that recognizes stress-induced ligands such as MICA and MICB. It is upregulated in virus-infected cells, transformed cells, or cells under duress. NKG2D is also expressed in other immune cells, including activated T lymphocytes, NKT cells, and macrophages.
• NKR-P1 (CD161): Receptor variants exist; human NKR-P1A functions as an activating receptor upon binding its ligand LLT1 (Lectin-like transcript-1) on target cells.
• Signaling Adaptors: Activation signaling through specific receptors (e.g., CD94/NKG2 NKR-P1) requires association with transmembrane adapter proteins possessing immunoreceptor tyrosine-based activation motifs (ITAMs) or similar signaling domains such as FcεRIγ DAP12 and DAP10.

The functional outcome of an NK cell-target cell interaction depends on integrating signals derived from the constellation of engaged inhibitory and activating receptors, the cell’s activation status, and cues from the local microenvironment.

Receptor Type	Function
KIRs	Recognize MHC I; mainly inhibitory
NKG2D	Activating receptor for stress-induced ligands (MICA, MICB)
NKR-P1 (CD161)	Activation via LLT1 ligand binding
Signaling Adaptors	ITAM-associated (e.g., FcεRIγ, DAP12, DAP10) needed for receptor signaling

Effector Functions

NK cells execute diverse effector functions critical for immune defense:

• Cytotoxicity: NK cells mediate rapid direct cytolysis of target cells.
  • They possess constitutively expressed lytic granules containing perforin and granzymes, which enable immediate killing upon activation, similar to that of Cytotoxic T Lymphocytes (CTLs).
  • They exhibit spontaneous MHC-unrestricted cytotoxicity, enabling the lysis of targets lacking or downregulating MHC class I expression. This phenomenon is explained by the “missing-self” hypothesis, in which the absence of inhibitory signals from self-MHC class I permits NK cell activation against aberrant cells.
  • NK cells mediate Antibody-Dependent Cellular Cytotoxicity (ADCC) via their CD16 receptor-engaging antibody-opsonized target cells.
  • The cytotoxic process is precisely regulated, balancing activating and inhibitory inputs.
• Cytokine Production: Primarily attributed to the CD56^bright^CD16^- subset, NK cells secrete immunomodulatory cytokines.
  • Interferon-gamma (IFN-γ) is a major product that enhances macrophage and dendritic cell functions, including phagocytosis antigen presentation (upregulation of MHC class I/II), costimulatory molecule expression and secretion of other cytokines, thereby amplifying the overall immune response.
  • NK cells can be activated by cytokines derived from other immune cells, notably Th1 cells, which secrete IL-2, IL-15, IL-21, and IFN-γ.

Regulator	Details
Cytokines	IL-15 (essential), IL-2, IL-12, IL-18, IL-21, IFN-α/β
Microbial products	Direct NK cell activation
DAMPs	Activation by cellular stress products
Trained immunity	Epigenetic/metabolic reprogramming for heightened secondary responses

Regulation of NK Cell Activity

Cytokine networks and other signals dynamically regulate NK cell activity development and maturation:

• Cytokine Dependence: IL-15 is critical for NK cell development, survival, and homeostasis. IL-2 and IL-12 also significantly influence their function. IL-18 IL-21 and Type I interferons (IFN-α/β) further enhance NK cell activity.
• Microbial Products: Components derived from bacteria or viruses can stimulate NK cell activation directly.
• DAMPs: Damage-associated Molecular Patterns (DAMPs or alarmin) released from stressed or necrotic cells activate innate immune pathways, including NK cells.
• Trained Immunity: Emerging evidence suggests NK cells can undergo epigenetic and metabolic reprogramming following certain stimuli, leading to enhanced responsiveness upon secondary challenge. This phenomenon is called trained immunity or innate immune memory, which involves the expansion of specific NK cell subsets.

Roles in Specific Biological Contexts

NK cells play specialized roles in various physiological and pathological states:

• Antiviral Defense: They are crucial effectors against viral infections, particularly within tissues like the skin, where they mediate the direct lysis of infected cells. Their involvement in trained immunity contributes to heightened antiviral responses upon re-infection.
• Antitumor Surveillance: NK cells are integral to cancer immunosurveillance.
  • They mediate the direct killing of malignant cells. Tumor infiltration by NK cells often correlates with a favorable prognosis.
  • Reduced NK cell activity can be associated with increased susceptibility to certain malignancies.
  • Their role is particularly significant during early oncogenesis when they target transformed cells that may have downregulated MHC class I expression or upregulated activating ligands (e.g., MICA/MICB recognized by NKG2D).
  • Antitumor immunity is complex, involving coordination with T cells and NKT cells. Tumor progression often consists of the evolution of immune evasion mechanisms that suppress NK cell function. Th1 responses support NK cell-mediated antitumor activity. ADCC represents a key mechanism employed by NK cells against antibody-targeted tumors. DAMPs released by dying tumor cells can further activate NK cells.
• Pregnancy: Specialized uterine NK (uNK) cells within the maternal decidua are critical regulators of placental development, secreting angiogenic factors (e.g., PLGF VEGF) essential for vascular remodeling. Peripheral blood NK cell assessment is not informative regarding the status of decidual NK cells in the context of infertility, and interventions aimed at suppressing systemic NK cell activity for treating infertility lack robust scientific validation. The placenta represents an immune-privileged site.
• Immunodeficiencies: NK cell function and development can be compromised in various primary immunodeficiencies.
  • Severe Combined Immunodeficiencies (SCID) arising from mutations in genes essential for lymphocyte development can affect NK cell lineages depending on the specific genetic defect. Some SCID subtypes exhibit normal NK cell numbers.
  • Syndromes characterized by intrinsic NK cell functional defects (e.g., Chediak-Higashi syndrome X-linked lymphoproliferative syndrome) are associated with increased cancer risk, underscoring their role in tumor control.
  • In ZAP-70 deficiency characterized by defective CD8+ T cell development, NK cell numbers and activity are often elevated, potentially representing a compensatory mechanism.
• Transplantation: NK cells mediate the beneficial graft-versus-leukemia (GvL) effect following allogeneic hematopoietic stem cell transplantation. Conversely, they can contribute to the rejection of solid organ allografts. Immune privilege in certain anatomical sites limits immune cell influx, including NK cells, which contribute to better graft survival.
• Inflammation: As IFN-γ producers (ILC1), NK cells contribute to inflammatory responses. They are recruited and activated by pro-inflammatory cytokines and DAMPs released during inflammation and can migrate into inflamed lymphoid tissues.

Comparison with Other Immune Cell Populations

Distinguishing NK cells from related lymphocyte subsets highlights their unique contributions:

• Cytotoxic T Lymphocytes (CTLs): Both are major cytotoxic effectors. CTLs recognize peptide antigens presented via MHC class I, whereas NK cells excel at eliminating cells lacking MHC class I (“missing-self” recognition). Their mechanisms are complementary in antiviral and antitumor immunity.
• Gamma Delta T cells (Tγδ cells): Share capabilities for MHC-unrestricted cytotoxicity and ADCC with NK cells. Considered an intermediate population bridging innate and adaptive responses. Both populations show increased activity in certain immunodeficiencies (e.g., ZAP-70 deficiency) and contribute to early responses against intracellular pathogens.
• NKT cells: Another lymphocyte subset with characteristics bridging innate and adaptive immunity collaborating with T cells and NK cells in antitumor surveillance and early responses to specific pathogens. Their cytotoxicity contributes to immune defense.
• Innate Lymphoid Cells (ILCs): NK cells are Group 1 ILCs defined by IFN-γ IFN-production. In healthy skin, NK cells are the predominant ILC population identified. While all ILC groups can modulate tumor responses, Group 3 ILCs (ILC3) appear particularly involved in antitumor activity, according to some studies referenced in the source.
• Phagocytes (Macrophages Neutrophils): Unlike these myeloid cells, NK cells are lymphocytes, not primarily phagocytic. Their main effector functions involve targeted cell lysis and cytokine secretion.

References

1. Gołąb, J., Lasek, W., Nowis, D., & Stokłosa, T. (Eds.). (2023). Immunologia (8th ed.). Wydawnictwo Naukowe PWN. https://doi.org/10.53271/2023.061
2. Abbas, A. K., Lichtman, A. H., & Pillai, S. (2014). Cellular and molecular immunology (8th ed.). Elsevier Saunders.
3. Caligiuri, M. A. (2008). Human natural killer cells. Blood, 112(3), 461–469. https://doi.org/10.1182/blood-2008-04-078022
4. Cooper, M. A., Fehniger, T. A., & Caligiuri, M. A. (2001). The biology of human natural killer-cell subsets. Trends in Immunology, 22(11), 633–640. https://doi.org/10.1016/S1471-4906(01)02060-9
5. Lanier, L. L. (2005). NK cell recognition. Annual Review of Immunology, 23, 225–274. https://doi.org/10.1146/annurev.immunol.23.021704.115526
6. Ljunggren, H.-G., & Kärre, K. (1990). In search of the “missing self”: MHC molecules and NK cell recognition. Immunology Today, 11(7), 237–244. https://doi.org/10.1016/0167-5699(90)90097-S
7. Orange, J. S. (2002). Formation and function of the lytic NK-cell immunological synapse. Nature Reviews Immunology, 2(9), 704–716. https://doi.org/10.1038/nri912
8. Vivier, E., Raulet, D. H., Moretta, A., Caligiuri, M. A., Zitvogel, L., Lanier, L. L., … Smyth, M. J. (2011). Innate or adaptive immunity? The example of natural killer cells. Nature Reviews Immunology, 11(10), 817–828. https://doi.org/10.1038/nri3063
9. Sun, J. C., & Lanier, L. L. (2011). NK cell development, homeostasis and function: Parallels with CD8⁺ T cells. Nature Reviews Immunology, 11(10), 645–657. https://doi.org/10.1038/nri3027

Main Definion of B Lymphocytes

B lymphocytes are some of the most important cells of the immune system, especially in specific immunity. Together with T lymphocytes, they form the basis of the body’s protective barrier. They can very precisely recognize antigens using special “sensors” on their surface – B cell receptors (BCR for short).

The main function of B lymphocytes is participation in the so-called humoral response. Simply put, after appropriate stimulation, they transform into complexes producing defensive proteins – immunoglobulins, which circulate in the blood and other body fluids, neutralizing threats.

Where do B Lymphocytes come from and how do they mature?

In the bone marrow, precursor cells subsequently undergo a complex process of “training” and maturation. During this process, various molecules appear and disappear on their surface – receptors for chemical signals (cytokines) or adhesion molecules. These guide the development of young lymphocytes, their proliferation, and migration to appropriate locations within the bone marrow. Simultaneously, genes controlling this entire process (so-called transcription factors) are activated and deactivated inside the cell.

A key moment of maturation is the “assembly” of genes encoding antibodies. It is a process of randomly selecting and assembling fragments from a genetic library (V, D, J gene segments for the heavy chain and V, J for the light chain) to create a unique BCR receptor. Importantly, this process occurs according to the principle of “allelic exclusion” – a B lymphocyte uses only one set of genes (one allele) for the heavy chain and one for the light chain, despite having two copies of each chromosome. This ensures that all BCR receptors on a single lymphocyte (and later the antibodies it produces) will be identical and will recognize only one specific antigen. The vast diversity of possible combinations of these gene segments, further increased by a certain “imprecision” during their joining (junctional diversity), means the body can produce B lymphocytes ready to recognize virtually any possible antigen – there is talk of even 1011 different possibilities!

The maturation process can be divided into stages: from early pro-B lymphocytes, through pro-B (where the heavy chain is assembled), pre-B (light chain assembled), to immature and finally mature B lymphocytes. At each stage, the cells undergo “quality control”. First, it is checked whether the gene for the heavy chain has been assembled correctly, which is a positive selection. If so, the cell receives a signal for intense proliferation, creating clones with the same heavy chain. Then, the assembly of light chain genes begins. Interestingly, at this stage, junctional diversity is limited because the enzyme TdT is absent. Next comes another selection – cells that accidentally create a receptor reacting to the body’s own tissues are eliminated (negative selection), which protects us from autoimmunity.

After leaving the bone marrow, young, so-called transitional B lymphocytes, migrate mainly to the spleen. There, they undergo the final stage of control and maturation. Those that react too strongly to self-antigens are eliminated – they undergo apoptosis. Those that react weakly or not at all transform into fully mature B lymphocytes. An important receptor for the survival signal for the cytokine BAFF appears on their surface, and the amount of another type of BCR receptor – sIgD – significantly increases, potentially being up to 10 times more abundant than sIgM. Such mature B lymphocytes are ready to travel throughout the body – mainly to lymphoid follicles in lymph nodes, the spleen, or mucous membranes – and await encounter with a foreign antigen.

Stage	Location	Key Events	Surface Markers / Molecules
Early pro-B	Bone marrow	Commitment to B-cell lineage; initiation of heavy-chain rearrangement	CD19⁺, CD34⁺
Late pro-B	Bone marrow	Completion of heavy-chain V(D)J recombination; positive selection	μ heavy-chain (pre-BCR), IL-7R
Large pre-B	Bone marrow	Pre-BCR signaling → proliferation	Pre-BCR (μ + surrogate light chain)
Small pre-B	Bone marrow	Light-chain VJ recombination	Igκ or Igλ light chains
Immature B	Bone marrow	Expression of complete BCR (IgM); negative selection	sIgM⁺, no sIgD
Transitional B	Spleen	Final negative selection; upregulation of survival signals	BAFF-R, low sIgD
Mature naïve B	Peripheral	Ready for antigen encounter; high sIgD	sIgM⁺, sIgD⁺, CD21/CD19/CD81

Different Types of B Lymphocytes

B lymphocytes are not a single group, but a whole family of cells with different specializations:

• Conventional B Lymphocytes (B2, follicular): This is the most numerous group in adults. They are the main players in adaptive humoral immunity. It is they who, after activation, form germinal centers in lymphoid follicles, and undergo the process of “refining” their antibodies – affinity maturation through somatic hypermutation. Later, they differentiate into plasma cells and memory cells. Their strength lies in the enormous diversity of the antibodies they create.
• Unconventional B Lymphocytes:
  • B1 Lymphocytes: They constitute a minority in the blood and spleen of adults (approx. 20%) but dominate in fetuses and newborns (40-60%). Most of them have the CD5 molecule on their surface (B1a), while a minority do not (B1b). They specialize in responding to certain types of antigens (T-independent), mainly bacterial polysaccharides. They primarily produce antibodies of the IgM class (although they can also produce IgG and IgA), which are often multispecific (can bind different, though similar, antigens) and constitute the first line of defense before a more precise B2 lymphocyte response develops. They have limited receptor diversity and do not undergo intensive “refinement”. They are considered a bridge between innate and acquired immunity.
  • Marginal Zone B Lymphocytes: They are located mainly in the spleen, in the marginal zone. Functionally, they resemble B1 lymphocytes. Their task is a rapid response to microorganisms that have entered the blood. Like B1 cells, they mainly produce multispecific IgM.
• Division based on function:
  • Effector B Lymphocytes: These are the ones that actively fight. After differentiation, they become plasma cells – specialized antibody factories. But they can also produce various chemical signals (cytokines), e.g., IFN-γ, IL-12, TNF-α or IL-4, IL-6, TNF-α, influencing other immune cells.
  • Memory B Lymphocytes: These are long-lived cells that remain in the body after infection. Upon subsequent contact with the same antigen, they react much faster and stronger, providing long-term immunity.
  • Regulatory B Lymphocytes (Breg): Also called suppressor B cells. Their role is to inhibit the immune response, which helps prevent excessive reactions and autoimmunity. They arise, among other factors, under the influence of cytokines IL-1β and IL-6.

Interestingly, some human B lymphocytes can even directly kill tumor cells, using TRAIL and FASL molecules on their surface for this purpose.

Subset	Location	Antigen Type	Main Antibody(s)	Diversity & Mutation
Follicular (B2)	Lymphoid follicles (nodes, spleen)	T-dependent proteins	IgG, IgM, IgA, IgE	High (somatic hypermutation)
B1a / B1b	Peritoneal & pleural cavities; blood	T-independent (polysaccharides)	IgM	Limited (no SHM)
Marginal zone	Splenic marginal zone	Blood-borne microbes	IgM	Limited
Memory B	Peripheral & bone marrow	Previously encountered	Class-switched	High
Plasma cells	Bone marrow, spleen, mucosae	—	All classes	N/A
Regulatory B (Breg)	Peripheral lymphoid organs	—	IL-10 producing	N/A

How are B Lymphocytes Activated?

B lymphocyte activation occurs mainly in peripheral lymphoid organs: lymph nodes, spleen, lymphoid follicles in mucous membranes, e.g., Peyer’s patches in the intestine or tonsils.

It all begins when a naive B lymphocyte encounters an antigen that matches its BCR receptor. Recognition and binding of the antigen is the first, crucial signal. A signaling cascade is triggered inside the cell. Molecules Igα and Igβ associated with the BCR, which possess ITAM sequences, participate in it. After antigen binding, enzymes – tyrosine kinases (from the SRC, SYK, and TEC families) – come into action. First, SRC-like kinases (LYN, FYN, BLK) “attach” phosphate groups to ITAMs. This attracts another kinase, SYK, which is activated and transmits the signal further.

However, the signal from the BCR alone is often insufficient for full activation, especially for B2 lymphocytes. Help from other cells is needed, primarily a subtype of helper T lymphocytes – follicular helper T cells (Tfh). A B lymphocyte that has bound an antigen engulfs it, “cuts” it into pieces, and presents these fragments on its surface using MHC class II molecules. If a Tfh lymphocyte recognizes this fragment using its TCR receptor, cooperation occurs between them. The interaction between the CD40 molecule on the B lymphocyte and CD154, also known as CD40 ligand or CD40L, on the Tfh lymphocyte is crucial here. Additionally, the Tfh lymphocyte secretes cytokines (e.g., IL-4, IL-5, IL-6, IL-10, IL-21, IFN-γ, TGF-β), which give the B lymphocyte signals for clonal expansion, differentiation into plasma cells and memory cells, and also for so-called antibody class switching – e.g., from IgM production to IgG, IgA, or IgE.

This cooperation between the B lymphocyte and Tfh occurs most effectively in lymphoid follicles, which are germinal centers. This is also where the aforementioned antibody “refinement” (affinity maturation) takes place. B lymphocytes begin to intensively mutate the genes encoding the antigen-binding fragments of antibodies. B lymphocytes that, as a result, create BCRs with a better fit for the antigen receive stronger signals for survival and proliferation, while those with weaker affinity die. This selection process, supported by Tfh lymphocytes, leads to the production of antibodies with very high efficacy.

The strength of the activation signal can also be modified by other molecules on the B lymphocyte surface. The CD19/CD21/CD81 complex enhances the signal from the BCR. In contrast, the molecules CD22 and FcγRIIB (CD32) have an inhibitory effect. Inhibition by FcγRIIB is used, for example, in the prevention of Rh disease (administering ready-made anti-D antibodies to the mother inhibits the activation of her own B lymphocytes).

Activated B lymphocytes proliferate, creating a clone of cells recognizing the same antigen. Some of them differentiate into plasma cells, which migrate mainly to the bone marrow and spleen, where they begin mass production of antibodies. Those destined to produce IgA migrate to the mucous membranes. Others become long-lived memory B lymphocytes.

Signal Type	Receptor(s)	Ligand / Source	Downstream Effect
Antigen binding	BCR (Igα/Igβ complex)	Specific antigen	ITAM phosphorylation → SYK activation → Ca²⁺ flux
T-cell help	CD40 (B cell) ↔ CD40L (Tfh)	Follicular helper T cell	NF-κB activation → proliferation, CSR, memory
Cytokines	IL-4R, IL-21R, etc.	IL-4, IL-6, IL-10, IL-21, IFN-γ	Class switch recombination; differentiation cues
Co-receptor enhancement	CD19/CD21/CD81 complex	C3d-opsonized antigen	Lowers activation threshold; amplifies BCR signal
Inhibition	CD22, FcγRIIB (CD32)	Self-antigen–IgG complexes	Dampens BCR signaling; maintains tolerance

Antibodies: The Precise Weapon of B Lymphocytes

Antibodies themselves rarely destroy pathogens directly. Their role is rather to “mark” the intruder for other elements of the immune system. They act as opsonins – they coat bacteria or viruses, which greatly facilitates their disposal by phagocytes, such as macrophages.

Furthermore, antibodies (especially IgM and IgG classes) can activate the complement system – a cascade of plasma proteins that leads to the direct destruction of bacterial cells (creating pores in them), intensification of inflammation, and further facilitation of phagocytosis. The binding of an antibody to an antigen on the bacterial surface is the starting signal for the so-called classical pathway of complement activation. Complement fragments generated during the process (e.g., C3a, C4a, C5a) can, for instance, activate mast cells to release histamine (acting as anaphylatoxins).

Antibodies play a particularly important role in mucous membranes (digestive, and respiratory systems). Secretory IgA (sIgA) predominates there. We find it in all secretions (saliva, tears, intestinal mucus), as well as in mother’s milk, where it provides the newborn with so-called passive immunity. In the intestines, sIgA “coats” bacteria of the physiological flora, controlling their numbers and preventing adherence to the epithelium, as well as neutralizing pathogens and toxins. It can agglutinate bacteria, facilitating their removal, and even help remove viruses from infected epithelial cells. In the upper respiratory tract, IgA plays the main role, but in the pulmonary alveoli, IgG antibodies, which arrive there from circulation, are more important.

The previously mentioned natural antibodies, mainly IgM produced by B1 and marginal zone B lymphocytes, are important in the initial phase of infection, especially upon first contact with a given microorganism. They are multispecific and very effectively activate complement.

Antibodies can also neutralize viruses and toxins, blocking their ability to infect cells or cause harmful effects. This is particularly important during reinfection, where, thanks to memory cells and pre-existing antibodies, the response is very rapid. Humoral immunity based on antibodies can last for many years.

Unfortunately, antibodies can also participate in detrimental processes. In transplant rejection (especially so-called humoral rejection), antibodies produced by B lymphocytes and plasma cells can attack antigens of the transplanted organ, activating complement and other tissue-destroying mechanisms. In type I allergic reactions (e.g., anaphylaxis, urticaria), IgE class antibodies play a key role; they bind to mast cells and basophils, causing the release of inflammatory mediators (e.g., histamine) upon contact with the allergen.

References

1. Gołąb, J., Lasek, W., Nowis, D., & Stokłosa, T. (Eds.). (2023). Immunologia (8th ed.). Wydawnictwo Naukowe PWN. https://doi.org/10.53271/2023.061
2. Janeway, C. A., Jr., Travers, P., Walport, M., & Shlomchik, M. J. (2017). Immunobiology: The immune system in health and disease (9th ed.). Garland Science.
3. Allman, D., & Pillai, S. (2008). Peripheral B cell subsets. Nature Immunology, 9(2), 199–207. https://doi.org/10.1038/ni1571
4. Baumgarth, N. (2011). The double life of a B-1 cell: Self-reactivity selects for protective effector functions. Nature Reviews Immunology, 11(1), 34–46. https://doi.org/10.1038/nri2880
5. Cambier, J. C., Gauld, S. B., Merrell, K. T., & Li, F. (2007). B-cell anergy: From transgenic models to naturally occurring anergic B cells? Nature Reviews Immunology, 7(9), 633–643. https://doi.org/10.1038/nri2131
6. Liu, W., & Clark, M. R. (2012). CD40 signaling and the regulation of immune responses. In B. M. Babior (Ed.), Advances in Experimental Medicine and Biology (Vol. 730, pp. 1–18). Springer. https://doi.org/10.1007/978-1-4419-5633-3_1
7. Schroeder, H. W., Jr., & Cavacini, L. (2010). Structure and function of immunoglobulins. Journal of Allergy and Clinical Immunology, 125(2, Suppl. 2), S41–S52. https://doi.org/10.1016/j.jaci.2009.09.046
8. Tonegawa, S. (1983). Somatic generation of antibody diversity. Nature, 302(5909), 575–581. https://doi.org/10.1038/302575a0
9. Schatz, D. G., & Swanson, P. C. (2011). V(D)J recombination: Mechanisms of initiation. Annual Review of Genetics, 45, 167–202. https://doi.org/10.1146/annurev-genet-110410-132552